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WO2018183366A1 - Polythérapies d'anticorps csf-1r ou csf-1 et thérapie reposant sur des lymphocytes t - Google Patents

Polythérapies d'anticorps csf-1r ou csf-1 et thérapie reposant sur des lymphocytes t Download PDF

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Publication number
WO2018183366A1
WO2018183366A1 PCT/US2018/024618 US2018024618W WO2018183366A1 WO 2018183366 A1 WO2018183366 A1 WO 2018183366A1 US 2018024618 W US2018024618 W US 2018024618W WO 2018183366 A1 WO2018183366 A1 WO 2018183366A1
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Prior art keywords
antibody
csf
cdr
seq
binding fragment
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PCT/US2018/024618
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English (en)
Inventor
Briggs W. Morrison
Peter Ordentlich
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Syndax Pharmaceuticals, Inc.
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Publication of WO2018183366A1 publication Critical patent/WO2018183366A1/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
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/243—Colony Stimulating Factors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C07K14/70503—Immunoglobulin superfamily
    • C07K14/7051—T-cell receptor (TcR)-CD3 complex
    • 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
    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • 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
    • C07K16/2866—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for cytokines, lymphokines, interferons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A61K2039/507—Comprising a combination of two or more separate antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/60—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments
    • C07K2317/62—Immunoglobulins specific features characterized by non-natural combinations of immunoglobulin fragments comprising only variable region components
    • C07K2317/622—Single chain antibody (scFv)
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
    • C07K2319/03—Fusion polypeptide containing a localisation/targetting motif containing a transmembrane segment
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
    • C07K2319/033—Fusion polypeptide containing a localisation/targetting motif containing a motif for targeting to the internal surface of the plasma membrane, e.g. containing a myristoylation motif

Definitions

  • This disclosure relates to therapies involving an anti-CSF-lR antibody or anti-CSF-1 antibody or antigen binding fragment thereof in combination with a T-cell engaging therapy, e.g., chimeric antigen receptor-modified T cell therapy (CAR-T) and/or Bispecific T cell Engagers (BiTE), methods of treating cancer and methods of treating or preventing a cytokine release syndrome (CRS).
  • a T-cell engaging therapy e.g., chimeric antigen receptor-modified T cell therapy (CAR-T) and/or Bispecific T cell Engagers (BiTE)
  • CRS cytokine release syndrome
  • Immunotherapy specifically T-cell engaging therapies using chimeric-antigen receptor T cells (CAR-T cells)
  • CAR-T cells targeting a tumor-associated antigen can result in robust tumor killing, in some cases resulting in complete remission of CD19 + hematological malignancies.
  • CAR-T cells possess the capacity to rapidly reproduce upon antigen recognition, thereby potentially eliminating the need for repeat treatments.
  • CAR-T cells must not only drive tumor destruction initially, but must also persist in the patient as a stable population of viable memory T cells to prevent potential cancer relapses.
  • immune-based therapies for cancer become potent, effective, and more widely available, the management of their unique toxicities also becomes vital.
  • Cytokine release syndrome is a potentially life-threatening toxicity that has been observed following administration of natural and bispecific antibodies as well as following adoptive T-cell therapies for cancer.
  • the distinctive feature of such active immunotherapies is non-physiologic T cell activation, which has shown increased efficacy, however has been associated with marked toxicity. See, e.g. , Maude et al , Caner J. 2014; 20(2): 119-122. Thus there is an unmet need for a targeted approach that has the potential to control toxicity while maintaining efficacy.
  • this disclosure provides a combination of an anti-CSF-lR antibody or antigen binding fragment thereof and a T-cell engaging therapy.
  • this disclosure provides a combination of an anti-CSF-1 antibody or antigen binding fragment thereof and a T-cell engaging therapy.
  • the T-cell engaging therapy is a chimeric antigen receptor- modified T cell therapy (CAR-T).
  • CAR-T chimeric antigen receptor- modified T cell therapy
  • the CAR-T is CAR-T against CD 19.
  • the CAR-T is selected from CTLOl 9, huCARTl 9, MesoCART, huEGFRVIII, JCAR014, JCAR015, JCAR016, JCAR017, JCAR018, JCAR020, JCAR023, JCAR024, KTE-C19, EGFRvIII, UCART19, UCART123, UCART5T4, UCARTCS1, CM- CS1, BPX-401, and BPX-601.
  • the T-cell engaging therapy is a bispecific T-cell engager (BiTE).
  • the BiTE is blinatumomab.
  • the anti-CSF-lR antibody or antigen binding fragment thereof comprises: a heavy chain, wherein the variable domain of the heavy chain comprises at least one of a CDR having the sequence given in SEQ ID NO:4 for CDR-H1, a CDR having the sequence given in SEQ ID NO:5 for CDR-H2 and a CDR having the sequence given in SEQ ID NO: 6 for CDR-H3; and/or a light chain, wherein the variable domain of the light chain comprises at least one of a CDR having the sequence given in SEQ ID NO: 1 for CDR-L1, a CDR having the sequence given in SEQ ID NO:2 for CDR-L2 and a CDR having the sequence given in SEQ ID NO: 3 for CDR-L3.
  • the anti-CSF-lR antibody or antigen binding fragment thereof comprises a heavy chain and a light chain
  • the variable domain of the heavy chain comprises three CDRs and the sequence of CDR-H1 has at least 60% identity or similarity to the sequence given in SEQ ID NO:4
  • the sequence of CDR-H2 has at least 60% identity or similarity to the sequence given in SEQ ID NO:5
  • the sequence of CDR-H3 has at least 60% identity or similarity to the sequence given in SEQ ID NO: 6
  • the variable domain of the light chain comprises three CDRs and the sequence of CDR-Ll has at least 60% identity or similarity to the sequence given in SEQ ID NO: 1
  • the sequence of CDR-L2 has at least 60% identity or similarity to the sequence given in SEQ ID NO:2
  • the sequence of CDR-L3 has at least 60% identity or similarity to the sequence given in SEQ ID NO:3.
  • the anti-CSF-lR antibody or antigen binding fragment thereof comprises a heavy chain, wherein the heavy chain comprises the sequence given in SEQ ID NO:23; and a light chain, wherein the light chain comprises the sequence given in SEQ ID NO: 15.
  • the anti-CSF-lR antibody or anti-CSF-1 antibody or antigen binding fragment thereof is selected from the group consisting of a complete antibody molecule having full length heavy and light chains, a Fab, modified Fab', Fab', F(ab')2, Fv, VH, VL and scFv fragment thereof.
  • the anti-CSF-lR antibody or antigen binding fragment thereof comprises a heavy chain, wherein the heavy chain comprises the sequence given in SEQ ID NO:23; and a light chain, wherein the light chain comprises the sequence given in SEQ ID NO: 15.
  • the anti-CSF-lR antibody or antigen binding fragment thereof comprises a heavy chain comprising the sequence given in SEQ ID NO:27 and a light chain comprising the sequence given in SEQ ID NO: 19.
  • the anti-CSF-lR antibody or anti-CSF-1 antibody or antigen binding fragment thereof comprises an effector or a reporter molecule attached to it.
  • the anti-CSF-lR antibody or antigen binding fragment thereof cross-blocks the binding of an antibody comprising the 6 CDRs given in sequence SEQ ID NO: l for CDR-Ll, SEQ ID NO:2 for CDR-L2, SEQ ID NO:3 for CDR-L3, SEQ ID NO:4 for CDR-H1, SEQ ID NO: 5 for CDR-H2 and SEQ ID NO: 6 for CDR-H3.
  • the anti-CSF-lR antibody or antigen binding fragment thereof cross-blocks the binding by binding the same epitope as the antibody which it blocks.
  • the anti-CSF-1 antibody or antigen binding fragment thereof cross-blocks the binding by binding the same epitope as the antibody which it blocks.
  • the anti-CSF-lR antibody or antigen binding fragment thereof comprises a binding affinity for human CSF-1R of 100 pM or less, or 10 pM or less.
  • the anti-CSF-1 antibody or antigen binding fragment thereof comprises a binding affinity for human CSF-1 of 100 pM or less, or 10 pM or less.
  • the anti-CSF-lR antibody or anti-CSF-1 antibody or antigen binding fragment thereof is in a pharmaceutical composition comprising the antibody or fragment thereof and a pharmaceutically acceptable carrier.
  • the anti-CSF-lR antibody or anti-CSF-1 antibody or antigen binding fragment thereof and the T-cell engaging therapy are administered in temporal proximity for treating cancer.
  • the anti-CSF-lR antibody or anti-CSF-1 antibody or antigen binding fragment thereof and the T-cell engaging therapy are administered simultaneously, sequentially or in alternation for treating cancer.
  • the anti-CSF-lR antibody or anti-CSF-1 antibody or antigen binding fragment thereof is at a dose ranging between about 0.1 mg/kg and about 10 mg/kg, inclusive of the endpoints.
  • the anti-CSF-lR antibody or anti-CSF-1 antibody or antigen binding fragment thereof is at a dose of about 0.1 mg/kg, 0.5 mg/kg, 1 mg/kg, 1.5 mg/kg, 3 mg/kg, 5 mg/kg, 6 mg/kg, 7.5 mg/kg, or about 10 mg/kg.
  • the anti-CSF-lR antibody or anti-CSF-1 antibody or antigen binding fragment thereof is at a dose of about 3 mg/kg or about 6 mg/kg.
  • this disclosure provides a method of treating cancer.
  • the method comprises administering to a subject in need thereof a T-cell engaging therapy and an effective amount of an anti-CSF-lR antibody or antigen binding fragment thereof.
  • this disclosure provides a method of treating cancer by administering to a subject in need thereof a T-cell engaging therapy and an effective amount of an anti-CSF-1 antibody or antigen binding fragment thereof.
  • the method includes the T-cell engaging therapy comprising a chimeric antigen receptor-modified T cell therapy (CAR-T).
  • CAR-T chimeric antigen receptor-modified T cell therapy
  • the CAR-T is CAR-T against CD19.
  • the CAR-T is selected from CTL019, huCART19, MesoCART, huEGFRVIII, JCAR014, JCAR015, JCAR016, JCAR017,
  • the method includes the T-cell engaging therapy comprising a bispecific T-cell engager (BiTE).
  • the BiTE is blinatumomab.
  • the cancer is a hematological cancer.
  • the cancer is a relapsed and/or refractory cancer.
  • the cancer is acute myeloid leukemia (AML), acute
  • ALL lymphoblastic leukemia
  • CALL chronic lymphoblastic leukemia
  • NHL non-Hodgkin lymphoma
  • MCL mantle cell lymphoma
  • DLBCL diffuse large b-cell lymphoma
  • PFBC primary mediastinal b-cell lymphoma
  • TNF transformed follicular lymphoma
  • the cancer is mesothelioma, pancreatic cancer, glioma, neuroblastoma, ovarian cancer, glioblastoma, myelodysplastic syndromes (MDS), breast cancer, prostate cancer, colorectal cancer, skin cancer, esophageal cancer, gastric cancer, astrocytic cancer, endometrial cancer, cervical cancer, bladder cancer, renal cancer, lung cancer, liver cancer, thyroid cancer, or head and neck cancer.
  • MDS myelodysplastic syndromes
  • the anti-CSF-lR antibody or anti-CSF-1 antibody or antigen binding fragment thereof and the T-cell engaging therapy are administered in temporal proximity.
  • the anti-CSF-lR antibody or anti-CSF-1 antibody or antigen binding fragment thereof and the T-cell engaging therapy are administered simultaneously, sequentially or in alternation.
  • this disclosure provides a method of treating or preventing cytokine release syndrome (CRS).
  • the method comprises administering to a subject in need thereof an effective amount of an anti-CSF-lR antibody or antigen binding fragment thereof.
  • this disclosure provides a method of treating or preventing CRS by administering to a subject in need thereof an effective amount of an anti-CSF-1 antibody or antigen binding fragment thereof.
  • the anti-CSF-lR antibody or antigen binding fragment thereof comprises: a heavy chain, wherein the variable domain of the heavy chain comprises at least one of a CDR having the sequence given in SEQ ID NO:4 for CDR-H1, a CDR having the sequence given in SEQ ID NO:5 for CDR-H2 and a CDR having the sequence given in SEQ ID NO: 6 for CDR-H3; and/or a light chain, wherein the variable domain of the light chain comprises at least one of a CDR having the sequence given in SEQ ID NO: 1 for CDR-L1, a CDR having the sequence given in SEQ ID NO:2 for CDR-L2 and a CDR having the sequence given in SEQ ID NO: 3 for CDR-L3.
  • the anti-CSF-lR antibody or antigen binding fragment thereof comprises a heavy chain and a light chain
  • the variable domain of the heavy chain comprises three CDRs and the sequence of CDR-H1 has at least 60% identity or similarity to the sequence given in SEQ ID NO: 4
  • the sequence of CDR-H2 has at least 60% identity or similarity to the sequence given in SEQ ID NO:5
  • the sequence of CDR-H3 has at least 60% identity or similarity to the sequence given in SEQ ID NO: 6
  • the variable domain of the light chain comprises three CDRs and the sequence of CDR-Ll has at least 60% identity or similarity to the sequence given in SEQ ID NO: 1
  • the sequence of CDR-L2 has at least 60% identity or similarity to the sequence given in SEQ ID NO:2
  • the sequence of CDR-L3 has at least 60% identity or similarity to the sequence given in SEQ ID NO:3.
  • the anti-CSF-lR antibody or antigen binding fragment thereof comprises a heavy chain, wherein the heavy chain comprises the sequence given in SEQ ID NO:23; and a light chain, wherein the light chain comprises the sequence given in SEQ ID NO: 15.
  • the anti-CSF-lR antibody or antigen binding fragment thereof cross-blocks the binding of an antibody comprising the 6 CDRs given in sequence SEQ ID NO:
  • the anti-CSF-lR antibody or antigen binding fragment thereof cross-blocks the binding by binding the same epitope as the antibody which it blocks.
  • the anti-CSF-lR antibody or antigen binding fragment thereof comprises a binding affinity for human CSF-1R of 100 pM or less, or 10 pM or less.
  • the anti-CSF-lR antibody or antigen binding fragment thereof comprises a heavy chain comprising the sequence given in SEQ ID NO:27 and a light chain comprising the sequence given in SEQ ID NO: 19.
  • the anti-CSF-lR antibody or anti-CSF-1 antibody or antigen binding fragment thereof is selected from the group consisting of a complete antibody molecule having full length heavy and light chains, a Fab, modified Fab', Fab', F(ab')2, Fv, VH, VL and scFv fragment thereof.
  • the anti-CSF-lR antibody or anti-CSF-1 antibody or antigen binding fragment thereof comprises an effector or a reporter molecule attached to it.
  • the anti-CSF-lR antibody or anti-CSF-1 antibody or antigen binding fragment thereof is in a pharmaceutical composition comprising the antibody or fragment thereof and a pharmaceutically acceptable carrier.
  • the anti-CSF-lR antibody or anti-CSF-1 antibody or antigen binding fragment thereof is administered at a dose ranging between about 0.1 mg/kg and about 10 mg/kg, inclusive of the endpoints.
  • the anti-CSF-lR antibody or anti-CSF-1 antibody or antigen binding fragment thereof is administered at a dose of about 0.1 mg/kg, 0.5 mg/kg, 1 mg/kg, 1.5 mg/kg, 3 mg/kg, 5 mg/kg, 6 mg/kg, 7.5 mg/kg, or about 10 mg/kg.
  • the binding fragment thereof is administered at a dose of about 3 mg/kg or about 6 mg/kg.
  • the anti-CSF-lR antibody or anti-CSF-1 antibody or antigen binding fragment thereof is administered once a week.
  • the anti-CSF-lR antibody or anti-CSF-1 antibody or antigen binding fragment thereof is administered once every two weeks.
  • the disclosure provides a synergistic composition of an anti- CSF-1R antibody or anti-CSF-1 antibody or antigen binding fragment thereof and a T-cell engaging therapy in the treatment of cancer, wherein the anti-CSF-lR antibody or anti-CSF-1 antibody or antigen binding fragment thereof and the T-cell engaging therapy come into contact with each other in the human body (e.g., only in the human body).
  • the disclosure provides a method of preparing a composition by bringing an anti-CSF-lR antibody or anti-CSF-1 antibody or antigen binding fragment thereof and a T-cell engaging therapy into contact with each other at a locus.
  • anti-CSF-lR antibody or antigen binding fragment thereof and a T-cell engaging therapy can be used in a combination to treat tumors with superior results (e.g., reduced toxicity or adverse effects) than those achieved with the anti-CSF-lR antibody or anti-CSF-1 antibody alone or the T-cell engaging therapy alone.
  • a T-cell engaging therapy e.g., CAR-T or BiTE
  • the present disclosure provides a combination comprising an anti-CSF- 1R antibody or anti-CSF-1 antibody or antigen binding fragment thereof and one or more CAR-T cells, and a method of using the combination to treat diseases, such as those the cause of which can be influenced by modulating T- cell mediated immune responses and/or other proteins, e.g., cancer.
  • the present disclosure features a combination comprising an anti-CSF-lR antibody and a CAR-T against CD19.
  • the present disclosure also provides a combination comprising an anti-CSF-lR antibody or anti-CSF-1 antibody and one or more bispecific T-cell engagers (BiTEs), and a method for using the combination to treat diseases, such as those the cause of which can be influenced by modulating T- cell mediated immune responses and/or other proteins, e.g., cancer.
  • the present disclosure features a combination comprising an anti-CSF-lR antibody and a BiTE, such as blinatumomab or solitomab.
  • the present disclosure provides a method of treating or preventing a cytokine release syndrome, e.g., from a CAR-T or BiTE therapy.
  • the method comprises administering to a subject in need thereof an effective amount of an anti-CSF-lR antibody or anti-CSF-1 antibody or antigen binding fragment thereof, e.g., by inhibiting macrophage bioactivity and/or cytokine dysfunction.
  • the combinations and methods disclosed herein are suitable for treating cancer or inhibiting cancer cell proliferation, such as a hematological cancer, e.g., leukemia.
  • a hematological cancer e.g., leukemia.
  • the cancer is a relapsed cancer.
  • the cancer is a refractory cancer.
  • the cancer is both a relapsed and refractory cancer.
  • the present disclosure further provides uses of any compositions or combinations described herein in the manufacture of medicament for treating a disease.
  • diseases include, for example, cancer, a precancerous condition, or a disease influenced by modulating the T- cell immune response or other proteins.
  • T-cell engaging therapy refers to a therapy designed to hamess the cell-mediated immune response and direct it against cancerous cells, bypassing the major histocompatibility complex.
  • a T-cell engaging therapy can harness a subject's T cells to eradicate cancer cells.
  • T-cell engaging therapies include CAR-T and BiTE.
  • a CAR-T cell generally comprises at least one transmembrane polypeptide comprising at least one extracellular ligand-binding domain and; one transmembrane polypeptide comprising at least one intracellular signaling domain; such that the polypeptides assemble together to form a chimeric antigen receptor.
  • artificial T cell receptors which are also known as “chimeric T cell receptors”, or “chimeric immunoreceptors, and/or chimeric antigen receptors (CARs)" are engineered receptors, which graft an arbitrary specificity onto an immune effector cell.
  • these receptors are used to graft the specificity of a monoclonal antibody onto a T cell; with transfer of their coding sequence facilitated by retroviral vectors.
  • the CAR construct is used to graft an anti-CD 19 binding domain onto a T cell.
  • the chimeric antigen receptor (CAR) constructs that include a domain that binds specifically to CD 19 protein, referred to herein as the anti-CD 19 binding domain of the CAR construct.
  • the CAR construct is used to graft an anti-CD 19 binding domain onto a T cell.
  • the CAR construct provided herein is a fusion of an anti-CD19 single chain antibody, e.g., and anti-CD19 single-chain variable fragment (scFv) derived from an anti-CD 19 monoclonal antibody of the disclosure, fused to CD3-zeta transmembrane and endodomain.
  • extracellular ligand-binding domain is defined as a polypeptide that is capable of binding a ligand.
  • the domain will be capable of interacting with a cell surface molecule.
  • the extracellular ligand-binding domain may be chosen to recognize a ligand that acts as a cell surface marker on target cells associated with a particular disease state.
  • the extracellular domain is the variable region of a T-cell receptor.
  • the extracellular ligand-binding domain comprises the variable region of a T-cell receptor specific for a tumor associated antigen or a self-antigen.
  • the T-cell receptor, the tumor associated antigen or self-antigen has been identified from a single T-cell obtained from a subject.
  • the T-cell receptor is identified from a tumor infiltrating lymphocyte, a lymphocyte from an autoimmune site or a lymphocyte from a graft tissue.
  • the CAR-T suitable for the combinations and methods of the disclosure is selected from CTL019, huCART19, MesoCART, huEGFRVIII, JCAR014, JCAR015, JCAR016, JCAR017, JCAR018, JCAR020, JCAR023, JCAR024, KTE-C19, EGFRvIII, UCART19, UCART123, UCART5T4, UCARTCS1, CM-CS1, BPX-401, and BPX-601.
  • a "bispecific T-cell engager" or "BiTE” is an artificial bispecific monoclonal antibody that directs a host's T cells cytotoxic activity, against cancer cells. Like other bispecific antibodies, and unlike ordinary monoclonal antibodies, BiTEs form a link between T cells and tumor cells. This causes T cells to exert cytotoxic activity on tumor cells by producing proteins like perforin and granzymes, independently of the presence of MHC I or co-stimulatory molecules. These proteins enter tumor cells and initiate the cell's apoptosis.
  • the BiTE suitable for the combinations and methods of the disclosure is blinatumomab or solitomab.
  • the BiTE is a MCSP (melanoma-associated chondroitin sulfate proteoglycan or chondroitin sulfate proteoglycan 4) specific BiTE, a CD33 specific BiTE, a BiTE against CD66e (Cluster of Differentiation 66e), or a BiTE against EphA2 (ephrin type-A receptor 2).
  • T cells engineered to express a chimeric antigen receptor (CAR-T) with CD 19 specificity and blinatumomab, a bispecific antibody linking CD3+ T cells with CD 19+ cells are two such therapies that have shown dramatic responses in early-phase clinical trials for relapsed/refractory B-cell leukemias and lymphomas (see, Maude et al., Caner J. 2014; 20(2): 119-122). Reports indicate that some patients develop clinical and laboratory findings similar to patients with macrophage activation syndrome and that cytokine-directed therapy can abrogate life-threatening cytokine release symptoms (CRS) without compromising efficacy.
  • CRS life-threatening cytokine release symptoms
  • cytokine is a generic term for proteins released by one cell population, which act on another cell as intercellular mediators. Certain examples of such cytokines are lymphokines, monokines, and traditional polypeptide hormones. Included among the cytokines are, e.g.
  • growth hormone such as human growth hormone, N-methionyl human growth hormone, and bovine growth hormone; parathyroid hormone; thyroxine; insulin; proinsulin; relaxin; prorelaxin; glycoprotein hormones such as follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH), and luteinizing hormone (LH); hepatic growth factor; fibroblast growth factor; prolactin; placental lactogen; tumor necrosis factor a and ⁇ ; mullerian-inhibiting substance; mouse gonadotropin-associated peptide; inhibin; activin; vascular endothelial growth factor; integrin; thrombopoietin (TPO); nerve growth factors such as NGF- ⁇ ; platelet- growth factor; transforming growth factors (TGFs) such as TGF-a and TGF- ⁇ ; insulin-like growth factor-I and-II; erythropoietin (EPO); osteoinductive factors; interferons such as interferon-a
  • hypocytokinemia is an aberrant, excessive and uncontrolled release of inflammatory cytokines in response to immune cells. In patients, this leads to a high fever, swelling and redness, extreme fatigue, nausea and in some instances is fatal.
  • CSF-1R CSF-1 receptor
  • CD115 c-fms gene product
  • CSF-1R is a 165kDa type 1 TM glycoprotein belonging to the type III receptor tyrosine kinase family.
  • IL-34 has also been shown to be a ligand for CSF-IR (Lin, et al, 2008, Science 320:807-811).
  • CSF-IR is restricted to cells of the monocyte-macrophage lineage, both circulating and resident tissue populations, and osteoclasts. In addition, it is expressed in a number of cells of the female reproductive system including oocytes, decidual cells and trophoblasts.
  • Binding of the ligand CSF-1 to the CSF-1 receptor results in the phosphorylation of the receptor on one or more tyrosine residues, through the action of the tyrosine kinase domain.
  • This phosphorylation can be detected because antibodies are available that bind to the receptor only after phosphorylation (for example Phospho-M-CSF-Receptor (Tyr546) antibody #3083 from Cell Signaling Technology).
  • TAMs Tumor-associated macrophages
  • TAMs can be the major component of tumor stroma and high levels of CSF-1 and CSF-IR are associated with high TAM infiltrations and poor prognosis in a number of tumor types.
  • Antibodies to CSF-IR are known in the art. Sherr, C.J. et al, 1989, Blood 73: 1786- 1793 describes antibodies against CSF-IR that inhibit the CSF-1 activity (Sherr, C.J. et al, 1989, Blood 73: 1786-1793).
  • WO2009/026303 discloses anti-CSF-lR antibodies which bind to human CSF-IR and in vivo mouse tumor models using an anti-murine CSF-IR antibody.
  • WO2011/123381 discloses anti-CSF-lR antibodies which internalize CSF-IR and have ADCC activity.
  • WO2011/123381 also discloses in vivo mouse tumor models using an anti-murine CSF-IR antibody.
  • WO2011/140249 discloses anti-CSF-lR antibodies which block binding of CSF-1 to CSF-IR and are stated to be useful in the treatment of cancer.
  • WO2009/112245 discloses an anti-CSF-lR IgGl antibody which inhibits CSF-1 binding to CSF-IR and is stated to be useful in the treatment of cancer, inflammatory bowel disease and rheumatoid arthritis.
  • WO2011/131407 discloses an anti-CSF-lR antibody which inhibits CSF-1 binding to CSF-IR and is stated to be useful in the treatment of bone loss and cancer.
  • WO2011/107553 discloses an anti-CSF-lR antibody which inhibits CSF-1 binding to CSF-IR thought to be useful in the treatment of bone loss and cancer.
  • WO2011/070024 discloses anti-CSF-lR antibodies which bind to human CSF-IR fragment delD4.
  • the antibodies provided by the present disclosure are capable of blocking ligand binding to CSF-IR.
  • Blocking as employed herein refers to physically blocking such as occluding the receptor but will also include where the antibody or fragments binds an epitope that causes, for example a conformational change which means that the natural ligand to the receptor no longer binds (referred to herein as allosteric blocking or allosteric inhibition).
  • the antibodies of the present disclosure bind all isotypes of CSF-1R, for example those with variations in the ECD domain, such as V23G, A245S, H247P, V279M and combinations of two, three or four of said variations.
  • CSF-1 and IL-34 are both ligands for CSF-1R and the antibodies of the disclosure preferably inhibit the activity both CSF-1 and IL-34 in a functional cellular screen.
  • the antibodies according to the present disclosure also preferably do not cause CSF-1R activation and/or CSF-1R internalization.
  • the antibodies according to the present disclosure also preferably, selectively deplete the non-classical population of monocytes in vivo.
  • Non-classic monocytes generally refer to monocytes with low expression of CD14 and high expression of CD 16. This population of monocytes are thought to be pre-cursors of tumor associated macrophages.
  • the antibody molecules of the present disclosure suitably have a high binding affinity.
  • Affinity may be measured using any suitable method known in the art, including techniques such as surface plasmon resonance, for example BIAcore, as described in the Examples herein, using isolated natural or recombinant CSF-1R or a suitable fusion protein/polypeptide.
  • affinity is measured using recombinant human CSF-1R extracellular domain as described in the Examples herein.
  • the antibody molecules of the present disclosure have a binding affinity for isolated human CSF-1R of about InM or less than InM. In one embodiment the antibody molecule of the present disclosure has a binding affinity of about 500pM or lower. In one embodiment the antibody molecule of the present disclosure has a binding affinity of about 250pM or lower. In one embodiment the antibody molecule of the present disclosure has a binding affinity of about 200pM or lower. In one embodiment the present disclosure provides an anti-CSF-lR antibody with a binding affinity of about lOOpM or lower.
  • the present disclosure provides a humanized anti-CSF-lR antibody with a binding affinity of about lOOpM or lower, preferably about ⁇ or lower, more preferably about 5pM or lower. In some embodiment the present disclosure provides a humanized anti-CSF-lR antibody with a binding affinity of about lOOpM or lower, preferably about ⁇ or lower, more preferably about 5pM or lower.
  • Human CSF-1R as employed herein refers to the human protein name CSF-1R or a biological active fragment thereof.
  • the present disclosure provides anti-CSF-lR antibodies, including humanized antibodies. The antibodies were generated from immunization of rats with rat fibroblasts that were transfected with a vector expressing CSF-1R extracellular domain.
  • the present disclosure provides an antibody comprising a heavy chain and/or a light chain, wherein the heavy chain and/or light chain comprise at least one CDR derived from the anti-CSF-lR antibody 969.2.
  • Ab969.2 is a full-length humanized IgG4 molecule; the light chain comprises a human kappa chain constant region (Km3 allotype) and the heavy chain comprises a human gamma-4 heavy chain constant region with the hinge stabilizing mutation S241P (Angal et al, 1993).
  • a potential DG isomerization motif is present within the light chain variable region at the junction of CDR-L2 and the framework.
  • the sequences of Ab969.2 full antibody heavy and light chains are shown in SEQ ID NOs: 27 and 19.
  • the Kabat residue designations do not always correspond directly with the linear numbering of the amino acid residues.
  • the actual linear amino acid sequence may contain fewer or additional amino acids than in the strict Kabat numbering corresponding to a shortening of, or insertion into, a structural component, whether framework or
  • CDR complementarity determining region
  • CDRs of the heavy chain variable domain are located at residues 31-35 (CDR-H1), residues 50-65 (CDR-H2) and residues 95-102 (CDR-H3) according to the Kabat numbering system.
  • CDR-H1 residues 31-35
  • CDR-H2 residues 50-65
  • CDR-H3 residues 95-102
  • the loop equivalent to CDR-H1 extends from residue 26 to residue 32.
  • CDR- ⁇ as employed herein is intended to refer to residues 26 to 35, as described by a combination of the Kabat numbering system and Chothia's topological loop definition.
  • the CDRs of the light chain variable domain are located at residues 24-34 (CDR-L1), residues 50-56 (CDR-L2) and residues 89-97 (CDR-L3) according to the Kabat numbering system.
  • Antibodies for use in the present disclosure may be obtained using any suitable method known in the art.
  • polypeptide (recombinantly or naturally) expressing the polypeptide can be used to produce antibodies which specifically recognize CSF-IR.
  • the polypeptide may be the 'mature' polypeptide or a biologically active fragment or derivative thereof.
  • the human protein is registered in UniProt under the number P07333.
  • Antibodies generated against the CSF-IR polypeptide may be obtained, where immunization of an animal is necessary, by administering the polypeptides to an animal, preferably a non-human animal, using well-known and routine protocols, see for example Handbook of Experimental Immunology, D. M. Weir (ed.), Vol 4, Blackwell Scientific Publishers, Oxford, England, 1986). Many warm-blooded animals, such as rabbits, mice, rats, sheep, cows, camels or pigs may be immunized. However, mice, rabbits, pigs and rats are generally most suitable.
  • Screening for antibodies can be performed using assays to measure binding to human CSF-IR and/or assays to measure the ability to block ligand binding to the receptor. Examples of suitable assays are described in the Examples herein.
  • the antibody is an anti-CSF-lR antibody or binding fragment thereof comprising a heavy chain
  • the variable domain of the heavy chain comprises at least one of a CDR having the sequence given in SEQ ID NO: 4 for CDR-H1, a CDR having the sequence given in SEQ ID NO:5 for CDR-H2 and a CDR having the sequence given in SEQ ID NO:6 for CDR-H3.
  • the variable domain of the heavy chain comprises the sequence given in SEQ ID NO: 4 for CDR-H1, the sequence given in SEQ ID NO:5 for CDR- H2 and the sequence given in SEQ ID NO:6 for CDR-H3.
  • the antibody of the disclosure is an anti-CSF-lR antibody or binding fragment thereof comprising a heavy chain as defined above and additionally comprising a light chain wherein the variable domain of the light chain comprises at least one of a CDR having the sequence given in SEQ ID NO: 1 for CDR-L1, a CDR having the sequence given in SEQ ID NO:2 for CDR-L2 and a CDR having the sequence given in SEQ ID NO: 3 for CDR-L3.
  • the variable domain of the light chain preferably comprises the sequence given in SEQ ID NO: 1 for CDR-L1, the sequence given in SEQ ID NO:2 for CDR- L2 and the sequence given in SEQ ID NO:3 for CDR-L3.
  • Monoclonal antibodies may be prepared by any method known in the art such as the hybridoma technique (Kohler & Milstein, 1975, Nature, 256:495-497), the trioma technique, the human B-cell hybridoma technique (Kozbor et al., 1983, Immunology Today, 4:72) and the EBV-hybridoma technique (Cole et al, 1985, Monoclonal Antibodies and Cancer Therapy, pp77-96, Alan R Liss, Inc.).
  • At least one amino acid is replaced with a conservative substitution in one or more CDRs selected from the group consisting independently of: any one of CDR- Hl, CDR-H2, CDR-H3, CDR-Ll, CDR-L2, CDR-L3; any one of the combinations CDR-H1 and H2, CDR-H1 and H3, CDR-H1 and LI, CDR-H1 and L2, CDR-H1 and L3, CDR-H2 and H3, CDR-H2 and LI, CDR-H2 and L2, CDR-H2 and L3, CDR-H3 and LI, CDR-H3 and L2, CDR-H3 and L3, CDR-Ll and L2, CDR-Ll and L3, CDR-L2 and L3; CDR-H1, H2 and H3, CDR-H1, H2 and LI, CDR-H1, H2 and L2, CDR-H1, H2 and L3, CDR-H2, H3 and LI, CDR- H2, H3
  • an anti-CSF-lR antibody or binding fragment thereof wherein the variable domain of the heavy chain comprises three CDRs and the sequence of CDR-H1 has at least 60%, 70%, 80%, 90% or 95% identity or similarity to the sequence given in SEQ ID NO:4, the sequence of CDR-H2 has at least 60%, 70%, 80%, 90% or 95% identity or similarity to the sequence given in SEQ ID NO:5 and the sequence of CDR-H-3 has at least 60%, 70%, 80%, 90% or 95% identity or similarity to the sequence given in SEQ ID NO:6.
  • the anti-CSF-lR antibody or binding fragment thereof additionally comprising a light chain
  • the variable domain of the light chain comprises three CDRs and the sequence of CDR-Ll has at least 60%, 70%, 80%, 90% or 95% identity or similarity to the sequence given in SEQ ID NO: 1
  • the sequence of CDR-L2 has at least 60%, 70%, 80%, 90% or 95% identity or similarity to the sequence given in SEQ ID NO:2
  • the sequence of CDR-L3 has at least 60% identity or similarity to the sequence given in SEQ ID N0 3.
  • the anti-CSF-lR antibody cross-blocks the binding of an antibody comprising the 6 CDRs given in sequence SEQ ID NO: l for CDR-Ll, SEQ ID NO:2 for CDR-L2, SEQ ID NO:3 for CDR-L3, SEQ ID NO:4 for CDR-H1, SEQ ID NO:5 for CDR- H2 and SEQ ID NO:6 for CDR-H3, for example with affinity of ⁇ or less, in particular wherein the cross blocking is allosteric.
  • the anti-CSF-lR-antibody or binding fragment thereof inhibits or overlaps with the binding of CSF-1 and/or IL-34 to the extracellular domain of the CSF-1R receptor.
  • an anti-CSF-lR antibody which cross-blocks the binding of an antibody comprising a the 6 CDRs given in sequence SEQ ID NO: l for CDR-Ll, SEQ ID NO:2 for CDR-L2, SEQ ID NO:3 for CDR-L3, SEQ ID NO:4 for CDR-H1, SEQ ID NO: 5 for CDR-H2 and SEQ ID NO: 6 for CDR-H3, for example with affinity of ⁇ or less, in particular wherein the antibody cross-blocks the binding by binding the same epitope as the antibody which it blocks.
  • the antibody has a heavy chain comprising the sequence given in SEQ ID NO: 27 and a light chain comprising the sequence given in SEQ ID NO: 19. Also provided is an anti-CSF-lR antibody or binding fragment thereof, in which the heavy and light chains are at least 80% (preferably 85%, 90%, 95% or 98%) identical or similar to a heavy chain comprising the sequence given in SEQ ID NO: 27 and a light chain comprising the sequence given in SEQ ID NO: 19.
  • the light chain has or consists of the sequence given in SEQ ID NO: 19 and the heavy chain has or consists of the sequence given in SEQ ID NO: 27.
  • the light chain has or consists of the sequence of SEQ ID NO: 19 and the heavy chain has or consists of the sequence of SEQ ID NO: 27, wherein the amino acid lysine at position 453 of SEQ ID NO: 27 is missing or deleted.
  • g2 comprising the heavy chain sequence gH2 (SEQ ID NO: 27) and/or the light chain sequence gL7 (SEQ ID NO: 19).
  • This specific region or epitope of the human CSF-1R polypeptide can be identified by any suitable epitope mapping method known in the art in combination with any one of the antibodies provided by the present disclosure. Examples of such methods include screening peptides of varying lengths derived from CSF-1R for binding to the antibody of the present disclosure with the smallest fragment that can specifically bind to the antibody containing the sequence of the epitope recognized by the antibody (for example a peptide in the region of about 5 to 20, preferably about 7 amino acids in length).
  • the CSF-1R peptides may be produced synthetically or by proteolytic digestion of the CSF-1R polypeptide.
  • Peptides that bind the antibody can be identified by, for example, mass spectrometric analysis.
  • NMR spectroscopy or X-ray crystallography can be used to identify the epitope bound by an antibody of the present disclosure. Once identified, the epitopic fragment, which binds an antibody of the present disclosure, can be used, if required, as an immunogen to obtain additional antibodies, which bind the same epitope.
  • Bio molecules such as antibodies or fragments, contain acidic and/or basic functional groups, thereby giving the molecule a net positive or negative charge.
  • the amount of overall "observed" charge will depend on the absolute amino acid sequence of the entity, the local environment of the charged groups in the 3D structure and the environmental conditions of the molecule.
  • the isoelectric point (pi) is the pH at which a particular molecule or solvent accessible surface thereof carries no net electrical charge.
  • the CSF-1R antibody and fragments of the disclosure may be engineered to have an appropriate isoelectric point. This may lead to antibodies and/or fragments with more robust properties, in particular suitable solubility and/or stability profiles and/or improved purification characteristics.
  • the disclosure provides a humanized CSF-1R antibody engineered to have an isoelectric point different to that of the originally identified antibody.
  • the antibody may, for example be engineered by replacing an amino acid residue such as replacing an acidic amino acid residue with one or more basic amino acid residues.
  • the engineered antibody or fragment has the same or substantially the same activity as the "unmodified" antibody or fragment.
  • a "chimeric antibody” is an antibody molecule in which (a) the constant region, or a portion thereof, is altered, replaced or exchanged so that the antigen binding site (variable region) is linked to a constant region of a different or altered class, effector function and/or species, or an entirely different molecule which confers new properties to the chimeric antibody, e.g. , an enzyme, toxin, hormone, growth factor, drug, etc.; or (b) the variable region, or a portion thereof, is altered, replaced or exchanged with a variable region having a different or altered antigen specificity.
  • the preferred antibodies of, and for use according to the disclosure include humanized and/or chimeric monoclonal antibodies.
  • the antibody of the present disclosure may be conjugated to one or more effector molecule(s).
  • the effector molecule may comprise a single effector molecule or two or more such molecules so linked as to form a single moiety that can be attached to the antibodies of the present disclosure.
  • this may be prepared by standard chemical or recombinant DNA procedures in which the antibody fragment is linked either directly or via a coupling agent to the effector molecule.
  • Techniques for conjugating such effector molecules to antibodies are well known in the art (see, Hellstrom et al., Controlled Drug Delivery, 2nd Ed., Robinson et al., eds., 1987, pp.
  • the linkage may be achieved using recombinant DNA procedures, for example as described in WO86/01533 and EP0392745.
  • effector molecule includes, for example, antineoplastic agents, drugs, toxins, biologically active proteins, for example enzymes, other antibody or antibody fragments, synthetic or naturally occurring polymers, nucleic acids and fragments thereof e.g. DNA, RNA and fragments thereof, radionuclides, particularly radioiodide, radioisotopes, chelated metals, nanoparticles and reporter groups, such as fluorescent compounds or compounds which may be detected by NMR or ESR spectroscopy.
  • antineoplastic agents for example enzymes, other antibody or antibody fragments, synthetic or naturally occurring polymers
  • nucleic acids and fragments thereof e.g. DNA, RNA and fragments thereof
  • radionuclides particularly radioiodide, radioisotopes, chelated metals, nanoparticles and reporter groups, such as fluorescent compounds or compounds which may be detected by NMR or ESR spectroscopy.
  • Effector molecules also include, but are not limited to, antimetabolites (e.g.
  • methotrexate 6-mercaptopurine, 6-thioguanine, cytarabine, 5-fluorouracil, dacarbazine
  • alkylating agents e.g. mechlorethamine, thiotepa, chlorambucil, melphalan, carmustine (BSNU) and lomustine (CCNU)
  • cyclophosphamide busulfan, dibromomannitol
  • anthracyclines e.g. daunorubicin (formerly daunomycin) and doxorubicin
  • antibiotics e.g. dactinomycin (formerly actinomycin)
  • bleomycin bleomycin
  • mithramycin anthramycin
  • AMC anthramycin
  • calicheamicins or duocarmycins e.g. vincristine and vinblastine
  • effector molecules include proteins, peptides and enzymes.
  • Enzymes of interest include, but are not limited to, proteolytic enzymes, hydrolases, lyases, isomerases, transferases.
  • Proteins, polypeptides and peptides of interest include, but are not limited to, immunoglobulins, toxins such as abrin, ricin A, pseudomonas exotoxin, or diphtheria toxin, a protein such as insulin, tumor necrosis factor, a-interferon, ⁇ -interferon, nerve growth factor, platelet derived growth factor or tissue plasminogen activator, a thrombotic agent or an anti- angiogenic agent, e.g. angiostatin or endostatin, or, a biological response modifier such as a lymphokine, interleukin-1 (IL-1), interleukin-2 (IL-2), nerve growth factor (NGF) or other growth factor and immunoglobulins.
  • IL-1 interleukin-1
  • the effector molecule may increase the half-life of the antibody in vivo, and/or reduce immunogenicity of the antibody 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, and albumin binding proteins or albumin binding compounds such as those described in WO05/117984.
  • the half-life provided by an effector molecule, which is independent of CSF-1R, is advantageous.
  • a purified anti-CSF-lR antibody or fragment for example a humanized antibody or fragment, in particular an antibody or fragment disclosed herein, in substantially purified from, in particular free or substantially free of endotoxin and/or host cell protein or DNA.
  • Purified form as used supra is intended to refer to at least 90% purity, such as 91, 92, 93, 94, 95, 96, 97, 98, 99% w/w or more pure.
  • Substantially free of endotoxin is generally intended to refer to an endotoxin content of 1 EU per mg antibody product or less such as 0.5 or 0.1 EU per mg product.
  • Substantially free of host cell protein or DNA is generally intended to refer to host cell protein and/or DNA content 400 ⁇ g per mg of antibody product or less such as 100 ⁇ g per mg or less, in particular 20 ⁇ g per mg, as appropriate.
  • CDR-L1 LASEDIYDNLA(SEQ ID NO: l)
  • CDRL2 YASSLQD (SEQ ID NO:2)
  • CDR-L3 LQDSEYPWT (SEQ ID NO:3)
  • CDR-H1 GFSLTTYGMGVG (SEQ ID NO:4)
  • CDR-H2 NIWWDDDKYYNPSLKN (SEQ ID NO:5)
  • CDR-H3 IGPIKYPTAPYRYFDF (SEQ ID NO:6)
  • Rat Ab 969 VL region with signal sequence underlined and italicized MGVPTQLL VL LLLWITDAIC DIQMTQSPAS LSASLGETVS IECLASEDIY DNLAWYQKKP GKSPHLLIYY ASSLQDGVPS RFSGSGSGTQ YSLKINSLES EDAATYFCLQ DSEYPWTFGG GTKLELK (SEQ ID NO:9)
  • Rat Ab 969 VH region with signal sequence underlined and italicized MDRL TSSFLL LIVPAYVLSQ VTLKESGPGI LQPSQTLSLT CTFSGFSLTT YGMGVGWIRQ PS GKGLEWLA NIWWDDDKYY NPSLKNRLTI SKDTSNNQAF LKLTNVHTSD SATYYCARIG PIKYPTAPYR YFDFWGPGTM VTVS (SEQ ID NO: 13)
  • gaagtgacac tcaaggagtc tggacccgct ctggtgaac caacccaaac actcactttg acatgtactt ttagtggctt ctcattgact acctatggaa tgggcgtggg atggatcaga cagccacctg gcaaggctct ggaatggctg gccaacatct ggtgggatga cgacaagtac tataacccgt ccctgaaaaaa ccggctgacc attagcaagg atacttctaa aaatcaagtg gtgetgacca tgacaaatat ggatcccgtt gacaccgcaa cctactactg cgcccgcatt ggtcccataaagtaccctac ggcacccaccgca
  • Human VK1 2-l-(l) 012 JK4 acceptor framework DIQMTQSPSS LSASVGDRVT ITCRASQSIS SYLNWYQQKP GKAPKLLIYA ASSLQSGVPS RFSGSGSGTD FTLTISSLQP EDFATYYCQQ SYSTPLTFGG GTKVEIK (SEQ ID NO: 31)
  • Human VH2 3-1 2-70 JH3 acceptor framework QVTLKESGPA LVKPTQTLTL TCTFSGFSLS TSGMRVSWIR QPPGKALEWL ARIDWDDDKF YSTSLKTRLT ISKDTSKNQV VLTMTNMDPV DTATYYCARI AFDIWGQGTM VTVS (SEQ ID NO: 33)
  • Human VH2 3-1 2-70 JH3 acceptor framework caggtcacct tgaaggagtc tggtcctgcg ctggtgaaac ccacacagac cctcacactg acctgcacct tctctgggtt ctcactcagc actagtggaa tgcgtgtgag ctggatccgt cagccccag ggaaggccct ggagtggctt gcacgcattg at
  • the present disclosure also provides, an antibody and antigen-binding fragment thereof that specifically binds to a CSF-1, preferably human CSF-1, and that functions to inhibit CSF- 1.
  • CSF-1 expression correlates with poor diagnosis and tumor progression in many cancer types. Increased level of CSF-1 is associated with increased levels of tumor-associated macrophages, which are a major factor of tumor stroma and poor disease prognosis.
  • the anti-CSF-1 antibody or antigen fragment thereof inhibits the activity of CSF-1.
  • the anti- CSF-1 antibody inhibits the binding of a CSF-1 to c- fms receptor and blocks or prevents activation of c-fms.
  • the anti-CSF-1 antibody or antigen binding fragment thereof is a humanized and/or human anti-CSF-1 antibody or fragment thereof.
  • human anti- CSF-1 antibodies are produced by immunizing a non-human transgenic animal, e.g., a rodent, whose genome comprises human immunoglobulin genes so that the rodent produces human antibodies.
  • Antibodies to CSF-1 are known in the art. Antibodies that preferably inhibit CSF-1 activity include those disclosed in US8652469 B2 and WO2013068902, the contents of each of which are hereby incorporated by reference in their entireties. For example, antibodies that inhibit CSF-1 include MCS110.
  • the anti-CSF-1 antibody or antigen binding fragment thereof comprises a binding affinity for human CSF-1 of 100 pM or less, or 10 pM or less. In some embodiments, the anti-CSF-1 antibody or antigen binding fragment thereof is administered at a dose ranging between about 0.1 mg/kg and about 30 mg/kg.
  • Any antibody e.g. , an anti-CSF-lR antibody or anti-CSF-1 antibody or antigen binding fragment thereof) disclosed herein can be used for the compositions or combination therapy of the disclosure.
  • a pharmaceutical composition of the disclosure comprises an anti-CSF-lR antibody or anti-CSF-1 antibody or antigen binding fragment thereof and a pharmaceutically acceptable carrier.
  • the anti-CSF-lR antibody or anti-CSF-1 antibody or antigen binding fragment thereof is suitable for administration as part of a combination therapy with a T-cell engaging therapy.
  • the anti-CSF-1 R antibody or antigen binding fragment thereof is suitable for administration as part of a combination therapy with one or more CAR-T cells (such as a CAR-T cells against CD 19), suitable to be administered together, sequentially, or in alternation.
  • the anti-CSF-lR antibody or anti-CSF-1 antibody or antigen binding fragment thereof is suitable for administration as part of a combination therapy with one or more BiTEs (such as blinatumomab), suitable to be administered together, sequentially, or in alternation.
  • BiTEs such as blinatumomab
  • the disclosure also relates to a combination of a pharmaceutical composition comprising a therapeutically effective amount of an anti-CSF-lR antibody or anti-CSF-1 antibody or antigen binding fragment thereof and a pharmaceutically acceptable carrier and a pharmaceutical composition comprising a therapeutically effective amount of CAR-T cells and a pharmaceutically acceptable carrier.
  • the disclosure also relates to a combination of a pharmaceutical composition comprising a therapeutically effective amount of an anti-CSF-lR antibody or anti-CSF-1 antibody or antigen binding fragment thereof and a pharmaceutically acceptable carrier and a pharmaceutical composition comprising a therapeutically effective amount of BiTEs and a pharmaceutically acceptable carrier.
  • the anti-CSF-lR antibody or anti-CSF-1 antibody or antigen binding fragment thereof and the T-cell engaging therapy are formulated into a single therapeutic composition, and the anti-CSF-lR antibody or anti-CSF-1 antibody or antigen binding fragment thereof and the T-cell engaging therapy (e.g., a CAR-T or BiTE) are administered simultaneously.
  • the anti-CSF-lR antibody or anti-CSF-1 antibody or antigen binding fragment thereof and the T-cell engaging therapy are separate from each other, e.g., each is formulated into a separate therapeutic composition, and the anti- CSF-1R antibody or anti-CSF-1 antibody or antigen binding fragment thereof and the T-cell engaging therapy (e.g., a CAR-T or BiTE) are administered simultaneously, or the anti-CSF- 1R antibody or anti-CSF-1 antibody or antigen binding fragment thereof and the T-cell engaging therapy comprising a CAR-T and/or BiTE are administered at different times during a treatment regimen.
  • the T-cell engaging therapy e.g., a CAR-T or BiTE
  • the anti-CSF-lR antibody or anti-CSF-1 antibody or antigen binding fragment thereof is administered prior to or concurrently with the administration of the T-cell engaging therapy (e.g., a CAR-T or BiTE), e.g., to treat cancer while preventing cytokine release symptoms (CRS).
  • the anti-CSF-lR antibody or anti-CSF-1 antibody or antigen binding fragment thereof is administered subsequent to the administration of the T-cell engaging therapy (e.g., a CAR-T or BiTE), e.g., to treat cancer and CRS.
  • the anti-CSF-lR antibody or anti-CSF-1 antibody or antigen binding fragment thereof and the T-cell engaging therapy are administered in an alternating fashion.
  • the anti-CSF-lR antibody or anti-CSF-1 antibody or antigen binding fragment thereof and the T-cell engaging therapy comprising a CAR-T and/or BiTE are administered in single doses or in multiple doses.
  • the combinations described herein are used for treating cancer or a cell proliferative disorder in a subject in need thereof.
  • cell proliferative disorder refers to conditions in which unregulated or abnormal growth, or both, of cells can lead to the development of an unwanted condition or disease, which may or may not be cancerous.
  • Exemplary cell proliferative disorders encompass a variety of conditions wherein cell division is deregulated.
  • Exemplary cell proliferative disorder includes, but are not limited to, neoplasms, benign tumors, malignant tumors, pre-cancerous conditions, in situ tumors, encapsulated tumors, metastatic tumors, liquid tumors, solid tumors, immunological tumors, hematological tumors, cancers, carcinomas, leukemias, lymphomas, sarcomas, and rapidly dividing cells.
  • the term "rapidly dividing cell” as used herein is defined as any cell that divides at a rate that exceeds or is greater than what is expected or observed among neighboring or juxtaposed cells within the same tissue.
  • Exemplary cancers include, but are not limited to, adrenocortical carcinoma, AIDS- related cancers, AIDS-related lymphoma, anal cancer, anorectal cancer, cancer of the anal canal, appendix cancer, childhood cerebellar astrocytoma, childhood cerebral astrocytoma, basal cell carcinoma, skin cancer (non-melanoma), biliary cancer, extrahepatic bile duct cancer, intrahepatic bile duct cancer, bladder cancer, urinary bladder cancer, bone and joint cancer, osteosarcoma and malignant fibrous histiocytoma, brain cancer, brain tumor, brain stem glioma, cerebellar astrocytoma, cerebral astrocytoma/malignant glioma, ependymoma,
  • medulloblastoma supratentorial primitive neuroectodermal tumors, visual pathway and hypothalamic glioma, breast cancer, bronchial adenomas/carcinoids, carcinoid tumor, gastrointestinal, nervous system cancer, nervous system lymphoma, central nervous system cancer, central nervous system lymphoma, cervical cancer, childhood cancers, chronic lymphocytic leukemia, chronic myelogenous leukemia, chronic myeloproliferative disorders, colon cancer, colorectal cancer, cutaneous T-cell lymphoma, lymphoid neoplasm, mycosis fungoides, Sezary Syndrome, endometrial cancer, esophageal cancer, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct cancer, eye cancer, intraocular melanoma,
  • retinoblastoma gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, ovarian germ cell tumor, gestational trophoblastic tumor glioma, head and neck cancer, hepatocellular (liver) cancer, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, ocular cancer, islet cell tumors (endocrine pancreas), Kaposi Sarcoma, kidney cancer, renal cancer, kidney cancer, laryngeal cancer, acute lymphoblastic leukemia, acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, hairy cell leukemia, lip and oral cavity cancer, liver cancer, lung cancer, non-small cell lung cancer, small cell lung cancer, AIDS-related lymphoma, non-Hodgkin lymphoma, primary central nervous system lympho
  • pineoblastoma and supratentorial primitive neuroectodermal tumors pineuitary tumor, plasma cell neoplasm/multiple myeloma, pleuropulmonary blastoma, prostate cancer, rectal cancer, renal pelvis and ureter, transitional cell cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, ewing family of sarcoma tumors, Kaposi Sarcoma, soft tissue sarcoma, uterine cancer, uterine sarcoma, skin cancer (non-melanoma), skin cancer (melanoma), merkel cell skin carcinoma, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, stomach (gastric) cancer, supratentorial primitive neuroectodermal tumors, testicular cancer, throat cancer, thymoma, thymoma and thymic carcinoma, thyroid cancer, transitional cell cancer of the renal pelvis and ureter and other urinar
  • a "cell proliferative disorder of the hematologic system” is a cell proliferative disorder involving cells of the hematologic system.
  • a cell proliferative disorder of the hematologic system can include lymphoma, leukemia, myeloid neoplasms, mast cell neoplasms, myelodysplasia, benign monoclonal gammopathy, lymphomatoid granulomatosis,
  • a cell proliferative disorder of the hematologic system can include hyperplasia, dysplasia, and metaplasia of cells of the hematologic system.
  • compositions or combinations of the present disclosure may be used to treat a cancer selected from the group consisting of a hematologic cancer or a hematologic cell proliferative disorder.
  • a hematologic cancer can include multiple myeloma, lymphoma (including Hodgkin's lymphoma, non-Hodgkin's lymphoma, childhood lymphomas, and lymphomas of lymphocytic and cutaneous origin), leukemia (including childhood leukemia, hairy-cell leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, chronic lymphocytic leukemia, chronic myelocytic leukemia, chronic myelogenous leukemia, and mast cell leukemia), myeloid neoplasms and mast cell neoplasms.
  • lymphoma including Hodgkin's lymphoma, non-Hodgkin's lymphoma, childhood lymphomas, and lymphomas of lymphocytic and cutaneous origin
  • leukemia including childhood leukemia, hairy-cell leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, chronic lymphocy
  • the cancer is acute myeloid leukemia (AML), acute
  • ALL lymphoblastic leukemia
  • CALL chronic lymphoblastic leukemia
  • NHL non-Hodgkin lymphoma
  • MCL mantle cell lymphoma
  • DLBCL diffuse large b-cell lymphoma
  • PFBC primary mediastinal b-cell lymphoma
  • TNF transformed follicular lymphoma
  • the cancer is mesothelioma, pancreatic cancer, glioma, neuroblastoma, ovarian cancer, glioblastoma, myelodysplastic syndromes (MDS), breast cancer, prostate cancer, colorectal cancer, skin cancer, oesophageal cancer, esophageal cancer, gastric cancer, astrocytic cancer, endometrial cancer, cervical cancer, bladder cancer, renal cancer, lung cancer, liver cancer, thyroid cancer, or head and neck cancer.
  • MDS myelodysplastic syndromes
  • treat means to include alleviating or abrogating a disorder, disease, or condition; or one or more of the symptoms associated with the disorder, disease, or condition; or alleviating or eradicating the cause(s) of the disorder, disease, or condition itself.
  • preventing or “prevent” describes reducing or eliminating the onset of the symptoms or complications of the disease, condition or disorder.
  • the term "alleviate” is meant to describe a process by which the severity of a sign or symptom of a disorder is decreased.
  • a sign or symptom can be alleviated without being eliminated.
  • the administration of pharmaceutical compositions disclosed herein leads to the elimination of a sign or symptom, however, elimination is not required.
  • Effective dosages are expected to decrease the severity of a sign or symptom.
  • a sign or symptom of a disorder such as cancer, which can occur in multiple locations, is alleviated if the severity of the cancer is decreased within at least one of multiple locations.
  • Treating cancer can result in a reduction in size of a tumor.
  • a reduction in size of a tumor may also be referred to as "tumor regression".
  • tumor size is reduced by 5% or greater relative to its size prior to treatment; more preferably, tumor size is reduced by 10% or greater; more preferably, reduced by 20% or greater; more preferably, reduced by 30% or greater; more preferably, reduced by 40% or greater; even more preferably, reduced by 50% or greater; and most preferably, reduced by greater than 75% or greater.
  • Size of a tumor may be measured by any reproducible means of measurement. The size of a tumor may be measured as a diameter of the tumor.
  • Treating cancer can result in an increase in average survival time of a population of treated subjects in comparison to a population of untreated subjects.
  • the average survival time is increased by more than 30 days; more preferably, by more than 60 days; more preferably, by more than 90 days; and most preferably, by more than 120 days.
  • An increase in average survival time of a population may be measured by any reproducible means.
  • An increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with an active compound.
  • An increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with the combination of this disclosure comprising anti- CSF-1R antibody or anti-CSF-1 antibody or fragment thereof and the T-cell engaging therapy (e.g., CAR-T or BiTE).
  • the T-cell engaging therapy e.g., CAR-T or BiTE.
  • T-cell engaging therapy e.g., via treating or preventing cytokine release syndrome.
  • cytokines such as IL-10 which are mainly produced by monocytes/macrophages and negatively regulate both innate and cell-mediated immunity by inhibiting activated macrophages (see, Maude et al., Caner J. 2014; 20(2): 119-122). Accordingly, the parallels in both clinical and laboratory findings between CRS and MAS suggest a similar pathophysiology of disease.
  • the disclosure also provides a method of treating or preventing cytokine release syndrome by administering to a subject in need thereof an effective amount of anti-CSF-lR antibody or antigen binding fragment thereof by, e.g., regulating macrophage function through the inhibition of macrophage colony-stimulating factor 1 (CSF-1) with an anti-CSF-lR antibody or antigen-binding fragment thereof.
  • an effective amount of anti-CSF-lR antibody or antigen binding fragment thereof by, e.g., regulating macrophage function through the inhibition of macrophage colony-stimulating factor 1 (CSF-1) with an anti-CSF-lR antibody or antigen-binding fragment thereof.
  • CSF-1 macrophage colony-stimulating factor 1
  • anti-CSF-lR antibody or anti-CSF-1 antibody or antigen binding fragment thereof and a T-cell engaging therapy such as CAR-T and/or BiTE can be formulated, dosed, and administered in a fashion consistent with good medical practice.
  • a "pharmaceutical composition” or “therapeutic composition” is a formulation containing the active ingredient, such as an anti-CSF-lR antibody or anti-CSF-1 antibody or antigen binding fragment thereof, CAR-T cells, or BiTEs disclosed herein in a form suitable for administration to a subject.
  • the pharmaceutical composition is in bulk or in unit dosage form.
  • the unit dosage form is any of a variety of forms, including, for example, a capsule, an IV bag, a tablet, a single pump on an aerosol inhaler or a vial.
  • the quantity of active ingredient e.g.
  • a formulation of the disclosed compound or salt, hydrate, solvate or isomer thereof) in a unit dose of composition is an effective amount and is varied according to the particular treatment involved.
  • One skilled in the art will appreciate that it is sometimes necessary to make routine variations to the dosage depending on the age and condition of the patient.
  • the dosage will also depend on the route of administration. A variety of routes are contemplated, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalational, buccal, sublingual, intrapleural, intrathecal, intranasal, and the like.
  • Dosage forms for the topical or transdermal administration of a compound of this disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that are required.
  • Active ingredient refers to an ingredient with a pharmacological effect, such as a therapeutic effect, at a relevant dose.
  • “Pharmaceutically acceptable carrier” means a carrier that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes excipient that is acceptable for veterinary use as well as human pharmaceutical use.
  • the pharmaceutically acceptable carrier should not itself induce the production of antibodies harmful to the individual receiving the composition and should not be toxic.
  • Suitable carriers may be large, slowly metabolised macromolecules such as proteins, polypeptides, liposomes, polysaccharides, polylactic acids, polygly colic acids, polymeric amino acids, amino acid copolymers and inactive virus particles.
  • salts can be used, for example mineral acid salts, such as hydrochlorides, hydrobromides, phosphates and sulphates, or salts of organic acids, such as acetates, propionates, malonates and benzoates.
  • mineral acid salts such as hydrochlorides, hydrobromides, phosphates and sulphates
  • organic acids such as acetates, propionates, malonates and benzoates.
  • Pharmaceutically acceptable carriers in therapeutic compositions may additionally contain liquids such as water, saline, glycerol and ethanol. Additionally, auxiliary substances, such as wetting or emulsifying agents or pH buffering substances, may be present in such compositions. Such carriers enable the pharmaceutical compositions to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries and suspensions, for ingestion by the patient.
  • Suitable forms for administration include forms suitable for parenteral administration, e.g. by injection or infusion, for example by bolus inj ection or continuous infusion.
  • the product may take the form of a suspension, solution or emulsion in an oily or aqueous vehicle and it may contain formulatory agents, such as suspending, preservative, stabilizing and/or dispersing agents.
  • formulatory agents such as suspending, preservative, stabilizing and/or dispersing agents.
  • the antibody molecule may be in dry form, for reconstitution before use with an appropriate sterile liquid.
  • compositions of the disclosure can be administered directly to the subject.
  • the pH of the final formulation is not similar to the value of the isoelectric point (pi) of the antibody or fragment, for example if the pH of the formulation is 7 then a pi of from 8-9 or above may be appropriate. Whilst not wishing to be bound by theory it is thought that this may ultimately provide a final formulation with improved stability, for example the antibody or fragment remains in solution.
  • the pharmaceutical formulation at a pH in the range of 4.0 to 7.0 comprises: 1 to 200 mg/mL of an antibody according to the present disclosure, 1 to 100 mM of a buffer, 0.001 to 1 % of a surfactant, a) 10 to 500mM of a stabilizer, b) 10 to 500 mM of a stabilizer and 5 to 500 mM of a tonicity agent, or c) 5 to 500 mM of a tonicity agent.
  • compositions of this disclosure may be administered by any number of routes including, but not limited to, oral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, intraventricular, transdermal, transcutaneous (for example, see WO98/20734), subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual, intravaginal or rectal routes. Hyposprays may also be used to administer the pharmaceutical compositions of the disclosure.
  • the therapeutic compositions may be prepared as injectables, either as liquid solutions or suspensions. Solid forms suitable for solution in, or suspension in, liquid vehicles prior to injection may also be prepared.
  • compositions will generally be accomplished by injection, subcutaneously, intraperitoneally, intravenously or intramuscularly, or delivered to the interstitial space of a tissue.
  • the compositions can also be administered into a lesion. Dosage treatment may be a single dose schedule or a multiple dose schedule.
  • the active ingredient in the composition will be an antibody molecule. As such, it will be susceptible to degradation in the gastrointestinal tract. Thus, if the composition is to be administered by a route using the gastrointestinal tract, the composition will need to contain agents which protect the antibody from degradation but which release the antibody once it has been absorbed from the gastrointestinal tract.
  • the formulation is provided as a formulation for topical administrations including inhalation.
  • Suitable inhalable preparations include inhalable powders, metering aerosols containing propellant gases or inhalable solutions free from propellant gases.
  • Inhalable powders according to the disclosure containing the active substance may consist solely of the abovementioned active substances or of a mixture of the abovementioned active substances with physiologically acceptable excipient.
  • These inhalable powders may include monosaccharides (e.g. glucose or arabinose), disaccharides (e.g. lactose, saccharose, and maltose), oligo- and polysaccharides (e.g.
  • dextrans dextrans
  • polyalcohols e.g. sorbitol, mannitol, and xylitol
  • salts e.g. sodium chloride, calcium carbonate
  • Mono- or disaccharides are suitably used, the use of lactose or glucose, particularly but not exclusively in the form of their hydrates.
  • Particles for deposition in the lung require a particle size less than 10 microns, such as 1 -9 microns for example from 0.1 to 5 ⁇ , in particular from 1 to 5 ⁇ .
  • the particle size of the active ingredient (such as the antibody or fragment) is of primary importance.
  • propellent gases which can be used to prepare the inhalable aerosols are known in the art.
  • Suitable propellent gases are selected from among hydrocarbons such as n-propane, n- butane or isobutane and halohydrocarbons such as chlorinated and/or fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane.
  • hydrocarbons such as n-propane, n- butane or isobutane
  • halohydrocarbons such as chlorinated and/or fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane.
  • the abovementioned propellent gases may be used on their own or in mixtures thereof.
  • Particularly suitable propellent gases are halogenated alkane derivatives selected from among TG 11, TG 12, TG 134a and TG227.
  • halogenated alkane derivatives selected from among TG 11, TG 12, TG 134a and TG227.
  • hydrocarbons TG134a (1,1,1,2-tetrafluoroethane) and TG227 (1,1,1,2,3,3,3- heptafluoropropane) and mixtures thereof are particularly suitable.
  • the propellent-gas-containing inhalable aerosols may also contain other ingredients such as cosolvents, stabilizers, surface-active agents (surfactants), antioxidants, lubricants and means for adjusting the pH. All these ingredients are known in the art.
  • the propellant-gas-containing inhalable aerosols according to the disclosure may contain up to 5 % by weight of active substance. Aerosols according to the disclosure contain, for example, 0.002 to 5 % by weight, 0.01 to 3 % by weight, 0.015 to 2 % by weight, 0.1 to 2 % by weight, 0.5 to 2 % by weight or 0.5 to 1 % by weight of active ingredient.
  • topical administrations to the lung may also be by administration of a liquid solution or suspension formulation, for example employing a device such as a nebulizer, for example, a nebulizer connected to a compressor (e.g., the Pari LC-Jet Plus(R) nebulizer connected to a Pari Master(R) compressor manufactured by Pari Respiratory Equipment, Inc., Richmond, Va.).
  • a nebulizer for example, a nebulizer connected to a compressor (e.g., the Pari LC-Jet Plus(R) nebulizer connected to a Pari Master(R) compressor manufactured by Pari Respiratory Equipment, Inc., Richmond, Va.).
  • the antibody of the disclosure can be delivered dispersed in a solvent, e.g., in the form of a solution or a suspension. It can be suspended in an appropriate physiological solution, e.g., saline or other pharmacologically acceptable solvent or a buffered solution.
  • Buffered solutions known in the art may contain 0.05 mg to 0.15 mg disodium edetate, 8.0 mg to 9.0 mg NaCl, 0.15 mg to 0.25 mg polysorbate, 0.25 mg to 0.30 mg anhydrous citric acid, and 0.45 mg to 0.55 mg sodium citrate per 1 ml of water so as to achieve a pH of about 4.0 to 5.0.
  • a suspension can employ, for example, lyophilized antibody.
  • the therapeutic suspensions or solution formulations can also contain one or more excipients.
  • Excipients are well known in the art and include buffers (e.g., citrate buffer, phosphate buffer, acetate buffer and bicarbonate buffer), amino acids, urea, alcohols, ascorbic acid, phospholipids, proteins (e.g., serum albumin), EDTA, sodium chloride, liposomes, mannitol, sorbitol, and glycerol. Solutions or suspensions can be encapsulated in liposomes or biodegradable microspheres.
  • the formulation will generally be provided in a substantially sterile form employing sterile manufacture processes. [0201] This may include production and sterilization by filtration of the buffered
  • solvent/solution used for the formulation aseptic suspension of the antibody in the sterile buffered solvent solution, and dispensing of the formulation into sterile receptacles by methods familiar to those of ordinary skill in the art.
  • Nebulizable formulation according to the present disclosure may be provided, for example, as single dose units (e.g., sealed plastic containers or vials) packed in foil envelopes. Each vial contains a unit dose in a volume, e.g., 2 mL, of solvent/solution buffer.
  • the antibodies disclosed herein may be suitable for delivery via nebulization.
  • the antibody of the present disclosure may be administered by use of gene therapy.
  • DNA sequences encoding the heavy and light chains of the antibody molecule under the control of appropriate DNA components are introduced into a patient such that the antibody chains are expressed from the DNA sequences and assembled in situ.
  • compositions suitably comprise a therapeutically effective amount of the anti-CSF-lR antibody or anti-CSF-1 antibody or antigen binding fragment thereof and/or T-cell engaging therapy comprising a CAR-T and/or BiTE of the present disclosure.
  • therapeutically effective amount refers to an amount of a therapeutic agent needed to treat, ameliorate or prevent a targeted disease or condition, or to exhibit a detectable therapeutic, pharmacological or preventative effect.
  • the therapeutically effective amount can be estimated initially either in cell culture assays, e.g.
  • neoplastic cells or in animal models, usually rats, mice, rabbits, dogs, pigs or primates.
  • the animal model may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans.
  • Therapeutic/prophylactic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g. , ED50 (the dose therapeutically effective in 50% of the population) and LD50 (the dose lethal to 50% of the population).
  • the dose ratio between toxic and therapeutic effects is the therapeutic index, and it can be expressed as the ratio, LD50/ED50.
  • Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The dosage may vary within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration.
  • Dosage and administration are adjusted to provide sufficient levels of the active agent(s) or to maintain the desired effect. Factors which may be taken into account include the severity of the disease state, general health of the subject, age, weight, and gender of the subject, diet, time and frequency of administration, drug interaction(s), reaction sensitivities, and tolerance/response to therapy. Generally, the dose should be sufficient to result in slowing, and preferably regressing, the growth of the tumors and preferably causing complete regression of the cancer. Dosages can range from about 0.01 mg/kg per day to about 10 mg/kg per day.
  • dosages can range from about 0.1 mg/kg, 0.5 mg/kg, 1 mg/kg, 1.5 mg/kg, 3 mg/kg, 5 mg/kg, 6 mg/kg, 7.5 mg/kg, or about 10 mg/kg.
  • the dose will be in the range of about 0.1 mg/day to about 5 mg/kg; about 0.1 mg/day to about 10 mg/kg; about 0.1 mg/day to about 20 mg/kg; about 0.1 mg to about 30 mg/kg; or about 0.1 mg to about 40 mg/kg or about 0.1 mg to about 50 mg/kg or in single, divided, or continuous doses (which dose may be adjusted for the patient's weight in kg, body surface area in m 2 , and age in years).
  • an effective amount of a pharmaceutical agent is that which provides an objectively identifiable improvement as noted by the clinician or other qualified observer. For example, regression of a tumor in a patient may be measured with reference to the diameter of a tumor. Decrease in the diameter of a tumor indicates regression. Regression is also indicated by failure of tumors to reoccur after treatment has stopped.
  • the term "dosage effective manner" refers to amount of an active compound to produce the desired biological effect in a subject or cell.
  • the precise therapeutically effective amount for a human subject will depend upon the severity of the disease state, the general health of the subject, the age, weight and gender of the subject, diet, time and frequency of administration, drug combination(s), reaction sensitivities and tolerance/response to therapy. This amount can be determined by routine experimentation and is within the judgement of the clinician.
  • a therapeutically effective amount of the anti-CSF-lR antibody of this disclosure will be from about 0.01 mg/kg to about 500 mg/kg, for example, about 0.1 mg/kg to about 200 mg/kg (such as about 100 mg/kg), or about 0.1 mg/kg to about 10 mg/kg (such as about 0.1 mg/kg, 0.5 mg/kg, 1 mg/kg, 1.5 mg/kg, 3 mg/kg, 5 mg/kg, 6 mg/kg, 7.5 mg/kg, or about 10 mg/kg).
  • the effective amount of the anti-CSF-lR antibody or antigen binding fragment thereof is about 3 mg/kg or about 6 mg/kg.
  • compositions may be conveniently presented in unit dose forms containing a predetermined amount of an active agent of the disclosure per dose.
  • Therapeutic doses of the antibodies show no apparent or limited toxicology effects in vivo.
  • Long-acting pharmaceutical compositions may be administered every 3 to 4 days, every week, or once every two weeks depending on half-life and clearance rate of the particular formulation.
  • the anti-CSF-lR antibody or anti-CSF-1 antibody or antigen binding fragment thereof is administered at least every other day, every week, every 2 weeks or every month.
  • the pulsed dose e.g., of anti- CSF-1R antibody or fragment thereof
  • the anti-CSF-lR antibody or anti-CSF-1 antibody or antigen binding fragment thereof and T-cell engaging therapy are administered at the same frequency, either simultaneously or sequentially, e.g., every 1 or 2 weeks but the
  • administration of each therapy is separated by at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 8 hours, 10 hours, 12 hours, 14 hours, 16 hours, 18 hours, 20 hours, 24 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or at least 7 days.
  • the anti-CSF-lR antibody or anti-CSF-1 antibody or antigen binding fragment thereof and the T-cell engaging therapy are administered at different frequencies and each independently is administered every day, every other day, every week, every 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, or every 20 weeks, or every month.
  • the frequency of dose will depend on the half-life of the antibody molecule and the duration of its effect. If the antibody molecule has a short half-life (e.g. 2 to 10 hours) it may be necessary to give one or more doses per day. Alternatively, if the antibody molecule has a long half-life (e.g. 2 to 15 days) and/or long lasting pharmacodynamics (PD) profile it may only be necessary to give a dosage once per day, once per week or even once every 1 or 2 months.
  • Half-life as employed herein is intended to refer the duration of the molecule in circulation, for example in serum/plasma.
  • an anti-CSF-lR antibody or anti-CSF-1 antibody or antigen binding fragment thereof and a T-cell engaging therapy are administered in temporal proximity (e.g., the anti-CSF-lR antibody or anti-CSF-1 antibody or antigen binding fragment thereof and a T-cell engaging therapy can be administered simultaneously).
  • the present disclosure provides a method of treating or preventing cancer comprising administering an anti-CSF-lR antibody or anti-CSF-1 antibody or antigen binding fragment thereof and a T-cell engaging therapy in temporal proximity.
  • “temporal proximity” means that administration of one therapeutic agent occurs within a time period before or after the administration of another therapeutic agent, such that the therapeutic effect of the one therapeutic agent overlaps with the therapeutic effect of the another therapeutic agent. In some embodiments, the therapeutic effect of the one therapeutic agent completely overlaps with the therapeutic effect of the other therapeutic agent. In some embodiments, “temporal proximity” means that administration of one therapeutic agent occurs within a time period before or after the administration of another therapeutic agent, such that there is a synergistic effect between the one therapeutic agent and the another therapeutic agent.
  • Temporal proximity may vary according to various factors, including but not limited to, the age, gender, weight, genetic background, medical condition, disease history, and treatment history of the subject to which the therapeutic agents are to be administered; the disease or condition to be treated or ameliorated; the therapeutic outcome to be achieved; the dosage, dosing frequency, and dosing duration of the therapeutic agents; the pharmacokinetics and pharmacodynamics of the therapeutic agents; and the route(s) through which the therapeutic agents are administered.
  • “temporal proximity” means within 15 minutes, within 30 minutes, within an hour, within two hours, within four hours, within six hours, within eight hours, within 12 hours, within 18 hours, within 24 hours, within 36 hours, within 2 days, within 3 days, within 4 days, within 5 days, within 6 days, within a week, within 2 weeks, within 3 weeks, within 4 weeks, with 6 weeks, or within 8 weeks.
  • multiple administration of one therapeutic agent can occur in temporal proximity to a single administration of another therapeutic agent.
  • temporal proximity may change during a treatment cycle or within a dosing regimen.
  • compositions or therapies disclosed herein may be administered individually to a patient or may be administered in combination (e.g. simultaneously, sequentially or separately).
  • Combination therapy is intended to embrace administration of the therapeutic agents disclosed herein in a sequential or simultaneous manner, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents concurrently, or in a substantially simultaneous manner.
  • Simultaneous administration can be accomplished, for example, by administering to the subject a single capsule having a fixed ratio of each therapeutic agent or in multiple, single capsules for each of the therapeutic agents.
  • Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues.
  • the therapeutic agents can be administered by the same route or by different routes.
  • a first therapeutic agent of the combination selected may be administered by intravenous injection while the other therapeutic agents of the combination may be administered orally.
  • all therapeutic agents may be administered orally or all therapeutic agents may be administered by intravenous injection.
  • the sequence in which the therapeutic agents are administered is not narrowly critical.
  • Therapeutic agents may also be administered in alternation.
  • the combinations and methods disclosed herein may further include treatments wherein they supplemented with one or more therapeutic agents or therapies, e.g., radiation therapy, surgery, or anti-cancer agents or chemotherapy.
  • treatments that can be used to supplement the combinations and methods disclosed herein include, but are not limited to, alkylating/DNA-damaging agents (e.g.
  • carboplatin cisplatin
  • antimetabolites e.g. capecitabine, gemcitabine, 5-fluorouracil
  • mitotic inhibitors e.g. paclitaxel, vincristine
  • IL-2 sipuleucel-T
  • talimogene laherparepvec peginterferon alfa-2a
  • antibody ingredients for example epidermal growth factor receptor family (EGFR, HER-2), vascular endothelial growth factor receptors (VEGFR), platelet derived growth factor receptor (PDGFR) antibodies, such as nivolumab, ipilimumab, atezolizumab, elotuzumab, daratumumab, pembrolizumab, ramucirumab, brentuximab, brentuximab vedotin, ofatumumab, denosumab, and combinations thereof), or non-antibody ingredients, such as imatinib, dasatini
  • a "subject in need thereof is a subject suffering from a cell proliferative disorder or having an increased risk of developing such disorder relative to the population at large, or is someone suffering from a cytokine release syndrome (CRS) or at an increased risk of developing CRS relative to the population at large.
  • the subject is a patient who is or is about to be administered with a T-cell engaging therapy.
  • the subject has a cytokine release syndrome when treated with CAR-T.
  • a subject in need thereof can have a precancerous condition.
  • a "subject” includes a mammal.
  • the mammal can be e.g., any mammal, e.g.
  • a human primate, bird, mouse, rat, fowl, dog, cat, cow, horse, goat, camel, sheep or pig.
  • the mammal is a human.
  • a subject in need thereof may have refractory cancer on most recent therapy.
  • Refractory cancer means cancer that does not respond to treatment.
  • the cancer may be resistant at the beginning of treatment or it may become resistant during treatment. Refractory cancer is also called resistant cancer.
  • the subject in need thereof has cancer recurrence following remission on most recent therapy.
  • the subject in need thereof received and failed all known effective therapies for cancer treatment.
  • the subject in need thereof received at least one prior therapy.
  • a subject in need thereof may have a secondary cancer as a result of a previous therapy.
  • Secondary cancer means cancer that arises due to or as a result from previous carcinogenic therapies, such as chemotherapy.
  • the term "antibody” is used according to its commonly known meaning in the art.
  • the antibody molecules of the present disclosure may comprise a complete antibody molecule having full length heavy and light chains or a binding fragment thereof and may be, but are not limited to Fab, modified Fab, Fab', modified Fab', F(ab')2, Fv, single domain antibodies (e.g. VH or VL or VHH), scFv, bi, tri or tetra-valent antibodies, Bis-scFv, diabodies, triabodies, tetrabodies and epitope-binding fragments of any of the above (see for example Holliger and Hudson, 2005, Nature Biotech. 23(9): 1126-1136; Adair and Lawson, 2005, Drug Design Reviews - Online 2(3), 209-217).
  • the methods for creating and manufacturing these antibody fragments are well known in the art (see for example Verma et al, 1998, Journal of
  • Multi-valent antibodies may comprise multiple specificities e.g. bispecific or may be monospecific (see for example W092/22853, WO05/113605, WO2009/040562 and WO2010/035012).
  • Binding fragment of an antibody as employed herein refers to a fragment capable of binding an antigen with affinity to characterize the fragment as specific for the antigen.
  • the antibody according to the present disclosure is provided as CSF-1R binding antibody fusion protein which comprises an immunoglobulin moiety, for example a Fab or Fab' fragment, and one or two single domain antibodies (dAb) linked directly or indirectly thereto, for example as described in WO2009/040562, WO2010/035012, WO2011/030107, WO2011/061492 and WO2011/086091 all incorporated herein by reference.
  • an immunoglobulin moiety for example a Fab or Fab' fragment
  • dAb single domain antibodies
  • the fusion protein comprises two domain antibodies, for example as a variable heavy (VH) and variable light (VL) pairing, optionally linked by a disulfide bond.
  • VH variable heavy
  • VL variable light
  • the Fab or Fab' element of the fusion protein has the same or similar specificity to the single domain antibody or antibodies.
  • the Fab or Fab' has a different specificity to the single domain antibody or antibodies, that is to say the fusion protein is multivalent.
  • a multivalent fusion protein according to the present disclosure has an albumin binding site, for example a VH/VL pair therein provides an albumin binding site.
  • the constant region domains of the antibody molecule of the present disclosure may be selected having regard to the proposed function of the antibody molecule, and in particular the effector functions which may be required.
  • the constant region domains may be human IgA, IgD, IgE, IgG or IgM domains.
  • human IgG constant region domains may be used, especially of the IgGl and IgG3 isotypes when the antibody molecule is intended for therapeutic uses and antibody effector functions are required.
  • IgG2 and IgG4 isotypes may be used when the antibody molecule is intended for therapeutic purposes and antibody effector functions are not required.
  • the term 'humanized antibody refers to an antibody or antibody molecule wherein the heavy and/or light chain contains one or more CDRs (including, if desired, one or more modified CDRs) from a donor antibody (e.g. a murine monoclonal antibody) grafted into a heavy and/or light chain variable region framework of an acceptor antibody (e.g. a human antibody) (see, e.g. US 5,585,089; WO91/09967). For a review, see Vaughan et al, Nature Biotechnology, 16, 535-539, 1998.
  • a donor antibody e.g. a murine monoclonal antibody
  • acceptor antibody e.g. a human antibody
  • only one or more of the specificity determining residues from any one of the CDRs described herein above are transferred to the human antibody framework (see for example, Kashmiri et al., 2005, Methods, 36:25-34).
  • the specificity determining residues from one or more of the CDRs described herein above are transferred to the human antibody framework.
  • only the specificity determining residues from each of the CDRs described herein above are transferred to the human antibody framework.
  • any appropriate, acceptor variable region framework sequence may be used having regard to the class/type of the donor antibody from which the CDRs are derived, including mouse, primate and human framework regions.
  • the terms “approximately” and “about,” as applied to one or more values of interest, refer to a value that is similar to a stated reference value.
  • the term “approximately” or “about” refers to a range of values that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11 %, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1 %, or less in either direction (greater than or less than) of the stated reference value unless otherwise stated or otherwise evident from the context (except where such number would exceed 100% of a possible value).
  • "about” may mean +/- 10% of the recited value.
  • Claims or descriptions that include "or" between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context.
  • the disclosure includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process.
  • the disclosure includes embodiments in which more than one, or all, of the group members are present in, employed in, or otherwise relevant to a given product or process.
  • compositions or combinations are described as having, including, or comprising specific components or steps, it is contemplated that compositions or combinations also consist essentially of, or consist of, the recited components. Similarly, where methods or processes are described as having, including, or comprising specific process steps, the processes also consist essentially of, or consist of, the recited processing steps. Further, it should be understood that the order of steps or order for performing certain actions is immaterial so long as the invention remains operable. Moreover, two or more steps or actions can be conducted simultaneously.

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Abstract

La présente invention concerne une combinaison d'un anticorps anti-CSF-1R ou d'un anticorps anti-CSF-1 ou d'un fragment de liaison à l'antigène de celui-ci et d'une thérapie reposant sur des lymphocytes T, et des procédés d'utilisation de la combinaison pour l'administration à des sujets en ayant besoin pour le traitement du cancer.
PCT/US2018/024618 2017-03-28 2018-03-27 Polythérapies d'anticorps csf-1r ou csf-1 et thérapie reposant sur des lymphocytes t WO2018183366A1 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11623958B2 (en) 2016-05-20 2023-04-11 Harpoon Therapeutics, Inc. Single chain variable fragment CD3 binding proteins
US11807692B2 (en) 2018-09-25 2023-11-07 Harpoon Therapeutics, Inc. DLL3 binding proteins and methods of use
US11976125B2 (en) 2017-10-13 2024-05-07 Harpoon Therapeutics, Inc. B cell maturation antigen binding proteins
WO2024156672A1 (fr) * 2023-01-25 2024-08-02 F. Hoffmann-La Roche Ag Anticorps se liant à csf1r et cd3
US12084518B2 (en) 2015-05-21 2024-09-10 Harpoon Therapeutics, Inc. Trispecific binding proteins and methods of use

Citations (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1986001533A1 (fr) 1984-09-03 1986-03-13 Celltech Limited Production d'anticorps chimeriques
WO1989000195A1 (fr) 1987-07-01 1989-01-12 Novo Industri A/S Procede d'immobilisation de matiere biologique par reticulation avec de la polyazetidine
WO1989001476A1 (fr) 1987-08-12 1989-02-23 Celltech Limited Macrocycles tetra-aza et complexes metalliques de tels macrocycles
EP0392745A2 (fr) 1989-04-05 1990-10-17 Celltech Limited Immunoconjuguées et prodrogues et leurs applications en association pour la délivrance des médicaments
WO1991009967A1 (fr) 1989-12-21 1991-07-11 Celltech Limited Anticorps humanises
WO1992022583A2 (fr) 1991-06-11 1992-12-23 Celltech Limited Proteines monospecifiques tri- et tetravalentes de liaison aux antigenes
WO1992022853A1 (fr) 1991-06-18 1992-12-23 Kodak Limited Appareil de traitement photographique
WO1993006231A1 (fr) 1991-09-26 1993-04-01 Celltech Limited Anticorps humanises diriges contre les globules de matiere grasse du lait humain
US5585089A (en) 1988-12-28 1996-12-17 Protein Design Labs, Inc. Humanized immunoglobulins
WO1998020734A1 (fr) 1996-11-14 1998-05-22 The Government Of The United States Of America, As Represented By The Secretary Of The Army Adjuvant pour immunisation transcutanee
WO2003031581A2 (fr) 2001-10-09 2003-04-17 Nektar Therapeutics Al, Corporation Polymeres hydrosolubles a terminaison thioester, et procede de modification de terminaison n sur un polypeptide faisant appel a ce type de polymere
WO2005003171A2 (fr) 2003-07-01 2005-01-13 Celltech R & D Limited Fragments d'anticorps modifies
WO2005003169A2 (fr) 2003-07-01 2005-01-13 Celltech R & D Limited Fragments d'anticorps fab modifies
WO2005003170A2 (fr) 2003-07-01 2005-01-13 Celltech R & D Limited Fragments d'anticorps modifies
WO2005113605A1 (fr) 2004-05-19 2005-12-01 Celltech R & D Limited Anticorps réticulés
WO2005117984A2 (fr) 2004-06-01 2005-12-15 Celltech R & D Limited Composes liant l'albumine
WO2009026303A1 (fr) 2007-08-21 2009-02-26 Amgen Inc. Protéines de liaison à un antigène de c-fms humain
WO2009040562A1 (fr) 2007-09-26 2009-04-02 Ucb Pharma S.A. Fusions d'anticorps à double spécificité
WO2009112245A1 (fr) 2008-03-14 2009-09-17 Transgene S.A. Anticorps contre le csf-1r
WO2010035012A1 (fr) 2008-09-26 2010-04-01 Ucb Pharma S.A. Produits biologiques
WO2011030107A1 (fr) 2009-09-10 2011-03-17 Ucb Pharma S.A. Anticorps multivalents
WO2011061492A2 (fr) 2009-11-17 2011-05-26 Ucb Pharma S.A. Anticorps multivalents
WO2011070024A1 (fr) 2009-12-10 2011-06-16 F. Hoffmann-La Roche Ag Anticorps se liant de façon préférentielle au domaine extracellulaire 4 de csf1r humain et leur utilisation
WO2011086091A1 (fr) 2010-01-12 2011-07-21 Ucb Pharma S.A. Anticorps multivalents
WO2011107553A1 (fr) 2010-03-05 2011-09-09 F. Hoffmann-La Roche Ag Anticorps dirigés contre le csf-1r humain et utilisations associées
WO2011123381A1 (fr) 2010-04-01 2011-10-06 Imclone Llc Anticorps contre le csf-1r
WO2011131407A1 (fr) 2010-03-05 2011-10-27 F. Hoffmann-La Roche Ag Anticorps contre le csf-1r humain et leurs utilisations
WO2011140249A2 (fr) 2010-05-04 2011-11-10 Five Prime Therapeutics, Inc. Anticorps liant csf1r
WO2013068902A1 (fr) 2011-11-08 2013-05-16 Pfizer Inc. Procédés de traitement de troubles inflammatoires utilisant des anticorps anti-m-csf
WO2013132044A1 (fr) * 2012-03-08 2013-09-12 F. Hoffmann-La Roche Ag Thérapie combinée d'anticorps contre le csf -1r humain et ses utilisations
US8652469B2 (en) 2005-07-28 2014-02-18 Novartis Ag M-CSF-specific monoclonal antibody and uses thereof
WO2015028455A1 (fr) 2013-08-30 2015-03-05 Ucb Biopharma Sprl Anticorps
WO2016168149A1 (fr) * 2015-04-13 2016-10-20 Five Prime Therapeutics, Inc. Polythérapie contre le cancer

Patent Citations (33)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1986001533A1 (fr) 1984-09-03 1986-03-13 Celltech Limited Production d'anticorps chimeriques
WO1989000195A1 (fr) 1987-07-01 1989-01-12 Novo Industri A/S Procede d'immobilisation de matiere biologique par reticulation avec de la polyazetidine
WO1989001476A1 (fr) 1987-08-12 1989-02-23 Celltech Limited Macrocycles tetra-aza et complexes metalliques de tels macrocycles
US5585089A (en) 1988-12-28 1996-12-17 Protein Design Labs, Inc. Humanized immunoglobulins
EP0392745A2 (fr) 1989-04-05 1990-10-17 Celltech Limited Immunoconjuguées et prodrogues et leurs applications en association pour la délivrance des médicaments
WO1991009967A1 (fr) 1989-12-21 1991-07-11 Celltech Limited Anticorps humanises
WO1992022583A2 (fr) 1991-06-11 1992-12-23 Celltech Limited Proteines monospecifiques tri- et tetravalentes de liaison aux antigenes
WO1992022853A1 (fr) 1991-06-18 1992-12-23 Kodak Limited Appareil de traitement photographique
WO1993006231A1 (fr) 1991-09-26 1993-04-01 Celltech Limited Anticorps humanises diriges contre les globules de matiere grasse du lait humain
WO1998020734A1 (fr) 1996-11-14 1998-05-22 The Government Of The United States Of America, As Represented By The Secretary Of The Army Adjuvant pour immunisation transcutanee
WO2003031581A2 (fr) 2001-10-09 2003-04-17 Nektar Therapeutics Al, Corporation Polymeres hydrosolubles a terminaison thioester, et procede de modification de terminaison n sur un polypeptide faisant appel a ce type de polymere
WO2005003171A2 (fr) 2003-07-01 2005-01-13 Celltech R & D Limited Fragments d'anticorps modifies
WO2005003169A2 (fr) 2003-07-01 2005-01-13 Celltech R & D Limited Fragments d'anticorps fab modifies
WO2005003170A2 (fr) 2003-07-01 2005-01-13 Celltech R & D Limited Fragments d'anticorps modifies
WO2005113605A1 (fr) 2004-05-19 2005-12-01 Celltech R & D Limited Anticorps réticulés
WO2005117984A2 (fr) 2004-06-01 2005-12-15 Celltech R & D Limited Composes liant l'albumine
US8652469B2 (en) 2005-07-28 2014-02-18 Novartis Ag M-CSF-specific monoclonal antibody and uses thereof
WO2009026303A1 (fr) 2007-08-21 2009-02-26 Amgen Inc. Protéines de liaison à un antigène de c-fms humain
WO2009040562A1 (fr) 2007-09-26 2009-04-02 Ucb Pharma S.A. Fusions d'anticorps à double spécificité
WO2009112245A1 (fr) 2008-03-14 2009-09-17 Transgene S.A. Anticorps contre le csf-1r
WO2010035012A1 (fr) 2008-09-26 2010-04-01 Ucb Pharma S.A. Produits biologiques
WO2011030107A1 (fr) 2009-09-10 2011-03-17 Ucb Pharma S.A. Anticorps multivalents
WO2011061492A2 (fr) 2009-11-17 2011-05-26 Ucb Pharma S.A. Anticorps multivalents
WO2011070024A1 (fr) 2009-12-10 2011-06-16 F. Hoffmann-La Roche Ag Anticorps se liant de façon préférentielle au domaine extracellulaire 4 de csf1r humain et leur utilisation
WO2011086091A1 (fr) 2010-01-12 2011-07-21 Ucb Pharma S.A. Anticorps multivalents
WO2011107553A1 (fr) 2010-03-05 2011-09-09 F. Hoffmann-La Roche Ag Anticorps dirigés contre le csf-1r humain et utilisations associées
WO2011131407A1 (fr) 2010-03-05 2011-10-27 F. Hoffmann-La Roche Ag Anticorps contre le csf-1r humain et leurs utilisations
WO2011123381A1 (fr) 2010-04-01 2011-10-06 Imclone Llc Anticorps contre le csf-1r
WO2011140249A2 (fr) 2010-05-04 2011-11-10 Five Prime Therapeutics, Inc. Anticorps liant csf1r
WO2013068902A1 (fr) 2011-11-08 2013-05-16 Pfizer Inc. Procédés de traitement de troubles inflammatoires utilisant des anticorps anti-m-csf
WO2013132044A1 (fr) * 2012-03-08 2013-09-12 F. Hoffmann-La Roche Ag Thérapie combinée d'anticorps contre le csf -1r humain et ses utilisations
WO2015028455A1 (fr) 2013-08-30 2015-03-05 Ucb Biopharma Sprl Anticorps
WO2016168149A1 (fr) * 2015-04-13 2016-10-20 Five Prime Therapeutics, Inc. Polythérapie contre le cancer

Non-Patent Citations (27)

* Cited by examiner, † Cited by third party
Title
"Handbook of Experimental Immunology", vol. 4, 1986, BLACKWELL SCIENTIFIC PUBLISHERS
"Remington's Pharmaceutical Sciences", 1991, MACK PUBLISHING COMPANY
ADAIR; LAWSON, DRUG DESIGN REVIEWS - ONLINE, vol. 2, no. 3, 2005, pages 209 - 217
BARRET ET AL., CURR OPIN PEDIATR., vol. 26, no. 1, 2014, pages 43 - 49
CHOTHIA, C.; LESK, A.M., J. MOL. BIOL., vol. 196, 1987, pages 901 - 917
COLE ET AL.: "Monoclonal Antibodies and Cancer Therapy", 1985, ALAN R LISS, INC., pages: 77 - 96
CRAMERI ET AL., NATURE, vol. 391, 1998, pages 288 - 291
DANIEL W LEE ET AL: "T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial", THE LANCET (LETTERS TO THE EDITOR), vol. 385, no. 9967, 1 February 2015 (2015-02-01), GB, pages 517 - 528, XP055388598, ISSN: 0140-6736, DOI: 10.1016/S0140-6736(14)61403-3 *
DUBOWCHIK ET AL., PHARMACOLOGY AND THERAPEUTICS, vol. 83, 1999, pages 67 - 123
HARRIS, RJ., JOURNAL OF CHROMATOGRAPHY, vol. 705, 1995, pages 129 - 134
HELLSTROM ET AL.: "Controlled Drug Delivery", 1987, pages: 623 - 53
HOLLIGER; HUDSON, NATURE BIOTECH., vol. 23, no. 9, 2005, pages 1126 - 1136
KABAT ET AL.: "Sequences of Proteins of Immunological Interest", 1987, US DEPARTMENT OF HEALTH AND HUMAN SERVICES, NIH
KASHMIRI ET AL., METHODS, vol. 36, 2005, pages 25 - 34
KOHLER; MILSTEIN, NATURE, vol. 256, 1975, pages 495 - 497
KOZBOR ET AL., IMMUNOLOGY TODAY, vol. 4, 1983, pages 72
LIN ET AL., SCIENCE, vol. 320, 2008, pages 807 - 811
LOW ET AL., J. MOL. BIOL., vol. 250, 1996, pages 359 - 368
MARKS ET AL., BIO/TECHNOLOGY, vol. 10, 1992, pages 779 - 783
MAUDE ET AL., CANER J., vol. 20, no. 2, 2014, pages 119 - 122
PATTEN ET AL., CURR. OPIN. BIOTECHNOL., vol. 8, 1997, pages 724 - 733
SHERR, C.J. ET AL., BLOOD, vol. 73, 1989, pages 1786 - 1793
THOMPSON ET AL., J. MOL. BIOL., vol. 256, 1996, pages 77 - 88
THORPE ET AL., IMMUNOL. REV., vol. 62, 1982, pages 119 - 58
VAUGHAN ET AL., NATURE BIOTECHNOLOGY, vol. 16, 1998, pages 535 - 539
VERMA ET AL., JOURNAL OF IMMUNOLOGICAL METHODS, vol. 216, 1998, pages 165 - 181
YANG ET AL., J. MOL. BIOL., vol. 254, 1995, pages 392 - 403

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12084518B2 (en) 2015-05-21 2024-09-10 Harpoon Therapeutics, Inc. Trispecific binding proteins and methods of use
US11623958B2 (en) 2016-05-20 2023-04-11 Harpoon Therapeutics, Inc. Single chain variable fragment CD3 binding proteins
US11976125B2 (en) 2017-10-13 2024-05-07 Harpoon Therapeutics, Inc. B cell maturation antigen binding proteins
US11807692B2 (en) 2018-09-25 2023-11-07 Harpoon Therapeutics, Inc. DLL3 binding proteins and methods of use
WO2024156672A1 (fr) * 2023-01-25 2024-08-02 F. Hoffmann-La Roche Ag Anticorps se liant à csf1r et cd3

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