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WO2024258967A1 - Anticorps anti-cd5 et leurs utilisations - Google Patents

Anticorps anti-cd5 et leurs utilisations Download PDF

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Publication number
WO2024258967A1
WO2024258967A1 PCT/US2024/033613 US2024033613W WO2024258967A1 WO 2024258967 A1 WO2024258967 A1 WO 2024258967A1 US 2024033613 W US2024033613 W US 2024033613W WO 2024258967 A1 WO2024258967 A1 WO 2024258967A1
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Prior art keywords
cdr
seq
antibody
amino acid
nos
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PCT/US2024/033613
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English (en)
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Dori THOMAS-KARYAT
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Synthis Therapeutics, Inc.
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Publication of WO2024258967A1 publication Critical patent/WO2024258967A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2896—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against molecules with a "CD"-designation, not provided for elsewhere
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/33—Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/52—Constant or Fc region; Isotype
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/52—Constant or Fc region; Isotype
    • C07K2317/524—CH2 domain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/52—Constant or Fc region; Isotype
    • C07K2317/53—Hinge
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/71—Decreased effector function due to an Fc-modification
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/77—Internalization into the cell
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Definitions

  • CD5 is a cluster of differentiation protein expressed on the surface of T cells.
  • WO 2020/256751 describes the use of anti-CD5 antibodies conjugated to ALK5 inhibitors to direct ALK5 inhibitors to T cells, where they can exert a therapeutic benefit, while limiting toxicity of ALK5 inhibitors in non-target tissue.
  • Anti-CD5 antibody-ALK5 inhibitor conjugates are described in WO 2020/256751 as being useful for the treatment of cancer.
  • Anti-CD5 antibodies have also been described as useful for treating CD5+ B or T cell related diseases such as B or T cell malignancies, autoimmune diseases, transplantation diseases, and graft rejections (US 8,679,500). 4.
  • the present disclosure provides anti-CD5 antibodies (e.g., humanized anti-CD5 antibodies) and antigen-binding fragments thereof.
  • the present disclosure further provides conjugates comprising ALK5 inhibitors and anti-CD5 antibodies (e.g., humanized anti-CD5 antibodies) and antigen-binding fragments thereof, nucleic acids encoding the anti-CD5 antibodies and antigen-binding fragments thereof, and cells engineered to express the nucleic acids.
  • a conjugate comprising an ALK5 inhibitor and an anti-CD5 antibody or antigen binding fragment thereof is sometimes referred to herein simply as a “conjugate” for convenience.
  • an anti-CD5 antibody or antigen-binding fragment of the disclosure comprises heavy and/or light chain variable sequences set forth in Tables 1A through 1K.
  • an anti-CD5 antibody or antigen-binding fragment of the disclosure e.g., humanized anti-CD5 antibody or antigen-binding fragment thereof
  • Tables 1A-1K further include CDR sequences defined by the combined regions of overlap for the CDR sequences defined by the IMGT, Kabat, and Chothia schemes, and further include CDR sequences defined by the common regions of overlap for the CDR sequences defined by the IMGT, Kabat, and Chothia schemes.
  • an anti-CD5 antibody or antigen-binding fragment of the disclosure comprises heavy chain CDRs of SEQ ID NOs:2, 11, and 14, and light chain CDRs of SEQ ID NOs:18, 19, and 21.
  • an anti-CD5 antibody or antigen-binding fragment of the disclosure comprises heavy chain CDRs of SEQ ID NOs:3, 8, and 15, and light chain CDRs of SEQ ID NOs:18, 19, and 21.
  • an anti-CD5 antibody or antigen-binding fragment of the disclosure comprises heavy chain CDRs of SEQ ID NOs:4, 8, and 15, and light chain CDRs of SEQ ID NO:17, ATS, and SEQ ID NO:20.
  • an anti-CD5 antibody or antigen-binding fragment of the disclosure comprises heavy chain CDRs of SEQ ID NOs:5, 11, and 13, and light chain CDRs of SEQ ID NOs:17, 19, and 21.
  • an anti-CD5 antibody or antigen-binding fragment of the disclosure comprises heavy chain CDRs of SEQ ID NOs:2, 7, and 14, and light chain CDRs of SEQ ID NOs:18, 19, and 21.
  • an anti-CD5 antibody or antigen-binding fragment of the disclosure comprises heavy chain CDRs of SEQ ID NOs:5, 7, and 13, and light chain CDRs of SEQ ID NOs:18, 19, and 21.
  • an anti-CD5 antibody or antigen-binding fragment of the disclosure comprises heavy chain CDRs of SEQ ID NOs:1, 6, and 16, and light chain CDRs of SEQ ID NO:17, ATS, and SEQ ID NO:20.
  • an anti-CD5 antibody or antigen-binding fragment of the disclosure comprises heavy chain CDRs of SEQ ID NOs:2, 9, and 14, and light chain CDRs of SEQ ID NOs:18, 19, and 21.
  • an anti-CD5 antibody or antigen-binding fragment of the disclosure comprises heavy chain CDRs of SEQ ID NOs:5, 9, and 16, and light chain CDRs of SEQ ID NOs:18, 19, and 21.
  • an anti-CD5 antibody or antigen-binding fragment of the disclosure comprises heavy chain CDRs of SEQ ID NOs:2, 10, and 14, and light chain CDRs of SEQ ID NOs:18, 19, and 21.
  • an anti-CD5 antibody or antigen-binding fragment of the disclosure comprises heavy chain CDRs of SEQ ID NOs:5, 12, and 13, and light chain CDRs of SEQ ID NOs:18, 19, and 21.
  • an anti-CD5 antibody or antigen-binding fragment of the disclosure comprises heavy chain CDRs of SEQ ID NOs:1, 88, and 89, and light chain CDRs of SEQ ID NO:94, WT, and SEQ ID NO:95.
  • an anti-CD5 antibody or antigen-binding fragment of the disclosure comprises heavy chain CDRs of SEQ ID NOs:2, 90, and 91, and light chain CDRs of SEQ ID NOs:96, 97, and 95.
  • an anti-CD5 antibody or antigen-binding fragment of the disclosure comprises heavy chain CDRs of SEQ ID NOs:2, 90, and 91, and light chain CDRs of SEQ ID NOs:99, 97, and 95.
  • an anti-CD5 antibody or antigen-binding fragment of the disclosure comprises heavy chain CDRs of SEQ ID NOs:3, 8, 91, and light chain CDRs of SEQ ID NOs:96, 97, 95.
  • an anti-CD5 antibody or antigen-binding fragment of the disclosure comprises heavy chain CDRs of SEQ ID NOs:3, 8, 91, and light chain CDRs of SEQ ID NOs:99, 97, 95.
  • an anti-CD5 antibody or antigen-binding fragment of the disclosure comprises heavy chain CDRs of SEQ ID NOs:4, 8, and 91, and light chain CDRs of SEQ ID NO:94, WT, and SEQ ID NO:95.
  • an anti-CD5 antibody or antigen-binding fragment of the disclosure comprises heavy chain CDRs of SEQ ID NOs:5, 90, and 89, and light chain CDRs of SEQ ID NOs:96, 97, and 95.
  • an anti-CD5 antibody or antigen-binding fragment of the disclosure comprises heavy chain CDRs of SEQ ID NOs:5, 90, and 89, and light chain CDRs of SEQ ID NOs:99, 97, and 95.
  • an anti-CD5 antibody or antigen-binding fragment of the disclosure comprises heavy chain CDRs of SEQ ID NOs:2, 102, and 91, and light chain CDRs of SEQ ID NOs:103, 97, and 95.
  • an anti-CD5 antibody or antigen-binding fragment of the disclosure comprises heavy chain CDRs of SEQ ID NOs:3, 8, and 91, and light chain CDRs of SEQ ID NOs:103, 97, and 95.
  • an anti-CD5 antibody or antigen-binding fragment of the disclosure comprises heavy chain CDRs of SEQ ID NOs:5, 102, and 89, and light chain CDRs of SEQ ID NOs:103, 97, and 95.
  • an anti-CD5 antibody or antigen-binding fragment of the disclosure comprises heavy chain CDRs of SEQ ID NOs:104, 8, and 91, and light chain CDRs of SEQ ID NOs:94, 97, and 105.
  • references to “heavy chain CDRs of SEQ ID NOs:X, Y, and Z” refer to CDR-H1, CDR-H2, and CDR-H3 sequences, respectively.
  • an anti-CD5 antibody or antigen-binding fragment of the disclosure comprises heavy and light chain variable regions of SEQ ID NOS:24 and 25, respectively.
  • the disclosure provides an anti-CD5 antibody or antigen-binding fragment having heavy and light chain variable regions having at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NOS:24 and 25, respectively.
  • an anti-CD5 antibody or antigen-binding fragment of the disclosure comprises heavy and light chain variable regions of SEQ ID NOS:26 and 27, respectively.
  • the disclosure provides an anti-CD5 antibody or antigen-binding fragment having heavy and light chain variable regions having at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NOS:26 and 27, respectively.
  • an anti-CD5 antibody or antigen-binding fragment of the disclosure comprises heavy and light chain variable regions of SEQ ID NOS:28 and 29, respectively.
  • the disclosure provides an anti-CD5 antibody or antigen-binding fragment having heavy and light chain variable regions having at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NOS:28 and 29, respectively.
  • the disclosure provides an anti-CD5 antibody or antigen-binding fragment having heavy and light chain variable regions having at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NOS:32 and 33, respectively.
  • an anti-CD5 antibody or antigen-binding fragment of the disclosure comprises heavy and light chain variable regions of SEQ ID NOS:49 and 50, respectively.
  • the disclosure provides an anti-CD5 antibody or antigen-binding fragment having heavy and light chain variable regions having at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NOS:49 and 50, respectively.
  • an anti-CD5 antibody or antigen-binding fragment of the disclosure comprises heavy and light chain variable regions of SEQ ID NOS:84 and 92, respectively.
  • the disclosure provides an anti-CD5 antibody or antigen-binding fragment having heavy and light chain variable regions having at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NOS:84 and 92, respectively.
  • an anti-CD5 antibody or antigen-binding fragment of the disclosure comprises heavy and light chain variable regions of SEQ ID NOS:84 and 93, respectively.
  • the disclosure provides an anti-CD5 antibody or antigen-binding fragment having heavy and light chain variable regions having at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NOS:84 and 93, respectively.
  • an anti-CD5 antibody or antigen-binding fragment of the disclosure comprises heavy and light chain variable regions of SEQ ID NOS:84 and 98, respectively.
  • the disclosure provides an anti-CD5 antibody or antigen-binding fragment having heavy and light chain variable regions having at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NOS:84 and 98, respectively.
  • an anti-CD5 antibody or antigen-binding fragment of the disclosure comprises heavy and light chain variable regions of SEQ ID NOS:85 and 92, respectively.
  • the disclosure provides an anti-CD5 antibody or antigen-binding fragment having heavy and light chain variable regions having at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NOS:84 and 92, respectively.
  • an anti-CD5 antibody or antigen-binding fragment of the disclosure comprises heavy and light chain variable regions of SEQ ID NOS:85 and 93, respectively.
  • the disclosure provides an anti-CD5 antibody or antigen-binding fragment having heavy and light chain variable regions having at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NOS:84 and 93, respectively.
  • an anti-CD5 antibody or antigen-binding fragment of the disclosure comprises heavy and light chain variable regions of SEQ ID NOS:85 and 98, respectively.
  • the disclosure provides an anti-CD5 antibody or antigen-binding fragment having heavy and light chain variable regions having at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NOS:84 and 98, respectively.
  • an anti-CD5 antibody or antigen-binding fragment of the disclosure comprises heavy and light chain variable regions of SEQ ID NOS:86 and 92, respectively.
  • the disclosure provides an anti-CD5 antibody or antigen-binding fragment having heavy and light chain variable regions having at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NOS:84 and 92, respectively.
  • an anti-CD5 antibody or antigen-binding fragment of the disclosure comprises heavy and light chain variable regions of SEQ ID NOS:86 and 93, respectively.
  • the disclosure provides an anti-CD5 antibody or antigen-binding fragment having heavy and light chain variable regions having at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NOS:84 and 93, respectively.
  • an anti-CD5 antibody or antigen-binding fragment of the disclosure comprises heavy and light chain variable regions of SEQ ID NOS:86 and 98, respectively.
  • the disclosure provides an anti-CD5 antibody or antigen-binding fragment having heavy and light chain variable regions having at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NOS:84 and 98, respectively.
  • an anti-CD5 antibody or antigen-binding fragment of the disclosure comprises heavy and light chain variable regions of SEQ ID NOS:87 and 92, respectively.
  • the disclosure provides an anti-CD5 antibody or antigen-binding fragment having heavy and light chain variable regions having at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NOS:84 and 92, respectively.
  • an anti-CD5 antibody or antigen-binding fragment of the disclosure comprises heavy and light chain variable regions of SEQ ID NOS:87 and 93, respectively.
  • the disclosure provides an anti-CD5 antibody or antigen-binding fragment having heavy and light chain variable regions having at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NOS:84 and 93, respectively.
  • an anti-CD5 antibody or antigen-binding fragment of the disclosure comprises heavy and light chain variable regions of SEQ ID NOS:87 and 98, respectively.
  • the disclosure provides an anti-CD5 antibody or antigen-binding fragment having heavy and light chain variable regions having at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NOS:84 and 98, respectively.
  • an anti-CD5 antibody or antigen-binding fragment of the disclosure comprises heavy and light chain variable regions of SEQ ID NOS:100 and 101, respectively.
  • the disclosure provides an anti-CD5 antibody or antigen-binding fragment having heavy and light chain variable regions having at least 90%, at least 95%, at least 98%, at least 99%, or 100% sequence identity to SEQ ID NOS:100 and 101, respectively.
  • an anti-CD5 antibody comprises a light chain and heavy chain of any one of AB-1 to AB-10 as set forth in Table 1L.
  • an anti-CD5 antibody comprises a light chain and heavy chain of SEQ ID NOs:69 and 70, respectively.
  • an anti-CD5 antibody comprises a light chain and heavy chain of SEQ ID NOs:71 and 72, respectively.
  • an anti-CD5 antibody comprises a light chain and heavy chain of SEQ ID NOs:73 and 74, respectively. In another aspect, an anti-CD5 antibody comprises a light chain and heavy chain of SEQ ID NOs:75 and 76, respectively. In another aspect, an anti-CD5 antibody comprises a light chain and heavy chain of SEQ ID NOs:77 and 78, respectively. In another aspect, an anti-CD5 antibody comprises a light chain and heavy chain of SEQ ID NOs:79 and 80, respectively. [0058] In certain aspects, an anti-CD5 antibody or antigen-binding fragment of the disclosure is cross- reactive with human and cynomolgus and/or rhesus monkey CD5.
  • anti-CD5 antibodies and antigen-binding fragments thereof of the disclosure are described in Section 6.1 and specific embodiments 1 to 197, infra.
  • Further exemplary features of conjugates of the disclosure and conjugate components are described in Sections 6.2 to 6.5 and specific embodiments 203 to 261, infra.
  • exemplary ALK5 inhibitors that can be used in conjugates of the disclosure are described in Section 6.3, including in Tables 2, 3A, 3B, and 4.
  • the ALK5 inhibitor can be directly conjugated to the antibody component or linked to the antibody component by a linker.
  • the linker can be a non- cleavable linker or, preferably, a cleavable linker (e.g., a protease-sensitive linker).
  • a cleavable linker e.g., a protease-sensitive linker
  • Exemplary non- cleavable and cleavable linkers are described in Section 6.4.
  • the average number of ALK5 inhibitor molecules attached per antibody or antigen binding fragment can vary, and generally ranges from 2 to 8 ALK5 inhibitor molecules per antibody or antigen binding fragment.
  • Drug loading is described in detail in Section 6.5.
  • Exemplary processes for making conjugates and exemplary kits useful for making conjugates are described in specific embodiments 474 to 482, infra.
  • Yet another aspect of the disclosure is a process for making an antibody-ALK5 inhibitor conjugate, where the antibody component is an anti-CD5 antibody or antigen-binding fragment thereof of the disclosure (e.g., a humanized anti-CD5 antibody or antigen-binding fragment thereof).
  • the antibody component is an anti-CD5 antibody or antigen-binding fragment thereof of the disclosure (e.g., a humanized anti-CD5 antibody or antigen-binding fragment thereof).
  • a kit comprising an anti-CD5 antibody or antigen-binding fragment thereof of the disclosure (e.g., a humanized anti-CD5 antibody or antigen-binding fragment thereof) and an ALK5 inhibitor.
  • the kits can be used, for example, to make a conjugate of the disclosure.
  • Other aspects of the disclosure are drawn to nucleic acids encoding the anti-CD5 antibodies and antibody-binding fragments of the disclosure.
  • the portion of the nucleic acid nucleic acid encoding an anti-CD5 antibody or antigen-binding fragment is codon-optimized for expression in a human cell.
  • Vectors e.g., plasmids
  • host cells comprising the nucleic acids are also within the scope of the disclosure.
  • the heavy and light chains coding sequences can be present on a single vector or on separate vectors.
  • Still another aspect of the disclosure is a method of making an anti-CD5 antibody or antigen- binding fragment thereof comprising incubating a cell comprising a nucleic acid or a vector according to the disclosure, under conditions suitable for expression of the coding region(s) and collecting the anti- CD5 antibody or antigen-binding fragment thereof.
  • Nucleic acids, vectors, host cells, and uses thereof are further described in Section 6.6 and specific embodiments 198 to 202, infra.
  • Yet another aspect of the disclosure is a pharmaceutical composition comprising an anti-CD5 antibody, antigen-binding fragment, conjugate, nucleic acid (or pair of nucleic acids), vector (or pair of vectors) or host cell according to the disclosure, and a physiologically suitable buffer, adjuvant, or diluent.
  • Exemplary pharmaceutical excipients that can be used to formulate a pharmaceutical composition and exemplary pharmaceutical compositions are described in Section 6.7 and specific embodiments 262 to 291, infra.
  • Yet another aspect of the disclosure is a method of treating cancer comprising administering a prophylactically or therapeutically effective amount of an anti-CD5 antibody (e.g., a humanized anti-CD5 antibody), antigen-binding fragment thereof, conjugate, nucleic acid, vector, host cell or pharmaceutical composition according to the disclosure to a subject in need thereof.
  • an anti-CD5 antibody e.g., a humanized anti-CD5 antibody
  • the methods of treating cancer comprise administering a conjugate of the disclosure or a pharmaceutical composition comprising the conjugate to a subject in need thereof.
  • the conjugates and pharmaceutical compositions can be administered as monotherapy or as part of a combination therapy, for example in combination with an immune checkpoint modulator (e.g., a checkpoint inhibitor).
  • an anti-CD5 antibody e.g., a humanized anti-CD5 antibody
  • antigen-binding fragment thereof conjugate, nucleic acid, vector, host cell or pharmaceutical composition according to the disclosure for use in the treatment of cancer.
  • use of an anti-CD5 antibody e.g., a humanized anti-CD5 antibody
  • antigen-binding fragment thereof conjugate, nucleic acid, vector, host cell or pharmaceutical composition according to the disclosure for the manufacture of a medicament for the treatment of cancer. 5.
  • FIGS.1A-1C show amino acid sequence alignments between parental mouse anti-CD5 antibody (Antibody B) and human germline Ig alleles.
  • FIG.1A is the amino acid sequence alignment of the parental mouse anti-CD5 antibody light chain and Ig alleles immunoglobulin kappa variable 3-11 allele 1 (IGKV3-11*01), immunoglobulin kappa variable 3-11 allele 2 (IGKV3-11*02), and immunoglobulin kappa variable 1-16 allele 1 (IGKV1-16*01).
  • Figure discloses SEQ ID NOS 107-110, respectively, in order of appearance.
  • FIG.1B is the amino acid sequence alignment of the parental mouse anti-CD5 antibody heavy chain and Ig alleles IGKV3-11*01, IGKV3-11*02, and IGKV1-16*01.
  • Figure discloses SEQ ID NOS 111-114, respectively, in order of appearance.
  • FIG.1C is the tabular representation of the percent mismatch between the human Ig alleles and parental mouse anti-CD5 antibody light and heavy chains.
  • FIGS.2A-2B show amino acid sequence alignments between parental mouse anti-CD5 antibody (Antibody B), the humanized anti-CD5 antibody AB-5, an exemplary human antibody 4JLR.pdb, and three human germline Ig alleles.
  • FIG.2A displays the light chain amino acid sequence alignments of parental anti-CD5 antibody, AB-5, 4JLR.pdb, and Ig alleles IGKV1-16*01, IGKV1-16*02, and IGKV1-39*01.
  • Figure discloses SEQ ID NOS 115-120, respectively, in order of appearance.
  • FIG.2B displays the heavy chain amino acid sequence alignments of parental anti-CD5 antibody, AB-5, 4JLR.pdb, and Ig alleles IGKV1- 16*01, IGKV1-16*02, and IGKV1-39*01.
  • Figure discloses SEQ ID NOS 121-126, respectively, in order of appearance.
  • FIGS.3A-3E show exemplary SDS-PAGE and endotoxin analyses of purified negative control and anti-CD5 antibodies of the disclosure.
  • FIG.3A is an SDS-PAGE image of the antibody AB-4.
  • FIG.3B is an SDS-PAGE image of a negative control antibody, NC-AB.
  • FIG.3C is an SDS-PAGE image of the antibody AB-6.
  • FIG.3D is an SDS-PAGE image of the antibody AN-8.
  • Non-reduced antibody samples in FIGS.3A-3D display a single high MW band and reduced antibody samples are associated with only two bands at 55 kDa and 25 kDa, corresponding to the IgG heavy chain and IgG light chain, respectively.
  • FIG.3E is a table that displays the purified concentrations of the antibodies shown in FIGS.3A-3D, as well as their optical density (OD) values at 545 nm and endotoxin units (EU) per mL and per mg antibody sample.
  • FIGS.4A-4F show the results of anti-CD5 antibody cell binding assays.
  • FIG.4A is a table that displays the antibody concentrations that were used in cell binding assays.
  • FIG.4B is a Jurkat T cell binding concentration-response graph of the antibodies AB-1, AB-2, AB-3, AB-4, and the negative control antibody NC-AB.
  • FIG.4C is a Jurkat T cell binding concentration-response graph of the antibodies AB-1, AB-5, AB-6, AB-7, AB-8, AB-9, and AB-10.
  • FIG.4D is a CD3+ T cell binding concentration-response graph of the antibodies AB-1, AB-2, AB-4, AB-5, AB-6, AB-7, AB-8, AB-9, and AB-10.
  • FIG.4E is a Jurkat T cell binding concentration-response graph of the parental mouse anti-human CD5 ( ⁇ -hCD5) antibody.
  • FIG.4F shows the raw data of a cell binding assay of ⁇ -hCD5 on mouse EL4 cells.
  • FIGS.5A-5F display the internalization profiles of exemplary humanized anti-CD5 antibodies of the disclosure.
  • FIG.5A is a graph showing the change in signal intensity over the course of 6 hours for antibodies AB-1, AB-2, AB-3, AB-4, and NC-AB.
  • FIG.5B is a graph that shows the percent internalization values over time for the same antibodies in FIG.5A.
  • FIG.5C is a graph displaying the change in signal intensity the course of 6 hours for antibodies AB-1, AB-5, AB-6, AB-7, AB-8, AB-9, and AB-10.
  • FIG.5D is a graph displaying the percent internalization values over time for the same antibodies in FIG.5C.
  • FIG.5A is a graph showing the change in signal intensity over the course of 6 hours for antibodies AB-1, AB-5, AB-6, AB-7, AB-8, AB-9, and AB-10.
  • FIG.5E is a bar graph that displays the percent reduction of CD5 binding of the antibody, AB-4.
  • FIG.5F is a bar graph that displays the percent reduction of CD5 binding of the antibody, AB-8.
  • FIG.6 is a bar graph that shows the percent cytotoxicity associated with the control and exemplary humanized anti-CD5 antibodies of the disclosure.
  • FIGS.7A-7C show binding of parental CD5 antibodies Antibody B and Antibody C to HEK293 cells (FIG.7A), human CD5 transfected HEK293 cells (FIG.7B) and rhesus monkey CD5 transfected HEK293 cells (FIG.7C) analyzed by flow cytometry.
  • Antibodies and antibody fragments of the disclosure are described in detail in Section 4 and Section 6.1.
  • the disclosure further provides conjugates useful for treating cancer comprising an antibody component covalently bonded to an ALK5 inhibitor, either directly or through a linker.
  • An overview of the conjugates of the disclosure is presented in Section 6.2.
  • the antibody component of the conjugates can be an intact antibody or a fragment thereof.
  • ALK5 inhibitors that can be used in the conjugates of the disclosure are described in Section 6.3.
  • the conjugates of the disclosure typically contain a linker between the antibody and ALK5 inhibitor. Exemplary linkers that can be used in conjugates of the disclosure are described in Section 6.4.
  • the conjugates of the disclosure can contain varying numbers of ALK5 inhibitor moieties per antibody. Drug loading is discussed in detail in Section 6.5.
  • mAb monoclonal antibody
  • mAb monoclonal antibody
  • Fab and F(ab′)2 fragments lack the Fc fragment of intact antibody, clear more rapidly from the circulation of the animal or plant, and may have less non-specific tissue binding than an intact antibody (Wahl et al., 1983, J. Nucl. Med.24:316).
  • scFv refers to a single chain Fv antibody in which the variable domains of the heavy chain and the light chain from a traditional antibody have been joined to form one chain.
  • Native antibodies and immunoglobulins are usually heterotetrameric glycoproteins of about 150,000 Daltons, composed of two identical light (L) chains and two identical heavy (H) chains. Each heavy chain has at the amino terminus a variable domain (VH) followed by a number of constant domains. Each light chain has a variable domain at the amino terminus (VL) and a constant domain at the carboxy terminus.
  • VH variable domain
  • VL variable domain at the amino terminus
  • the antibodies are preferably internalizing. Internalizing antibodies, after binding to their target molecules on cellular surface, are internalized by the cells as a result of the binding. The effect of this is that the conjugate is taken up by cells.
  • antibody fragment refers to a portion of a full-length antibody, generally the target binding or variable region. Examples of antibody fragments include Fab, Fab′, F(ab′)2 and Fv fragments.
  • an “Fv” fragment is the minimum antibody fragment which contains a complete target recognition and binding site. This region consists of a dimer of one heavy and one light chain variable domain in a tight, noncovalent association (VH-VL dimer). It is in this configuration that the three CDRs of each variable domain interact to define a target binding site on the surface of the VH-VL dimer. Often, the six CDRs confer target binding specificity to the antibody. However, in some instances even a single variable domain (or half of an Fv comprising only three CDRs specific for a target) can have the ability to recognize and bind target. “Single chain Fv” or “scFv” antibody fragments comprise the VH and VL domains of an antibody in a single polypeptide chain.
  • the Fv polypeptide further comprises a polypeptide linker between the VH and VL domain that enables the scFv to form the desired structure for target binding.
  • the Fab fragment contains the constant domain of the light chain and the first constant domain (CH1) of the heavy chain.
  • Fab′ fragments differ from Fab fragments by the addition of a few residues at the carboxyl terminus of the heavy chain CH1 domain including one or more cysteines from the antibody hinge region.
  • F(ab′) fragments are produced by cleavage of the disulfide bond at the hinge cysteines of the F(ab′) 2 pepsin digestion product. Additional chemical couplings of antibody fragments are known to those of ordinary skill in the art.
  • the antibodies of the disclosure are monoclonal antibodies.
  • the term “monoclonal antibody” as used herein is not limited to antibodies produced through hybridoma technology.
  • the term “monoclonal antibody” refers to an antibody that is derived from a single clone, including any eukaryotic, prokaryotic, or phage clone and not the method by which it is produced.
  • Monoclonal antibodies useful in connection with the present disclosure can be prepared using a wide variety of techniques known in the art including the use of hybridoma, recombinant, and phage display technologies or a combination thereof.
  • “Humanized” forms of non-human (e.g., murine) antibodies are chimeric immunoglobulins, immunoglobulin chains or fragments thereof (such as Fv, Fab, Fab′, F(ab′) 2 or other target-binding subdomains of antibodies) which contain minimal sequences derived from non-human immunoglobulin.
  • the humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDR regions correspond to those of a non-human immunoglobulin and all or substantially all of the FR regions are those of a human immunoglobulin sequence.
  • the humanized antibody can also comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin consensus sequence.
  • Fc immunoglobulin constant region
  • Methods of antibody humanization are known in the art. See, e.g., Riechmann et al., 1988, Nature 332:323-7; U.S. patent nos. 5,530,101; 5,585,089; 5,693,761; 5,693,762; and 6,180,370 to Queen et al.; European patent publication no. EP239400; PCT publication WO 91/09967; U.S. patent no.5,225,539; European patent publication no. EP592106; European patent publication no. EP519596; Padlan, 1991, Mol.
  • the antibodies of the disclosure include derivatized antibodies.
  • derivatized antibodies are typically modified by glycosylation, acetylation, pegylation, phosphorylation, amidation, derivatization by known protecting/blocking groups, proteolytic cleavage, linkage to a cellular ligand or other protein (see Section 6.1 for a discussion of antibody conjugates), etc. Any of numerous chemical modifications can be carried out by known techniques, including, but not limited to, specific chemical cleavage, acetylation, formylation, metabolic synthesis of tunicamycin, etc. Additionally, the derivative can contain one or more non-natural amino acids, e.g., using ambrx technology (See, e.g., Wolfson, 2006, Chem.
  • the antibodies or fragments thereof can be antibodies or antibody fragments whose sequence has been modified to alter at least one constant region-mediated biological effector function relative to the corresponding wild type sequence.
  • an antibody of the disclosure can be modified to reduce at least one constant region-mediated biological effector function relative to an unmodified antibody, e.g., reduced binding to the Fc receptor (Fc ⁇ R) or to C1q.
  • Fc ⁇ R and C1q binding can be reduced by mutating the immunoglobulin constant region segment of the antibody at particular regions necessary for Fc ⁇ R or C1q interactions (See, e.g., Canfield and Morrison, 1991, J. Exp.
  • Reduction in Fc ⁇ R binding ability of the antibody can also reduce other effector functions which rely on Fc ⁇ R interactions, such as opsonization, phagocytosis and antibody-dependent cellular cytotoxicity (“ADCC”), while reduction of C1q binding can reduce complement-dependent cytotoxicity (“CDCC). Reduction or elimination of effector function can thus prevent T cells targeted by an conjugate of the disclosure from being destroyed via ADCC or CDC.
  • ADCC antibody-dependent cellular cytotoxicity
  • effector function of an antibody is modified by selective mutation of the Fc portion of the antibody, so that it maintains antigen specificity and internalization capacity but eliminates ADCC/CDC function.
  • Numerous mutations have been described in the art for reducing Fc ⁇ R and C1q binding and such mutations can be included in an antibody of the disclosure. For example, U.S. Pat.
  • No.6,737,056 discloses that single position Fc region amino acid modifications at positions 238, 265, 269, 270, 292, 294, 295, 298, 303, 324, 327, 329, 333, 335, 338, 373, 376, 414, 416, 419, 435, 438 or 439 result in reduced binding to Fc ⁇ RII and Fc ⁇ RII.
  • numbering of amino acid residues in an Fc domain or constant region is according to the EU numbering system, also called the EU index, as described in Kabat et al., 1991, Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD. U.S.
  • patent no.9,790,268 discloses that an asparagine residue at amino acid position 298 and a serine or threonine residue at amino acid position 300 reduce Fc ⁇ R binding.
  • PCT publication no. WO 2014/190441 describes modified Fc domains with reduced Fc ⁇ R binding having L234D/L235E : L234R/L235R/E233K, L234D/L235E/D265S : E233K/L234R/L235R/D265S, L234D/L235E/E269K : E233K/L234R/L235R/E269K, L234D/L235E/K322A : E233K/L234R/L235R/K322A, L234D/L235E/P329W : E233K/L234R/L235R/P329W, L234D/L235E/E269K/D265S/K322A
  • antibodies or antigen binding fragments of the disclosure comprise a first Fc region and a second Fc region that dimerize to form an Fc domain.
  • sequences derived from human IgG1 include the following: APELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST YRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLV KGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYT QKSLSLSPGK (SEQ ID NO:51) (WT sequence) APEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNST YRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLV K
  • an anti-CD5 antibody or antigen binding fragment thereof of the disclosure has a first Fc region and/or a second Fc region comprising a sequence at least 90% identical (e.g., at least 95%, at least 97%, at least 99%, or 100% identical) to SEQ ID NO:54.
  • an anti-CD5 antibody or antigen binding fragment thereof of the disclosure has a first Fc region and/or a second Fc region comprising a sequence at least 90% identical (e.g., at least 95%, at least 97%, at least 99%, or 100% identical) to SEQ ID NO:81.
  • Anti-CD5 antibodies and antigen binding fragments can comprise a hinge region, for example connecting a CH1 domain to a Fc region comprising a CH2 and CH3 domain.
  • a human IgG1, IgG2, or IgG4 hinge can be used.
  • Exemplary hinge sequences include EPKSCDKTHTCPPCP (SEQ ID NO:66) (human IgG1), ESKYGPPCPSCP (SEQ ID NO:67) (human IgG4), ESKYGPPCPPCP (SEQ ID NO:68) (human IgG4 with a S228P substitution), and ERKCCVECPPCP (SEQ ID NO:83) (human IgG2).
  • Exemplary amino acid sequences comprising a CH1 domain (which can be C-terminal to a VH, for example), hinge, CH2 domain, and CH3 domain include the following: ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVV TVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRT PEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVS NKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTT PPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSPGK (SEQ ID NO:62) (derived from
  • an antibody or fragment thereof can be modified to acquire or improve at least one constant region-mediated biological effector function relative to an unmodified antibody, e.g., to enhance Fc ⁇ R interactions (See, e.g., US 2006/0134709).
  • an antibody of the disclosure can have a constant region that binds Fc ⁇ RIIA, Fc ⁇ RIIB and/or Fc ⁇ RIIIA with greater affinity than the corresponding wild type constant region.
  • antibodies of the disclosure can have alterations in biological activity that result in decreased opsonization, phagocytosis, or ADCC. Such alterations are known in the art. For example, modifications in antibodies that reduce ADCC activity are described in U.S. patent no.
  • the antibodies or fragments thereof can be antibodies or antibody fragments that have been modified to increase or reduce their binding affinities to the fetal Fc receptor, FcRn, for example, by mutating the immunoglobulin constant region segment at particular regions involved in FcRn interactions (See, e.g., WO 2005/123780). Such mutations can increase the antibody’s binding to FcRn, which protects the antibody from degradation and increases its half-life.
  • an antibody has one or more amino acids inserted into one or more of its hypervariable regions, for example as described in Jung and Plückthun, 1997, Protein Engineering 10(9):959-966; Yazaki et al., 2004, Protein Eng. Des Sel.17(5):481-9; and U.S. patent publication no. 2007/0280931.
  • the conjugates of the disclosure are generally composed of an ALK5 inhibitor covalently attached to an anti-CD5 antibody (e.g., a humanized anti-CD5) or antigen binding fragment thereof, typically via a linker, such that covalent attachment does not interfere with binding to CD5.
  • an ALK5 inhibitor can be conjugated to the antibody component via one or more native or engineered cysteine, lysine, or glutamine residues, one or more unnatural amino acids (e.g., p-acetylphenylalanine (pAcF), p-azidomethyl-L- phenylalanine (pAMF), or selenocysteine (Sec)), one or more glycans (e.g., fucose, 6-thiofucose, galactose, N-acetylgalactosamine (GalNAc), N-acetylglucosamine (GlcNAc), or sialic acid (SA)), or one or more short peptide tags of four to six amino acids.
  • pAcF p-acetylphenylalanine
  • pAMF p-azidomethyl-L- phenylalanine
  • Sec sialic acid
  • the antibody or fragment thereof is fused via a covalent bond (e.g., a peptide bond), through the antibody’s N-terminus or the C-terminus or internally, to an amino acid sequence of another protein (or portion thereof; for example, at least a 10, 20 or 50 amino acid portion of the protein).
  • the antibody, or fragment thereof can linked to the other protein at the N-terminus of the constant domain of the antibody. Recombinant DNA procedures can be used to create such fusions, for example as described in WO 86/01533 and EP0392745.
  • the effector molecule can increase half-life in vivo, and/or enhance the delivery of an antibody across an epithelial barrier to the immune system.
  • suitable effector molecules of this type include polymers, albumin, albumin binding proteins or albumin binding compounds such as those described in PCT publication no. WO 2005/117984.
  • the metabolic process or reaction may be an enzymatic process, such as proteolytic cleavage of a peptide linker of the conjugate, or hydrolysis of a functional group such as a hydrazone, ester, or amide.
  • Intracellular metabolites include, but are not limited to, antibodies and free drug which have undergone intracellular cleavage after entry, diffusion, uptake or transport into a cell.
  • the terms “intracellularly cleaved” and “intracellular cleavage” refer to a metabolic process or reaction inside a cell on a conjugate whereby the covalent attachment, i.e. linker, between the drug moiety (D) and the antibody (Ab) is broken, resulting in the free drug dissociated from the antibody inside the cell.
  • the cleaved moieties of the conjugate are thus intracellular metabolites.
  • the ALK5 Inhibitor [0114]
  • the ALK5 inhibitors of the disclosure are preferably small molecules that competitively and reversibly bind to ATP binding site in the cytoplasmic kinase domain of the ALK5 receptor, preventing downstream R-Smad phosphorylation.
  • the ALK5 inhibitors may but not need be specific or selective for ALK5 vs. other TGF- ⁇ family receptors, such as ALK4 and/or ALK7 and/or TGF- ⁇ receptor II.
  • the ALK5 inhibitors have activity towards both ALK5 and TGF- ⁇ receptor II. While it is preferable that the ALK5 inhibitor have limited inhibitory activity towards the BMP II receptor, this is not necessary because the conjugates of the disclosure are targeted to T cells, in which BMP II activity is minimal or absent.
  • the ALK5 inhibitors of the disclosure preferably have an IC50 of 100 nM or less, more preferably 50 nM or less, and most preferably 20 nM or less when measured in an in vitro cellular assay using T cells from at least 3 subjects, at least 5 subjects or at least 10 subjects.
  • ALK5 inhibitors suitable for use in the antibody-drug conjugates of the present disclosure include imidazole-benzodioxol compounds, imidazole-quinoxaline compounds, pyrazole-pyrrolo compounds and thiazole type compounds.
  • imidazole-benzodioxol type ALK5 inhibitors have the formula
  • R 2 is hydrogen or methyl
  • halogens include fluorine or chlorine
  • A has 1 carbon atom and B is a direct bond to the benzyl group and R 3 is an amide.
  • R 2 is hydrogen or methyl
  • A has 1 carbon atom and B is a direct bond to the benzyl group.
  • pyrazole type ALK5 inhibitors have the formula to about 5 carbon atoms
  • R 4 is hydrogen, halogen, lower alkyl having from 1 to about 5 carbon atoms, alkoxy having from 1 to about 5 carbon atoms, haloalkyl, carboxyl, carboxyalkylester, nitrile, alkylamine or a group having the formula
  • R 5 is lower alkyl having from 1 to about 5 carbon atoms, halogen or morpholino
  • R 6 is pyrole, cyclohexyl, morpholino, pyrazole, pyran, imidazole, oxane, pyrrolidinyl or alkylamine
  • A is a direct bond or an alkyl having from 1 to about 5 carbon atoms.
  • pyrazole-pyrrolo type ALK5 inhibitors have the formula 1 to about 5 carbon atoms, alkanol, morpholino or alkylamine, R 2 is hydrogen, halogen or lower alkyl having from 1 to about 5 carbon atoms and R 8 is hydrogen, hydroxyl, amino, halogen or a group having the formula
  • R 5 is piperazinyl
  • R 6 is morpholino, piperidinyl, piperazinyl, alkoxy, hydroxyl, oxane, halogen, thioalkyl or alkylamine
  • A is a lower alkyl having from 1 to about 5 carbon atoms.
  • thiazole type ALK5 inhibitors have the formula or lower alkyl having from 1 to about 5 carbon atoms, and R 10 is or about 5 carbon atoms.
  • the ALK5 inhibitor has the formula a halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C(O)R 10 , -C(O)N(R 10 )2, -N(R 10 )C(O)R 10 - C(O)OR 10 , -OC(O)R 10 , - S(O)R 10 , -S(O)2R 10 , -S(O)2N(R 10 )2, -P(O)(OR 10 )2, -OP(O)(OR 10 )2, -N02, and -CN; -C1-C10 alkyl, -C2- C l0 alkenyl, and -C 2 -C l0 alkynyl, each of which is optionally substituted at each occurrence with one or more substituents independently selected from a halogen, -OR 10 , -SR 10 , -N(R 10 )2, -C
  • the ALK5 inhibitor has the formula , -NO2, -CN, or - - one or more independently selected from halogen, -OR 11 , -SR 11 , -S(O)R 10 , -S(O) 2 R 11 , -S(O) 2 N(R 11 ) 2 -N(R 11 ) 2 , - C(O)R 10 , -C(O)N(R 11 )2, -N(R 11 )C(O)R 10 , -C(O)OR 11 , -OC(O)R 10 , -NO2, and -CN;
  • R 3 is, at each occurrence, independently halogen, -C 1 -C 3 alkyl, -C 1 -C 3 haloalkyl, -OH, -NO 2 , -CN, -O-C 1
  • the ALK5 inhibitor is an ALK5 inhibitor described in Table 16 of WO 2021/011834.
  • the ALK5 inhibitor has the formula L’ is absent, ⁇ S ⁇ , ⁇ O ⁇ , or ⁇ NH ⁇ ; A is absent, carbocycle, or heterocycle; Q 3 is N or CR 3 ; Q 4 is N or CR 4 ; Q 5 is N or CR 5 ; Q 6 is N or CR 6 ; Q 7 is C or N; R 1 is hydrogen, halo, C1–3 alkyl, or C1–3 haloalkyl; R 2 is, at each occurrence, independently halo, C1–3 alkyl, C1–3 alkoxy, C1–3 haloalkyl, or C1-3 haloalkoxy; R 3 is H, halo, C 1–3 alkyl, C 1–3 hal
  • the ALK5 inhibitor has the formula Q 4 is N or CR 4 ; Q 5 is N or CR 5 ; Q 6 is N or CR 6 ; R a and R b are each H, or R a and R b , together with the atoms to which they are attached, form a heterocyclic ring;
  • R 1 is H, C 1-3 alkyl, or C 1-3 haloalkyl;
  • R 2 is, at each occurrence, independently halo, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, or C1-3 haloalkoxy;
  • R 3 is H, halo, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, or C1-3 haloalkoxy;
  • R 4 is H, halo, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, or C1-3 haloalkoxy;
  • R 5 is H, halo, C1-3 alkyl, C
  • the ALK5 inhibitor has the formula R 1 is H, C 1-3 alkyl, or C 1-3 haloalkyl; R 2 is, at each occurrence, independently halo, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, or C 1-3 haloalkoxy; R 6 is H, halo, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, or C 1-3 haloalkoxy; wherein R 1 , R 2 , and R 6 are, at each occurrence, independently substituted with 0-3 R 10 ; R 7 is a reactive moiety capable of attachment to a linker or a reactive moiety capable of attachment to an antibody; R 10 is, at each occurrence, independently C 1-3 alkoxy or C 1-3 haloalkoxy; and m is 0-3;
  • the ALK5 inhibitor has the formula R 1 is H, C 1-3 alkyl, or C 1-3 haloalkyl; R 2 is, at each occurrence, independently halo, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, or C 1-3 haloalkoxy; R 6 is H, halo, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, or C 1-3 haloalkoxy; wherein R 1 , R 2 , and R 6 are each substituted with 0-3 R 10 ; R 7 is a reactive moiety capable of attachment to a linker or a reactive moiety capable of attachment to an antibody, an antibody construct, or a targeting moiety; R 10 is, at each occurrence, independently C 1-3 alkoxy or C 1-3 haloalkoxy; and m
  • the ALK5 inhibitor has the formula ring B is carbocycle or heterocycle;
  • R 1 is H, C 1-3 alkyl, or C 1-3 haloalkyl;
  • R 2 is, at each occurrence, independently halo, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, or C 1-3 haloalkoxy; wherein R 1 and R 2 are, at each occurrence, independently substituted with 0-3 R 10 ;
  • R 7 is a reactive moiety capable of attachment to a linker or a reactive moiety capable of attachment to an antibody, an antibody construct, or a targeting moiety;
  • R 9 is, at each occurrence, independently halo, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, or C 1-3 haloalkoxy;
  • R 10 is, at each occurrence, independently C 1-3 al 1-3 al
  • PCT publication no. WO 2000/61576 and U.S. patent publication no. US 2003/0149277 disclose triarylimidazole derivatives and their use as ALK5 inhibitors.
  • PCT publication no. WO 2001/62756 discloses pyridinylimidazole derivatives and their use as ALK5 inhibitors.
  • PCT publication no. WO 2002/055077 discloses use of imidazolyl cyclic acetal derivatives as ALK5 inhibitors.
  • PCT publication no. WO 2003/087304 discloses tri-substituted heteroaryls and their use as ALK5 and/or ALK4 inhibitors.
  • ALK5 inhibitors are commercially available, including SB-525334 (CAS 356559-20-1), SB-505124 (CAS 694433-59-5), SB-431542 (CAS 301836-41-9), SB-202474 (EMD4 Biosciences Merck KGaA, Darmstadt, Germany), LY-364947 (CAS 396129-53-6), IN-1130, GW-788388 and D4476 (EMD4 Biosciences Merck KGaA, Darmstadt, Germany). [0143] The structures and names of ALK5 inhibitors described herein refer to the molecule prior to the attachment to the antibody and/or linker.
  • Preferred ALK5 inhibitors are those which can be attached to a linker via a free NH or NH 2 group, preferably an NH or NH2 group attached to or part of an alkyl, heteroaryl, or aryl group (e.g., as in Compounds 1-23, 26-29, 31, 35, 37, 39, 40, 42, 43, 45-48, 50-85, 87-90, 93, 96, 98-104, 106, 108, 109, 111, 112, 114, 116-120, 132, 146, 149, 156, 184, 187, 193, 218, 260-277, 282, and 283 shown in Table 3A).
  • ALK5 inhibitors can be derivatized to add a free NH or NH 2 group. Design of derivatized ALK5 inhibitors should preferably take into account the inhibitors’ structure activity relationships (SAR) to reduce the likelihood of abolishing inhibitory activity when adding an NH or NH2 group, although the activity may also be determined empirically. Exemplary derivatized counterparts of several compounds shown in Table 2 are shown below in Table 4. Table 4 Table 2 Derivative 1 Derivative 2
  • the conjugates comprise a linker between the ALK5 inhibitor and the antibody.
  • Linkers are moieties comprising a covalent bond or a chain of atoms that covalently attaches an antibody to a drug moiety.
  • linkers include a divalent radical such as an alkyldiyl, an aryldiyl, a heteroaryldiyl, moieties such as:-(CR 2 ) n O(CR 2 ) n -, repeating units of alkyloxy (e.g., polyethylenoxy, PEG, polymethyleneoxy) and alkylamino (e.g., polyethyleneamino, JeffamineTM); and diacid ester and amides including succinate, succinamide, diglycolate, malonate, and caproamide.
  • PEG containing linkers are known in the art and commercially available (e.g., from BroadPharm (broadpharm.com).
  • Exemplary PEG containing linkers include Mal-PEG2-Val-Cit-PAB-OH (BroadPharm cat. no. BP-23203), Mal-PEG4-Val-Cit-PAB-OH (BroadPharm cat. no. BP-23204), Mal-PEG4-Val-Cit- PAB-PNP (BroadPharm cat. no. BP-23668), Mal-amido-PEG2-Val-Cit-PAB-PNP (BroadPharm cat. no. BP-23675), Azido-PEG3-Val-Cit-PAB-OH (BroadPharm cat. no. BP-23206), Azido-PEG4-Val-Cit-PAB- OH (BroadPharm cat.
  • a linker may comprise one or more linker components, such as stretcher and spacer moieties.
  • a peptidyl linker can comprise a peptidyl component of two or more amino acids and, optionally, one or more stretcher and/or spacer moieties.
  • linker components are known in the art, some of which are described below.
  • a linker may be a “cleavable linker,” facilitating release of a drug in the cell.
  • an acid- labile linker e.g., hydrazone
  • protease-sensitive linker e.g., peptidase-sensitive
  • photolabile linker e.g., dimethyl linker or disulfide-containing linker
  • linkers and linker components known in the art include aleimidocaproyl (mc); maleimidocaproyl-p-aminobenzylcarbamate; maleimidocaproyl-peptide-aminobenzylcarbamate linkers, e.g., maleimidocaproyl-L-phenylalanine-L-lysine-p-aminobenzylcarbamate and maleimidocaproyl-L- valine-L-citrulline-p-aminobenzylcarbamate (vc); N-succinimidyl 3-(2-pyridyldithio)proprionate (also known as N-succinimidyl 4-(2-pyridyldithio)pentanoate or SPP); 4-succinimidyl-oxycarbonyl-2-methyl-2-(2- pyridyldithio)-toluene (SMPT); N-succinimidyl-oxycarbony
  • the linker is cleavable under intracellular or extracellular conditions, such that cleavage of the linker releases the ALK5 inhibitor from the antibody in the appropriate environment.
  • the linker is not cleavable and the drug is released, for example, by antibody degradation in lysosomes (see U.S. patent publication 2005/0238649 incorporated by reference herein in its entirety and for all purposes).
  • Examples of non-cleavable linkers that can be used in the conjugates of the disclosure include N- maleimidomethylcyclohexane1-carboxylate, maleimidocaproyl or mercaptoacetamidocaproyl linkers.
  • the linker is cleavable by a cleaving agent that is present in the intracellular environment (for example, within a lysosome or endosome or caveolea).
  • the linker can be, for example, a peptidyl linker that is cleaved by an intracellular peptidase or protease enzyme, including, but not limited to, a lysosomal or endosomal protease.
  • the peptidyl linker comprises a peptidyl component that is at least two amino acids long or at least three amino acids long or more.
  • Cleaving agents can include, without limitation, cathepsins B and D and plasmin, all of which are known to hydrolyze dipeptide drug derivatives resulting in the release of active drug inside target cells (see, e.g., Dubowchik and Walker, 1999, Pharm. Therapeutics 83:67-123).
  • a peptidyl linker that is cleavable by the thiol-dependent protease cathepsin-B e.g., a Phe-Leu or a Gly-Phe-Leu-Gly linker (SEQ ID NO: 106).
  • Other examples of such linkers are described, e.g., in U.S. patent no.
  • the peptidyl linker cleavable by an intracellular protease is a Val-Cit linker or a Phe-Lys linker (see, e.g., U.S. patent no.6,214,345, which describes the synthesis of doxorubicin with the val-cit linker).
  • the cleavable linker is pH-sensitive, that is, sensitive to hydrolysis at certain pH values. Typically, the pH-sensitive linker hydrolyzable under acidic conditions.
  • an acid-labile linker that is hydrolyzable in the lysosome for example, a hydrazone, semicarbazone, thiosemicarbazone, cis-aconitic amide, orthoester, acetal, ketal, or the like
  • a hydrazone, semicarbazone, thiosemicarbazone, cis-aconitic amide, orthoester, acetal, ketal, or the like may be used.
  • a hydrazone, semicarbazone, thiosemicarbazone, cis-aconitic amide, orthoester, acetal, ketal, or the like may be used.
  • the hydrolyzable linker is a thioether linker (such as, e.g., a thioether attached to the therapeutic agent via an acylhydrazone bond (see, e.g., U.S. patent no. 5,622,929).
  • the linker is cleavable under reducing conditions (for example, a disulfide linker).
  • disulfide linkers are known in the art, including, for example, those that can be formed using SATA (N-succinimidyl-5-acetylthioacetate), SPDP (N-succinimidyl-3-(2- pyridyldithio)propionate), SPDB (N-succinimidyl-3-(2-pyridyldithio)butyrate) and SMPT (N-succinimidyl- oxycarbonyl-alpha-methyl-alpha-(2-pyridyl-dithio)toluene)-, SPDB and SMPT.
  • SATA N-succinimidyl-5-acetylthioacetate
  • SPDP N-succinimidyl-3-(2- pyridyldithio)propionate
  • SPDB N-succinimidyl-3-(2-pyridyldithio)butyrate
  • SMPT N
  • the linker is a malonate linker (Johnson et al., 1995, Anticancer Res.
  • the linker is a polyvalent linker that can be used to link many drug molecules to a single antibody molecule.
  • the Fleximer linker technology developed by Mersana is based on incorporating drug molecules into a solubilizing poly-acetal backbone via a sequence of ester bonds.
  • the methodology enables highly-loaded conjugates (e.g., having a drug antibody ratio (DAR) up to 20) while maintaining good physicochemical properties.
  • DAR drug antibody ratio
  • Exemplary polyvalent linker are described, for example, in WO 2009/073445; WO 2010/068795; WO 2010/138719; WO 2011/120053; WO 2011/171020; WO 2013/096901; WO 2014/008375; WO 2014/093379; WO 2014/093394; and WO 2014/093640, the contents of which are incorporated herein by reference in their entireties. [0158] Often the linker is not substantially sensitive to the extracellular environment.
  • linker in the context of a linker, means that no more than about 20%, 15%, 10%, 5%, 3%, or no more than about 1% of the linkers, in a sample of conjugate, are cleaved when the conjugate presents in an extracellular environment (for example, in plasma).
  • Whether a linker is not substantially sensitive to the extracellular environment can be determined, for example, by incubating with plasma the conjugate for a predetermined time period (for example, 2, 4, 8, 16, or 24 hours) and then quantitating the amount of free drug present in the plasma.
  • the linker can promote cellular internalization.
  • An conjugate of the disclosure may be of Formula I, below, wherein an antibody (Ab) is conjugated to one or more ALK5 inhibitor drug moieties (D) through an optional linker (L) A b-(L-D) p I [0164] Accordingly, the antibody may be conjugated to the drug either directly or via a linker.
  • p is the average number of drug (i.e., ALK5 inhibitor) moieties per antibody, which can range, e.g., from about 1 to about 20 drug moieties per antibody, and in certain embodiments, from 2 to about 8 drug moieties per antibody. Further details of drug loading are described in Section 6.5 below.
  • a linker component may comprise a “stretcher” that links an antibody e.g., via a cysteine residue, to another linker component or to a drug moiety. Exemplary stretchers are shown below (wherein the left wavy line indicates the site of covalent attachment to an antibody and the right wavy line indicates the site of covalent attachment to another linker component or drug moiety):
  • a linker component may comprise an amino acid unit.
  • the amino acid unit allows for cleavage of the linker by a protease, thereby facilitating release of the drug from the conjugate upon exposure to intracellular proteases, such as lysosomal enzymes. See, e.g., Doronina et al., 2003, Nat. Biotechnol.21:778-784.
  • Exemplary amino acid units include, but are not limited to, a dipeptide, a tripeptide, a tetrapeptide, and a pentapeptide.
  • Exemplary dipeptides include: valine-citrulline (VC or val-cit), alanine-phenylalanine (AF or ala-phe); phenylalanine- lysine (FK or phe-lys); or N-methyl-valine-citrulline (Me-val-cit).
  • Exemplary tripeptides include: glycine- valine-citrulline (gly-val-cit) and glycine-glycine-glycine (gly-gly-gly).
  • a spacer unit may be “self-immolative” or a “non-self-immolative.”
  • a “non-self-immolative” spacer unit is one in which part or all of the spacer unit remains bound to the drug moiety upon enzymatic (e.g., proteolytic) cleavage of the conjugate.
  • Examples of non-self-immolative spacer units include, but are not limited to, a glycine spacer unit and a glycine-glycine spacer unit.
  • a “self-immolative” spacer unit allows for release of the drug moiety without a separate hydrolysis step.
  • a spacer unit of a linker comprises a p-aminobenzyl unit.
  • a p-aminobenzyl alcohol is attached to an amino acid unit via an amide bond, and a carbamate, methylcarbamate, or carbonate is made between the benzyl alcohol and a cytotoxic agent.
  • the spacer unit is p-aminobenzyloxycarbonyl (PAB).
  • a spacer unit is a branched bis(hydroxymethyl)styrene (BHMS) unit as depicted below, which can be used to incorporate and release multiple drugs.
  • BHMS branched bis(hydroxymethyl)styrene
  • a linker may comprise any one or more of the above linker components.
  • a linker is as shown in brackets in the following conjugate formula: Ab–(–[Aa-Ww-Yy]-D) p II wherein Ab, A, a, W, w, D, and p are as defined in the preceding paragraph; Y is a spacer unit, and y is 0, 1, or 2; and. Exemplary embodiments of such linkers are described in U.S. patent publication no. 2005/0238649 A1, which is incorporated herein by reference. [0170] Exemplary linker components and combinations thereof are shown below in the context of conjugates of Formula II: O H N Y y D PAB
  • Linkers components including stretcher, spacer, and amino acid units, may be synthesized by methods known in the art, such as those described in U.S. patent publication no.2005/0238649. 6.5.
  • Drug loading is represented by p and is the average number of ALK5 inhibitor moieties per antibody in a molecule. Drug loading (“p”) may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 or more moieties (D) per antibody, although frequently the average number is a fraction or a decimal. Generally, ALK5 inhibitor loading averages from 2 to 8 drug moieties per antibody, more preferably 2 to 4 drug moieties per antibody or 5 to 7 drug moieties per antibody.
  • conjugate molecules (sometimes in the context of a pharmaceutical composition), each molecule composed of an antibody covalently attached to one or more ALK5 inhibitor moieties, with the drug loading ratio representing the average drug loading in the population or collection, although the ratio on an individual molecule basis may vary from one conjugate molecule to another in the population.
  • the population or collection contains conjugate molecules comprising an antibody covalently attached to anywhere between 1 and 30 drug moieties, and in some embodiments anywhere between 1 and 20, between 1 and 15, between 2 and 12, between 2 and 8, between 4 and 15, or between 6 and 12 drug moieties.
  • the loading (drug/antibody ratio) of an conjugate may be controlled in different ways, e.g., by:(i) limiting the molar excess of drug-linker intermediate or linker reagent relative to antibody, (ii) limiting the conjugation reaction time or temperature, (iii) partial or limiting reductive conditions for cysteine thiol modification, (iv) engineering by recombinant techniques the amino acid sequence of the antibody such that the number and position of cysteine residues is modified for control of the number and/or position of linker-drug attachments (such as thioMab or thioFab prepared as disclosed in PCT publication no. WO 2006/034488 (herein incorporated by reference in its entirety)).
  • the resulting product is a mixture of conjugate compounds with a distribution of one or more drug moieties attached to an antibody.
  • the average number of drugs per antibody may be calculated from the mixture by a dual ELISA antibody assay, which is specific for antibody and specific for the drug.
  • Individual conjugate molecules may be identified in the mixture by mass spectroscopy and separated by HPLC, e.g. hydrophobic interaction chromatography.
  • HPLC e.g. hydrophobic interaction chromatography.
  • a homogeneous conjugate with a single loading value may be isolated from the conjugation mixture by electrophoresis or chromatography. 6.6.
  • a host cell is transfected with one or more recombinant expression vectors carrying DNA fragments encoding the immunoglobulin light and heavy chains of the antibody such that the light and heavy chains are expressed in the host cell and, optionally, secreted into the medium in which the host cells are cultured, from which medium the antibodies can be recovered.
  • Standard recombinant DNA methodologies are used to obtain antibody heavy and light chain genes, incorporate these genes into recombinant expression vectors and introduce the vectors into host cells, such as those described in Molecular Cloning; A Laboratory Manual, Second Edition (Sambrook, Fritsch and Maniatis (eds), Cold Spring Harbor, N. Y., 1989), Current Protocols in Molecular Biology (Ausubel, F.
  • DNA encoding a V H region can be converted to a full-length heavy chain gene by operatively linking the VH-encoding DNA to another DNA molecule encoding heavy chain constant regions (CH1, CH2, CH3 and, optionally, CH4).
  • heavy chain constant regions CH1, CH2, CH3 and, optionally, CH4.
  • the sequences of human heavy chain constant region genes are known in the art (See, e.g., Kabat et al., 1991, Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No.91-3242) and DNA fragments encompassing these regions can be obtained by standard PCR amplification.
  • the heavy chain constant region can be an IgG1, IgG2, IgG3, IgG4, IgA, IgE, IgM or IgD constant region, but in certain embodiments is an IgG 1 or IgG 4 constant region.
  • DNA encoding a VL region can be converted to a full-length light chain gene (as well as a Fab light chain gene) by operatively linking the V L -encoding DNA to another DNA molecule encoding the light chain constant region, CL.
  • the sequences of human light chain constant region genes are known in the art (See, e.g., Kabat et al., 1991, Sequences of Proteins of Immunological Interest, Fifth Edition, U.S.
  • DNAs encoding partial or full-length light and heavy chains obtained as described above, are inserted into expression vectors such that the genes are operatively linked to transcriptional and translational control sequences.
  • operatively linked is intended to mean that an antibody gene is ligated into a vector such that transcriptional and translational control sequences within the vector serve their intended function of regulating the transcription and translation of the antibody gene.
  • the expression vector and expression control sequences are chosen to be compatible with the expression host cell used.
  • the antibody light chain gene and the antibody heavy chain gene can be inserted into separate vectors or, more typically, both genes are inserted into the same expression vector.
  • the antibody genes are inserted into the expression vector by standard methods (e.g., ligation of complementary restriction sites on the antibody gene fragment and vector, or blunt end ligation if no restriction sites are present).
  • the expression vector Prior to insertion of the anti-CD5 antibody-related light or heavy chain sequences, the expression vector can already carry antibody constant region sequences.
  • one approach to converting the anti-CD5 monoclonal antibody-related VH and VL sequences to full-length antibody genes is to insert them into expression vectors already encoding heavy chain constant and light chain constant regions, respectively, such that the V H segment is operatively linked to the CH segment(s) within the vector and the V L segment is operatively linked to the CL segment within the vector.
  • the recombinant expression vector can encode a signal peptide that facilitates secretion of the antibody chain from a host cell.
  • the antibody chain gene can be cloned into the vector such that the signal peptide is linked in-frame to the amino terminus of the antibody chain gene.
  • the signal peptide can be an immunoglobulin signal peptide or a heterologous signal peptide (i.e., a signal peptide from a non-immunoglobulin protein).
  • exemplary signal peptides include MGSTAILGLLLAVLQGGRA (SEQ ID NO:60) and METDTLLLWVLLLWVPGSTGAS (SEQ ID NO:61).
  • the recombinant expression vectors of the disclosure carry regulatory sequences that control the expression of the antibody chain genes in a host cell.
  • regulatory sequence is intended to include promoters, enhancers and other expression control elements (e.g., polyadenylation signals) that control the transcription or translation of the antibody chain genes.
  • promoters e.g., promoters, enhancers and other expression control elements (e.g., polyadenylation signals) that control the transcription or translation of the antibody chain genes.
  • expression control elements e.g., polyadenylation signals
  • Such regulatory sequences are described, for example, in Goeddel, Gene Expression Technology: Methods in Enzymology 185, Academic Press, San Diego, Calif., 1990. It will be appreciated by those skilled in the art that the design of the expression vector, including the selection of regulatory sequences may depend on such factors as the choice of the host cell to be transformed, the level of expression of protein desired, etc.
  • Suitable regulatory sequences for mammalian host cell expression include viral elements that direct high levels of protein expression in mammalian cells, such as promoters and/or enhancers derived from cytomegalovirus (CMV) (such as the CMV promoter/enhancer), Simian Virus 40 (SV40) (such as the SV40 promoter/enhancer), adenovirus, (e.g., the adenovirus major late promoter (AdMLP)) and polyoma.
  • CMV cytomegalovirus
  • SV40 Simian Virus 40
  • AdMLP adenovirus major late promoter
  • DHFR selectable marker e.g., as described in Kaufman and Sharp, 1982, Mol. Biol.159:601-621
  • NSO myeloma cells e.g., as described in Kaufman and Sharp, 1982, Mol. Biol.159:601-621
  • NSO myeloma cells e.g., as described in Kaufman and Sharp, 1982, Mol. Biol.159:601-621
  • NSO myeloma cells e.g., as described in Kaufman and Sharp, 1982, Mol. Biol.159:601-621
  • NSO myeloma cells e.g., as described in Kaufman and Sharp, 1982, Mol. Biol.159:601-621
  • NSO myeloma cells e.g., as described in Kaufman and Sharp, 1982, Mol. Biol.159:601-621
  • NSO myeloma cells e.g., as described in Kaufman and Sharp, 1982, Mol. Biol.159:601-621
  • the host cell can be co- transfected with two expression vectors of the disclosure, the first vector encoding a heavy chain derived polypeptide and the second vector encoding a light chain derived polypeptide.
  • the two vectors can contain identical selectable markers, or they can each contain a separate selectable marker.
  • a single vector can be used which encodes both heavy and light chain polypeptides.
  • nucleic acid encoding one or more portions of an anti-CD5 antibody further alterations or mutations can be introduced into the coding sequence, for example to generate nucleic acids encoding antibodies with different CDR sequences, antibodies with reduced affinity to the Fc receptor, or antibodies of different subclasses.
  • the anti-CD5 antibodies of the disclosure can also be produced by chemical synthesis (e.g., by the methods described in Solid Phase Peptide Synthesis, 2nd ed., 1984 The Pierce Chemical Co., Rockford, Ill.).
  • Variant antibodies can also be generated using a cell-free platform (See, e.g., Chu et al., Biochemia No.2, 2001 (Roche Molecular Biologicals) and Murray et al., 2013, Current Opinion in Chemical Biology, 17:420-426).
  • a cell-free platform See, e.g., Chu et al., Biochemia No.2, 2001 (Roche Molecular Biologicals) and Murray et al., 2013, Current Opinion in Chemical Biology, 17:420-426).
  • an anti-CD5 antibody or antigen-binding fragment thereof of the disclosure Once an anti-CD5 antibody or antigen-binding fragment thereof of the disclosure has been produced by recombinant expression, it can be purified by any method known in the art for purification of an immunoglobulin molecule, for example, by chromatography (e.g., ion exchange, affinity, and sizing column chromatography), centrifugation, differential solubility, or by any other standard technique for the purification of proteins.
  • the anti-CD5 antibodies of the present disclosure and/or binding fragments can be fused to heterologous polypeptide sequences described herein or otherwise known in the art to facilitate purification.
  • the anti-CD5 antibody or antigen-binding fragment can, if desired, be further purified, e.g., by high performance liquid chromatography (see, e.g., Fisher, Laboratory Techniques In Biochemistry And Molecular Biology, Work and Burdon, eds., Elsevier, 1980), or by gel filtration chromatography on a SuperdexTM 75 column (Pharmacia Biotech AB, Uppsala, Sweden). 6.7.
  • Suitable routes of administration of the conjugates, the antibodies, and antigen binding fragments of the disclosure include, without limitation, oral, parenteral, rectal, transmucosal, intestinal administration, intramedullary, intrathecal, direct intraventricular, intravenous, intravitreal, intracavitary, intraperitoneal, or intratumoral injections.
  • the preferred routes of administration are parenteral, more preferably intravenous.
  • compositions of the disclosure can be formulated according to known methods to prepare pharmaceutically useful compositions, for example whereby a conjugate is combined in a mixture with a pharmaceutically suitable excipient.
  • a conjugate is combined in a mixture with a pharmaceutically suitable excipient.
  • Sterile phosphate-buffered saline is one example of a pharmaceutically suitable excipient.
  • Other suitable excipients are well-known to those in the art. See, for example, Ansel et al., Pharmaceutical Dosage Forms And Drug Delivery Systems, 5th Edition (Lea & Febiger 1990), and Gennaro (ed.), Remington's Pharmaceutical Sciences, 18th Edition (Mack Publishing Company 1990), and revised editions thereof.
  • a conjugate is formulated in Good’s biological buffer (pH 6-7), using a buffer selected from the group consisting of N-(2-acetamido)-2-aminoethanesulfonic acid (ACES); N-(2- acetamido)iminodiacetic acid (ADA); N,N-bis(2-hydroxyethyl)-2-aminoethanesulfonic acid (BES); 4-(2- hydroxyethyl)piperazine-1-ethanesulfonic acid (HEPES); 2-(N-morpholino)ethanesulfonic acid (MES); 3- (N-morpholino)propanesulfonic acid (MOPS); 3-(N-morpholinyl)-2-hydroxypropanesulfonic acid (MOPSO); and piperazine-N,N'-bis(2-ethanesulfonic acid) [Pipes].
  • a buffer selected from the group consisting of N-(2-acetamido)-2-aminoethan
  • More preferred buffers are MES or MOPS, preferably in the concentration range of 20 to 100 mM, more preferably about 25 mM. Most preferred is 25 mM MES, pH 6.5.
  • the formulation may further comprise 25 mM trehalose and 0.01% v/v polysorbate 80 as excipients, with the final buffer concentration modified to 22.25 mM as a result of added excipients.
  • the preferred method of storage is as a lyophilized formulation of the conjugates, stored in the temperature range of -20°C to 2°C, with the most preferred storage at 2°C to 8°C. [0198]
  • a conjugate can be formulated for intravenous administration via, for example, bolus injection, slow infusion or continuous infusion.
  • the conjugate is infused over a period of less than about 4 hours, and more preferably, over a period of less than about 3 hours.
  • the first 25-50 mg could be infused within 30 minutes, preferably even 15 min, and the remainder infused over the next 2-3 hrs.
  • Formulations for injection can be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the compositions can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the rate of release of an conjugate from such a matrix depends upon the molecular weight of the conjugate, the amount of conjugate within the matrix, and the size of dispersed particles. Saltzman et al., 1989, Biophys. J.55:163; Sherwood et al., supra. Other solid dosage forms are described in Ansel et al., Pharmaceutical Dosage Forms And Drug Delivery Systems, 5th Edition (Lea & Febiger 1990), and Gennaro (ed.), Remington's Pharmaceutical Sciences, 18th Edition (Mack Publishing Company 1990), and revised editions thereof. [0200] Generally, the dosage of an administered conjugate for humans will vary depending upon such factors as the patient’s age, weight, height, sex, general medical condition and previous medical history.
  • a dosage of 0.3-5 mg/kg for a 70 kg patient is 21- 350 mg, or 12-20 6 mg/m2 for a 1.7-m patient.
  • the dosage may be repeated as needed, for example, once per week for 2-10 weeks, once per week for 8 weeks, or once per week for 4 weeks. It may also be given less frequently, such as every other week for several months, or monthly or quarterly for many months, as needed in a maintenance therapy.
  • Preferred dosages may include, but are not limited to, 0.3 mg/kg, 0.5 mg/kg, 0.7 mg/kg, 1.0 mg/kg, 1.2 mg/kg, 1.5 mg/kg, 2.0 mg/kg, 2.5 mg/kg, 3.0 mg/kg, 3.5 mg/kg, 4.0 mg/kg, 4.5 mg/kg, and 5.0 mg/kg. More preferred dosages are 0.6 mg/kg for weekly administration and 1.2 mg/kg for less frequent dosing. Any amount in the range of 0.3 to 5 mg/kg may be used. The dosage is preferably administered multiple times, once a week.
  • a minimum dosage schedule of 4 weeks, more preferably 8 weeks, more preferably 16 weeks or longer may be used, with the dose frequency dependent on toxic side-effects and recovery therefrom, mostly related to hematological toxicities.
  • the schedule of administration may comprise administration once or twice a week, on a cycle selected from the group consisting of:(i) weekly; (ii) every other week; (iii) one week of therapy followed by two, three or four weeks off; (iv) two weeks of therapy followed by one, two, three or four weeks off; (v) three weeks of therapy followed by one, two, three, four or five week off; (vi) four weeks of therapy followed by one, two, three, four or five week off; (vii) five weeks of therapy followed by one, two, three, four or five week off; and (viii) monthly.
  • a conjugate may be administered as one dosage every 2 or 3 weeks, repeated for a total of at least 3 dosages. Or, twice per week for 4-6 weeks. The dosage may be administered once every other week or even less frequently, so the patient can recover from any drug-related toxicities. Alternatively, the dosage schedule may be decreased, namely every 2 or 3 weeks for 2-3 months. The dosing schedule can optionally be repeated at other intervals and dosage may be given through various parenteral routes, with appropriate adjustment of the dose and schedule. 6.8. Methods of Treatment Using Conjugates of the Disclosure [0202] The conjugates of the disclosure can be used for the treatment of various cancers.
  • the conjugates can be used as monotherapy or as part of a combination therapy regimen, for example with a standard of care agent or regimen.
  • the combination therapy comprises administering an conjugate in combination with immunotherapy, for example, checkpoint modulator (e.g., checkpoint inhibitor) therapy, chimeric antigen receptor (CAR) therapy, adoptive T cell therapy (e.g., autologous T cell therapy), oncolytic virus therapy, dendritic cell vaccine therapy, stimulator of interferon genes (STING) agonist therapy, toll-like receptor (TLR) agonist therapy, intratumoral CpG therapy, cytokine therapy (e.g., IL2, IL12, IFN- ⁇ , or INF- ⁇ therapy), or a combination thereof.
  • immunotherapy for example, checkpoint modulator (e.g., checkpoint inhibitor) therapy, chimeric antigen receptor (CAR) therapy, adoptive T cell therapy (e.g., autologous T cell therapy), oncolytic virus therapy, dendritic cell vaccine therapy, stimulator of inter
  • the combination therapy comprises administering an conjugate in combination with immune preserving chemotherapy (e.g., an antimetabolite, such as 5-fluorouracil, gemcitabine, or methotrexate, an alkylating agent such as cyclophosphamide, dacarbazine, mechlorethamine, diaziquone, or temozolomide, an anthracycline such as doxorubicin or epirubicin, an antimicrotubule agent such as vinblastine, a platinum compound such as cisplatin or oxaliplatin, a taxane such as paclitaxel or docetaxel, or a topoisomerase inhibitor such as etoposide or mitoxantrone, or a vinca alkaloid such as vincristine).
  • immune preserving chemotherapy e.g., an antimetabolite, such as 5-fluorouracil, gemcitabine, or methotrexate, an alkylating agent such as cyclophosp
  • Conjugates of the disclosure can be used in combination with a checkpoint modulator (e.g., a checkpoint inhibitor), for example an agent targeting PD1, PDL1, CTLA4, TIGIT, LAG3, OX40, ICOS, GITR, CD40 or VISTA.
  • a checkpoint modulator e.g., a checkpoint inhibitor
  • Exemplary checkpoint modulators targeting TIGIT include etigilimab, tiragolumab, and AB154.
  • Exemplary checkpoint modulators targeting LAG3 include LAG525, Sym022, relatlimab, and TSR-033.
  • Exemplary checkpoint modulators targeting OX40 include MEDI6469, PF-04518600, and BMS 986178.
  • Exemplary checkpoint modulators targeting ICOS include MEDI-570, feladilimab, and BMS 986226.
  • Exemplary checkpoint modulators targeting GITR include TRX-518, AMG 228, MK-4166, MEDI1873, INCAGN01876, and GWN323.
  • Exemplary checkpoint modulators targeting CD40 include selicrelumab, CP-870,893, and APX005M.
  • An exemplary checkpoint modulator targeting VISTA is HMBD-002.
  • the conjugates of the disclosure can be used in combination with drugs that specifically target the BRAF mutations, such as venurafenibm, dabrafenib and trametinib.
  • the conjugates of the disclosure can be used in combination with a checkpoint modulator (e.g., inhibitor), such as ipilimumab, nivolumab, pembrolizumab, cemiplimab, or avelumab.
  • a checkpoint modulator e.g., inhibitor
  • the conjugates of the disclosure can be used in combination with standard of care chemotherapy treatments such as cisplatin, carboplatin, paclitaxel, gemcitabine, vinorelbin, irinotecan, etoposide, or vinblastine would be included.
  • conjugates can be used in combination with targeted therapies, such as bevacizumab or Erbitux.
  • conjugates can be used in combination with a checkpoint modulator (e.g., inhibitor), such as pembrolizumab, nivolumab, cemiplimab, dostarlimab, atezolizumab, avelumab, durvalumab, or ipilimumab.
  • a checkpoint modulator e.g., inhibitor
  • pembrolizumab nivolumab, cemiplimab, dostarlimab, atezolizumab, avelumab, durvalumab, or ipilimumab.
  • the conjugates of the disclosure can be used in combination with standard of care treatments, including but not limited to cisplatin, mitomycin-C, carboplatin, docetaxel, paclitaxel, doxorubicin, 5-FU, methotrexate, vinblastine, ifosfamide, and pemetrexed.
  • the conjugates can be used in combination with a checkpoint modulator (e.g., inhibitor), such as ipilimumab.
  • the conjugates of the disclosure can be used in combination with standard of care treatments, for example agents that block angiogenesis and/or specific tyrosine kinases, such as sorafenib, sunitinib, temsirolimus, everolimus, pazopanib, and axitinib.
  • agents that block angiogenesis and/or specific tyrosine kinases such as sorafenib, sunitinib, temsirolimus, everolimus, pazopanib, and axitinib.
  • the conjugates can be used in combination with a checkpoint modulator (e.g., inhibitor), such as nivolumab.
  • the conjugates of the disclosure can be used in combination with standard of care chemotherapeutic agents, such as the anthracyclines (doxorubicin or epirubicin) and the taxanes (paclitaxel or docetaxel), as well as fluorouracil, cyclophosphamide and carboplatin.
  • chemotherapeutic agents such as the anthracyclines (doxorubicin or epirubicin) and the taxanes (paclitaxel or docetaxel), as well as fluorouracil, cyclophosphamide and carboplatin.
  • the conjugates of the disclosure can be used in combination with targeted therapies.
  • Targeted therapies for HER2/neu positive tumors include trastuzumab and pertuzumab and for estrogen receptor (ER) positive tumors include tamoxifen, toremifene and fulvestrant.
  • the conjugates can be used in combination with a checkpoint modulator (e.g., inhibitor), such as atezolizumab.
  • a checkpoint modulator e.g., inhibitor
  • the conjugates of the disclosure can be used in combination with standard of care chemotherapeutic agents, such as gemcitabine, 5-fluouracil, irinotecan, oxaliplatin, paclitaxel, capecitabine, cisplatin, or docetaxel.
  • conjugates can be used in combination with targeted therapies, such as erlotinib, which inhibits EGFR.
  • the conjugates of the disclosure can be used in combination with standard of care chemotherapeutic agents, such as carboplatin, cyclophosphamide, etoposide, lomustine, methotrexate or procarbazine.
  • standard of care chemotherapeutic agents such as carboplatin, cyclophosphamide, etoposide, lomustine, methotrexate or procarbazine.
  • the conjugates of the disclosure can be used in combination with standard of care chemotherapeutic agents, including docetaxel, optionally with the steroid prednisone, or cabazitaxel.
  • the conjugates can be used in combination with a checkpoint modulator (e.g., inhibitor), such as ipilimumab.
  • an conjugate of the disclosure in combination with one or more therapies does not restrict the order in which the therapies are administered.
  • the conjugate of the disclosure can be administered before, during or after a subject is treated with one or more therapies.
  • an conjugate of the disclosure is administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) treatment of a patient with another therapy (e.g., a second therapeutic agent as described above).
  • another therapy e.g., a second
  • the conjugate of the disclosure is incorporated into the same regimen as a second therapeutic agent.
  • Example 1 Generation of Humanized Anti-CD5 Antibodies with Human IgG Backbones 7.1.1. Overview [0216] Antibodies against human proteins or peptides isolated from non-human animal cells (e.g., mouse anti-human CD5 antibodies) often elicit immune responses when used as therapeutics. Although humanized antibodies are considered to be less immunogenic than their parental counterparts, they may still be associated with antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), triggered by the interactions of the constant Fc regions of these antibodies with the Fc receptors on immune cells.
  • ADCC antibody-dependent cellular cytotoxicity
  • CDC complement-dependent cytotoxicity
  • the first parental antibody was a humanized anti-CD5 antibody (referred to herein as “Antibody A”)
  • the second parental antibody was a mouse anti-human CD5 antibody (referred to herein as “Antibody B”).
  • Antibody A humanized anti-CD5 antibody
  • Antibody B mouse anti-human CD5 antibody
  • the variable region sequences of the first parental antibody (Antibody A) (VH of SEQ ID NO:49 and VL of SEQ ID NO:50) were integrated into human IgG backbones.
  • the heavy chain of the parental antibody was integrated into either wildtype human IgG1, an IgG1 with the mutations L234A and L235A (IgG1(LALA)), an IgG1 with an N297A mutation (IgG1(N297A), or an IgG4 with an S228P mutation (IgG4(S228P).
  • the heavy chains with the human IgG backbones were then combined with the light chains integrated into human IgKappa.
  • Full light chain and heavy chain sequences for the antibodies, referred to as AB-1 to AB-4, are set forth in Table 1L. 7.1.2.2.
  • the parental mouse anti-human CD5 antibody was humanized as follows: The amino acid sequences of the parental light and heavy chains were aligned with the human germline Ig alleles, IGKV3-11*01, IGKV3-11*02, and IGKV1-16*01.
  • FIGS.1A-1C display amino acid residue alignment mismatches between the parental mouse antibody and the germline Ig frameworks.
  • the light and heavy chain complementarity-determining region (CDR) amino acid sequences of the parental antibody were grafted onto a human Ig framework sequence. The resulting sequence was further modified, such as by introducing back-mutations of various residues in order to retain the antigen-binding activity of the parent antibody.
  • FIGS 2A and 2B illustrate the humanization of the parental mouse anti- human CD5 antibody VH and VL amino acid sequences into AB-5 VH and VL amino acid sequences, by using the antibody 4JLR.pdb as a reference framework.
  • Resulting sequences were checked for confounding issues, such as N-glycosylation, interface changes, and potentially problematic proline residues.
  • Six humanized anti-CD5 antibody VH-VL sequences were selected for further analyses. Full light chain and heavy chain sequences for the humanized antibodies, referred to as AB-5 to AB-10, are shown in Table 1L. The VH and VL were subsequently cloned into human IgG1(LALA) Fc backbones. 7.1.2.3.
  • Anti-CD5 Construct VH/VL Isot es [0225] Antibody constructs were cloned into Expi293 cells and antibodies were produced and purified as described in Section 7.1.2.3. Exemplary SDS-PAGE images of three anti-CD5 antibodies, AB-4, AB-6, and AB-8, and the negative control antibody, NC-AB, are shown in FIGS.3A-3D. Furthermore, the purified antibodies had low endotoxin levels, which was below 1 EU/mg for all samples at the highest concentration evaluated (FIG.3E). 7.2.
  • Example 2 Target Cell Binding of Humanized Anti-CD5 Antibodies with Human IgG Backbones 7.2.1.
  • CD5 is a surface glycoprotein expressed on T cells.
  • a cell binding assay using Jurkat T cells was utilized. 7.2.2. Methods 7.2.2.1. Cell Culture and Maintenance [0227] Jurkat T cells were maintained in RPMI medium supplemented with 10% FBS. EL4 cells were maintained in DMEM medium supplemented with 10% FBS. CD3+ T cells were maintained in K5 medium supplemented with 10% FBS, 1X non-essential amino acids, 1 mM sodium pyruvate, 2 mM L-glutamine, and 55 ⁇ M 2-mercaptoethanol.
  • AB-4 was associated with a 44% and AB-8 was associated with a 53% reduction of surface CD5 binding at 6 hours, further supporting efficient internalization of humanized anti-CD5 antibodies derived from both parental antibodies.
  • Example 4 ADCC Assessment of Humanized Anti-CD5 Antibodies with Human IgG Backbones 7.4.1. Overview [0239] Fc regions of humanized antibodies are often associated with antibody-dependent cellular cytotoxicity (ADCC). Therefore, humanized anti-CD5 antibodies comprising human IgG chains with low ADCC activity, such as IgG1-LALA, can help overcome this limitation. 7.4.2. Methods [0240] An ADCC assay was developed to evaluate ADCC effects of anti-CD5 antibodies.
  • NK cells were isolated from PBMCs and co-cultured with Jurkat T cells (4 x 10 4 cells/well) at an effector: target cell ratio (E:T) of 5:1.
  • Humanized anti-CD5 antibodies, as well as the parental mouse anti-hCD5 antibody, a positive control antibody (Anti-human MHC Class I antibody) and a negative control antibody (NC-AB) were diluted to a concentration of 30 ⁇ g/mL and added to wells.
  • the plates were incubated for 4 hours at 37 °C, 5% CO2. Cells were incubated with CytoTox 96® reagent for 30 minutes at room temperature before data collection on a plate reader at 490nm. 7.4.3.
  • the mixture was incubated for 30 minutes at room temperature and then added drop-wise to the HEK-293 cells. After 48 hours, the transfected cells were gently detached from the plates with Accutase® cell detachment solution, washed 2X in ice-cold stain buffer (1X dPBS, 1% FBS, 0.05% sodium azide) and counted.1.5 x 10 5 cells were incubated with either 7.5 ⁇ g/mL Antibody C-PE (phycoerythrin) conjugate or Antibody B-PE in 100 ⁇ L stain buffer. After 60 minutes on ice, the cells were washed 2X in stain buffer to completely remove unbound antibody.
  • Example 6 Internalization of AB-4, AB-6, and AB-8 [0246] Internalization of humanized antibodies AB-4, AB-6, and AB-8 following binding to CD5 expressing Jurkat cells was studied. Briefly, antibodies were incubated with Jurkat cells for two to six hours, and antibody internalization was measured by FACS staining. [0247] Results are shown in FIGS.8A-8C. AB-4, AB-6, and AB-8 were each internalized. 7.7.
  • Example 7 Humanized Antibodies with Human IgG4 Fc 7.7.1.
  • Fc regions of humanized anti-human CD5 antibodies AB-5, AB-6, AB-7, AB-8, AB-9, and AB-10, and mouse anti-human CD5 Antibody B were substituted with human IgG4 Fc regions having a S228P substitution. Binding to Jurkat cells was assessed. 7.7.2. Methods [0249] Serial dilutions of anti-CD5 antibodies and isotype control antibody were prepared and incubated with Jurkat cells at 4 °C for 60 minutes. Cells were then washed three times. PE-goat anti-human IgG secondary antibody was added to the cells, and incubated for 30 minutes at 4 °C. Cells were washed and analyzed by FACS. 7.7.3.
  • Log phase Jurkat cells (2E5/sample) were washed in cell culture medium, and plated in a 96-well U-bottom plate in cell culture medium. Antibodies at 1 ⁇ g/ml were incubated with the cells at 4 °C for 60 minutes. Cells were then washed two time and resuspended in growth medium (RPMI1640 + 10% FBS). Cells were incubated at 37 °C for 0 hours, 4 hours, or 6 hours. Cells were then washed two times in staining buffer. Secondary antibody in staining buffer (PE-goat anti-human IgG) was added and incubated for 30 minutes at 4°C.
  • Primary antibody in staining buffer PE-goat anti-human IgG
  • Results are shown in FIGS.10A-10B. All antibodies showed internalization at 4 hours and 6 hours. Percent internalization at 4 hours and 6 hours is summarized in Table 11. Table 11 Antibody Time (hours) Percent 7.9. Exam agonist-Conjugates (ATAC s) [0254] Antibodies AB-4, AB-8, and Antibody B were conjugated to ALK5 inhibitor compound C (see Table 2) and evaluated in a HEK-CD5 SBE luciferase assay to monitory the activity of the TGF ⁇ /SMAD signaling pathway following exposure to the antibody-ALK5 inhibitor conjugates. 7.9.1.
  • HEK-CD5 cells were plated in triplicate on a 96-well plate. After the cells attached, the conjugated antibodies were titrated and incubated for 18 hours in a 37°C/5% CO 2 incubator. TGF ⁇ was added to the plate and incubated for an additional 3 hours. The assay was developed using a commercially available luciferase detection reagent, the data was acquired on a luminometer and plotted using GraphPad Prism TM software. 7.9.2. Results [0256] Results are shown in FIG.11A-11B. Each conjugate was active in the assay. EC50 values are reported in Table 12. Table 12 Antibody-ALK5 inhibitor conjugate EC50 . . .
  • T cells were isolated from human PBMCs and plated in triplicate on round-bottom 96-well plates. Antibody was added to the cells and incubated on ice for 0.5 hours. Complement from rabbit sera was then added to a final concentration of 5%. The cells were incubated for 2 hours in a 37°C/5% CO 2 incubator. Propidium iodide was added to the cells and the data was acquired on a FACS instrument, analyzed using FlowJo TM software and plotted using GraphPad Prism TM . 7.10.3. Results [0259] Results are shown in FIG.12.
  • An anti-CD5 antibody or antigen binding fragment thereof comprising: (a) a VH comprising CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs:1, 6, and 13, respectively, and a VL comprising CDR-L1, CDR-L2, and CDR- L3 having the amino acid sequences of SEQ ID NO:17, ATS, and SEQ ID NO:20, respectively; (b) a VH comprising CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs:2, 11, and 14, respectively, and a VL comprising CDR-L1, CDR-L2, and CDR- L3 having the amino acid sequences of SEQ ID NOs:18, 19, and 21, respectively; (c
  • An anti-CD5 antibody or antigen binding fragment thereof which is optionally an anti- CD5 antibody or antigen binding fragment according to embodiment 1, comprising: (a) a VH comprising CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs:2, 7, and 14, respectively, and a VL comprising CDR-L1, CDR-L2, and CDR- L3 having the amino acid sequences of SEQ ID NOs:18, 19, and 21, respectively; (b) a VH comprising CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs:5, 7, and 13, respectively, and a VL comprising CDR-L1, CDR-L2, and CDR- L3 having the amino acid sequences of SEQ ID NOs:18, 19, and 21, respectively; (c) a VH comprising CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs:1, 6, and 13, respectively, and
  • VH comprises CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs:1, 6, and 13, respectively
  • VL comprises CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NO:17, ATS, and SEQ ID NO:20, respectively.
  • An anti-CD5 antibody or antigen binding fragment thereof which is optionally an antibody or antigen binding fragment according to any one of embodiments 1 to 17, comprising: (a) a VH having a sequence at least 90% identical (e.g., at least 95%, at least 97%, at least 99%, or 100% identical) to SEQ ID NO:22 and a VL having a sequence at least 90% identical (e.g., at least 95%, at least 97%, at least 99%, or 100% identical) to SEQ ID NO:23; (b) a VH having a sequence at least 90% identical (e.g., at least 95%, at least 97%, at least 99%, or 100% identical) to SEQ ID NO:24 and a VL having a sequence at least 90% identical (e.g., at least 95%, at least 97%, at least 99%, or 100% identical) to SEQ ID NO:25; (c) a VH having a sequence at least 90% identical (e.g., at least 95%, at least 97%, at
  • the VH has a sequence at least 95% identical to SEQ ID NO:22 and the VL has a sequence at least 95% identical to SEQ ID NO:23. 21.
  • the VH has a sequence at least 95% identical to SEQ ID NO:26 and the VL has a sequence at least 95% identical to SEQ ID NO:27. 31.
  • the anti-CD5 antibody or antigen binding fragment thereof of embodiment 34 wherein the VH has a sequence at least 97% identical to SEQ ID NO:28 and the VL has a sequence at least 97% identical to SEQ ID NO:29. 37.
  • the VH has a sequence at least 95% identical to SEQ ID NO:30 and the VL has a sequence at least 95% identical to SEQ ID NO:31.
  • the anti-CD5 antibody or antigen binding fragment thereof of embodiment 39 wherein the VH has a sequence at least 97% identical to SEQ ID NO:30 and the VL has a sequence at least 97% identical to SEQ ID NO:31. 42.
  • the anti-CD5 antibody or antigen binding fragment thereof of embodiment 39 wherein the VH has a sequence at least 99% identical to SEQ ID NO:30 and the VL has a sequence at least 99% identical to SEQ ID NO:31.
  • the anti-CD5 antibody or antigen binding fragment thereof of embodiment 39 wherein the VH has a sequence identical to SEQ ID NO:30 and the VL has a sequence identical to SEQ ID NO:31. 44.
  • the anti-CD5 antibody or antigen binding fragment thereof of embodiment 44 wherein the VH has a sequence at least 97% identical to SEQ ID NO:32 and the VL has a sequence at least 97% identical to SEQ ID NO:33. 47.
  • the anti-CD5 antibody or antigen binding fragment thereof of embodiment 44 wherein the VH has a sequence at least 99% identical to SEQ ID NO:32 and the VL has a sequence at least 99% identical to SEQ ID NO:33.
  • An anti-CD5 antibody or antigen binding fragment thereof comprising: (a) a VH comprising CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs:34, 39, and 43, respectively, and a VL comprising CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NO:45, RAN, and SEQ ID NO:48, respectively; (b) a VH comprising CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs:35, 40, 44, respectively, and a VL comprising CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs:46, 47, and 48, respectively; (c) a VH comprising CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs:36, 41, and 44, respectively, and a V
  • the anti-CD5 antibody or antigen binding fragment thereof of embodiment 49 which is a humanized anti-CD5 antibody or antigen binding fragment thereof.
  • the anti-CD5 antibody or antigen binding fragment thereof of embodiment 49 or embodiment 50 wherein the VH comprises CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs:35, 40, 44, respectively, and the VL comprises CDR-L1, CDR-L2, and CDR- L3 having the amino acid sequences of SEQ ID NOs:46, 47, and 48, respectively. 53.
  • the anti-CD5 antibody or antigen binding fragment thereof of embodiment 49 or embodiment 50 wherein the VH comprises CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs:36, 41, and 44, respectively, and the VL comprises CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs:18, 19, and 21, respectively. 54.
  • VH comprises CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of NYG, SEQ ID NO:3741, and SEQ ID NO:44, respectively
  • VL comprises CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NO:45, RAN, and SEQ ID NO:48, respectively. 55.
  • the anti-CD5 antibody or antigen binding fragment thereof of embodiment 49 or embodiment 50 wherein the VH comprises CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs:38, 42, and 43, respectively, and the VL comprises CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOS:46, 47, and 48, respectively 56.
  • An anti-CD5 antibody or antigen binding fragment thereof which is optionally an antibody or antigen binding fragment according to any one of embodiments 49 to 55, comprising a VH having a sequence at least 90% identical (e.g., at least 95%, at least 97%, at least 99%, or 100% identical) to SEQ ID NO:49 and a VL having a sequence at least 90% identical (e.g., at least 95%, at least 97%, at least 99%, or 100% identical) to SEQ ID NO:50.
  • the anti-CD5 antibody or antigen binding fragment thereof of embodiment 56 wherein the VH has a sequence at least 97% identical to SEQ ID NO:49 and the VL has a sequence at least 97% identical to SEQ ID NO:50. 59.
  • the anti-CD5 antibody or antigen binding fragment thereof of embodiment 56 wherein the VH has a sequence at least 99% identical to SEQ ID NO:49 and the VL has a sequence at least 99% identical to SEQ ID NO:50. 60.
  • An anti-CD5 antibody or antigen binding fragment thereof comprising: (a) a VH comprising CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs:1, 88, and 89, respectively, and a VL comprising CDR-L1, CDR-L2, and CDR- L3 having the amino acid sequences of SEQ ID NO:94, WT, and SEQ ID NO:95, respectively; (b) a VH comprising CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs:2, 90, and 91, respectively, and a VL comprising CDR-L1, CDR-L2, and CDR- L3 having the amino acid sequences of SEQ ID NOs:96, 97, and 95, respectively; (c) a VH comprising CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs:2, 90, and 91, respectively, and
  • VH comprises CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs:1, 88, and 89, respectively
  • VL comprises CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NO:94, WT, and SEQ ID NO:95, respectively.
  • the anti-CD5 antibody or antigen binding fragment thereof of embodiment 61 wherein the VH comprises CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs:2, 90, and 91, respectively, and the VL comprises CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs:96, 97, and 95, respectively. 64.
  • the anti-CD5 antibody or antigen binding fragment thereof of embodiment 61 wherein the VH comprises CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs:2, 90, and 91, respectively, and the VL comprises CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs:99, 97, and 95, respectively. 65.
  • the anti-CD5 antibody or antigen binding fragment thereof of embodiment 61 wherein the VH comprises CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs:3, 8, 91, respectively, and the VL comprises CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs:96, 97, 95, respectively. 66.
  • the anti-CD5 antibody or antigen binding fragment thereof of embodiment 61 wherein the VH comprises CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs:3, 8, 91, respectively, and the VL comprises CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs:99, 97, 95, respectively. 67.
  • the anti-CD5 antibody or antigen binding fragment thereof of embodiment 61 wherein the VH comprises CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs:4, 8, and 91, respectively, and the VL comprises CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NO:94, WT, and SEQ ID NO:95, respectively.
  • the VH comprises CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs:4, 8, and 91, respectively
  • the VL comprises CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NO:94, WT, and SEQ ID NO:95, respectively.
  • the anti-CD5 antibody or antigen binding fragment thereof of embodiment 61 wherein the VH comprises CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs:5, 90, and 89, respectively, and the VL comprises CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs:96, 97, and 95, respectively. 69.
  • the anti-CD5 antibody or antigen binding fragment thereof of embodiment 61 wherein the VH comprises CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs:5, 90, and 89, respectively, and the VL comprises CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs:99, 97, and 95, respectively. 70.
  • the anti-CD5 antibody or antigen binding fragment thereof of embodiment 61 wherein the VH comprises CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs:2, 102, and 91, respectively, and the VL comprises CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs:103, 97, and 95, respectively. 71.
  • the anti-CD5 antibody or antigen binding fragment thereof of embodiment 61 wherein the VH comprises CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs:3, 8, and 91, respectively, and the VL comprises CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs:103, 97, and 95, respectively. 72.
  • the anti-CD5 antibody or antigen binding fragment thereof of embodiment 61 wherein the VH comprises CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs:5, 102, and 89, respectively, and the VL comprises CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs:103, 97, and 95, respectively. 73.
  • the anti-CD5 antibody or antigen binding fragment thereof of embodiment 61 wherein the VH comprises CDR-H1, CDR-H2, and CDR-H3 having the amino acid sequences of SEQ ID NOs:104, 8, and 91, respectively, and the VL comprises CDR-L1, CDR-L2, and CDR-L3 having the amino acid sequences of SEQ ID NOs:94, 97, and 105, respectively.
  • the anti-CD5 antibody or antigen binding fragment thereof of any one of embodiments 61 to 73 which is a humanized anti-CD5 antibody or antigen binding fragment thereof.
  • An anti-CD5 antibody or antigen binding fragment thereof which is optionally an antibody or antigen binding fragment according to any one of embodiments 61 to 74, comprising: (a) a VH having a sequence at least 90% identical (e.g., at least 95%, at least 97%, at least 99%, or 100% identical) to SEQ ID NO:84 and a VL having a sequence at least 90% identical (e.g., at least 95%, at least 97%, at least 99%, or 100% identical) to SEQ ID NO:92; (b) a VH having a sequence at least 90% identical (e.g., at least 95%, at least 97%, at least 99%, or 100% identical) to SEQ ID NO:84 and a VL having a sequence at least 90% identical (e.g., at least 95%, at least 97%, at least 99%, or 100% identical) to SEQ ID NO:93; (c) a VH having a sequence at least 90% identical (e.g., at least 95%, at least 9
  • the anti-CD5 antibody or antigen binding fragment thereof of embodiment 75 wherein the VH has a sequence at least 90% identical (e.g., at least 95%, at least 97%, at least 99%, or 100% identical) to SEQ ID NO:84 and the VL has a sequence at least 90% identical (e.g., at least 95%, at least 97%, at least 99%, or 100% identical) to SEQ ID NO:92.
  • the anti-CD5 antibody or antigen binding fragment thereof of embodiment 76 wherein the VH has a sequence at least 97% identical to SEQ ID NO:84 and the VL has a sequence at least 97% identical to SEQ ID NO:92. 79.
  • the anti-CD5 antibody or antigen binding fragment thereof of embodiment 75 wherein the VH has a sequence at least 90% identical (e.g., at least 95%, at least 97%, at least 99%, or 100% identical) to SEQ ID NO:84 and the VL has a sequence at least 90% identical (e.g., at least 95%, at least 97%, at least 99%, or 100% identical) to SEQ ID NO:93.
  • the anti-CD5 antibody or antigen binding fragment thereof of embodiment 81 wherein the VH has a sequence at least 97% identical to SEQ ID NO:84 and the VL has a sequence at least 97% identical to SEQ ID NO:93. 84.
  • the anti-CD5 antibody or antigen binding fragment thereof of embodiment 75 wherein the VH has a sequence at least 90% identical (e.g., at least 95%, at least 97%, at least 99%, or 100% identical) to SEQ ID NO:84 and the VL has a sequence at least 90% identical (e.g., at least 95%, at least 97%, at least 99%, or 100% identical) to SEQ ID NO:98. 87.
  • the anti-CD5 antibody or antigen binding fragment thereof of embodiment 75 wherein the VH has a sequence at least 90% identical (e.g., at least 95%, at least 97%, at least 99%, or 100% identical) to SEQ ID NO:85 and the VL has a sequence at least 90% identical (e.g., at least 95%, at least 97%, at least 99%, or 100% identical) to SEQ ID NO:92. 92.
  • the anti-CD5 antibody or antigen binding fragment thereof of embodiment 91 wherein the VH has a sequence at least 97% identical to SEQ ID NO:85 and the VL has a sequence at least 97% identical to SEQ ID NO:92. 94.
  • the anti-CD5 antibody or antigen binding fragment thereof of embodiment 75 wherein the VH has a sequence at least 90% identical (e.g., at least 95%, at least 97%, at least 99%, or 100% identical) to SEQ ID NO:85 and the VL has a sequence at least 90% identical (e.g., at least 95%, at least 97%, at least 99%, or 100% identical) to SEQ ID NO:93. 97.
  • the anti-CD5 antibody or antigen binding fragment thereof of embodiment 96 wherein the VH has a sequence at least 97% identical to SEQ ID NO:85 and the VL has a sequence at least 97% identical to SEQ ID NO:93. 99.
  • the anti-CD5 antibody or antigen binding fragment thereof of embodiment 75 wherein the VH has a sequence at least 90% identical (e.g., at least 95%, at least 97%, at least 99%, or 100% identical) to SEQ ID NO:85 and the VL has a sequence at least 90% identical (e.g., at least 95%, at least 97%, at least 99%, or 100% identical) to SEQ ID NO:98. 102.
  • the anti-CD5 antibody or antigen binding fragment thereof of embodiment 101 wherein the VH has a sequence at least 97% identical to SEQ ID NO:85 and the VL has a sequence at least 97% identical to SEQ ID NO:98. 104.
  • the anti-CD5 antibody or antigen binding fragment thereof of embodiment 101 wherein the VH has a sequence at least 99% identical to SEQ ID NO:85 and the VL has a sequence at least 99% identical to SEQ ID NO:98. 105.
  • the anti-CD5 antibody or antigen binding fragment thereof of embodiment 75 wherein the VH has a sequence at least 90% identical (e.g., at least 95%, at least 97%, at least 99%, or 100% identical) to SEQ ID NO:86 and the VL has a sequence at least 90% identical (e.g., at least 95%, at least 97%, at least 99%, or 100% identical) to SEQ ID NO:92. 107.
  • the anti-CD5 antibody or antigen binding fragment thereof of embodiment 106 wherein the VH has a sequence at least 97% identical to SEQ ID NO:86 and the VL has a sequence at least 97% identical to SEQ ID NO:92. 109.
  • the anti-CD5 antibody or antigen binding fragment thereof of embodiment 75 wherein the VH has a sequence at least 90% identical (e.g., at least 95%, at least 97%, at least 99%, or 100% identical) to SEQ ID NO:86 and the VL has a sequence at least 90% identical (e.g., at least 95%, at least 97%, at least 99%, or 100% identical) to SEQ ID NO:93. 112.
  • the anti-CD5 antibody or antigen binding fragment thereof of embodiment 111 wherein the VH has a sequence at least 97% identical to SEQ ID NO:86 and the VL has a sequence at least 97% identical to SEQ ID NO:93. 114.
  • the anti-CD5 antibody or antigen binding fragment thereof of embodiment 75 wherein the VH has a sequence at least 90% identical (e.g., at least 95%, at least 97%, at least 99%, or 100% identical) to SEQ ID NO:86 and the VL has a sequence at least 90% identical (e.g., at least 95%, at least 97%, at least 99%, or 100% identical) to SEQ ID NO:98.
  • the VH has a sequence at least 95% identical to SEQ ID NO:86 and the VL has a sequence at least 95% identical to SEQ ID NO:98.
  • the anti-CD5 antibody or antigen binding fragment thereof of embodiment 116 wherein the VH has a sequence at least 97% identical to SEQ ID NO:86 and the VL has a sequence at least 97% identical to SEQ ID NO:98. 119.
  • the anti-CD5 antibody or antigen binding fragment thereof of embodiment 75 wherein the VH has a sequence at least 90% identical (e.g., at least 95%, at least 97%, at least 99%, or 100% identical) to SEQ ID NO:87 and the VL has a sequence at least 90% identical (e.g., at least 95%, at least 97%, at least 99%, or 100% identical) to SEQ ID NO:92. 122.
  • the anti-CD5 antibody or antigen binding fragment thereof of embodiment 121 wherein the VH has a sequence at least 97% identical to SEQ ID NO:87 and the VL has a sequence at least 97% identical to SEQ ID NO:92. 124.
  • the anti-CD5 antibody or antigen binding fragment thereof of embodiment 126 wherein the VH has a sequence at least 97% identical to SEQ ID NO:87 and the VL has a sequence at least 97% identical to SEQ ID NO:93. 129.
  • the anti-CD5 antibody or antigen binding fragment thereof of embodiment 75 wherein the VH has a sequence at least 90% identical (e.g., at least 95%, at least 97%, at least 99%, or 100% identical) to SEQ ID NO:87 and the VL has a sequence at least 90% identical (e.g., at least 95%, at least 97%, at least 99%, or 100% identical) to SEQ ID NO:98. 132.
  • the anti-CD5 antibody or antigen binding fragment thereof of embodiment 131 wherein the VH has a sequence at least 97% identical to SEQ ID NO:87 and the VL has a sequence at least 97% identical to SEQ ID NO:98. 134.
  • the anti-CD5 antibody or antigen binding fragment thereof of embodiment 75 wherein the VH has a sequence at least 90% identical (e.g., at least 95%, at least 97%, at least 99%, or 100% identical) to SEQ ID NO:100 and the VL has a sequence at least 90% identical (e.g., at least 95%, at least 97%, at least 99%, or 100% identical) to SEQ ID NO:101. 137.
  • the anti-CD5 antibody or antigen binding fragment thereof of embodiment 136 wherein the VH has a sequence at least 97% identical to SEQ ID NO:100 and the VL has a sequence at least 97% identical to SEQ ID NO:101.
  • the anti-CD5 antibody or antigen binding fragment thereof of embodiment 136 wherein the VH has a sequence at least 99% identical to SEQ ID NO:100 and the VL has a sequence at least 99% identical to SEQ ID NO:101.
  • 140. The anti-CD5 antibody or antigen binding fragment thereof of embodiment 136, wherein the VH has a sequence identical to SEQ ID NO:100 and the VL has a sequence identical to SEQ ID NO:101. 141.
  • the anti-CD5 antibody or antigen binding fragment thereof of any one of embodiments 1 to 146 which comprises an antigen binding fragment. 149.
  • the anti-CD5 antibody or antigen binding fragment thereof of any one of embodiments 1 to 148 which comprises a first Fc region and a second Fc region forming an Fc domain, optionally wherein the Fc domain is a human Fc domain.
  • the anti-CD5 antibody or antigen binding fragment thereof of embodiment 150 wherein the one or more substitutions comprise N297A, N297Q, N297G, D265A/N297A, D265A/N297G, L235E, L234A/L235A, L234A/L235A/P329A, L234D/L235E : L234R/L235R/E233K, L234D/L235E/D265S : E233K/L234R/L235R/D265S, L234D/L235E/E269K : E233K/L234R/L235R/E269K, L234D/L235E/K322A : E233K/L234R/L235R/K322A, L234D/L235E/P329W : E233K/L234R/L235R/P329W, L234D/L235E/E269K
  • the anti-CD5 antibody or antigen binding fragment thereof of embodiment 150 or embodiment 151, wherein the one or more substitutions comprise N297A. 153.
  • the anti-CD5 antibody or antigen binding fragment thereof embodiment 150 or embodiment 151, wherein the one or more substitutions comprise N297Q.
  • the anti-CD5 antibody or antigen binding fragment thereof of embodiment 150 or embodiment 151, wherein the one or more substitutions comprise N297G.
  • the anti-CD5 antibody or antigen binding fragment thereof of embodiment 150 or embodiment 151, wherein the one or more substitutions comprise D265A/N297A. 156.
  • the anti-CD5 antibody or antigen binding fragment thereof of embodiment 169 wherein the first Fc region and/or second Fc region comprise an amino acid sequence that is at least 90% identical (e.g., at least 95%, at least 97%, at least 99%, or 100% identical) to SEQ ID NO:51, SEQ ID NO:52, or SEQ ID NO:53. 171.
  • the anti-CD5 antibody or antigen binding fragment thereof of embodiment 170 wherein the first Fc region and/or second Fc region comprise an amino acid sequence that is at least 90% identical (e.g., at least 95%, at least 97%, at least 99%, or 100% identical) to SEQ ID NO:52. 173.
  • 176 The anti-CD5 antibody or antigen binding fragment thereof of any one of embodiments 149 to 168, wherein the Fc domain comprises a human IgG4 Fc domain or a variant thereof. 177.
  • the anti-CD5 antibody or antigen binding fragment thereof of embodiment 176 wherein the first Fc region and/or second Fc region comprise an amino acid sequence that is at least 90% identical (e.g., at least 95%, at least 97%, at least 99%, or 100% identical) to SEQ ID NO:54.
  • the anti-CD5 antibody or antigen binding fragment thereof of embodiment 178, wherein the hinge region comprises one or more amino acid substitutions that reduce half-antibody exchange. 180.
  • the anti-CD5 antibody or antigen binding fragment thereof of embodiment 183, wherein the hinge region comprises the amino acid sequence of SEQ ID NO:83. 185.
  • the anti-CD5 antibody or antigen binding fragment thereof of embodiment 1 which comprises a light chain having the amino acid sequence of SEQ ID NO:77 and a heavy chain having the amino acid sequence of SEQ ID NO:78. 193.
  • the anti-CD5 antibody or antigen binding fragment thereof of embodiment 49 which comprises a light chain having the amino acid sequence of SEQ ID NO:55 and a heavy chain having the amino acid sequence of SEQ ID NO:56. 195.
  • the anti-CD5 antibody or antigen binding fragment thereof of embodiment 49 which comprises a light chain having the amino acid sequence of SEQ ID NO:55 and a heavy chain having the amino acid sequence of SEQ ID NO:57. 196.
  • the anti-CD5 antibody or antigen binding fragment thereof of embodiment 49 which comprises a light chain having the amino acid sequence of SEQ ID NO:55 and a heavy chain having the amino acid sequence of SEQ ID NO:58.
  • the anti-CD5 antibody or antigen binding fragment thereof of embodiment 49 which comprises a light chain having the amino acid sequence of SEQ ID NO:55 and a heavy chain having the amino acid sequence of SEQ ID NO:59. 198.
  • the nucleic acid of embodiment 198 which is codon optimized for expression in a mammalian cell, optionally wherein the mammalian cell is a human cell.
  • a method of producing an anti-CD5 antibody or antigen binding fragment thereof comprising culturing the cell of embodiment 201 in conditions under which the anti-CD5 antibody or antigen binding fragment thereof is expressed; and recovering the anti-CD5 antibody or antigen binding fragment thereof from the cell culture.
  • An antibody-ALK5 inhibitor conjugate comprising the anti-CD5 antibody or antigen binding fragment thereof of any one of embodiments 1 to 197 conjugated to an ALK5 inhibitor.
  • the antibody-ALK5 inhibitor conjugate of embodiment 205 wherein the ALK5 inhibitor is an imidazole type compound which is an imidazole-benzodioxol compound or an imidazole-quinoxaline compound.
  • the antibody-ALK5 inhibitor conjugate of embodiment 209 wherein the ALK5 inhibitor is an imidazole-benzodioxol compound.
  • the antibody-ALK5 inhibitor conjugate of embodiment 209 wherein the ALK5 inhibitor is an imidazole-quinoxaline compound.
  • the antibody-ALK5 inhibitor conjugate of embodiment 205 wherein the ALK5 inhibitor is an imidazole-benzodioxol compound, an imidazole-quinoxaline compound, a pyrazole-pyrrolo compound, or a thiazole type compound.
  • the antibody-ALK5 inhibitor conjugate of embodiment 203, wherein the ALK5 inhibitor is an ALK5 inhibitor identified in Table 2.
  • 216 The antibody-ALK5 inhibitor conjugate of embodiment 203, wherein the ALK5 inhibitor is an ALK5 inhibitor identified in Table 3A. 217.
  • the antibody-ALK5 inhibitor conjugate of embodiment 203 wherein the ALK5 inhibitor is an ALK5 inhibitor identified in Table 3B. 218.
  • the antibody-ALK5 inhibitor conjugate of embodiment 203, wherein the ALK5 inhibitor is an ALK5 inhibitor identified in Table 4. 219.
  • the antibody-ALK5 inhibitor conjugate of embodiment 203, wherein the ALK5 inhibitor has the structure . has the structure 221.
  • the antibody-ALK5 inhibitor conjugate of embodiment 203, wherein the ALK5 inhibitor has the structure . conjugate of embodiment 203, wherein the ALK5 inhibitor has the . inhibitor conjugate of any one of embodiments 203 to 222, wherein the antibody or antigen binding fragment via a linker. 224.
  • the antibody-ALK5 inhibitor conjugate of embodiment 240, wherein the ALK5 inhibitor is conjugated via one or more lysine residues on the antibody or antigen binding fragment.
  • the antibody-ALK5 inhibitor conjugate of embodiment 244, wherein the one or more unnatural amino acid residues comprise p-azidomethyl-L-phenylalanine (pAMF) 247.
  • the antibody-ALK5 inhibitor conjugate of embodiment 244, wherein the one or more unnatural amino acid residues comprise selenocysteine (Sec). 248.
  • the antibody-ALK5 inhibitor conjugate of embodiment 248, wherein the one or more glycans comprise galactose. 252.
  • the antibody-ALK5 inhibitor conjugate of embodiment 248, wherein the one or more glycans comprise N-acetylgalactosamine (GalNAc). 253.
  • SA sialic acid
  • An antibody-ALK5 inhibitor conjugate comprising the anti-CD5 antibody or antigen binding fragment thereof of any one of embodiments 1 to 197 conjugated to a means for inhibiting ALK5, optionally wherein the conjugate further comprises a means for linking the anti-CD5 antibody or antigen binding fragment thereof to the means for inhibiting ALK5. 263.
  • a pharmaceutical composition comprising the antibody-ALK5 inhibitor conjugate of any one of embodiments 203 to 262 and a pharmaceutically acceptable carrier. 264.
  • the pharmaceutical composition of embodiment 263, wherein at least 30% of the antibody-ALK5 inhibitor conjugate molecules in the pharmaceutical composition have a DAR between 1 and 15. 267.
  • a method of treating cancer comprising administering to a subject in need thereof an antibody-ALK5 inhibitor conjugate according to any one of embodiments 203 to 262 or a pharmaceutical composition according to any one of embodiments 263 to 291. 293.
  • the method of embodiment 292, wherein the cancer is an immunogenic cancer.
  • the method of embodiment 293, wherein the cancer is a solid tumor that expresses a tumor antigen. 295.
  • the method of embodiment 294, wherein the tumor antigen is gp100, melanA or MAGE A1. 296.
  • the method of embodiment 295, wherein the tumor antigen is gp100.
  • the tumor antigen is melanA. 298.
  • the method of embodiment 295, wherein the tumor antigen is MAGE A1. 299.
  • the method of embodiment 292, wherein the cancer is a solid tumor comprising immune infiltrates.
  • the immunotherapy is cytokine therapy, adoptive T cell therapy, chimeric antigen receptor (CAR) therapy, checkpoint modulator (e.g., checkpoint inhibitor) therapy, oncolytic virus therapy, dendritic cell vaccine therapy, STING agonist therapy, TLR agonist therapy, or intratumoral CpG therapy.
  • CAR chimeric antigen receptor
  • checkpoint modulator e.g., checkpoint inhibitor
  • the method of embodiment 300, wherein the immunotherapy is cytokine therapy, adoptive T cell therapy, chimeric antigen receptor (CAR) therapy or checkpoint modulator (e.g., checkpoint inhibitor) therapy.
  • 303. The method of embodiment 302, wherein the immunotherapy is cytokine therapy.
  • 304. The method of embodiment 303, wherein the cytokine therapy is IL2 therapy.
  • 305. The method of embodiment 303, wherein the cytokine therapy is IL12 therapy.
  • the method of embodiment 303, wherein the cytokine therapy is IFN- ⁇ therapy. 307.
  • the method of embodiment 303, wherein the cytokine therapy is IFN- ⁇ therapy. 308.
  • the method of embodiment 302, wherein the immunotherapy is adoptive T cell therapy. 309.
  • the method of embodiment 308, wherein the adoptive T cell therapy is autologous T cell therapy.
  • the immunotherapy is chimeric antigen receptor (CAR) therapy.
  • CAR chimeric antigen receptor
  • the immunotherapy is checkpoint modulator (e.g., checkpoint inhibitor) therapy.
  • the checkpoint modulator is an antibody.
  • the method of embodiment 302, embodiment 311, or embodiment 312, wherein the checkpoint modulator is an inhibitor of PD1, PDL1, or CTLA4. 314.
  • the method of embodiment 313, wherein the checkpoint modulator is an inhibitor of PD1. 315.
  • the method of embodiment 314, wherein the inhibitor of PD1 is an antibody. 316.
  • the method of embodiment 315, wherein the inhibitor of PD1 is pembrolizumab, nivolumab, cemiplimab, or dostarlimab. 317.
  • the method of embodiment 316, wherein the inhibitor of PD1 is pembrolizumab. 318.
  • the method of embodiment 316, wherein the inhibitor of PD1 is nivolumab. 319.
  • the method of embodiment 316, wherein the inhibitor of PD1 is cemiplimab. 320.
  • the method of embodiment 316, wherein the inhibitor of PD1 is dostarlimab. 321.
  • the checkpoint modulator is an inhibitor of PDL1. 322.
  • the method of embodiment 321, wherein the inhibitor of PDL1 is an antibody. 323.
  • the method of embodiment 322, wherein the inhibitor of PDL1 is atezolizumab, avelumab, or durvalumab. 324.
  • the method of embodiment 323, wherein the inhibitor of PDL1 is atezolizumab. 325.
  • the method of embodiment 323, wherein the inhibitor of PDL1 is avelumab. 326.
  • the method of embodiment 323, wherein the inhibitor of PDL1 is durvalumab. 327.
  • the method of embodiment 313, wherein the checkpoint modulator is an inhibitor of CTLA4. 328.
  • the method of embodiment 327, wherein the inhibitor of CTLA4 is an antibody. 329.
  • the method of embodiment 328, wherein the inhibitor of CTLA4 is ipilimumab. 330.
  • the method of embodiment 337, wherein the cancer is non-small cell lung cancer (NSCLC), liver cancer, urothelial cancer, renal cancer, breast cancer, or melanoma. 342.
  • the method of embodiment 337, wherein the cancer is lung cancer. 343.
  • the method of embodiment 342, wherein the cancer is NSCLC. 344.
  • the method of embodiment 343, wherein the NSCLC is adenocarcinoma. 345.
  • the method of embodiment 343, wherein the NSCLC is squamous cell carcinoma. 346.
  • the method of embodiment 343, wherein the NSCLC is large cell carcinoma. 347.
  • the method of embodiment 342, wherein the cancer is small cell lung cancer. 348.
  • the method of embodiment 337, wherein the cancer is liver cancer. 349.
  • the method of embodiment 348, wherein the liver cancer is hepatocellular carcinoma. 350.
  • the method of embodiment 337, wherein the cancer is urothelial cancer. 351.
  • the method of embodiment 350, wherein the cancer is bladder cancer. 352.
  • the method of embodiment 350, wherein the cancer is urethral cancer. 353.
  • the method of embodiment 350, wherein the cancer is ureteral cancer. 354.
  • the method of embodiment 337, wherein the cancer is renal cancer. 355.
  • the method of embodiment 354, wherein the renal cancer is renal cell carcinoma. 356.
  • method of embodiment 354, wherein the renal cancer is urothelial carcinoma. 357.
  • the method of embodiment 337, wherein the cancer is breast cancer. 358.
  • the method of embodiment 337, wherein the cancer is melanoma. 359.
  • the method of embodiment 337, wherein the cancer is pancreatic cancer. 360. The method of embodiment 337, wherein the cancer is glioblastoma. 361. The method of embodiment 337, wherein the cancer is a myelodysplastic syndrome. 362. The method of embodiment 337, wherein the cancer is prostate cancer. 363. The method of embodiment 337, wherein the cancer is colorectal cancer. 364. The method of embodiment 363, wherein the colorectal cancer is adenocarcinoma. 365. The method of embodiment 363, wherein the colorectal cancer is a carcinoid tumor. 366. The method of embodiment 363, wherein the colorectal cancer is a gastrointestinal stromal tumor. 367.
  • any one of embodiments 292 to 369 wherein the antibody-ALK5 inhibitor conjugate or pharmaceutical composition is administered as part of a combination therapy regimen which optionally comprises administering one or more agents which are not an antibody-ALK5 inhibitor conjugate according to any one of embodiments 203 to 261 (each a “second therapeutic agent”). 372.
  • the method of embodiment 371, wherein the antibody-ALK5 inhibitor conjugate or pharmaceutical composition is administered in combination with a standard of care therapy or therapeutic regimen. 373.
  • the combination therapy comprises administering at least one second therapeutic agent to the subject. 374.
  • the combination therapy regimen comprises immunotherapy, optionally wherein the immunotherapy is checkpoint modulator (e.g., checkpoint inhibitor) therapy, chimeric antigen receptor (CAR) therapy, adoptive T cell therapy, oncolytic virus therapy, dendritic cell vaccine therapy, STING agonist therapy, TLR agonist therapy, intratumoral CpG therapy, or cytokine therapy.
  • the combination therapy comprises checkpoint modulator (e.g., checkpoint inhibitor) therapy.
  • the checkpoint modulator therapy comprises T cell checkpoint modulator (e.g., checkpoint inhibitor) therapy.
  • the T cell checkpoint modulator therapy comprises an antibody or an antigen-binding fragment thereof.
  • the checkpoint modulator therapy targets PD1, PDL1, CTLA4, TIGIT, LAG3, OX40, ICOS, GITR, CD40, VISTA, or a combination thereof.
  • the checkpoint modulator therapy targets PD1.
  • a second therapeutic agent comprises a means for targeting PD1. 381.
  • the method of any one of embodiments 371 to 379, wherein a second therapeutic agent is pembrolizumab. 382.
  • a second therapeutic agent is nivolumab. 383.
  • the method of any one of embodiments 371 to 379, wherein a second therapeutic agent is cemiplimab. 384.
  • the method of any one of embodiments 371 to 379, wherein a second therapeutic agent is dostarlimab. 385.
  • the method of any one of embodiments 378 to 384, wherein the checkpoint modulator therapy targets PDL1.
  • the method of any one of embodiments 371 to 385, wherein a second therapeutic agent comprises a means for targeting PDL1. 387.
  • the method of any one of embodiments 371 to 385, wherein a second therapeutic agent is atezolizumab. 388.
  • a second therapeutic agent is avelumab. 389.
  • the method of any one of embodiments 371 to 385, wherein a second therapeutic agent is durvalumab. 390.
  • the method of any one of embodiments 378 to 389 wherein the checkpoint modulator therapy targets CTLA4. 391.
  • the method of any one of embodiments 371 to 390, wherein a second therapeutic agent comprises a means for targeting CTLA4. 392.
  • the method of any one of embodiments 371 to 390, wherein a second therapeutic agent is ipilimumab. 393.
  • the method of any one of embodiments 378 to 391, wherein the checkpoint modulator therapy targets TIGIT. 394.
  • a second therapeutic agent comprises a means for targeting TIGIT. 395.
  • the method of any one of embodiments 371 to 393, wherein a second therapeutic agent is etigilimab. 396.
  • the method of any one of embodiments 371 to 393, wherein a second therapeutic agent is tiragolumab. 397.
  • the method of any one of embodiments 371 to 393, wherein a second therapeutic agent is AB154. 398.
  • the method of any one of embodiments 378 to 397, wherein the checkpoint modulator therapy targets LAG3. 399.
  • the method of any one of embodiments 371 to 398, wherein a second therapeutic agent comprises a means for targeting LAG3. 400.
  • a second therapeutic agent is LAG525.
  • 401 The method of any one of embodiments 371 to 398, wherein a second therapeutic agent is Sym022. 402.
  • the method of any one of embodiments 371 to 398, wherein a second therapeutic agent is relatlimab. 403.
  • a second therapeutic agent is TSR-033.
  • 404 The method of any one of embodiments 378 to 403, wherein the checkpoint modulator therapy targets OX40. 405.
  • a second therapeutic agent is a means for targeting OX40. 406.
  • a second therapeutic agent is MEDI6469. 407.
  • the method of any one of embodiments 371 to 404, wherein a second therapeutic agent is PF-04518600. 408.
  • the method of any one of embodiments 371 to 404, wherein a second therapeutic agent is BMS 986178. 409.
  • the method of any one of embodiments 378 to 408, wherein the checkpoint modulator therapy targets CD40.
  • the method of any one of embodiments 371 to 409, wherein a second therapeutic agent comprises a means for targeting CD40. 411.
  • the method of any one of embodiments 371 to 409, wherein a second therapeutic agent is selicrelumab. 412.
  • a second therapeutic agent is CP-870,893. 413.
  • the method of any one of embodiments 371 to 409, wherein a second therapeutic agent is APX005M. 414.
  • the method of any one of embodiments 378 to 413, wherein the checkpoint modulator therapy targets ICOS. 415.
  • the method of any one of embodiments 371 to 414, wherein a second therapeutic agent comprises a means for targeting ICOS. 416.
  • a second therapeutic agent is MEDI-570. 417.
  • the method of any one of embodiments 371 to 414, wherein a second therapeutic agent is feladilimab. 418.
  • a second therapeutic agent is BMS 986226. 419.
  • the method of any one of embodiments 371 to 419, wherein a second therapeutic agent comprises a means for targeting GITR. 421.
  • the method of any one of embodiments 371 to 419, wherein a second therapeutic agent is TRX-518. 422.
  • the method of any one of embodiments 371 to 419, wherein a second therapeutic agent is AMG 228. 423.
  • the method of any one of embodiments 371 to 419, wherein a second therapeutic agent is MK-4166. 424.
  • a second therapeutic agent is MEDI1873. 425.
  • the method of any one of embodiments 371 to 419, wherein a second therapeutic agent is INCAGN01876. 426.
  • the method of any one of embodiments 371 to 419, wherein a second therapeutic agent is GWN323. 427.
  • the method of any one of embodiments 378 to 426, wherein the checkpoint modulator therapy targets VISTA. 428.
  • the method of any one of embodiments 371 to 427, wherein a second therapeutic agent comprises a means for targeting VISTA. 429.
  • the method of any one of embodiments 371 to 427, wherein a second therapeutic agent is HMBD-002. 430.
  • a second therapeutic agent is a chimeric antigen receptor (CAR). 431.
  • the method of any one of embodiments 371 to 430 wherein the combination therapy comprises adoptive T cell therapy.
  • the method of embodiment 431, wherein the adoptive T cell therapy is autologous T cell therapy. 433.
  • the method of any one of embodiments 371 to 432, wherein the combination therapy comprises oncolytic virus therapy.
  • the method of any one of embodiments 371 to 433, wherein the combination therapy comprises dendritic cell vaccine therapy. 435.
  • the method of any one of embodiments 371 to 434, wherein the combination therapy comprises STING agonist therapy. 436.
  • the method of any one of embodiments 371 to 435, wherein the combination therapy comprises TLR agonist therapy. 437.
  • the method of any one of embodiments 371 to 436, wherein the combination therapy comprises chemotherapy. 438.
  • a second therapeutic agent is an antimetabolite, an alkylating agent, an anthracycline, an antimicrotubule agent, a platinum compound, a taxane, a topoisomerase inhibitor, or a vinca alkaloid.
  • a second therapeutic agent is an antimetabolite.
  • the antimetabolite is 5-fluorouracil. 441.
  • the method of embodiment 439, wherein the antimetabolite is gemcitabine. 442.
  • the method of embodiment 439, wherein the antimetabolite is methotrexate. 443.
  • a second therapeutic agent is an alkylating agent. 444.
  • the method of embodiment 443, wherein the alkylating agent is cyclophosphamide. 445.
  • the method of embodiment 443, wherein the alkylating agent is dacarbazine. 446.
  • the method of embodiment 443, wherein the alkylating agent is mechlorethamine. 447.
  • the method of embodiment 443, wherein the alkylating agent is diaziquone. 448.
  • the method of embodiment 443, wherein the alkylating agent is temozolomide.
  • a second therapeutic agent is an anthracycline. 450.
  • the method of embodiment 449, wherein the anthracycline is doxorubicin. 451.
  • the method of embodiment 449, wherein the anthracycline is epirubicin. 452.
  • the method of embodiment 438, wherein a second therapeutic agent is an antimicrotubule agent. 453.
  • the method of embodiment 452, wherein the antimicrotubule agent is vinblastine. 454.
  • the method of embodiment 438, wherein a second therapeutic agent is a platinum compound. 455.
  • the method of embodiment 454, wherein the platinum compound is cisplatin. 456.
  • the method of embodiment 454, wherein the platinum compound is oxaliplatin. 457.
  • a second therapeutic agent is a taxane. 458.
  • the method of embodiment 457, wherein the taxane is paclitaxel. 459.
  • the method of embodiment 457, wherein the taxane is docetaxel.
  • a second therapeutic agent is a topoisomerase inhibitor. 461.
  • the method of embodiment 460, wherein the topoisomerase inhibitor is etoposide. 462.
  • the method of embodiment 460, wherein the topoisomerase inhibitor is mitoxantrone. 463.
  • the method of embodiment 438, wherein a second therapeutic agent is a vinca alkaloid. 464.
  • a second therapeutic agent is a cytokine. 467.
  • the method of embodiment 466, wherein the cytokine is IL2. 468.
  • the method of embodiment 466, wherein the cytokine is IL12. 469.
  • the method of embodiment 466, wherein the cytokine is IFN- ⁇ . 470.
  • the method of embodiment 466, wherein the cytokine is IFN- ⁇ . 471.
  • the method of any one of embodiments 371 to 470 which comprises treating the subject with the combination therapy. 472.
  • a method of treating a subject having a disease or disorder associated with elevated CD5 expression comprising administering the anti-CD5 antibody or antigen binding fragment of any one of embodiments 1 to 197 to the subject, optionally wherein the disease or disorder is a B or T cell malignancy, an autoimmune disease, a transplantation disease, or a graft rejection. 474.
  • a process for making antibody-ALK5 inhibitor conjugate comprising conjugating the antibody or antigen binding fragment thereof of any one of embodiments 1 to 197 to an ALK5 inhibitor, optionally wherein the antibody or antigen binding fragment thereof is conjugated to the ALK5 inhibitor via a linker.
  • the ALK5 inhibitor is an ALK5 inhibitor described in any one of embodiments 203 to 261.
  • the linker is a linker described in any one of embodiments 223 to 238. 477.
  • a kit comprising the antibody or antigen binding fragment thereof of any one of embodiments 1 to 197 and an ALK5 inhibitor. 479.
  • the kit of embodiment 478, wherein the ALK5 inhibitor is an ALK5 inhibitor as described in any one of embodiments 203 to 261.
  • 480. The kit of embodiment 478 or embodiment 479, further comprising a linker. 481.
  • the kit of embodiment 478 or embodiment 479, wherein the ALK5 inhibitor is conjugated to a linker. 482.
  • a method of delivering an ALK5 inhibitor to a T cell comprising administering the antibody-ALK5 inhibitor conjugate of any one of embodiments 203 to 262 to a subject, e.g., a subject as described in any one of embodiments 292 to 472.
  • a method of inducing an immune response in a subject comprising administering the antibody-ALK5 inhibitor conjugate of any one of embodiments 203 to 262 to the subject, e.g., a subject as described in any one of embodiments 292 to 472. 485.
  • a method of stimulating T cells in a subject comprising administering the antibody-ALK5 inhibitor conjugate of any one of embodiments 203 to 262 to the subject, e.g., a subject as described in any one of embodiments 292 to 472.
  • All publications, patents, patent applications and other documents cited in this application are hereby incorporated by reference in their entireties for all purposes to the same extent as if each individual publication, patent, patent application or other document were individually indicated to be incorporated by reference for all purposes. In the event that there is an inconsistency between the teachings of one or more of the references incorporated herein and the present disclosure, the teachings of the present specification are intended.

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Abstract

La présente divulgation concerne des anticorps anti-CD5 et leurs utilisations, y compris des conjugués ALK5-anticorps et leur utilisation pour le traitement du cancer.
PCT/US2024/033613 2023-06-13 2024-06-12 Anticorps anti-cd5 et leurs utilisations WO2024258967A1 (fr)

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