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WO2013068874A1 - Conjugués anticorps-médicament - Google Patents

Conjugués anticorps-médicament Download PDF

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Publication number
WO2013068874A1
WO2013068874A1 PCT/IB2012/055940 IB2012055940W WO2013068874A1 WO 2013068874 A1 WO2013068874 A1 WO 2013068874A1 IB 2012055940 W IB2012055940 W IB 2012055940W WO 2013068874 A1 WO2013068874 A1 WO 2013068874A1
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WO
WIPO (PCT)
Prior art keywords
antibody
xaa
seq
amino acid
drug conjugate
Prior art date
Application number
PCT/IB2012/055940
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English (en)
Inventor
Russell Dushin
Eric Feyfant
Puja Sapra
Lioudmila Gennadievna Tchistiakova
Feng Tian
Original Assignee
Pfizer Inc.
Ambrx Inc.
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Application filed by Pfizer Inc., Ambrx Inc. filed Critical Pfizer Inc.
Publication of WO2013068874A1 publication Critical patent/WO2013068874A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6851—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a determinant of a tumour cell
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/6807—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug or compound being a sugar, nucleoside, nucleotide, nucleic acid, e.g. RNA antisense
    • A61K47/6809—Antibiotics, e.g. antitumor antibiotics anthracyclins, adriamycin, doxorubicin or daunomycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention generally relates to anti-5T4 antibody-drug conjugates for the treatment of cancer.
  • ADCs Antibody-drug conjugates combine the binding specificity of monoclonal antibodies with the potency of chemotherapeutic agents.
  • a tumor associated antigen Once a tumor associated antigen is identified as a target, numerous challenges remain. Each monoclonal antibody must be characterized separately, an appropriate linker designed, and a suitable cytotoxic agent identified that retains its potency upon delivery to tumor cells.
  • the drug moiety must be linked to specific amino acid residues on the antibody without compromising the pharmacokinetics of the ADC, binding activity of the antibody, and/or the potency of the drug. Cysteine, lysine , or histidine residues have functional groups that are commonly used as a site to link the drug moiety, but the location within the tertiary structure of the antibody may present limitations on availability for conjugation. Recently, a new technology in the protein sciences has evolved that overcomes the limitations associated with site-specific modifications of proteins [US Patent No.
  • the human 5T4 tumor associated antigen is the target antigen of the present invention.
  • An antibody to the 5T4 antigen previously described [US 2007/0231333] has been modified by the incorporation of non-natural amino acids as sites for conjugation of dolastatin linker derivatives.
  • the novel anti-5T4 ADCs of the present invention overcome the challenges associated with ADC technology.
  • the resulting ADCs have an improved pharmacokinetics profile compared to anti-5T4 ADCs without non-natural amino acid conjugation sites.
  • the ADCs of the present invention retain 5T4 antigen specificity and drug potency, thus delivering sufficient cytotoxic drug to the target cells, providing an innovative and effective treatment for cancer.
  • an antibody-drug conjugate of the present invention has the formula: Ab-(D)p wherein, Ab is an anti-5T4 antibody comprising a non-natural amino acid; D is a dolastatin linker derivative; and p is from about 1 to about 8.
  • the present invention further provides anti-5T4 antibody-drug conjugates wherein (a) said anti-5T4 antibody comprises a non-natural amino acid at a position selected from the group consisting of positions 120, 121 , 164, or 178 of the heavy chain and further comprises a heavy chain variable region having (i) a VH CDR1 region as shown in SEQ ID NO: 5, (ii) a VH CDR2 region as shown in SEQ ID NO: 6, and (iii) a VH CDR3 region as shown in SEQ ID NO: 7; (b) said dolastatin linker derivative is selected from the group consisting of NC-D-1 , HC-D-1 , NCA-D-2, PHC-D-2, SC-D-1 , and SHC-D-1 ; and (c) p is from about 1 to about 8.
  • the present invention further provides an anti-5T4 antibody-drug conjugate wherein said anti-5T4 antibody comprises one or more non-natural amino acids at a position selected from the group consisting of positions 120, 121 , 164, or 178 of the heavy chain and further comprises a light chain variable region having (a) a VL CDR1 region as shown in SEQ ID NO: 8, (b) a VL CDR2 region as shown in SEQ ID NO: 9, and (c) a VL CDR3 region as shown in SEQ ID NO: 10.
  • the present invention further provides an anti-5T4 antibody-drug conjugate wherein said anti-5T4 antibody comprises one or more non-natural amino acids at a position selected from the group consisting of positions 120, 121 , 164, or 178 of the heavy chain and further comprises a heavy chain variable region having (a) a VH CDR1 region as shown in SEQ ID NO: 5, (b) a VH CDR2 region as shown in SEQ ID NO: 6, and (c) a VH CDR3 region as shown in SEQ ID NO: 7 and a light chain variable region having (a) a VL CDR1 region as shown in SEQ ID NO: 8, (b) a VL CDR2 region as shown in SEQ ID NO: 9, and (c) a VL CDR3 region as shown in SEQ ID NO: 10.
  • the present invention further provides an anti-5T4 antibody-drug conjugate wherein said anti-5T4 antibody comprises one or more non-natural amino acids at a position selected from the group consisting of positions 120, 121 , 164, or 178 of the heavy chain and comprises the VH region of SEQ ID NO: 3 and the VL region of SEQ ID NO: 4.
  • the present invention further provides anti-5T4 antibody-drug conjugates wherein said non-natural amino acid at a position selected from the group consisting of positions 120, 121 , 164, or 178 of the heavy chain is p-acetyl-L-phenylalanine.
  • the present invention further provides an anti-5T4 antibody-drug conjugate wherein said anti-5T4 antibody comprises one or more non-natural amino acids at a position selected from the group consisting of positions 120, 121 , 164, or 178 of the heavy chain, and wherein said anti-5T4 antibody-drug conjugate has an improved pharmacokinetic profile compared to anti-5T4 ADCs without non-natural amino acid conjugation sites.
  • the present invention further provides an anti-5T4 antibody-drug conjugate wherein said anti-5T4 antibody consists of a light chain having SEQ ID NO: 2 and a heavy chain having SEQ ID NO: 1 wherein Xaa 120 is serine, Xaa 164 is alanine, Xaa 178 is serine, and Xaa 121 is the non-natural amino acid p-acetyl-L-phenylalanine, said dolastatin linker derivative is NC-D-1 , and p is about 2.
  • the present invention further provides an antibody-drug conjugate wherein: said anti-5T4 antibody consists of a light chain having SEQ ID NO: 2 and a heavy chain having SEQ ID NO:1 wherein Xaa 121 is serine, Xaa 164 is alanine, Xaa 178 is serine, and Xaa 120 is the non-natural amino acid p-acetyl-L-phenylalanine, said dolastatin linker derivative is NC-D-1 , and p is about 2.
  • the present invention further provides an antibody-drug conjugate wherein: said anti-5T4 antibody consists of a light chain having SEQ ID NO: 2 and a heavy chain having SEQ ID NO:1 wherein Xaa 120 is serine, Xaa 121 is serine, Xaa 178 is serine, and Xaa 164 is the non-natural amino acid p-acetyl-L-phenylalanine, said dolastatin linker derivative is NC-D-1 , and p is about 2.
  • the present invention further provides an antibody-drug conjugate wherein: said anti-5T4 antibody consists of a light chain having SEQ ID NO: 2 and a heavy chain having SEQ ID NO:1 wherein Xaa 120 is serine, Xaa 121 is serine, Xaa 164 is alanine, and Xaa 178 is the non-natural amino acid p-acetyl-L-phenylalanine, said dolastatin linker derivative is NC-D-1 , and p is about 2.
  • the present invention further provides an antibody-drug conjugate wherein: said anti-5T4 antibody consists of a light chain having SEQ ID NO: 2 and a heavy chain having SEQ ID NO:1 wherein Xaa 121 is serine, Xaa 164 is alanine, Xaa 178 is serine, and Xaa 120 is the non-natural amino acid p-acetyl-L-phenylalanine, said dolastatin linker derivative is SC-D-1 , and p is about 2.
  • the present invention further provides an antibody-drug conjugate wherein: said anti-5T4 antibody consists of a light chain having SEQ ID NO: 2 and a heavy chain having SEQ ID NO:1 wherein Xaa 121 is serine, Xaa 164 is alanine, Xaa 178 is serine, and Xaa 120 is the non-natural amino acid p-acetyl-L-phenylalanine, said dolastatin linker derivative is SC-D-1 , and p is about 2.
  • the present invention further provides an antibody-drug conjugate wherein: said anti-5T4 antibody consists of a light chain having SEQ ID NO: 2 and a heavy chain having SEQ ID NO:1 wherein Xaa 120 is serine, Xaa 164 is alanine, Xaa 178 is serine, and Xaa 121 is the non-natural amino acid p-acetyl-L-phenylalanine, said dolastatin linker derivative is SC-D-1 , and p is about 2.
  • the present invention further provides an antibody-drug conjugate wherein: said anti-5T4 antibody consists of a light chain having SEQ ID NO: 2 and a heavy chain having SEQ ID NO:1 wherein Xaa 120 is serine, Xaa 164 is alanine, Xaa 178 is serine, and Xaa 121 is the non-natural amino acid p-acetyl-L-phenylalanine, said dolastatin linker derivative is SHC-D-1 , and p is about 2.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising an antibody-drug conjugate indicated above and a pharmaceutically acceptable carrier.
  • the present invention further provides a method of treating a 5T4-positive cancer in a patient in need thereof, comprising administering to said patient an antibody-drug conjugate indicated above.
  • the present invention further provides a method of treating a 5T4-positive cancer wherein said cancer is selected from the group consisting of carcinomas of the bladder, breast, cervix, colon, endometrium, kidney, lung, esophagus, ovary, prostate, pancreas, skin, stomach, and testes.
  • the present invention provides a method of treating a 5T4- positive cancer wherein said cancer is selected from the group consisting of colorectal, breast, pancreatic, and non-small cell lung carcinomas.
  • the invention further provides an antibody-drug conjugate indicated above for use in therapy.
  • the invention further provides the use of an antibody-drug conjugate indicated above for the manufacture of a medicament.
  • the invention further provides the use indicated above, wherein said use is for the treatment of a 5T4-positive cancer and wherein said cancer is selected from the group consisting of carcinomas of the bladder, breast, cervix, endometrium, kidney, lung, esophagus, ovary, prostate, pancreas, skin, stomach, and testes.
  • the invention further provides the use indicated above, wherein said use is for the treatment of a 5T4-positive cancer wherein said cancer is selected from the group consisting of colorectal, breast, pancreatic, and non-small cell lung carcinomas.
  • the invention further provides a nucleic acid that encodes an anti-5T4 antibody comprising a non-natural amino acid at a position selected from the group consisting of positions 120, 121 , 164, or 178 of the heavy chain, a vector comprising said nucleic acid, and a host cell comprising said vector.
  • the invention further provides a process for producing an anti-5T4 antibody comprising one or more non-natural amino acids at a position selected from the group consisting of positions 120, 121 , 164, or 178 of the heavy chain wherein said process comprises cultivating the host cell comprising the above mentioned vector and recovering the antibody from the cell culture.
  • the invention further provides a process for producing an anti-5T4 antibody-drug conjugate comprising: (a) chemically synthesizing a dolastatin linker derivative selected from the group consisting of NC-D-1 , HC-D-1 , NCA-D-2, PHC-D-2, SC-D-1 , and SHC- D-1 ; (b) conjugating said dolastatin linker derivative to the anti-5T4 antibody recovered from the cell culture, and; (c) purifying the antibody-drug conjugate.
  • the present invention provides anti-5T4 antibody-drug conjugates for the treatment of cancer.
  • certain terms and general techniques are first defined.
  • 5T4 refers to the 5T4 oncofetal antigen, a 72 kDa highly glycosylated
  • transmenbrance glycoprotein comprising a 42 kDa non-glycosylated core
  • Human 5T4 is expressed in numerous cancer types, including carcinomas of the bladder, breast, cervix, colon, endometrium, kidney, lung,
  • Anti-5T4 antibodies of the invention include antibodies that specifically bind the human 5T4 antigen (see US 20140060600A1 ).
  • an “antibody” is an immunoglobulin molecule capable of specific binding to a target, such as a carbohydrate, polynucleotide, lipid, polypeptide, etc., through at least one antigen recognition site, located in the variable region of the immunoglobulin molecule.
  • antibody encompasses not only intact polyclonal or monoclonal antibodies, but also any antigen binding fragment (i.e., "antigen-binding portion") or single chain thereof, fusion proteins comprising an antibody, and any other modified configuration of the immunoglobulin molecule that comprises an antigen recognition site including, for example without limitation, scFv, single domain antibodies ⁇ e.g., shark and camelid antibodies), maxibodies, minibodies, intrabodies, diabodies, triabodies, tetrabodies, v-NAR and bis-scFv (see, e.g., Hollinger and Hudson, 2005, Nature Biotechnology 23(9): 1 126-1 136).
  • An antibody includes an antibody of any class, such as IgG, IgA, or IgM (or sub-class thereof), and the antibody need not be of any particular class.
  • immunoglobulins can be assigned to different classes.
  • immunoglobulins There are five major classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., lgG1 , lgG2, lgG3, lgG4, lgA1 and lgA2.
  • the heavy-chain constant regions that correspond to the different classes of immunoglobulins are called alpha, delta, epsilon, gamma, and mu, respectively.
  • the subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known.
  • antigen binding portion of an antibody refers to one or more fragments of an intact antibody that retain the ability to specifically bind to a given antigen ⁇ e.g., target X). Antigen binding functions of an antibody can be performed by fragments of an intact antibody. Examples of binding fragments encompassed within the term "antigen binding portion" of an antibody include Fab; Fab'; F(ab')2; an Fd fragment consisting of the VH and CH1 domains; an Fv fragment consisting of the VL and VH domains of a single arm of an antibody; a single domain antibody (dAb) fragment (Ward et al., 1989 Nature 341 :544-546), and an isolated complementarity determining region (CDR).
  • Fab fragment antigen binding portion
  • variable region of an antibody refers to the variable region of the antibody light chain (LCVR) or the variable region of the antibody heavy chain (HCVR), either alone or in combination.
  • LCVR variable region of the antibody light chain
  • HCVR variable region of the antibody heavy chain
  • the variable regions of the heavy and light chain each consist of four framework regions (FRs) connected by three
  • CDRs complementarity determining regions
  • CDRs complementarity determining regions
  • appropriate amino acid substitution preferably, conservative amino acid substitution
  • FRs from antibodies which contain CDR1 and CDR2 sequences in the same canonical class are preferred.
  • a "CDR" of a variable domain are amino acid residues within the variable region that are identified in accordance with the definitions or methods of CDR determination well known in the art.
  • antibody CDRs may be identified as the
  • hypervariable regions originally defined by Kabat et al. See, e.g., Kabat et al., 1992, Sequences of Proteins of Immunological Interest, 5th ed., Public Health Service, NIH, Washington D.C.
  • the positions of the CDRs may also be identified as the structural loop structures originally described by Chothia and others. See, e.g., Chothia et al., 1989, Nature 342:877-883.
  • CDR formational definition
  • the positions of the CDRs may be identified as the residues that make enthalpic contributions to antigen binding. See, e.g., Makabe et al., 2008, Journal of Biological Chemistry, 283:1 156-1 166. Still other CDR boundary definitions may not strictly follow one of the above approaches, but will nonetheless overlap with at least a portion of the Kabat CDRs, although they may be shortened or lengthened in light of prediction or experimental findings that particular residues or groups of residues or even entire CDRs do not significantly impact antigen binding.
  • a CDR may refer to CDRs defined by any approach known in the art, including combinations of approaches. The methods used herein may utilize CDRs defined according to any of these approaches.
  • mAb refers to an antibody that is derived from a single copy or clone, including e.g., any eukaryotic, prokaryotic, or phage clone, and not the method by which it is produced.
  • a monoclonal antibody of the invention exists in a homogeneous or substantially homogeneous population.
  • Humanized antibody refers to forms of non-human (e.g. murine) antibodies that are chimeric immunoglobulins, immunoglobulin chains, or fragments thereof (such as Fv, Fab, Fab', F(ab') 2 or other antigen-binding subsequences of antibodies) that contain minimal sequence derived from non-human immunoglobulin.
  • humanized antibodies are human immunoglobulins (recipient antibody) in which residues from a complementary determining region (CDR) of the recipient are replaced by residues from a CDR of a non-human species (donor antibody) such as mouse, rat, or rabbit having the desired specificity, affinity, and capacity.
  • CDR complementary determining region
  • chimeric antibody is intended to refer to antibodies in which the variable region sequences are derived from one species and the constant region sequences are derived from another species, such as an antibody in which the variable region sequences are derived from a mouse antibody and the constant region sequences are derived from a human antibody.
  • Antibodies of the invention can be produced using techniques well known in the art, e.g., recombinant technologies, phage display technologies, synthetic technologies or combinations of such technologies or other technologies readily known in the art (see, for example, Jayasena, S.D., Clin. Chem., 45: 1628-50 (1999) and Fellouse, F.A., et al, J. Mol. Biol., 373(4):924-40 (2007)).
  • non-natural amino acid refers to an amino acid that is not one of the 20 common amino acids or pyrolysine or selenocysteine.
  • Other terms that may be used synonymously with the term “non-natural amino acid” is “non-naturally encoded amino acid,” “unnatural amino acid,” “non-naturally-occurring amino acid,” and variously hyphenated and non-hyphenated versions thereof.
  • the term “non-natural amino acid” includes, but is not limited to, amino acids which occur naturally by modification of a naturally encoded amino acid (including but not limited to, the 20 common amino acids or pyrrolysine and selenocysteine) but are not themselves incorporated into a growing polypeptide chain by the translation complex.
  • non-natural amino acid includes, but is not limited to, amino acids which do not occur naturally and may be obtained synthetically or may be obtained by modification of natural or other non-natural amino acids.
  • the monoclonal antibodies of the present invention are derived from the A1 anti-
  • 5T4 antibody (a humanized anti-5T4 lgG1 antibody) wherein said anti-5T4 antibody comprises a non-natural amino acid at a position selected from the group consisting of positions 120, 121 , 164, or 178 of the heavy chain.
  • the preferred monoclonal antibodies of the invention are selected from the group consisting of A1 -120, A1 -121 , A1 -164, and A1 -178, wherein a non-natural amino acid is at the indicated numbered position of the heavy chain of the A1 antibody.
  • the most preferred antibody of the present invention is A1 -121 .
  • All of the preferred monoclonal antibodies of the invention comprise: (a) a LCVR of SEQ ID NO: 4, further comprising: a LCDR1 of SEQ ID NO: 8, a LCDR2 of SEQ ID NO: 9, and a LCDR3 of SEQ ID NO: 10; and, b) a HCVR of SEQ ID NO: 3, further comprising: a HCDR1 of SEQ ID NO: 5, a HCDR2 of SEQ ID NO: 6, and a HCDR3 of SEQ ID NO: 7.
  • all of the preferred antibodies of the present invention comprise a LC of SEQ ID NO: 2 and a HC of SEQ ID NO: 1 , wherein the Xaa positions of SEQ ID NO: 1 are indicated in Table 1 for the anti-5T4 monoclonal antibodies A1 -120, A1 -121 , A1 - 164, and A1 -178.
  • *pAF designates the non-natural amino acid p-acetyl-L-phenylalanine
  • the term "specifically binds" as used herein in reference to the binding between an antibody and a 5T4 antigen refers to an antibody that only binds to cells expressing the 5T4 antigen.
  • pharmaceutically acceptable refers to a material, including but not limited to, a salt, carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively nontoxic, i.e., the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
  • potency is a measurement of biological activity and may be designated as IC 50 , or the effective concentration of antibody needed to inhibit 50% of growth of a 5T4 positive cell line as described in Example 2.
  • potency may refer to anti-tumor activity as determined in an in vivo tumor xenograft model as shown in Example 3.
  • Pharmacokinetics refers to the study of absorption, distribution, metabolism and excretion (ADME) of bioactive compounds in a higher organism.
  • An improved pharmacokinetics profile generally refers to increased in vivo half-life (e.g. plasma half life) allowing more effective tissue distribution.
  • nucleic acid molecule is intended to include DNA molecules and RNA molecules.
  • a nucleic acid molecule may be single-stranded or double-stranded, but preferably is double-stranded DNA.
  • the polynucleotides that encode the antibodies of the present invention may include the following: only the coding sequence for the variant, the coding sequence for the variant and additional coding sequences such as a functional polypeptide, or a signal or secretory sequence or a pro-protein sequence; the coding sequence for the antibody and non-coding sequence, such as introns or non-coding sequence 5' and/or 3' of the coding sequence for the antibody.
  • the term 'polynucleotide encoding an antibody encompasses a polynucleotide which includes additional coding sequence for the variant but also a polynucleotide which includes additional coding and/or non- coding sequence. It is known in the art that a polynucleotide sequence that is optimized for a specific host cell/expression system can readily be obtained from the amino acid sequence of the desired protein (see GENEART AG, Regensburg,
  • the polynucleotides encoding the antibodies of the present invention will typically include an expression control polynucleotide sequence operably linked to the antibody coding sequences, including naturally-associated or heterologous promoter regions known in the art.
  • the expression control sequences will be eukaryotic promoter systems in vectors capable of transforming or transfecting eukaryotic host cells, but control sequences for prokaryotic hosts may also be used.
  • Preferred eukaryotic cell lines include the CHO cell lines, various COS cell lines, HeLa cells, myeloma cell lines, transformed B-cells, or human embryonic kidney cell lines.
  • the most preferred host cell is a CHO cell line.
  • linkages as used herein to refer to bonds or chemical moieties formed from a chemical reaction between the functional group of a linker and another molecule. Such bonds may include, but are not limited to, covalent linkages and non-covalent bonds, while such chemical moieties may include, but are not limited to, esters, carbonates, carbamates, imines phosphate esters, oximes, hydrazones, acetals, orthoesters, amides, peptide linkages, and oligonucleotide linkages.
  • Hydrolytically stable linkages means that the linkages are substantially stable in water and do not react with water at useful pH values, including but not limited to, under physiological conditions for an extended period of time.
  • Hydrolytically unstable or degradable linkages means that the linkages are degradable in water or in aqueous solutions, including for example, blood.
  • Enzymatically unstable or degradable linkages means that the linkage can be degraded by one or more enzymes.
  • PEG and related polymers may include degradable linkages in the polymer backbone or in the linker group between the polymer backbone and one or more of the terminal functional groups of the polymer molecule.
  • degradable linkages include, but are not limited to, ester linkages formed by the reaction of PEG carboxylic acids or activated PEG carboxylic acids with alcohol groups on a biologically active agent, wherein such ester groups generally hydrolyze under physiological conditions to release the biologically active agent.
  • hydrolytically degradable linkages include but are not limited to carbonate linkages; imine linkages resulting from reaction of an amine and an aldehyde; phosphate ester linkages formed by reacting an alcohol with a phosphate group; hydrazone linkages which are a reaction product of a hydrazide and an aldehyde; acetal linkages that are the reaction product of an aldehyde and an alcohol; orthoester linkages that are the reaction product of a formate and an alcohol; peptide linkages formed by an amine group, including but not limited to, at an end of a polymer such as PEG, and a carboxyl group of a peptide; and oligonucleotide linkages formed by a phosphoramidite group, including but not limited to, at the end of a polymer, and a 5' hydroxyl group of an oligonucleotide.
  • Dolastatins and their peptidic analogs and derivatives, auristatins are highly potent antimitotic agents that have been shown to have anticancer and antifungal activity. See, e.g., U.S. Pat. No. 5,663,149 and Pettit et al., Antimicrob. Agents
  • exemplary dolastatins and auristatins include, but are not limited to, auristatin E, auristatin EB (AEB), auristatin EFP (AEFP), monomethyl auristatin F (MMAF), monomethylauristatin-D (MMAD), monomethyl auristatin E
  • MMAE 5-benzoylvaleric acid-AE ester
  • AEVB 5-benzoylvaleric acid-AE ester
  • the preferred dolastatin derivative or analog is MMAD.
  • dolastatin linker derivatives or analogs comprising at least one non-natural amino acid or modified non-natural amino acid with an oxime, aromatic amine, or heterocycle (e.g.indole, quinoxaline,phenazine, pyrazole, triazole, etc.).
  • Such dolastatin linker derivatives comprising non-natural amino acids may contain further functionality, including but not limited to, a polymer; a water-soluble polymer; a derivative of polyethylene glycol; a second protein or polypeptide or polypeptide analog; an antibody or antibody fragment; and any combination thereof.
  • a polymer including but not limited to, a polymer; a water-soluble polymer; a derivative of polyethylene glycol; a second protein or polypeptide or polypeptide analog; an antibody or antibody fragment; and any combination thereof.
  • Dolastatin derivatives with linkers containing a hydroxylamine ether (also called an aminooxy) group allow for reaction with a variety of electrophilic groups to form conjugates (including but not limited to, with PEG or other water soluble polymers).
  • a hydroxylamine ether also called an aminooxy
  • the enhanced nucleophilicity of the aminooxy group permits it to react efficiently and selectively with a variety of molecules that contain carbonyl- or dicarbonyl-groups, including but not limited to, ketones, aldehydes or other functional groups with similar chemical reactivity. See, e.g., Shao, J. and Tarn, J., J. Arn. Chern. Soc. 1 17:3893-3899 (1995); H.
  • the non-natural amino acids used in the methods and compositions described herein have at least one of the following four properties: (1 ) at least one functional group on the sidechain of the non-natural amino acid has at least one characteristics and/or activity and/or reactivity orthogonal to the chemical reactivity of the 20 common, genetically-encoded amino acids (i.e., alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine), or at least orthogonal to the chemical reactivity of the naturally occurring amino acids present in the polypeptide that includes the nonnatural amino acid; (2) the introduced non-natural amino acids are substantially chemically inert toward the 20 common, genetically-encoded amino acids; (3) the non-natural amino acid can be
  • non-natural amino acids of the present invention include, but are not limited to, compounds selected from a group consisting of O-methyl-L-tyrosine, L-3-(2- naphthyl)-alanine, 3-methyl-L-phenylalanine, fluorinated phenylalanine, p-benzoyl-L- phenylalanine, p-iodo-L-phenylalanine, p-bromo-L-phenylalanine, p-amino-L- phenylalanine, 3,4-dihydroxy-L-phenylalanine, and isopropylL- phenylalanine, p-azido- L-phenylalanine, p-acetyl-L-phenylalanine, m-acetyl-L-phenylalanine, 4-(2-oxo- propoxy)-L-phenylalanine.
  • the non-natural amino acids of the present invention are selected from the group consisting of p-azido-L-phenylalanine, p-acetyl-L- phenylalanine, m-acetyl-L-phenylalanine, and 4-(2-oxo-propoxy)-L-phenylalanine.
  • the most preferred non-natural amino acid of the present invention is p-acetyl-L- phenylalanine.
  • Non-natural amino acids of the present invention may include protected or masked carbonyl or dicarbonyl groups, which can be transformed into a carbonyl or dicarbonyl group after deprotection of the protected group or unmasking of the masked group and thereby are available to react with hydroxylamine ethers or oximes to form oxime groups.
  • Non-natural amino acids that may be used in the methods and compositions described herein include, but are not limited to, amino acids comprising novel functional groups, amino acids that covalently or noncovalently interact with other molecules, glycosylated amino acids such as a sugar substituted serine, other carbohydrate modified amino acids, keto-containing amino acids, aldehyde containing amino acids, amino acids comprising polyethylene glycol or other polyethers, heavy atom substituted amino acids, chemically deavable and/or photodeavable amino acids, amino acids with elongated side chains as compared to natural amino acids, including but not limited to, polyethers or long chain hydrocarbons, including but not limited to, greater than about 5 or greater than about 10 carbons, carbon-linked sugar-containing amino acids, redox- active amino acids, amino thioacid containing amino acids, and amino acids comprising one or more toxic moieties.
  • amino acids comprising novel functional groups such as a sugar substituted serine, other carbohydrate modified amino acids, keto-containing amino acids
  • polypeptides For example, the unique reactivity of a carbonyl or dicarbonyl functional group (including a keto- or aldehyde- functional group) allows selective modification of proteins with any of a number of hydrazine- or hydroxylamine containing reagents in vivo and in vitro.
  • a carbonyl or dicarbonyl functional group including a keto- or aldehyde- functional group
  • Amino acids with an electrophilic reactive group allow for a variety of reactions to link molecules via various chemical reactions, including, but not limited to, nucleophilic addition reactions.
  • electrophilic reactive groups include a carbonyl- or dicarbonyl- group (including a keto- or aldehyde group), a carbonyl-like or dicarbonyl-like-group (which has reactivity similar to a carbonyl- or dicarbonyl-group and is structurally similar to a carbonyl- or dicarbonyl-group), a masked carbonyl- or masked dicarbonyl-group (which can be readily converted into a carbonyl- or dicarbonyl-group), or a protected carbonyl- or protected dicarbonyl-group (which has reactivity similar to a carbonyl- or dicarbonyl-group upon deprotection).
  • Non-natural amino acid dolastatin linked derivatives containing an oxime group allow for reaction with a variety of reagents that contain certain reactive carbonyl- or dicarbonyl- groups (including but not limited to, ketones, aldehydes, or other groups with similar reactivity) to form new non-natural amino acids comprising a new oxime group.
  • Such an oxime exchange reaction allows for the further functionalization of dolastatin linked derivatives.
  • the number of drug moieties, p, conjugated per antibody molecule via the oxime linkage ranges from an average of about 1 to about 8; about 1 to about 7, about 1 to about 6, about 1 to about 5, about 1 to about 4, about 1 to about 3, or about 1 to about 2.
  • p ranges from an average of about 2 to about 8, about 2 to about 7, about 2 to about 6, about 2 to about 5, about 2 to about 4 or about 2 to about 3. In other embodiments, p is an average of 1 , 2, 3, 4, 5, 6, 7, or 8.
  • p is an average of 1 , 2, 3, 4, 5, 6, 7, or 8.
  • non-natural amino acid dolastiatin linked derivatives with side chains comprising a masked oxime group (which can be readily converted into an oxime group), or a protected oxime group (which has reactivity similar to an oxime group upon deprotection).
  • the ADC A1 -mc-MMAD and/or A1 -vc-MMAD were used.
  • the linker payload, mc-MMAD (6-maleimidocaproyl-monomethylauristatin-D) was conjugated to the A1 anti-5T4 monoclonal antibody through a cysteine residue at a ratio of approximately 4 drug moieties per antibody molecule.
  • linker payload mc- Val-Cit-PABA-MMAD or vc-MMAD maleimidocapronic -valine-citruline-p- aminobenzyloxycarbonyl- monomethylauristatin-D was conjugated to the A1 anti-5T4 monoclonal antibody through a cysteine residue at a ratio of approximately 4 drug moieties per antibody molecule (see Sun, et al., Bioconjugate Chem. 16: 1282-1290, 2005, herein incorporated by reference).
  • an antibody can be conjugated to a suitable drug, such as a cytotoxic or cytostatic agent, an immunosuppressive agent, a radioisotope, a toxin, or the like.
  • a suitable drug such as a cytotoxic or cytostatic agent, an immunosuppressive agent, a radioisotope, a toxin, or the like.
  • the conjugate can be used for inhibiting the multiplication of a tumor cell or cancer cell, causing apoptosis in a tumor or cancer cell, or for treating cancer in a patient.
  • the conjugate can be used accordingly in a variety of settings for the treatment of animal cancers.
  • the conjugate can be used to deliver a drug to a tumor cell or cancer cell.
  • the conjugate binds to or associates with a cancer-cell or a tumor-associated antigen
  • the conjugate and/or drug can be taken up inside a tumor cell or cancer cell through receptor- mediated endocytosis.
  • the antigen can be attached to a tumor cell or cancer cell or can be an extracellular matrix protein associated with the tumor cell or cancer cell.
  • one or more specific peptide sequences within the conjugate are hydrolytically cleaved by one or more tumor-cell or cancer-cell- associated proteases, resulting in release of the drug.
  • the released drug is then free to migrate within the cell and induce cytotoxic or cytostatic or other activities.
  • cancers positive for the 5T4 antigen including, but not limited to, a tumor, metastasis, or other disease or disorder characterized by
  • the present invention provides a method of treating a 5T4-positive cancer wherein said cancer is selected from the group consisting of carcinomas of the bladder, breast, cervix, colon, endometrium, kidney, lung, esophagus, ovary, prostate, pancreas, skin (i.e. melanoma), stomach, and testes. More preferably, the present invention provides a method of treating a 5T4-positive cancer wherein said cancer is selected from the group consisting of colorectal, breast, pancreatic, and non-small cell lung carcinomas.
  • methods for treating or preventing cancer including administering to a patient in need thereof an effective amount of a conjugate and a chemotherapeutic agent.
  • the chemotherapeutic agent is that with which treatment of the cancer has not been found to be refractory.
  • the chemotherapeutic agent is that with which the treatment of cancer has been found to be refractory.
  • the conjugate can be administered to a patient that has also undergone a treatment, such as surgery for treatment for the cancer.
  • the additional method of treatment is radiation therapy.
  • Methods for treating cancer include administering to a patient in need thereof an effective amount of an antibody-drug conjugate and another therapeutic agent that is an anti-cancer agent.
  • Suitable anticancer agents include, but are not limited to,
  • methotrexate methotrexate, taxol, L-asparaginase, mercaptopurine, thioguanine, hydroxyurea, cytarabine, cyclophosphamide, ifosfamide, nitrosoureas, cisplatin, carboplatin, mitomycin, dacarbazine, procarbizine, topotecan, nitrogen mustards, Cytoxan, etoposide, 5-fluorouracil, BCNU, irinotecan, camptothecins, bleomycin, doxorubicin, idarubicin, daunorubicin, dactinomycin, plicamycin, mitoxantrone, asparaginase, vinblastine, vincristine, vinorelbine, paclitaxel, calicheamicin, and docetaxel.
  • the ADCs of the present invention can be in the form of a pharmaceutical composition for administration that are formulated to be appropriate for the selected mode of administration, and pharmaceutically acceptable diluent or excipients, such as buffers, surfactants, preservatives, solubilizing agents, isotonicity agents, stabilizing agents, carriers, and the like.
  • pharmaceutically acceptable diluent or excipients such as buffers, surfactants, preservatives, solubilizing agents, isotonicity agents, stabilizing agents, carriers, and the like.
  • compositions may be administered by any means known in the art that achieve the generally intended purpose to treat cancer.
  • the preferred route of administration is parenteral, defined herein as referring to modes of administration that include but not limited to intravenous, intramuscular, intraperitoneal, subcutaneous, and intraarticular injection and infusion.
  • the dosage administered will be dependent upon the age, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired.
  • compositions within the scope of the invention include all compositions wherein an ADC is present in an amount that is effective to achieve the desired medical effect for treating cancer. While individual needs may vary from one patient to another, the determination of the optimal ranges of effective amounts of all of the components is within the ability of the clinician of ordinary skill.
  • Compound 1 d is conjugated to A1 -121 mAb via the non-natural amino acid p- acetyl-L-phenylalanine resulting in the compound A1 -121 -NC-D-1 .
  • the amount of drug-linker needed is calculated using the equation below:
  • Drug - lin ker(mg) x ratioiDrug - lin ker : mAb) x MWiDrug - lin ker)
  • NC-D-1 conjugated to pAF residue on an anti-5T4 mAb Structure of NC-D-1 conjugated to pAF residue on an anti-5T4 mAb:
  • Compound 2b Compound 2a (1 .0 g, 3.12 mmol), N-hydroxyphthalimide (61 1 mg, 3.744 mmol) and triphenylphosphine (1 .23 g, 4.68 mmol) are dissolved in 20 mL of tetrahydrofuran followed by addition of DIAD (0.84 mL, 4.06 mmol) at 0°C. The resulting solution is stirred at room temperature overnight, and then concentrated to dryness. The residue is purified by flash column chromatography using SiliaSep Cartridges (80g), eluting with 0-100% ethyl acetate/hexanes, to give 1 .0 g (100%) of compound 2b.
  • Compound 2e is made according to the literature (Bioconjugate Chem. 2002, 13 (4), 855-869).
  • HC-D-1 is conjugated to A1 -121 mAb via the non-natural amino acid p-acetyl-L- phenylalanine, as described above, resulting in the compound A1 -121 -HC-D-1 .
  • Cell lines expressing 5T4, and the negative control Raji cell line are cultured with increasing concentrations of ADC. After four days, viability of each culture is assessed. IC 50 values are calculated by logistic non-linear regression and are presented as Ab ng/mL. A1 -121 -NC-D-1 , A1 -121 -HC-D-1 , A1 -121 -NCA-D-2, and A1 - 121 -PHC-D-2 are shown to inhibit the growth of 5T4 expressing cell lines that express a high level of the 5T4 antigen (MDAMB435/5T4) or express moderate levels of the 5T4 antigen (MDAMB468, and MDAMB361 DYT2), while being relatively inactive on 5T4 negative cells (Raji), Table 2.
  • MDAMB435/5T4 high level of the 5T4 antigen
  • MDAMB468, and MDAMB361 DYT2 express moderate levels of the 5T4 antigen
  • MDAMB435/5T4 xenografts at the 10 mg/kg dose while A1 -mcMMAD was not active in this model at doses of 1 , 3, or 10 mg/kg.
  • Table 5
  • Amino acid positions of the anti-5T4 antibody, A1 selected for mutation and subsequent location of non-natural amino acids as conjugation sites of dolastatin linked derivatives are selected based on structural information.
  • the desired mutations sites have certain characteristics: (1 ) the mutations sites have to be accessible for conjugation i.e. the calculated solvent accessible surface is above 40%. (2) The mutation sites cannot be involved in the integrity of the 3D structure of the antibody. A preference is given to residues outside secondary structure. (3) All residues in interface with other domains (VH-CH1 , VL-CL, CH1 -CL, and CH1 -CH2) are not considered. (4) Finally, proline and glycine are deselected for their role in the structural integrity of the protein.
  • Modeling of the 3D structure of the anti-5T4 antibody of the present invention is done using other antibodies with high sequence homology with the anti-5T4 antibody. This provides comparative modeling to predict the 3D structure of the anti-5T4 Fab. This modeling is subsequently validated with the X-ray structure of the anti-5T4 Fab.
  • Protein Data Base codes 1 T3F: Humanized murine anti-IFN-gamma Fab (HuZAF); 1 B2W: humanized murine anti-gamma-interferon antibody; 1 L7I: humanized murine anti-ErbB2antibody.
  • the sequences are aligned using the Salign algorithm implemented in the comparative modeling software MODELER 9v7 (A. Sali and T. L. Blundell, J. Mol. Biol. 234, 779-815, 1993). Using the three templates and the sequence alignment described above, 50 models are built and selected based on PDF score and DOPE evaluation. All algorithms are implemented in MODELER 9v7.
  • SASA solvent accessible surface area
  • Pharmacokinetic analysis is done with the ADC's containing the non-natural amino acid p-acetyl-L-phenylalanine at positions 120, 121 , 164 or 178 of the A1 antibody heavy chain conjugated with the dolastatin linked derivative NC-D-1 .
  • the ADC's A1 -mc-MMAD and A1 -vc-MMAD, which do not contain a non- natural amino acid are used.
  • mice Female nu/nu mice (5 per dose group) are injected with a single IV bolus at 3 mg/kg for each ADC tested.
  • the whole blood sample is diluted to 200 ⁇ _ with buffer and centrifuged.
  • the supernatant is then transferred to a 96 well plate for ELISA analysis.
  • the ELISA is a standard capture assay utilizing the 5T4 antigen as the capturing reagent and biotinylated anti-dolastatin antibody/ streptavidin- HRP as the detection reagents.
  • the data in Table 9 indicates that all of the ADC's containing the non-natural amino acid p-acetyl-L-phenylalanine conjugated with the dolastatin linked derivative NC-D-1 have a longer t1/2 (plasma half life) and a greater area under the curve (AUC) or exposure than the comparator ADCs, A1 -mc-MMAD and A1 -vc-MMAD.
  • This data unexpectedly demonstrates that the insertion of a single non-natural amino acid into the heavy chain of an antibody conjugated to a dolastatin linked derivative provides the advantage of an improved pharmacokinetics profile indicated by a longer plasma half life and higher AUC compared to a similar ADC lacking a non-natural amino acid.
  • the data in Table 10 indicates that the ADCs containing the non-natural amino acid p-acetyl-L-phenylalanine at position 121 conjugated with the dolastatin linked derivatives NC-D-1 , NCA-D-2, HC-D-1 , or PHC-D-2 have a longer t1/2 (plasma half life) and a greater AUC compared with the controls A1 IgG antibody or the A1 -121 mutant IgG antibody.
  • A1 -5T4-D-M-1 ADCs in mouse, rat, and human plasma is done with the ADCs containing the non-natural amino acid p-acetyl-L-phenylalanine at positions 120 or 121 of the A1 antibody heavy chain conjugated with the dolastatin linked derivatives HC-D-1 , SHC-D-1 , or SC-D-1 , which are synthesized as described in Example 1 under the synthesis of HC-D-1 .
  • HC, SHC, and SC designate a linker derivative of polyethylene glycol (PEG) in decreasing order of chain length of the PEG derivative i.e. HC PEG chain length > SHC PEG chain length > SC PEG chain length, as shown in the following structures of the dolastatin linked derivatives HC-D-1 , SHC-D-1 , and SC-D-1 :
  • the stability analysis of the A1 -5T4 -D-M-1 ADCs (A1 -5T4-120-HC-D-1 , A1 -5T4- 120-SHC-D-1 , A1 -5T4-120-SC-D-1 , A1 -5T4-121 -HC-D-1 , A1 -5T4-121 -SHC-D-1 , and A1 -5T4-121 -SC-D-1 ) as measured by the release of MMAD from the cleavable linker, is performed in fresh nu/nu female mouse, rat, or human plasma.
  • Xaa is alanine or non-natural amino acid p-acetyl-L- phenyalanine
  • Xaa is serine or non-natural amino acid p-acetyl-L- phenyalanine
  • Xaa 164 is alanine or non-natural amino acid p-acetyl-L- phenyalanine
  • Xaa is serine or non-natural amino acid p-acetyl-L- phenyalanine

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Abstract

La présente invention concerne des conjugués anticorps anti-5T4-médicament présentant un profil pharmacocinétique amélioré, ainsi que leurs procédés de préparation et d'utilisation. Dans un mode de réalisation, le conjugué anticorps-médicament est de formule Ab-(D)p, dans laquelle Ab représente un anticorps anti-5T4 comprenant un acide aminé non naturel ; D est un dérivé d'une séquence de liaison de la dolastatine ; et p est compris entre environ 1 et environ 8.
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