WO2023173091A1 - Récepteur de type ig associé aux ostéoclastes (oscar) et ses méthodes d'utilisation - Google Patents

Récepteur de type ig associé aux ostéoclastes (oscar) et ses méthodes d'utilisation Download PDF

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Publication number
WO2023173091A1
WO2023173091A1 PCT/US2023/064145 US2023064145W WO2023173091A1 WO 2023173091 A1 WO2023173091 A1 WO 2023173091A1 US 2023064145 W US2023064145 W US 2023064145W WO 2023173091 A1 WO2023173091 A1 WO 2023173091A1
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seq
amino acid
acid sequence
cdr2
cdr3
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PCT/US2023/064145
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English (en)
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Jiawei Huang
Jeong Kim
Betty Chan LI
Lee Benjamin RIVERA
Igor MIKAELIAN
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Ngm Biopharmaceuticals, Inc.
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Publication of WO2023173091A1 publication Critical patent/WO2023173091A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—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
    • 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
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57484—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites
    • G01N33/57492—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites involving compounds localized on the membrane of tumor or cancer cells
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • the immune system is a highly complex system made up of a great number of cell types, including but not limited to, T-cells, B-cells, natural killer (NK) cells, antigen-presenting cells (APCs), dendritic cells, monocytes, and macrophages. These cells possess complex and subtle systems for controlling their interactions and responses.
  • the cells utilize both activating and inhibitory mechanisms and feedback loops to keep responses in check and not allow negative consequences of an uncontrolled immune response (e.g., autoimmune diseases or a cytokine storm).
  • Some of the inhibitory mechanisms of the immune system rely on signaling proteins that contain ITIMs (i.e., immunoreceptor tyrosine-based inhibitory motifs).
  • ITIMs are generally cell-surface receptors comprising the ITIMs in their cytoplasmic tails.
  • the majority of cells in the immune system express at least one, and often many, inhibitory receptors.
  • Inhibitory receptors (i) use specific intracellular effector pathways that affect a variety of activation signals, (ii) recognize distinct ligands across a range of locations cells and tissues, and (iii) are differentially expressed between cell types and during differentiation and activation of cells. This allows these receptors to have an important part in a myriad of immune responses throughout the body.
  • LILRBl leukocyte immunoglobulin-like receptor subfamily B members
  • LAIR1 leukocyte-associated immunoglobulin-like receptor-1
  • LAIR-2 leukocyte-associated immunoglobulin-like receptor-1
  • New cancer/tumor immunotherapy focuses on the development of new and novel agents that can activate and/or boost the immune system to achieve a more effective attack against cancer/tumor cells resulting in increased killing of cancer/tumor cells and/or inhibition of cancer/tumor growth. Methods for effectively using these agents are still needed in the art. 3.
  • a method of identifying a subject having or suspected of having a cancer or a tumor who is likely or not likely to be responsive to a binding agent comprising: (a) determining the expression level of osteoclast-associated Ig-like receptor (OSCAR) in a sample of the subject; and (b) identifying the subject as likely to be responsive to the binding agent if the expression level of the OSCAR in the sample of the subject is higher than a reference expression level of OSCAR, and identifying the subject as not likely to be responsive to the binding agent if the expression level of the OSCAR in the sample of the subject is not higher than a reference expression level of OSCAR; wherein the binding agent is a leukocyte-associated immunoglobulin-like receptor 1 (LAIR1) binding agent.
  • LAIR1 leukocyte-associated immunoglobulin-like receptor 1
  • the method further comprises obtaining the sample from the subject.
  • a method of predicting the responsiveness of a subject having or suspected of having a cancer or a tumor to a binding agent comprising: (a) determining the expression level of OSCAR in a sample from the subject; and (b) predicting the subject as likely to be responsive to the binding agent if the expression level of the OSCAR in the sample of the subject is higher than a reference expression level of OSCAR; wherein the binding agent is a LAIR1-binding agent.
  • the method further comprises obtaining the sample from the subject.
  • a method of selectively treating a cancer or a tumor comprising administering a therapeutically effective amount of a LAIR1-binding agent to a subject identified as likely to be responsive to the LAIR1-binding agent according to a method comprising: (a) determining the expression level of OSCAR in the sample; and (b) identifying the subject as likely to be responsive to the LAIR1-binding agent if the expression level of the OSCAR in the sample of the subject is higher than a reference expression level of OSCAR.
  • the method further comprises obtaining the sample from the subject.
  • a method of selectively treating a cancer or a tumor in a subject identified to have a higher expression level of OSCAR than a reference expression level of OSCAR comprising administering a therapeutically effective amount of a LAIR1-binding agent to the subject.
  • a method of selectively treating a cancer or a tumor in a subject with a LAIR1-binding agent comprising: (a) determining the expression level of OSCAR in a sample from the subject; (b) identifying the subject as likely to be responsive to the LAIR1-binding agent if the expression level of the OSCAR in the sample of the subject is higher than a reference expression level of OSCAR; and (c) administering a therapeutically effective amount of the LAIR1-binding agent to the subject identified as likely to be responsive to the LAIR1-binding agent.
  • the method further comprises obtaining the sample from the subject.
  • the reference expression level of OSCAR is: (a) a predetermined expression level of OSCAR; (b) an OSCAR expression level in a corresponding normal tissue; (c) an OSCAR expression level measured in a neighboring non-cancerous tissue in the same subject; or (d) an OSCAR expression level in a corresponding tissue measured in a cohort of healthy subjects.
  • the expression level of OSCAR is the mRNA expression level of OSCAR.
  • the mRNA expression level of OSCAR is determined by quantitative reverse-transcriptase PCR (RT-qPCR), microarray, Northern blot or RNA sequencing.
  • the expression level of OSCAR is the protein expression level of OSCAR.
  • the protein expression level of OSCAR is determined by mass spectrometry (MS).
  • MS comprises liquid chromatography- tandem mass spectrometry (LC MS/MS).
  • the protein expression level of OSCAR is determined by an immunoassay.
  • the immunoassay comprises flow cytometry, immunohistochemistry, western blot or enzyme-linked immunosorbent assay (ELISA).
  • the immunoassay comprises detecting OSCAR using an anti- OSCAR antibody.
  • the anti-OSCAR antibody comprises: (i) a VH comprising a VH-CDR1, a VH-CDR2 and a VH-CDR3 from SEQ ID NO:196, and a VL comprising a VL-CDR1, a VL-CDR2 and a VL-CDR3 from SEQ ID NO:197; (ii) a VH comprising a VH-CDR1, a VH-CDR2 and a VH-CDR3 from SEQ ID NO:198, and a VL comprising a VL-CDR1, a VL-CDR2 and a VL-CDR3 from SEQ ID NO:199; (iii) a VH comprising a VH-CDR1, a VH-CDR2 and a VH-CDR3 from SEQ ID NO:200, and a VL comprising a VL-CDR1, a VL-CDR2 and a VL-CDR3
  • the VH comprises the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:154, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:155, and the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:156; and the VL comprises the VL-CDR1 comprising the amino acid sequence of SEQ ID NO:157, the VL- CDR2 comprising the amino acid sequence of SEQ ID NO:158, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO:159; (ii) the VH comprises the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:160, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:161, and the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:162; and the VL comprises the VL-CDR1 comprising the amino acid sequence of SEQ ID NO:163, the VL-CDR2
  • the VH has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:196 and/or the VL has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:197; (2) the VH has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:198 and/or the VL has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:199; (3) the VH has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:200 and/or the VL has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:201; (4) the VH has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:202 and/or the VL has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:203; (5) the VH has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:204 and/or the VL has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:
  • a method of identifying a subject having or suspected of having a cancer or a tumor who is likely or not likely to be responsive to a binding agent comprising: (a) determining the percentage of cells that express both OSCAR and LAIR1 (OSCAR + /LAIR1 + cells) in a sample of the subject; and (b) identifying the subject as likely to be responsive to the binding agent if the percentage of OSCAR + /LAIR1 + cells in the sample of the subject is higher than a reference percentage of OSCAR + /LAIR1 + cells, wherein the binding agent is a LAIR1-binding agent.
  • the method further comprises obtaining the sample from the subject.
  • a method of predicting the responsiveness of a subject having or suspected of having a cancer or a tumor to a binding agent comprising: (a) determining the percentage of cells that express both OSCAR and LAIR1 (OSCAR + /LAIR1 + cells) in a sample of the subject; and (b) predicting the subject as likely to be responsive to the binding agent if the percentage of OSCAR + /LAIR1 + cells in the sample of the subject is higher than a reference percentage OSCAR + /LAIR1 + cells; wherein the binding agent is a (LAIR1) binding agent.
  • the method further comprises obtaining the sample from the subject.
  • a method of selectively treating a cancer or a tumor comprising administering a therapeutically effective amount of a LAIR1-binding agent to a subject identified as likely to be responsive to the LAIR1-binding agent according to a method comprising: (a) determining the percentage of cells that express both OSCAR and LAIR1 (OSCAR + /LAIR1 + cells) in a sample of the subject; and (b) identifying the subject as likely to be responsive to the binding agent if the percentage of OSCAR + /LAIR1 + cells in the sample of the subject is higher than a reference percentage of OSCAR + /LAIR1 + cells.
  • the method further comprises obtaining the sample from the subject.
  • a method of selectively treating a cancer or a tumor in a subject identified to have a higher percentage of cells that express both OSCAR and LAIR1 (OSCAR + /LAIR1 + cells) than a reference percentage of OSCAR + /LAIR1 + cells comprising administering a therapeutically effective amount of a LAIR1-binding agent to the subject.
  • a method of selectively treating a cancer or a tumor in a subject with a LAIR1-binding agent comprising: (a) determining the percentage of cells that express both OSCAR and LAIR1 in a sample of the subject; (b) identifying the subject as likely to be responsive to the LAIR1-binding agent if the percentage of OSCAR + /LAIR1 + cells in the sample of the subject is higher than a reference percentage of OSCAR + /LAIR1 + cells; and (c) administering a therapeutically effective amount of the LAIR1-binding agent to the subject identified as likely to be responsive to the LAIR1-binding agent.
  • the method further comprises obtaining the sample from the subject.
  • the OSCAR + /LAIR1 + cells comprise myeloid cells.
  • the myeloid cells comprise at least one of monocytes, macrophages, neutrophils, and dendritic cells.
  • the monocytes comprise classical monocytes, non- classical monocytes, or a combination thereof.
  • the percentage of OSCAR + /LAIR1 + cells is determined by flow cytometry. [0024] In some embodiments, the flow cytometry comprises detecting OSCAR using an anti-OSCAR antibody.
  • the anti-OSCAR antibody comprises: (i) a VH comprising a VH-CDR1, a VH-CDR2 and a VH-CDR3 from SEQ ID NO:196, and a VL comprising a VL-CDR1, a VL-CDR2 and a VL-CDR3 from SEQ ID NO:197; (ii) a VH comprising a VH-CDR1, a VH-CDR2 and a VH-CDR3 from SEQ ID NO:198, and a VL comprising a VL-CDR1, a VL-CDR2 and a VL-CDR3 from SEQ ID NO:199; (iii) a VH comprising a VH-CDR1, a VH-CDR2 and a VH-CDR3 from SEQ ID NO:200, and a VL comprising a VL-CDR1, a VL-CDR2 and a VL-CDR3
  • the VH comprises the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:154, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:155, and the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:156; and the VL comprises the VL-CDR1 comprising the amino acid sequence of SEQ ID NO:157, the VL- CDR2 comprising the amino acid sequence of SEQ ID NO:158, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO:159; (ii) the VH comprises the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:160, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:161, and the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:162; and the VL comprises the VL-CDR1 comprising the amino acid sequence of SEQ ID NO:163, the VL-CDR2
  • the VH has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:196 and/or the VL has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:197; (2) the VH has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:198 and/or the VL has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:199; (3) the VH has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:200 and/or the VL has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:201; (4) the VH has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:202 and/or the VL has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:203; (5) the VH has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:204 and/or the VL has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:
  • the reference percentage of OSCAR + /LAIR1 + cells is: (a) a predetermined percentage of OSCAR + /LAIR1 + cells; (b) a percentage of OSCAR + /LAIR1 + cells in a corresponding normal tissue; (c) a percentage of OSCAR + /LAIR1 + cells in a neighboring non-cancerous tissue in the same subject; or (d) a percentage of OSCAR + /LAIR1 + cells in a corresponding tissue measured in a cohort of healthy subjects.
  • the subject has never been treated with an anti-cancer therapy. In some embodiments, the subject has previously been treated with at least one anti-cancer therapy.
  • the subject has a relapsed or a refractory cancer or tumor after receiving one or more anti-cancer therapies.
  • the LAIR1-binding agent is an antibody comprising: (a) a heavy chain variable region (VH) comprising a VH-complementarity determining region (CDR)1, a VH-CDR2 and a VH-CDR3 from SEQ ID NO:117, and a light chain variable region (VL) comprising a VL-CDR1, a VL-CDR2 and a VL-CDR3 from SEQ ID NO:118; (b) a VH comprising a VH-CDR1, a VH-CDR2 and a VH-CDR3 from SEQ ID NO:119, and a VL comprising a VL-CDR1, a VL-CDR2 and a VL-CDR3 from SEQ ID NO:120; (c) a VH comprising a VH comprising a VH comprising a
  • the VH comprises the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:25, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:26, and the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:27; and the VL comprises the VL-CDR1 comprising the amino acid sequence of SEQ ID NO:28, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO:29, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO:30; (2) the VH comprises the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:31, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:32, and the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:27; and the VL comprises the VL-CDR1 comprising the amino acid sequence of SEQ ID NO:28, the VL-CDR2 comprising the
  • the VH has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:117 and/or the VL has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:118; (2) the VH has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:119 and/or the VL has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:120; (3) the VH has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:115 and/or the VL has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:116; (4) the VH has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:121 and/or the VL has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:122; (5) the VH has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:123 and/or the VL has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:
  • the LAIR1 antibody further comprises: (a) a heavy chain comprising an amino acid sequence with 80% identity to the sequence of SEQ ID NO:134 and/or a light chain comprising an amino acid sequence with 80% identity to the sequence of SEQ ID NO:136; (b) a heavy chain comprising an amino acid sequence with 80% identity to the sequence of SEQ ID NO:138 and/or a light chain comprising an amino acid sequence with 80% identity to the sequence of SEQ ID NO:140; (c) a heavy chain comprising the amino acid sequence of SEQ ID NO:134 and/or a light chain comprising the amino acid sequence of SEQ ID NO:136; or (d) a heavy chain comprising the amino acid sequence of SEQ ID NO:138 and/or a light chain comprising the amino acid sequence of SEQ ID NO:140.
  • the sample comprises a tumor biopsy.
  • the sample comprises whole blood.
  • the tumor biopsy or whole blood comprises myeloid cells.
  • the myeloid cells comprise at least one of monocytes, macrophages, neutrophils, and dendritic cells.
  • the monocytes comprise classical monocytes, non-classical monocytes, or a combination thereof.
  • the cancer or tumor is osteosarcoma, pancreatic cancer, breast cancer, mesothelioma, gastric cancer, non-small cell lung cancer (NSCLC), cervical and endocervical cancer, biliary duct cancer, squamous cell carcinoma of head and neck (SCCHN), bladder cancer, urothelial cancer, colorectal cancer (CRC), esophageal cancer, ovarian cancer, renal cell carcinoma (RCC), prostate cancer, melanoma or cholangiocarcinoma.
  • NSCLC non-small cell lung cancer
  • SCCHN squamous cell carcinoma of head and neck
  • bladder cancer urothelial cancer
  • CRCC colorectal cancer
  • esophageal cancer ovarian cancer
  • RRCC renal cell carcinoma
  • prostate cancer melanoma or cholangiocarcinoma.
  • kits for identifying a subject having or suspected of having a cancer or a tumor who is likely to be responsive to a LAIR1-binding agent comprising an agent for determining the expression level of OSCAR in a sample of the subject.
  • the kit further comprises an instruction of identifying the subject as likely to be responsive to the LAIR1-binding agent if the expression level of the OSCAR in the sample is higher than a reference expression level of OSCAR, and/or identifying the subject as not likely to be responsive to the LAIR1-binding agent if the expression level of the OSCAR in the sample is not higher as compared to a reference expression level of OSCAR.
  • kits for predicting the responsiveness of a subject having or suspected of having a cancer or a tumor to a LAIR1-binding agent comprising an agent for determining the expression level of OSCAR in a sample of the subject.
  • the kit further comprises an instruction that describes predicting the subject as likely to be responsive to the LAIR1-binding agent if the expression level of the OSCAR in the sample is higher than a reference expression level of OSCAR, and/or predicting the subject as not likely to be responsive to LAIR1-binding agent if the expression level of the OSCAR in the sample is not higher as compared to a reference expression level of OSCAR.
  • the kit further comprises a tool for obtaining a sample from the subject.
  • the kit further comprises an agent for determining a reference expression level of OSCAR.
  • the kit provides a pre-determined level of OSCAR as a reference expression level.
  • a kit for identifying a subject having or suspected of having a cancer or a tumor who is likely to be responsive to a LAIR1-binding agent comprising an agent for determining the percentage of cells that express both OSCAR and LAIR1 (OSCAR + /LAIR1 + cells) in a sample of the subject.
  • the kit further comprises an instruction of identifying the subject as likely to be responsive to the LAIR1-binding agent if the percentage of OSCAR + /LAIR1 + cells in the sample of the subject is higher than a reference percentage of OSCAR+/LAIR1+ cells, or identifying the subject as not likely to be responsive to the LAIR1- binding agent if the percentage of OSCAR + /LAIR1 + cells in the sample of the subject is lower as compared to a reference percentage of OSCAR+/LAIR1+ cells.
  • kits for predicting the responsiveness of a subject having or suspected of having a cancer or a tumor to a LAIR1-binding agent comprising an agent for determining the percentage of cells that express both OSCAR and LAIR1 (OSCAR + /LAIR1 + cells) in a sample of the subject.
  • the kit further comprises an instruction of predicting the subject as likely to be responsive to the LAIR1-binding agent if the percentage of OSCAR + /LAIR1 + cells in the sample of the subject is higher than a reference percentage of OSCAR + /LAIR1 + cells, or predicting the subject as not likely to be responsive to the LAIR1- binding agent if the percentage of OSCAR + /LAIR1 + cells in the sample of the subject is not higher as compared to a reference percentage of OSCAR + /LAIR1 + cells.
  • the kit further comprises a tool for obtaining a sample from the subject.
  • the kit further comprises an agent for determining a reference percentage of OSCAR + /LAIR1 + cells. In some embodiments, the kit provides a pre- determined percentage of OSCAR + /LAIR1 + cells as a reference percentage of OSCAR + /LAIR1 + cells.
  • the present disclosure further provides a binding agent that specifically binds OSCAR, wherein the binding agent comprises: (i) a VH comprising a VH-CDR1, a VH- CDR2 and a VH-CDR3 from SEQ ID NO:196, and a VL comprising a VL-CDR1, a VL- CDR2 and a VL-CDR3 from SEQ ID NO:197; (ii) a VH comprising a VH-CDR1, a VH- CDR2 and a VH-CDR3 from SEQ ID NO:198, and a VL comprising a VL-CDR1, a VL- CDR2 and a VL-CDR3 from SEQ ID NO:199; (iii) a VH comprising a VH-CDR1, a VH- CDR2 and a VH-CDR3 from SEQ ID NO:200, and a VL comprising a VL-CDR1, a
  • the VH comprises the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:154, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:155, and the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:156; and the VL comprises the VL-CDR1 comprising the amino acid sequence of SEQ ID NO:157, the VL- CDR2 comprising the amino acid sequence of SEQ ID NO:158, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO:159; (ii) the VH comprises the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:160, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:161, and the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:162; and the VL comprises the VL-CDR1 comprising the amino acid sequence of SEQ ID NO:163, the VL-CDR2
  • the VH has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:196 and/or the VL has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:197; (2) the VH has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:198 and/or the VL has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:199; (3)the VH has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:200 and/or the VL has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:201; (4) the VH has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:202 and/or the VL has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:203; (5) the VH has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:204 and/or the VL has at least 80% sequence identity to the amino acid sequence of SEQ ID NO:
  • the binding agent is an antibody.
  • the antibody is a monoclonal antibody, a chimeric antibody, a humanized antibody, a bispecific antibody, or a multispecific antibody.
  • the antibody is an IgG1 antibody, an IgG2 antibody, or an IgG4 antibody; optionally wherein the antibody is a human IgG1 antibody, a human IgG2 antibody, or a human IgG4 antibody.
  • the antibody comprises a kappa light chain or a lambda light chain, optionally wherein the antibody comprises a human kappa light chain or a human lambda light chain.
  • the binding agent is an antigen-binding fragment.
  • the antigen-binding fragment is a Fab, Fab′, F(ab′) 2 , Fv, scFv, (scFv) 2 , single chain antibody, dual variable region antibody, diabody, or nanobody.
  • the binding agent comprises a detectable moiety.
  • the detectable moiety is a fluorescent label, a bioluminescent label, a chemiluminescent label, an enzyme, a small molecule, a radioisotope, or colloidal gold.
  • the present disclosure provides a pharmaceutical composition comprising the binding agent disclosed herein, and a pharmaceutically acceptable carrier.
  • the present disclosure provides an isolated polynucleotide or polynucleotides encoding the binding agent disclosed herein.
  • the present disclosure provides a vector or vectors comprising the polynucleotide or polynucleotides disclosed herein.
  • the present disclosure provides an isolated cell comprising the polynucleotide or polynucleotides disclosed herein or the vector or vectors disclosed herein.
  • the present disclosure provides an isolated cell producing the binding agent disclosed herein.
  • the present disclosure provides a method of making the binding agent disclosed herein, comprising: (a) culturing the cell disclosed herein, and (b) isolating the binding agent.
  • the present disclosure provides a method of detecting OSCAR in a biological sample comprising: (a) contacting the biological sample with the binding agent of disclosed herein; and (b) detecting the binding between the binding agent and OSCAR in the sample.
  • the method comprises using flow cytometry, immunohistochemistry (IHC), western blot analysis, or ELISA. 4. BRIEF DESCRIPTION OF THE DRAWINGS [0060]
  • FIG.1A shows an anti-LAIR1 antibody Hz47H1.v4 induced cytokine (e.g., CCL3) release from OCI-AML6 cells in a collagen dependent manner.
  • FIG.1B shows that knockout of OSCAR abolished the anti-LAIR1 antibody Hz47H1.v4 induced cytokine release from OCI- AML6 cells.
  • Anti-KLH antibody was used as a negative control.
  • FIG.2A shows the expression of LAIR1 and OSCAR from primary moDCs in 10 donors assayed by flow cytometry.
  • Anti-KLH antibody was used as a negative control.
  • FIG. 2B shows an estimation of average OSCAR and LAIR1 protein numbers per cell across the 10 donors based on the flow cytometry data from FIG.2A.
  • FIG.3 shows that knockout of OSCAR but not other signaling receptors abolished the anti-LAIR1 antibody induced cytokine secretion from moDCs.
  • Anti-KLH antibody was used as a negative control.
  • moDCs derived from 3 donors were assayed.
  • FIG.4A shows the dose dependent blockage of cytokine secretion in moDCs by anti-OSCAR antibody incubated with 10 ⁇ g/mL of the anti-LAIR1 antibody assayed in collagen I coated plates.
  • FIG.4B shows no effect on cytokine secretion in moDCs when anti-ITGB1 and/or anti-ITGB2 were incubated with 10 ⁇ g/mL of the anti-LAIR1 antibody assayed in collagen I coated plates. ** indicates p ⁇ 0.01.
  • FIG.5A shows induction of cytokine secretion by crosslinking OSCAR to the assay plate.
  • the anti-FC panel indicates coating the assay plates with anti-mouse Fc Fab followed by incubation with mouse anti-OSCAR antibody or control mouse anti-KLH antibody.
  • the collagen I panel indicates coating the assay plates with collagen I. Anti-KLH antibody was used as a control.
  • FIG.5B shows that crosslinking ITGB1 and/or ITGB2 to assay plates failed to induce cytokine, in contrast with crosslinking OSCAR to assay plates. *** indicates p ⁇ 0.001. **** indicates p ⁇ 0.0001.
  • FIGS.6A &6 B show gene expression profiles of moDCs after treatment with anti- KLH antibody, anti-KLH antibody + anti-LAIR1 antibody, or anti-LAIR1 antibody + anti- OSCAR antibody assayed in collagen I coated plates. MoDCs were derived from 3 donors.
  • FIG 6A shows heat map of the gene expression in indicated assay conditions.
  • FIG 6B shows the numbers of upregulated or downregulated genes in indicated assay conditions.
  • FIG.7 shows increased secretion of inflammatory signaling proteins and ECM turnover related proteins from moDCs induced by an anti-LAIR1 antibody in moDCs. The increased secretion of these proteins was suppressed upon OSCAR blockage by an anti-OSCAR antibody.
  • FIG.8A shows 128 genes uncovered in RNAseq that were (1) up-regulated in moDCs upon LAIR1 blockage (i.e., comparing cells treated with an anti-LAIR1 and anti-KLH with cells treated with anti-KLH), (2) down-regulated upon blockage of OSCAR (i.e., comparing cells treated with an anti-LAIR1 and anti-OSCAR with cells treated with anti-LAIR1 and anti-KLH), and (3) not up-regulated upon blockage of both LAIR1 and OSCAR (i.e., comparing cells treated with anti-LAIR1 and anti-OSCAR with cells treated with anti-KLH).
  • FIG.8B shows mapping of the 128 genes to various pathways and networks using Ingenuity Pathway Analysis (IPA).
  • FIG.9 shows the effects of LAIR1 blockage by an anti-LAIR1 antibody and OSCAR blockage by an anti-OSCAR antibody on T cell proliferation in a MLR assay.
  • Figures 10A-10D show LAIR1 and OSCAR expression in immune cells in healthy donors and CPI-treated patients.
  • FIG. 10B depicts distribution of LAIR1 (upper row) or OSCAR (lower row) expressing cells across immune cell clusters. LAIR1 was distributed across all immune cell subsets in both NHD and CPI-treated PBMCs. The distribution of OSCAR was enriched in classical and non-classical monocytes and dendritic cells but was also detected in basophils and plasmacytoid dendritic cells.
  • Figure 10C shows LAIR1 expression level in immune cell subsets from NHD (first bar of each cell type) and CPI-treated patients (second bar of each cell type).
  • DN double negative;
  • NK natural killer,
  • DC dendritic cells,
  • pDCs plasmacytoid dendritic cells,
  • NC monos non-classical monocytes,
  • NKT natural killer T cells,
  • Lineage neg lineage negative cells.
  • Figure 10D shows OSCAR expression level in immune cell subsets NHD (first bar of each cell type) and CPI-treated patients (second bar of each cell type).
  • Figure 11A shows IL1RA secretion in CPI-treated PBMCs from nine cancer patients after treatment with anti-LAIR1 antibody in the presence or absence of anti-OSCAR antibody.
  • the PBMCs were seeded on uncoated (left dark column of each donor) or collagen-coated (right light column of each donor) surfaces as indicated, and treated with 10 ⁇ g/mL of each antibody.
  • Figure 11B shows identification of anti-LAIR1 responders and non-responders using the mean fold change (FC) of the response (i.e., IL1RA secretion) after treatment with anti-LAIR1+anti- KLH versus the response after treatment with anti-KLH alone.
  • FC mean fold change
  • FIG. 11C shows LAIR1 or OSCAR expression level in myeloid cells from the responders (right bar of each cell type) versus the non-responders (left bar of each cell type) prior to the treatment with anti-LAIR1 antibody. Statistical significance was assessed using an unpaired T Test and defined as p ⁇ 0.05.
  • Figure 12A shows OSCAR mRNA expression in various cell lines assayed by in-situ hybridization (ISH). AML6, MV411 and AML3 expressed OSCAR. THP-1 and Her-KI3DL3 did not express OSCAR.
  • Figure 12B shows OSCAR protein expression assayed by immunohistochemistry using an anti-human OSCAR antibody (clone 18D12).
  • Figure 12C shows concordant expression of OSCAR protein (left panel) and mRNA (middle panel) in consecutive sections of human osteosarcoma biopsy. PPIB was used as a control for in-situ hybridization (ISH).
  • Figure 12D shows the expression of OSCAR in normal human tissues by immunohistochemistry using clone 18D12. 5.
  • DETAILED DESCRIPTION [0072] Unless otherwise defined herein, technical and scientific terms used in the present description have the meanings that are commonly understood by those of ordinary skill in the art. Whenever appropriate, terms used in the singular will also include the plural and vice versa.
  • binding agent refers to a molecule that binds a specific antigen or target (e.g., LAIR1).
  • a binding agent may comprise a protein, peptide, nucleic acid, carbohydrate, lipid, or small molecular weight compound.
  • a binding agent comprises a full-length antibody.
  • a binding agent is an antigen- binding fragment of an antibody.
  • a binding agent comprises an alternative protein scaffold or artificial scaffold (e.g., a non-immunoglobulin backbone).
  • a binding agent is a fusion protein comprising an antigen-binding site. In some embodiments, a binding agent is a bispecific or multispecific molecule comprising at least one antigen-binding site.
  • antibody is used herein in the broadest sense and encompasses various antibody structures, including but not limited to, an immunoglobulin molecule that recognizes and binds a target through at least one antigen-binding site, polyclonal antibodies, recombinant antibodies, monoclonal antibodies, chimeric antibodies, humanized antibodies, human antibodies, bispecific antibodies, multispecific antibodies, diabodies, tribodies, tetrabodies, single chain Fv (scFv) antibodies, and antibody fragments as long as they exhibit the desired antigen-binding activity.
  • scFv single chain Fv
  • antibody fragment refers to a molecule other than an intact antibody that comprises a portion of an antibody and generally an antigen-binding site.
  • antibody fragments include, but are not limited to, Fab, Fab′, F(ab′)2, Fv, single chain antibody molecules, scFv, sc(Fv) 2 , disulfide-linked scFv (dsscFv), diabodies, tribodies, tetrabodies, minibodies, dual variable domain antibodies (DVD), single variable domain antibodies (e.g., camelid antibodies), and multispecific antibodies formed from antigen-binding antibody fragments.
  • the term “monoclonal antibody” as used herein refers to a substantially homogenous antibody population involved in the highly specific recognition and binding of a single antigenic determinant or epitope.
  • the term “monoclonal antibody” encompasses intact and full-length antibodies as well as antibody fragments (e.g., Fab, Fab′, F(ab′) 2 , Fv), single chain antibodies, scFv, fusion proteins comprising an antigen-binding antibody fragment, and any other modified immunoglobulin molecule comprising at least one antigen-binding site.
  • “monoclonal antibody” refers to such antibodies made by any number of techniques, including but not limited to, hybridoma production, phage library display, recombinant expression, and transgenic animals.
  • the term “chimeric antibody” refers to an antibody in which a portion of the heavy and/or light chain is derived from a first source or species, while the remainder of the heavy and/or light chain is derived from a different source or species.
  • humanized antibody refers to an antibody that comprises a human heavy chain variable region and a light chain variable region wherein the native CDR amino acid residues are replaced by residues from corresponding CDRs from a non-human antibody (e.g., mouse, rat, rabbit, or non-human primate), wherein the non-human antibody has the desired specificity, affinity, and/or activity.
  • a non-human antibody e.g., mouse, rat, rabbit, or non-human primate
  • one or more framework region amino acid residues of the human heavy chain or light chain variable regions are replaced by corresponding residues from the non-human antibody.
  • humanized antibodies can comprise amino acid residues that are not found in the human antibody or in the non-human antibody. In some embodiments, these modifications are made to further refine and/or optimize antibody characteristics.
  • the humanized antibody comprises at least a portion of a human immunoglobulin constant region (e.g., CH1, CH2, CH3, Fc, and/or hinge region).
  • a human immunoglobulin constant region e.g., CH1, CH2, CH3, Fc, and/or hinge region.
  • human antibody refers to an antibody that possesses an amino acid sequence that corresponds to an antibody produced by a human and/or an antibody that has been made using any of the techniques that are known to those of skill in the art for making human antibodies. These techniques include, but not limited to, phage display libraries, yeast display libraries, transgenic animals, recombinant protein production, and B-cell hybridoma technology.
  • epitopes and “antigenic determinant” are used interchangeably herein and refer to that portion of an antigen or target capable of being recognized and bound by a particular antibody.
  • epitopes can be formed both from contiguous amino acids and noncontiguous amino acids juxtaposed by tertiary folding of the protein.
  • Epitopes formed from contiguous amino acids also referred to as linear epitopes
  • epitopes formed by tertiary folding also referred to as conformational epitopes
  • An epitope typically includes at least 3, and more usually, at least 5, 6, 7, or 8-10 amino acids in a unique spatial conformation. Epitopes can be predicted using any one of a large number of publicly available bioinformatic software tools. X-ray crystallography may be used to characterize an epitope on a target protein by analyzing the amino acid residue interactions of an antigen/antibody complex. [0081]
  • the term “specifically binds” as used herein refers to an agent that interacts more frequently, more rapidly, with greater duration, with greater affinity, or with some combination of the above to a particular antigen, epitope, protein, or target molecule than with alternative substances.
  • a binding agent that specifically binds an antigen can be identified, for example, by immunoassays, ELISAs, surface plasmon resonance (SPR), or other techniques known to those of skill in the art.
  • an agent that specifically binds an antigen e.g., human LAIR1
  • can bind related antigens e.g., cyno LAIR1.
  • a binding agent that specifically binds an antigen will bind the target antigen at a higher affinity than its affinity for a different antigen.
  • the different antigen can be a related antigen.
  • a binding agent that specifically binds an antigen can bind the target antigen with an affinity that is at least 20 times greater, at least 30 times greater, at least 40 times greater, at least 50 times greater, at least 60 times greater, at least 70 times greater, at least 80 times greater, at least 90 times greater, or at least 100 times greater, than its affinity for a different antigen.
  • a binding agent that specifically binds a particular antigen binds a different antigen at such a low affinity that binding cannot be detected using an assay described herein or otherwise known in the art.
  • affinity is measured using SPR technology in a Biacore system as described herein or as known to those of skill in the art.
  • polypeptide and “peptide” and “protein” are used interchangeably herein and refer to polymers of amino acids of any length.
  • the polymer may be linear or branched, it may comprise modified amino acids, and it may be interrupted by non-amino acids.
  • the terms also encompass an amino acid polymer that has been modified naturally or by intervention; for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation or modification.
  • polypeptides containing one or more analogs of an amino acid including but not limited to, unnatural amino acids, as well as other modifications known in the art.
  • polypeptide encompasses polypeptides as a single chain and polypeptides of two or more associated chains.
  • polynucleotide and nucleic acid and nucleic acid molecule are used interchangeably herein and refer to polymers of nucleotides of any length, and include DNA and RNA.
  • the nucleotides can be deoxyribonucleotides, ribonucleotides, modified nucleotides or bases, and/or their analogs, or any substrate that can be incorporated into a polymer by DNA or RNA polymerase.
  • nucleic acids or polypeptides refer to two or more sequences or subsequences that are the same or have a specified percentage of nucleotides or amino acid residues that are the same, when compared and aligned (introducing gaps, if necessary) for maximum correspondence, not considering any conservative amino acid substitutions as part of the sequence identity.
  • the percent identity may be measured using sequence comparison software or algorithms or by visual inspection.
  • Various algorithms and software that may be used to obtain alignments of amino acid or nucleotide sequences are well-known in the art. These include, but are not limited to, BLAST, ALIGN, Megalign, BestFit, GCG Wisconsin Package, and variants thereof.
  • two nucleic acids or polypeptides of the disclosure are substantially identical, meaning they have at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, and in some embodiments at least 95%, 96%, 97%, 98%, 99% nucleotide or amino acid identity, when compared and aligned for maximum correspondence, as measured using a sequence comparison algorithm or by visual inspection.
  • identity exists over a region of the sequences that is at least about 10, at least about 20, at least about 20-40, at least about 40-60, at least about 60-80 nucleotides or amino acids in length, or any integral value there between.
  • identity exists over a longer region than 60-80 nucleotides or amino acids, such as at least about 80-100 nucleotides or amino acids, and in some embodiments the sequences are substantially identical over the full length of the sequences being compared, for example, (i) the coding region of a nucleotide sequence or (ii) an amino acid sequence.
  • conserve amino acid substitution refers to a substitution in which one amino acid residue is replaced with another amino acid residue having a similar side chain.
  • Families of amino acid residues having similar side chains have been generally defined in the art, including basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine).
  • basic side chains e.g., lysine, arginine, histidine
  • acidic side chains e.g., aspartic
  • vector means a construct that is capable of delivering, and usually expressing, one or more gene(s) or sequence(s) of interest in a host cell.
  • vectors include, but are not limited to, viral vectors, naked DNA or RNA expression vectors, plasmid, cosmid, or phage vectors, DNA or RNA expression vectors associated with cationic condensing agents, and DNA or RNA expression vectors encapsulated in liposomes.
  • isolated refers to a polypeptide, soluble protein, antibody, polynucleotide, vector, cell, or composition that is in a form not found in nature.
  • An “isolated” antibody is substantially free of material from the cellular source from which it is derived.
  • isolated polypeptides, soluble proteins, antibodies, polynucleotides, vectors, cells, or compositions are those that have been purified to a degree that they are no longer in a form in which they are found in nature.
  • a polypeptide, soluble protein, antibody, polynucleotide, vector, cell, or composition that is isolated is substantially pure.
  • a polypeptide, soluble protein, antibody, polynucleotide, vector, cell, or composition can be isolated from a natural source (e.g., tissue) or from a source such as an engineered cell line.
  • tissue e.g., tissue
  • substantially pure refers to material that is at least 50% pure (i.e., free from contaminants), at least 90% pure, at least 95% pure, at least 98% pure, or at least 99% pure.
  • subject refers to any animal (e.g., a mammal), including, but not limited to, humans, non-human primates, canines, felines, rabbits, rodents, and the like.
  • pharmaceutically acceptable refers to a substance approved or approvable by a regulatory agency or listed in the U.S. Pharmacopeia, European Pharmacopeia, or other generally recognized pharmacopeia for use in animals, including humans.
  • pharmaceutically acceptable excipient, carrier, or adjuvant or “acceptable pharmaceutical carrier” as used herein refer to an excipient, carrier, or adjuvant that can be administered to a subject, together with at least one therapeutic agent, and that is generally safe, non-toxic, and has no effect on the pharmacological activity of the therapeutic agent.
  • pharmaceutically acceptable excipient or adjuvant to be an inactive ingredient of any formulation or any pharmaceutical composition.
  • pharmaceutical formulation or “pharmaceutical composition” as used herein refers to a preparation that is in such form as to permit the biological activity of the agent to be effective.
  • a pharmaceutical formulation or composition generally comprises additional components, such as a pharmaceutically acceptable excipient, carrier, adjuvant, buffers, etc.
  • an effective amount or “therapeutically effective amount” as used herein refers to the amount of an agent that is sufficient to reduce and/or ameliorate the severity and/or duration of (i) a disease, disorder or condition in a subject, and/or (ii) a symptom in a subject.
  • the term also encompasses an amount of an agent necessary for the (i) reduction or amelioration of the advancement or progression of a given disease, disorder, or condition, (ii) reduction or amelioration of the recurrence, development, or onset of a given disease, disorder, or condition, and/or (iii) the improvement or enhancement of the prophylactic or therapeutic effect(s) of another agent or therapy (e.g., an agent other than the binding agents provided herein).
  • therapeutic effect refers to the effect and/or ability of an agent to reduce and/or ameliorate the severity and/or duration of (i) a disease, disorder, or condition in a subject, and/or (ii) a symptom in a subject.
  • the term also encompasses the ability of an agent to (i) reduce or ameliorate the advancement or progression of a given disease, disorder, or condition, (ii) reduce or ameliorate the recurrence, development, or onset of a given disease, disorder, or condition, and/or (iii) to improve or enhance the prophylactic or therapeutic effect(s) of another agent or therapy (e.g., an agent other than the binding agents provided herein).
  • treat or “treatment” or “treating” or “to treat” or “alleviate” or alleviation” or “alleviating” or “to alleviate” as used herein refers to therapeutic measures that aim to cure, slow down, lessen symptoms of, and/or halt progression of a pathologic condition or disorder. Thus, those in need of treatment include those already with the disorder.
  • prevent or “prevention” or “preventing” as used herein refers to the partial or total inhibition of the development, recurrence, onset, or spread of a disease, disorder, or condition, or a symptom thereof in a subject.
  • the term “immune response” as used herein includes responses from both the innate immune system and the adaptive immune system. It includes both cell-mediated and/or humoral immune responses. It includes both T-cell and B-cell responses, as well as responses from other cells of the immune system such as natural killer (NK) cells, monocytes, macrophages, dendritic cells, etc.
  • NK natural killer
  • the term “a subject suspected of having a cancer or a tumor” can be determined by the presence of certain risk factors that are well known in the art. Such risk factors include, without limitation, a genetic predisposition, a personal disease history, a lifestyle factor, an environmental factor, a diagnostic indicator and the like.
  • the term “responsive” or “responsiveness” when used in reference to any one of the methods provided herein refers to the degree of effectiveness of a binding agent in lessening or decreasing the symptoms of a disease, e.g., a cancer or a tumor.
  • the term “likely” refers to an increase in the probability of an event.
  • the term “likely” when used in reference to any one of the methods provided herein contemplates an increased probability that the cancer or tumor will be lessened or decreased.
  • the term “predict” or “predicting” generally means to determine or tell in advance.
  • predicting when used in reference to any one of the methods provided herein means that the likelihood of the outcome of the method can be determined at the outset, before administration of a binding agent has begun, or before period of administration has progressed substantially.
  • the terms “determining”, “measuring”, “evaluating”, “assessing” and “assaying” are used interchangeably herein to refer to a form of measurement, including determining if an element is present or not. The measurement can be a quantitative and/or qualitative determination. “Determining the expression level of” can include measuring the amount of something present, as well as determining whether it is present or absent.
  • level refers to the amount, accumulation, or concentration of a molecule.
  • the term “level” refers to an absolute amount of a molecule in a sample or to a relative amount of the molecule, determined under steady-state or non-steady-state conditions.
  • the term “reference expression level” refers to a level of a biomarker (e.g., OSCAR) which is of interest for comparative purposes.
  • a reference expression level of OSCAR may be determined in the subject by any one of the methods provided herein.
  • the reference expression level of OSCAR is a predetermined expression level of OSCAR.
  • a predetermined reference expression level of OSCAR can be found in a public database, such as eGTex (gtexportal.org), a public RNA sequence resource for tissue specific gene expression.
  • the reference expression level of OSCAR is the expression level of OSCAR in a corresponding normal tissue. In some embodiments, the reference expression level of OSCAR is the expression level of OSCAR in a corresponding normal tissue in a different subject. In some embodiments, the reference expression level (e.g., mean or median value) of OSCAR is the expression level of OSCAR in a corresponding normal tissue in a cohort of different subjects. In some embodiments, the reference expression level of OSCAR is the expression level of OSCAR measured in a neighboring non-cancerous tissue in the same subject. In some embodiments, the reference expression level of OSCAR is the expression level of OSCAR in a corresponding tissue measured in a healthy subjects.
  • the reference expression level of OSCAR is the expression level of OSCAR in a corresponding normal tissue measured in a healthy subjects.
  • the reference expression level of OSCAR is the expression level (e.g., mean or median value) of OSCAR in a corresponding tissue measured in a cohort of healthy subjects.
  • the term “higher” when used in the context of expression level means that an expression level is higher (e.g., statistically significantly higher) than a reference expression level using an assay (for example, any one of the assays disclosed herein).
  • reference to “about” or “approximately” a value or parameter includes (and describes) embodiments that are directed to that value or parameter. For example, a description referring to “about X” includes description of “X”.
  • the present disclosure is based, in part, on the surprising finding that OSCAR mediates anti-LAIR1 agent induced inflammatory activation in myeloid lineage cells, and thus provides methods of identifying a subject having or suspected of having a cancer or a tumor who is likely to be responsive to an anti-LAIR1 agent based on OSCAR levels (e.g., OSCAR expression levels, or percentage of OSCAR + /LAIR1 + cells).
  • OSCAR levels e.g., OSCAR expression levels, or percentage of OSCAR + /LAIR1 + cells.
  • the present disclosure also provides methods of predicting the responsiveness of a subject having or suspected of having a cancer or a tumor to an anti-LAIR1 agent based on OSCAR levels (e.g., OSCAR expression levels, or percentage of OSCAR + /LAIR1 + cells).
  • OSCAR levels e.g., OSCAR expression levels, or percentage of OSCAR + /LAIR1 + cells.
  • the present disclosure further provides methods of selectively treating a cancer or a tumor with an anti-LAIR1 agent based on OSCAR levels (e.g., OSCAR expression levels, or percentage of OSCAR + /LAIR1 + cells).
  • a method of identifying a subject having or suspected of having a cancer or a tumor who is likely or not likely to be responsive to a binding agent comprising: (a) obtaining a sample from the subject; (b) determining the expression level of OSCAR in the sample; and (c) identifying said subject as likely to be responsive to said binding agent if the expression level of said OSCAR in said sample of said subject is higher than a reference expression level of OSCAR, and identifying said subject as not likely to be responsive to said binding agent if the expression level of said OSCAR in said sample of said subject is not higher than a reference expression level of OSCAR; wherein said binding agent is a LAIR1-binding agent.
  • a method of identifying a subject having or suspected of having a cancer or a tumor who is likely or not likely to be responsive to a binding agent comprising: (a) determining the expression level of OSCAR in a sample from the subject; and (b) identifying said subject as likely to be responsive to said binding agent if the expression level of said OSCAR in said sample of said subject is higher than a reference expression level of OSCAR, and identifying said subject as not likely to be responsive to said binding agent if the expression level of said OSCAR in said sample of said subject is not higher than a reference expression level of OSCAR; wherein said binding agent is a LAIR1-binding agent.
  • the method further comprises obtaining the sample from the subject.
  • the reference expression level of OSCAR can be a pre- determined expression level of OSCAR, for example, an expression level of OSCAR determined based on a database (e.g., eGTex (gtexportal.org)).
  • the reference expression level of OSCAR is determined based on the OSCAR expression level in a subject or a cohort of subjects non-responsive to the treatment with the LAIR1-binding agent (such as the anti-LAIR1 antibodies provided herein).
  • the reference expression level of OSCAR is a minimal expression level of OSCAR required to be responsive to the treatment with a LAIR1-binding agent (such as the anti-LAIR1 antibodies provided herein).
  • the reference expression level of OSCAR is an OSCAR expression level in a corresponding normal tissue.
  • the reference expression level of OSCAR is an OSCAR expression level in a corresponding normal tissue from a subject or a cohort of subjects who are different from the subject from whom the sample is obtained (i.e., a different subject or a cohort of different subjects).
  • the reference expression level of OSCAR is an OSCAR expression level measured in a neighboring non-cancerous tissue in the same subject from whom the sample is obtained.
  • the reference expression level of OSCAR is an OSCAR expression level in a corresponding tissue measured in a cohort of healthy subjects.
  • the reference expression level of OSCAR is the OSCAR expression level measured in a cohort of subjects (e.g., a cohort of different subjects, a cohort of non-responsive subjects to the treatment with the LAIR1-binding agent, a cohort of heathy subjects)
  • the reference expression level of OSCAR is a mean or a median value of the OSCAR expression levels measured in the cohort of subjects.
  • a method of predicting the responsiveness of a subject having or suspected of having a cancer or a tumor to a binding agent comprising: (a) obtaining a sample from said subject; (b) determining the expression level of OSCAR in said sample; and (c) predicting said subject as likely to be responsive to said binding agent if the expression level of said OSCAR in said sample of said subject is higher than a reference expression level of OSCAR; wherein said binding agent is a LAIR1-binding agent.
  • a method of predicting the responsiveness of a subject having or suspected of having a cancer or a tumor to a binding agent comprising: (a) determining the expression level of OSCAR in a sample from the subject; and (b) predicting said subject as likely to be responsive to said binding agent if the expression level of said OSCAR in said sample of said subject is higher than a reference expression level of OSCAR; wherein said binding agent is a LAIR1-binding agent.
  • the method further comprises obtaining the sample from the subject.
  • the reference expression level of OSCAR can be a pre- determined expression level of OSCAR, for example, an expression level of OSCAR determined based on a database (e.g., eGTex (gtexportal.org)). In some embodiments, the reference expression level of OSCAR is determined based on the OSCAR expression level in a subject or a cohort of subjects non-responsive to the treatment with the LAIR1-binding agent (such as the anti-LAIR1 antibodies provided herein). In some embodiments, the reference expression level of OSCAR is a minimal expression level of OSCAR required to be responsive to the treatment with a LAIR1-binding agent (such as the anti-LAIR1 antibodies provided herein).
  • the reference expression level of OSCAR is an OSCAR expression level in a corresponding normal tissue. In other embodiments, the reference expression level of OSCAR is an OSCAR expression level in a corresponding normal tissue from a subject or a cohort of subjects who are different from the subject from whom the sample is obtained (i.e., a different subject or a cohort of different subjects). In other embodiments, the reference expression level of OSCAR is an OSCAR expression level measured in a neighboring non-cancerous tissue in the same subject from whom the sample is obtained. In yet other embodiments, the reference expression level of OSCAR is an OSCAR expression level in a corresponding tissue measured in a cohort of healthy subjects.
  • the reference expression level of OSCAR when the reference expression level of OSCAR is the OSCAR expression level measured in a cohort of subjects (e.g., a cohort of different subjects, a cohort of non-responsive subjects to the treatment with the LAIR1-binding agent, a cohort of heathy subjects), the reference expression level of OSCAR is a mean or a median value of the OSCAR expression levels measured in the cohort of subjects.
  • a method of selectively treating a cancer or a tumor comprising administering a therapeutically effective amount of a LAIR1-binding agent to a subject identified as likely to be responsive to said LAIR1-binding agent according to a method comprising: (a) obtaining a sample from said subject; (b) determining the expression level of OSCAR in said sample; (c) identifying said subject as likely to be responsive to said LAIR1- binding agent if the expression level of said OSCAR in said sample of said subject is higher than a reference expression level of OSCAR.
  • a method of selectively treating a cancer or a tumor comprising administering a therapeutically effective amount of a LAIR1-binding agent to a subject identified as likely to be responsive to said LAIR1-binding agent according to a method comprising: (a) determining the expression level of OSCAR in a sample of the subject; (b) identifying said subject as likely to be responsive to said LAIR1-binding agent if the expression level of said OSCAR in said sample of said subject is higher than a reference expression level of OSCAR.
  • the method further comprises obtaining the sample from the subject.
  • the reference expression level of OSCAR can be a pre- determined expression level of OSCAR, for example, an expression level of OSCAR determined based on a database (e.g., eGTex (gtexportal.org)). In some embodiments, the reference expression level of OSCAR is determined based on the OSCAR expression level in a subject or a cohort of subjects non-responsive to the treatment with the LAIR1-binding agent (such as the anti-LAIR1 antibodies provided herein). In some embodiments, the reference expression level of OSCAR is a minimal expression level of OSCAR required to be responsive to the treatment with a LAIR1-binding agent (such as the anti-LAIR1 antibodies provided herein).
  • the reference expression level of OSCAR is an OSCAR expression level in a corresponding normal tissue. In other embodiments, the reference expression level of OSCAR is an OSCAR expression level in a corresponding normal tissue from a subject or a cohort of subjects who are different from the subject from whom the sample is obtained (i.e., a different subject or a cohort of different subjects). In other embodiments, the reference expression level of OSCAR is an OSCAR expression level measured in a neighboring non-cancerous tissue in the same subject from whom the sample is obtained. In yet other embodiments, the reference expression level of OSCAR is an OSCAR expression level in a corresponding tissue measured in a cohort of healthy subjects.
  • the reference expression level of OSCAR when the reference expression level of OSCAR is the OSCAR expression level measured in a cohort of subjects (e.g., a cohort of different subjects, a cohort of non-responsive subjects to the treatment with the LAIR1-binding agent, a cohort of heathy subjects), the reference expression level of OSCAR is a mean or a median value of the OSCAR expression levels measured in the cohort of subjects.
  • a method of selectively treating a cancer or a tumor in a subject identified to have a higher expression level of OSCAR than a reference expression level of OSCAR the method comprising administering a therapeutically effective amount of a LAIR1-binding agent to said subject.
  • the reference expression level of OSCAR can be a pre-determined expression level of OSCAR, for example, an expression level of OSCAR determined based on a database (e.g., eGTex (gtexportal.org)). In some embodiments, the reference expression level of OSCAR is determined based on the OSCAR expression level in a subject or a cohort of subjects non-responsive to the treatment with the LAIR1-binding agent (such as the anti-LAIR1 antibodies provided herein). In some embodiments, the reference expression level of OSCAR is a minimal expression level of OSCAR required to be responsive to the treatment with a LAIR1-binding agent (such as the anti-LAIR1 antibodies provided herein).
  • the reference expression level of OSCAR is an OSCAR expression level in a corresponding normal tissue. In other embodiments, the reference expression level of OSCAR is an OSCAR expression level in a corresponding normal tissue from a subject or a cohort of subjects who are different from the subject from whom the sample is obtained (i.e., a different subject or a cohort of different subjects). In other embodiments, the reference expression level of OSCAR is an OSCAR expression level measured in a neighboring non-cancerous tissue in the same subject from whom the sample is obtained. In yet other embodiments, the reference expression level of OSCAR is an OSCAR expression level in a corresponding tissue measured in a cohort of healthy subjects.
  • the reference expression level of OSCAR when the reference expression level of OSCAR is the OSCAR expression levels measured in a cohort of subjects (e.g., a cohort of different subjects, a cohort of non-responsive subjects to the treatment with the LAIR1-binding agent, a cohort of heathy subjects), the reference expression level of OSCAR is a mean or a median value of the OSCAR expression levels measured in the cohort of subjects.
  • a method of selectively treating a cancer or a tumor in a subject with a LAIR1-binding agent comprising: (a) obtaining a sample from said subject; (b) determining the expression level of OSCAR in said sample; (c) identifying said subject as likely to be responsive to said LAIR1-binding agent if the expression level of said OSCAR in said sample of said subject is higher than a reference expression level of OSCAR; and (d) administering a therapeutically effective amount of said LAIR1-binding agent to said subject identified as likely to be responsive to said LAIR1-binding agent.
  • a method of selectively treating a cancer or a tumor in a subject with a LAIR1-binding agent comprising: (a) determining the expression level of OSCAR in said sample; (b) identifying said subject as likely to be responsive to said LAIR1- binding agent if the expression level of said OSCAR in said sample of said subject is higher than a reference expression level of OSCAR; and (c) administering a therapeutically effective amount of said LAIR1-binding agent to said subject identified as likely to be responsive to said LAIR1- binding agent.
  • the method further comprises obtaining the sample from the subject.
  • the reference expression level of OSCAR can be a pre- determined expression level of OSCAR, for example, an expression level of OSCAR determined based on a database (e.g., eGTex (gtexportal.org)). In some embodiments, the reference expression level of OSCAR is determined based on the OSCAR expression level in a subject or a cohort of subjects non-responsive to the treatment with the LAIR1-binding agent (such as the anti-LAIR1 antibodies provided herein). In some embodiments, the reference expression level of OSCAR is a minimal expression level of OSCAR required to be responsive to the treatment with a LAIR1-binding agent (such as the anti-LAIR1 antibodies provided herein).
  • the reference expression level of OSCAR is an OSCAR expression level in a corresponding normal tissue. In other embodiments, the reference expression level of OSCAR is an OSCAR expression level in a corresponding normal tissue from a subject or a cohort of subjects who are different from the subject from whom the sample is obtained (i.e., a different subject or a cohort of different subjects). In other embodiments, the reference expression level of OSCAR is an OSCAR expression level measured in a neighboring non-cancerous tissue in the same subject from whom the sample is obtained. In yet other embodiments, the reference expression level of OSCAR is an OSCAR expression level in a corresponding tissue measured in a cohort of healthy subjects.
  • the reference expression level of OSCAR when the reference expression level of OSCAR is the OSCAR expression levels measured in a cohort of subjects (e.g., a cohort of different subjects, a cohort of non-responsive subjects to the treatment with the LAIR1-binding agent, a cohort of heathy subjects), the reference expression level of OSCAR is a mean or a median value of the OSCAR expression levels measured in the cohort of subjects.
  • the expression level of OSCAR in the subject’s sample is higher than the reference expression level of OSCAR, the subject is predicted to be responsive to a binding agent.
  • treatment with a binding agent is effective.
  • higher means that the expression level of OSCAR is higher (e.g., statistically significantly higher) than the reference expression level of OSCAR according to an assay (including those assays disclosed herein).
  • an assay including those assays disclosed herein.
  • Detection and/or quantification of LAIR1 and/or OSCAR may comprise an assay that utilizes a capture agent.
  • the capture agent is a binding agent, an antibody, antibody fragment, or nucleic acid.
  • the expression level of OSCAR is determined by measuring the nucleic acid expression level of OSCAR.
  • Nucleic acid which can also be referred to herein as a gene, polynucleotide, nucleotide sequence, primer, oligonucleotide or probe, refers to natural or modified purine- and pyrimidine-containing polymers of any length, either polyribonucleotides or polydeoxyribonucleotides or mixed polyribo-polydeoxyribo nucleotides and ⁇ -anomeric forms thereof.
  • the two or more purine- and pyrimidine-containing polymers are typically linked by a phosphoester bond or analog thereof.
  • the terms can be used interchangeably to refer to all forms of nucleic acid, including deoxyribonucleic acid (DNA) and ribonucleic acid (RNA).
  • the nucleic acids can be single strand, double, or triplex, linear or circular.
  • DNA can include genomic DNA and cDNA.
  • RNA can be spliced or unspliced mRNA, rRNA, tRNA or antisense.
  • Nucleic acids include naturally occurring, synthetic, as well as nucleotide analogs and derivatives.
  • the nucleic acid expression level of OSCAR can be determined using all currently available methods for measuring nucleic acid expression in the art. In some embodiments, the mRNA expression level of OSCAR is determined, for example, by using quantitative reverse- transcriptase PCR (RT-qPCR), microarray, Northern blot or RNA sequencing.
  • RT-qPCR quantitative reverse- transcriptase PCR
  • the expression level of OSCAR is determined by measuring the protein expression level of OSCAR.
  • Protein which can also be referred to herein as a peptide or polypeptide, refers to natural or modified amino acid polymers of any length. The terms can be used interchangeably to refer to all forms of protein including antibodies, enzymes, contractile proteins, hormonal proteins, structural proteins, storage proteins and transport proteins. Proteins include naturally occurring, synthetic, as well as protein analogs and derivatives.
  • the protein expression level of OSCAR can be determined using all currently available methods for measuring protein expression in the art. For example, in some embodiments, the protein expression level of OSCAR is determined by using an immunoassay.
  • the immunoassay comprises Western blots, enzyme-linked immunosorbent assay (ELISA), flow cytometry, immunoprecipitation, immunohistochemistry, immunofluorescence, radioimmunoassay (RIA), dot blotting, and flow cytometry.
  • ELISA enzyme-linked immunosorbent assay
  • the ELISA is direct ELISA (enzyme-linked immunosorbent assay), indirect ELISA, sandwich ELISA, competitive ELISA, multiplex ELISA, ELISPOT technologies, and other similar techniques known in the art.
  • the immunoassay uses an OSCAR-binding agent (e.g., an anti-OSCAR antibody disclosed in Section 5.5) to detect the protein level of OSCAR in the sample.
  • OSCAR-binding agent e.g., an anti-OSCAR antibody disclosed in Section 5.5
  • the protein expression level of OSCAR is determined by using mass spectrometry (MS).
  • MS comprises liquid chromatography- tandem mass spectrometry (LC MS/MS), liquid chromatography-mass spectrometry (LC-MS), multiple reaction monitoring (MRM), selected reaction monitoring (SRM), affinity-capture MS (AC-MS), matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) MS, MALDI-TOF post-source-decay (PSD), MALDI- TOF/TOF, surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF) MS, electrospray ionization mass spectrometry (ESI-MS), ESI-MS/MS, ESI-MS/(MS)n (n is an integer greater than zero), ESI 3D or linear (2D) ion trap MS, ESI triple quadrupole MS,
  • LC MS/MS liquid chromatography-
  • a method of identifying a subject having or suspected of having a cancer or a tumor who is likely or not likely to be responsive to a binding agent comprising: (a) obtaining a sample from said subject; (b) determining the percentage of cells that express both OSCAR and LAIR1 (OSCAR + /LAIR1 + cells) in said sample; and (c) identifying said subject as likely to be responsive to said binding agent if the percentage of OSCAR + /LAIR1 + cells in said sample of said subject is higher than a reference percentage of OSCAR + /LAIR1 + cells, wherein said binding agent is a LAIR1-binding agent.
  • a method of identifying a subject having or suspected of having a cancer or a tumor who is likely or not likely to be responsive to a binding agent comprising: (a) determining the percentage of cells that express both OSCAR and LAIR1 (OSCAR + /LAIR1 + cells) in a sample of the subject; and (b) identifying said subject as likely to be responsive to said binding agent if the percentage of OSCAR + /LAIR1 + cells in said sample of said subject is higher than a reference percentage of OSCAR + /LAIR1 + cells, wherein said binding agent is a LAIR1-binding agent.
  • the method further comprises obtaining the sample from the subject.
  • the reference percentage of OSCAR + /LAIR1 + cells can be a pre-determined percentage of OSCAR + /LAIR1 + cells, for example, a percentage of OSCAR + /LAIR1 + cells obtained is based on a certain database. In some embodiments, the reference percentage of OSCAR + /LAIR1 + cells is determined based on the percentage of OSCAR + /LAIR1 + cells in a subject or a cohort of subjects non-responsive to the treatment with the LAIR1-binding agent (such as the anti-LAIR1 antibodies provided herein).
  • the reference percentage of OSCAR + /LAIR1 + cells is a minimal percentage of OSCAR + /LAIR1 + cells required to be responsive to the treatment with a LAIR1-binding agent (such as the anti-LAIR1 antibodies provided herein). In other embodiments, the reference percentage of OSCAR + /LAIR1 + cells is a percentage of OSCAR + /LAIR1 + cells in a corresponding normal tissue.
  • the reference percentage of OSCAR + /LAIR1 + cells is a percentage of OSCAR + /LAIR1 + cells in a corresponding normal tissue from a subject or a cohort of subjects who are different from the subject from whom the sample is obtained (i.e., a different subject or a cohort of different subjects).
  • the reference percentage of OSCAR + /LAIR1 + cells is a percentage of OSCAR + /LAIR1 + cells measured in a neighboring non-cancerous tissue in the same subject.
  • the reference percentage of OSCAR + /LAIR1 + cells is a percentage of OSCAR + /LAIR1 + cells in a corresponding tissue measured in a cohort of healthy subjects.
  • the reference percentage of OSCAR + /LAIR1 + cells is the percentage of OSCAR + /LAIR1 + cells measured in a cohort of subjects (e.g., a cohort of different subjects, a cohort of non-responsive subjects to the treatment with the LAIR1-binding agent, a cohort of heathy subjects)
  • the reference percentage of OSCAR + /LAIR1 + cells is a mean or median value of the percentages of OSCAR + /LAIR1 + cells measured in the cohort of subjects.
  • a method of predicting the responsiveness of a subject having or suspected of having a cancer or a tumor to a binding agent comprising: (a) obtaining a sample from said subject; (b) determining the percentage of cells that express both OSCAR and LAIR1 (OSCAR + /LAIR1 + cells) in said sample; and (c) predicting said subject as likely to be responsive to said binding agent if the percentage of OSCAR + /LAIR1 + cells in said sample of said subject is higher than a reference percentage of OSCAR + /LAIR1 + cells; wherein said binding agent is a (LAIR1) binding agent.
  • a method of predicting the responsiveness of a subject having or suspected of having a cancer or a tumor to a binding agent comprising: (a) determining the percentage of cells that express both OSCAR and LAIR1 (OSCAR + /LAIR1 + cells) in a sample of the subject; and (b) predicting said subject as likely to be responsive to said binding agent if the percentage of OSCAR + /LAIR1 + cells in said sample of said subject is higher than a reference percentage of OSCAR + /LAIR1 + cells; wherein said binding agent is a (LAIR1) binding agent.
  • the method further comprises obtaining the sample from the subject.
  • the reference percentage of OSCAR + /LAIR1 + cells can be a pre-determined percentage of OSCAR + /LAIR1 + cells, for example, a percentage of OSCAR + /LAIR1 + cells obtained is based on a certain database. In some embodiments, the reference percentage of OSCAR + /LAIR1 + cells is determined based on the percentage of OSCAR + /LAIR1 + cells in a subject or a cohort of subjects non-responsive to the treatment with the LAIR1-binding agent (such as the anti-LAIR1 antibodies provided herein).
  • the reference percentage of OSCAR + /LAIR1 + cells is a minimal percentage of OSCAR + /LAIR1 + cells required to be responsive to the treatment with a LAIR1-binding agent (such as the anti-LAIR1 antibodies provided herein). In other embodiments, the reference percentage of OSCAR + /LAIR1 + cells is a percentage of OSCAR + /LAIR1 + cells in a corresponding normal tissue.
  • the reference percentage of OSCAR + /LAIR1 + cells is a percentage of OSCAR + /LAIR1 + cells in a corresponding normal tissue from a subject or a cohort of subjects who are different from the subject from whom the sample is obtained (i.e., a different subject or a cohort of different subjects).
  • the reference percentage of OSCAR + /LAIR1 + cells is a percentage of OSCAR + /LAIR1 + cells measured in a neighboring non-cancerous tissue in the same subject.
  • the reference percentage of OSCAR + /LAIR1 + cells is a percentage of OSCAR + /LAIR1 + cells in a corresponding tissue measured in a cohort of healthy subjects.
  • the reference percentage of OSCAR + /LAIR1 + cells is the percentage of OSCAR + /LAIR1 + cells measured in a cohort of subjects (e.g., a cohort of different subjects, a cohort of non-responsive subjects to the treatment with the LAIR1-binding agent, a cohort of heathy subjects)
  • the reference percentage of OSCAR + /LAIR1 + cells is a mean or median value of the percentages of OSCAR + /LAIR1 + cells measured in the cohort of subjects.
  • a method of selectively treating a cancer or a tumor comprising administering a therapeutically effective amount of a LAIR1-binding agent to a subject identified as likely to be responsive to said LAIR1-binding agent according to a method comprising: (a) obtaining a sample from said subject; (b) determining the percentage of cells that express both OSCAR and LAIR1 (OSCAR + /LAIR1 + cells) in said sample; and (c) identifying said subject as likely to be responsive to said binding agent if the percentage of OSCAR + /LAIR1 + cells in said sample of said subject is higher than a reference percentage of OSCAR + /LAIR1 + cells.
  • a method of selectively treating a cancer or a tumor comprising administering a therapeutically effective amount of a LAIR1-binding agent to a subject identified as likely to be responsive to said LAIR1-binding agent according to a method comprising: (a) determining the percentage of cells that express both OSCAR and LAIR1 (OSCAR + /LAIR1 + cells) in a sample of the subject; and (b) identifying said subject as likely to be responsive to said binding agent if the percentage of OSCAR + /LAIR1 + cells in said sample of said subject is higher than a reference percentage of OSCAR + /LAIR1 + cells.
  • the method further comprises obtaining the sample from the subject.
  • the reference percentage of OSCAR + /LAIR1 + cells can be a pre-determined percentage of OSCAR + /LAIR1 + cells, for example, a percentage of OSCAR + /LAIR1 + cells obtained is based on a certain database. In some embodiments, the reference percentage of OSCAR + /LAIR1 + cells is determined based on the percentage of OSCAR + /LAIR1 + cells in a subject or a cohort of subjects non-responsive to the treatment with the LAIR1-binding agent (such as the anti-LAIR1 antibodies provided herein).
  • the reference percentage of OSCAR + /LAIR1 + cells is a minimal percentage of OSCAR + /LAIR1 + cells required to be responsive to the treatment with a LAIR1-binding agent (such as the anti-LAIR1 antibodies provided herein). In other embodiments, the reference percentage of OSCAR + /LAIR1 + cells is a percentage of OSCAR + /LAIR1 + cells in a corresponding normal tissue.
  • the reference percentage of OSCAR + /LAIR1 + cells is a percentage of OSCAR + /LAIR1 + cells in a corresponding normal tissue from a subject or a cohort of subjects who are different from the subject from whom the sample is obtained (i.e., a different subject or a cohort of different subjects).
  • the reference percentage of OSCAR + /LAIR1 + cells is a percentage of OSCAR + /LAIR1 + cells measured in a neighboring non-cancerous tissue in the same subject.
  • the reference percentage of OSCAR + /LAIR1 + cells is a percentage of OSCAR + /LAIR1 + cells in a corresponding tissue measured in a cohort of healthy subjects.
  • the reference percentage of OSCAR + /LAIR1 + cells is the percentage of OSCAR + /LAIR1 + cells measured in a cohort of subjects (e.g., a cohort of different subjects, a cohort of non-responsive subjects to the treatment with the LAIR1-binding agent, a cohort of heathy subjects)
  • the reference percentage of OSCAR + /LAIR1 + cells is a mean or median value of the percentages of OSCAR + /LAIR1 + cells measured in the cohort of subjects.
  • a method of selectively treating a cancer or a tumor in a subject identified to have a higher percentage of cells that express both OSCAR and LAIR1 (OSCAR + /LAIR1 + cells) than a reference percentage of OSCAR + /LAIR1 + cells comprising administering a therapeutically effective amount of a LAIR1-binding agent to the subject.
  • the reference percentage of OSCAR + /LAIR1 + cells can be a pre-determined percentage of OSCAR + /LAIR1 + cells, for example, a percentage of OSCAR + /LAIR1 + cells obtained is based on a certain database.
  • the reference percentage of OSCAR + /LAIR1 + cells is determined based on the percentage of OSCAR + /LAIR1 + cells in a subject or a cohort of subjects non-responsive to the treatment with the LAIR1-binding agent (such as the anti-LAIR1 antibodies provided herein). In some embodiments, the reference percentage of OSCAR + /LAIR1 + cells is a minimal percentage of OSCAR + /LAIR1 + cells required to be responsive to the treatment with a LAIR1-binding agent (such as the anti-LAIR1 antibodies provided herein). In other embodiments, the reference percentage of OSCAR + /LAIR1 + cells is a percentage of OSCAR + /LAIR1 + cells in a corresponding normal tissue.
  • the reference percentage of OSCAR + /LAIR1 + cells is a percentage of OSCAR + /LAIR1 + cells in a corresponding normal tissue from a subject or a cohort of subjects who are different from the subject from whom the sample is obtained (i.e., a different subject or a cohort of different subjects).
  • the reference percentage of OSCAR + /LAIR1 + cells is a percentage of OSCAR + /LAIR1 + cells measured in a neighboring non-cancerous tissue in the same subject.
  • the reference percentage of OSCAR + /LAIR1 + cells is a percentage of OSCAR + /LAIR1 + cells in a corresponding tissue measured in a cohort of healthy subjects.
  • the reference percentage of OSCAR + /LAIR1 + cells is the percentage of OSCAR + /LAIR1 + cells measured in a cohort of subjects (e.g., a cohort of different subjects, a cohort of non-responsive subjects to the treatment with the LAIR1-binding agent, a cohort of heathy subjects)
  • the reference percentage of OSCAR + /LAIR1 + cells is a mean or median value of the percentages of OSCAR + /LAIR1 + cells measured in the cohort of subjects.
  • a method of selectively treating a cancer or a tumor in a subject with a LAIR1-binding agent comprising:(a) obtaining a sample from said subject; (b) determining the percentage of cells that express both OSCAR and LAIR1 in said sample; (c) identifying said subject as likely to be responsive to said LAIR1-binding agent if the percentage of OSCAR + /LAIR1 + cells in said sample of said subject is higher than a reference expression level of OSCAR; and (d) administering a therapeutically effective amount of said LAIR1- binding agent to the subject identified as likely to be responsive to said LAIR1-binding agent.
  • a method of selectively treating a cancer or a tumor in a subject with a LAIR1-binding agent comprising: (a) determining the percentage of cells that express both OSCAR and LAIR1 in said sample; (b) identifying said subject as likely to be responsive to said LAIR1-binding agent if the percentage of OSCAR + /LAIR1 + cells in said sample of said subject is higher than a reference expression level of OSCAR; and (c) administering a therapeutically effective amount of said LAIR1-binding agent to the subject identified as likely to be responsive to said LAIR1-binding agent.
  • the method further comprises obtaining the sample from the subject.
  • the reference percentage of OSCAR + /LAIR1 + cells can be a pre-determined percentage of OSCAR + /LAIR1 + cells, for example, a percentage of OSCAR + /LAIR1 + cells obtained is based on a certain database. In some embodiments, the reference percentage of OSCAR + /LAIR1 + cells is determined based on the percentage of OSCAR + /LAIR1 + cells in a subject or a cohort of subjects non-responsive to the treatment with the LAIR1-binding agent (such as the anti-LAIR1 antibodies provided herein).
  • the reference percentage of OSCAR + /LAIR1 + cells is a minimal percentage of OSCAR + /LAIR1 + cells required to be responsive to the treatment with a LAIR1-binding agent (such as the anti-LAIR1 antibodies provided herein). In other embodiments, the reference percentage of OSCAR + /LAIR1 + cells is a percentage of OSCAR + /LAIR1 + cells in a corresponding normal tissue.
  • the reference percentage of OSCAR + /LAIR1 + cells is a percentage of OSCAR + /LAIR1 + cells in a corresponding normal tissue from a subject or a cohort of subjects who are different from the subject from whom the sample is obtained (i.e., a different subject or a cohort of different subjects).
  • the reference percentage of OSCAR + /LAIR1 + cells is a percentage of OSCAR + /LAIR1 + cells measured in a neighboring non-cancerous tissue in the same subject.
  • the reference percentage of OSCAR + /LAIR1 + cells is a percentage of OSCAR + /LAIR1 + cells in a corresponding tissue measured in a cohort of healthy subjects.
  • the reference percentage of OSCAR + /LAIR1 + cells is the percentage of OSCAR + /LAIR1 + cells measured in a cohort of subjects (e.g., a cohort of different subjects, a cohort of non-responsive subjects to the treatment with the LAIR1-binding agent, a cohort of heathy subjects)
  • the reference percentage of OSCAR + /LAIR1 + cells is a mean or median value of the percentages of OSCAR + /LAIR1 + cells measured in the cohort of subjects.
  • the OSCAR + /LAIR1 + cells comprise myeloid cells.
  • the myeloid cells comprise one or more cell types selected from the group consisting of monocytes, macrophages, neutrophils, and dendritic cells.
  • the sample comprises one or more cell types selected from the group consisting of monocytes, macrophages, neutrophils and dendritic cells.
  • the sample comprises monocytes.
  • the sample comprises classical monocytes.
  • the sample comprises non-classical monocytes.
  • the sample comprises macrophages.
  • the sample comprises neutrophils.
  • the sample comprises dendritic cells.
  • the sample comprises basophils.
  • the sample comprises plasmacytoid dendritic cells.
  • the sample comprises classical monocytes, non-classical monocytes, dendritic cells, or a combination thereof.
  • the percentage of OSCAR + /LAIR1 + cells can be determined by any currently available methods for measuring co-expression of two proteins on cells in the art.
  • the percentage of OSCAR + /LAIR1 + cells is determined by using an immunoassay.
  • the immunoassay comprises flow cytometry or double immunocytochemical labeling.
  • the immunoassay uses an OSCAR- binding agent (e.g., an anti-OSCAR antibody disclosed in Section 5.5) to detect the presence of OSCAR in the sample.
  • the percentage of OSCAR + /LAIR1 + cells in the subject is higher than the reference percentage of OSCAR + /LAIR1 + cells.
  • the subject is identified as likely to be responsive to a binding agent.
  • the methods provided herein further comprise administering the binding agent to the subject identified as likely to be responsive to a binding agent.
  • the methods provided herein further comprise administering the binding agent to the subject identified as likely to be responsive to a binding agent.
  • the percentage of OSCAR + /LAIR1 + cells in the subject’s sample is higher than the reference percentage of OSCAR + /LAIR1 + cells, the subject is predicted to be responsive to a binding agent.
  • the percentage of OSCAR + /LAIR1 + cells in the subject’s sample is higher than the reference percentage of OSCAR + /LAIR1 + cells, treatment with a binding agent is effective.
  • the sample comprises a tumor biopsy.
  • the sample comprises whole blood.
  • the tumor biopsy or whole blood comprises myeloid cells.
  • the myeloid cells comprise one or more cell types selected from the group consisting of monocytes, macrophages, neutrophils and dendritic cells.
  • the sample comprises one or more cell types selected from the group consisting of monocytes, macrophages, neutrophils and dendritic cells.
  • the sample comprises monocytes.
  • the sample comprises classical monocytes.
  • the sample comprises non-classical monocytes.
  • the sample comprises macrophages.
  • the sample comprises neutrophils.
  • the sample comprises dendritic cells. In some embodiments, the sample comprises basophils. In some embodiments, the sample comprises plasmacytoid dendritic cells. In some embodiments, the sample comprises classical monocytes, non-classical monocytes, dendritic cells, or a combination thereof. [00153] In some embodiments, the sample comprises a liquid. In some embodiments, the liquid comprises whole blood. In some embodiments, the sample comprises a solid tissue. In some embodiments, the solid tissue is non-diseased. In some embodiments, the soid tissue is diseased. In some embodiments, the diseased tissue comprises a malignant tumor. In some embodiments, the malignant tumor comprises tumor cells. In some embodiments, the diseased tissue comprises a tumor biopsy.
  • the tumor biopsy comprises myeloid cells.
  • the myeloid cells comprises one or more cell types selected from the group consisting of monocytes, macrophages, neutrophils and dendritic cells.
  • the sample comprises one or more cell types selected from the group consisting of monocytes, macrophages, neutrophils and dendritic cells.
  • the sample comprises monocytes.
  • the sample comprises classical monocytes.
  • the sample comprises non-classical monocytes.
  • the sample comprises macrophages.
  • the sample comprises neutrophils.
  • the sample comprises dendritic cells.
  • the sample comprises basophils.
  • the sample comprises plasmacytoid dendritic cells.
  • the sample comprises classical monocytes, non-classical monocytes, dendritic cells, or a combination thereof.
  • Types of cells in the samples can be identified or isolated using an immunoassay.
  • the immunoassay comprises flow cytometry or double immunocytochemical labeling.
  • a panel of fluorophore-conjugated antibodies are used to recognize the markers of the types of cells, and then the samples are assayed by multi-color spectral flow cytometry.
  • CD4 + T cells are defined as CD45 + CD3 + CD56- CD4 + CD8-.
  • CD8 + T cells are defined as CD45 + CD3 + CD56- CD4- CD8 + .
  • double negative T cells are defined as CD45 + CD3 + CD56- CD4- CD8-.
  • B cells are defined as CD45 + CD3 not CD33- CD19 + .
  • natural killer cells are defined as CD45 + CD3 not CD19 not CD56 + CD14-.
  • plasmacytoid dendritic cells are defined as CD45 + CD3 not CD19 not CD56 not CD123 high HLA-DR + .
  • classical monocytes are defined as CD45 + CD3 not CD19 not CD56 not CD123 low HLA-DR + CD33 high CD14 high .
  • dendritic cells are defined as CD45 + CD3 not CD19 not CD56 not CD123 low HLA-DR + CD33 high CD14 low/neg .
  • non-classical monocytes are defined as CD45 + CD3 not CD19 not CD56 not CD123 low HLA-DR + CD33 low/neg .
  • basophils are defined as CD45 + CD3 not CD19 not CD56 not CD123 high HLA-DR-.
  • natural killer T cells are defined as CD45 + CD3 + CD56 + .
  • lineage negative cells are defined as CD45 + CD3 not CD19 not CD56 not CD123- HLADR-.
  • the sample comprises cells.
  • the cells comprise non-diseased cells.
  • the cells comprise diseased cells.
  • the diseased cells comprise cancer cells.
  • the sample comprises a liquid.
  • the liquid is obtained from a diseased subject.
  • the liquid is obtained from a non-disease subject.
  • the liquid comprises whole blood.
  • the cancer is a solid tumor (e.g., an advanced solid tumor).
  • the cancer is pancreatic cancer, breast cancer, lung cancer (e.g., non-small cell lung cancer (NSCLC)), head and neck cancer (e.g., squamous cell carcinoma of the head and neck (SCCHN)), colorectal cancer (CRC), prostate cancer, skin cancer, melanoma, stomach cancer, gastric cancer, intestinal cancer, ovarian cancer, cervical and endocervical cancer, biliary cancer, uterine cancer, endometrial cancer, urinary bladder cancer, urothelial cancer, brain cancer, mesothelioma, esophageal cancer, liver cancer, kidney cancer (e.g., renal cell carcinoma (RCC)), testicular cancer, or cholangiocarcinoma.
  • NSCLC non-small cell lung cancer
  • SCCHN squamous cell carcinoma of the head and neck
  • CRCC colorectal cancer
  • prostate cancer skin cancer, mel
  • the cancer is gastric cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is urothelial cancer. In some embodiments, the cancer is insensitive to treatment with an immune-checkpoint inhibitor (e.g., an anti-PD-1 antibody). In some embodiments, the cancer has become resistant to treatment with an immune-checkpoint inhibitor (e.g., an anti-PD-1 antibody). [00158] In some embodiments, the subject is suspected of having a cancer or a tumor. In some embodiments, the subject has a cancer or a tumor. In some embodiments, subject has never been treated with an anti-cancer therapy.
  • an immune-checkpoint inhibitor e.g., an anti-PD-1 antibody
  • the subject has never been treated with an anti-cancer therapy.
  • OSCAR Osteoclast-Associated Ig-Like Receptor
  • OSCAR is a protein of 282 amino acids (aa)-the signal sequence is aa 1-21, the extracellular domain is aa 22- 116, the transmembrane region is aa 117-125, and the cytoplasmic domain is aa 126-219.
  • OSCAR comprises two immunoglobulin-like domains, one in the extracellular domain and the other in the intracellular, cytoplasmic domain.
  • OSCAR is known to bind to triple-helical motifs of collagens. See, Barrow et al., The Journal of clinical investigation 121.9 (2011); Zhou, Long, et al., The Journal of the American Society of Hematology 127.5: 529-537 (2016).
  • LAIR1-binding agents include, but are not limited to, polypeptides such as antibodies that specifically bind LAIR1.
  • the agents may be referred to herein as “LAIR1-binding agents.”
  • the LAIR1- binding agent inhibits LAIR1 activity.
  • the LAIR1-binding agent enhances an immune response.
  • the LAIR1-binding agent reverses suppression of an immune cell.
  • the LAIR1-binding agent is used in a combination with a companion diagnostic.
  • any of the LAIR1-binding agents disclosed in U.S. Application No. 17/353,295, U.S. Publication No.2019/0338026 A1, International Publication No. WO 2018/027039 A8, and International Publication No. WO 1998/024906 A2 can be used in any of the methods disclosed herein.
  • the LAIR1-binding agents of the disclosure are useful in a variety of applications including, but not limited to, therapeutic treatment methods, such as treatment of cancer.
  • the therapeutic treatment methods comprise immunotherapy for cancer.
  • the LAIR1-binding agent is useful for activating, promoting, increasing, and/or enhancing an immune response to cancer or cancer cells.
  • the LAIR1-binding agent is useful for activating, promoting, increasing, and/or enhancing an immune response to a tumor or tumor cells.
  • the methods of use may be in vitro, ex vivo, or in vivo methods.
  • the present disclosure provides methods of disrupting, inhibiting, or blocking the binding of LAIR1 to collagen.
  • a method of disrupting, inhibiting, or blocking the binding of LAIR1 to collagen in a cell mixture comprises contacting the cell mixture with a LAIR1-binding agent described herein. In some embodiments, a method of disrupting, inhibiting, or blocking the binding of LAIR1 to collagen in a cell mixture comprises contacting the cell mixture with a LAIR1-binding agent described herein, wherein the method results in disrupting, inhibiting, or blocking collagen-induced LAIR1 activity.
  • a method of disrupting, inhibiting, or blocking the binding of LAIR1 to collagen in a cell mixture comprises contacting the cell mixture with a LAIR1-binding agent described herein, wherein the method results in disrupting, inhibiting, or blocking LAIR1-induced suppression of myeloid cells.
  • a method of disrupting, inhibiting, or blocking the binding of LAIR1 to collagen in a cell mixture comprises contacting the cell mixture with a LAIR1-binding agent described herein, wherein the method results in disrupting, inhibiting, or blocking of LAIR1-induced suppression of myeloid cell activity.
  • a method of disrupting, inhibiting, or blocking the binding of LAIR1 to collagen in a cell mixture comprises contacting the cell mixture with a LAIR1-binding agent described herein, wherein the method results in disrupting, inhibiting, or blocking of LAIR1-induced suppression of NK cells or NK cell activity.
  • a method of disrupting, inhibiting, or blocking the binding of LAIR1 to collagen in a cell mixture comprises contacting the cell mixture with a LAIR1-binding agent described herein, wherein the method results in disrupting, inhibiting, or blocking of LAIR1-induced suppression of T-cells or T-cell activity.
  • a method of disrupting, inhibiting, or blocking the binding of LAIR1 to collagen (i) restores FcR signaling activity in myeloid cells; (ii) restores cytokine and/or chemokine production by myeloid cells; and/or (iii) restores immune cell (e.g., T-cell) proliferation and/or activity.
  • the myeloid cell is a monocyte.
  • the myeloid cell is a macrophage.
  • the myeloid cell is a dendritic cell.
  • the myeloid cell is an APC.
  • a method of disrupting, inhibiting, or blocking collagen- induced LAIR1 activity in a cell comprises contacting the cell with a LAIR1-binding agent described herein.
  • a method of disrupting and/or inhibiting LAIR1 signaling in a cell comprises contacting the cell with a LAIR1-binding agent described herein.
  • a method of disrupting, inhibiting, or blocking LAIR1-induced suppression of a myeloid cell comprises contacting the myeloid cell with a LAIR1-binding agent described herein.
  • a method of disrupting, inhibiting, or blocking LAIR1- induced suppression of myeloid cell activity comprises contacting the cell with a LAIR1-binding agent described herein.
  • the myeloid cell is a monocyte, a macrophage, a dendritic cell, or an APC.
  • a method of disrupting, inhibiting, or blocking LAIR1- induced suppression of a natural killer cell or natural killer cell activity comprises contacting the natural killer cell with a LAIR1-binding agent described herein.
  • a method of disrupting, inhibiting, or blocking LAIR1-induced suppression of a T-cell or T-cell activity comprises contacting the T-cell with a LAIR1-binding agent described herein.
  • the T-cell is a cytotoxic T-cell (CTL).
  • CTL cytotoxic T-cell
  • a method of disrupting, inhibiting, or blocking the activity of a myeloid-derived suppressor cell (MDSC) comprises contacting the MDSC with a LAIR1-binding agent described herein.
  • a method of disrupting, inhibiting, or blocking the activity of a regulatory T-cell (Treg) comprises contacting the regulatory T-cell with a LAIR1-binding agent described herein.
  • a method of disrupting, inhibiting, or blocking collagen- induced LAIR1 activity in a subject comprises administering to the subject a therapeutically effective amount of a LAIR1-binding agent described herein.
  • a method of disrupting, inhibiting, or blocking LAIR1-induced suppression of a myeloid cell in a subject comprises administering to the subject a therapeutically effective amount of a LAIR1-binding agent described herein.
  • a method of disrupting, inhibiting, or blocking LAIR1-induced suppression of myeloid cell activity in a subject comprises administering to the subject a therapeutically effective amount of a LAIR1-binding agent described herein.
  • a method of disrupting, inhibiting, or blocking LAIR1-induced suppression of a myeloid cell or myeloid cell activity in a subject (i) restores FcR activity in myeloid cells; (ii) restores cytokine and/or chemokine production by myeloid cells; and/or (iii) restores immune cell (e.g., T-cell) proliferation and/or activity.
  • the myeloid cell is a monocyte.
  • the myeloid cell is a macrophage.
  • the myeloid cell is a dendritic cell.
  • the myeloid cell is an APC.
  • a method of disrupting, inhibiting, or blocking LAIR1- induced suppression of a natural killer cell or natural killer cell activity in a subject comprises administering to the subject a therapeutically effective amount of a LAIR1-binding agent described herein.
  • a method of disrupting, inhibiting, or blocking LAIR1- induced suppression of a T-cell or T-cell activity in a subject comprises administering to the subject a therapeutically effective amount of a LAIR1-binding agent described herein.
  • the T-cell is a cytotoxic T-cell (CTL).
  • the T-cell is a tumor-associated T-cell.
  • a method of disrupting, inhibiting, or blocking the activity of a MDSC in a subject comprises administering to the subject a therapeutically effective amount of a LAIR1-binding agent described herein.
  • a method of disrupting, inhibiting, or blocking the activity of a regulatory T-cell (Treg) in a subject comprises administering to the subject a therapeutically effective amount of a LAIR1-binding agent described herein.
  • the present disclosure provides methods for activating an immune response in a subject using a LAIR1-binding agent described herein.
  • the disclosure provides methods for promoting an immune response in a subject using a LAIR1-binding agent described herein.
  • the disclosure provides methods for increasing an immune response in a subject using a LAIR1-binding agent described herein. In some embodiments, the disclosure provides methods for enhancing an immune response in a subject using a LAIR1-binding agent described herein. In some embodiments, the activating, promoting, increasing, and/or enhancing of an immune response comprises stimulating myeloid cells. In some embodiments, the activating, promoting, increasing, and/or enhancing of an immune response comprises stimulating monocytes. In some embodiments, the activating, promoting, increasing, and/or enhancing of an immune response comprises stimulating macrophages. In some embodiments, the activating, promoting, increasing, and/or enhancing of an immune response comprises stimulating dendritic cells.
  • the activating, promoting, increasing, and/or enhancing of an immune response comprises stimulating APCs. In some embodiments, the activating, promoting, increasing, and/or enhancing of an immune response comprises increasing cell-mediated immunity. In some embodiments, the activating, promoting, increasing, and/or enhancing of an immune response comprises increasing effector T-cell activity. In some embodiments, the activating, promoting, increasing, and/or enhancing of an immune response comprises increasing CTL activity. In some embodiments, the activating, promoting, increasing, and/or enhancing of an immune response comprises inhibiting or decreasing the suppressive activity of Tregs.
  • the activating, promoting, increasing, and/or enhancing of an immune response comprises inhibiting or decreasing the suppressive activity of MDSCs.
  • the immune response is a result of antigenic stimulation.
  • the antigenic stimulation is a tumor cell.
  • the antigenic stimulation is cancer.
  • the present disclosure also provides methods for inhibiting growth of a tumor using a LAIR1-binding agent described herein.
  • a method of inhibiting growth of a tumor comprises contacting a cell mixture with a LAIR1-binding agent in vitro.
  • an immortalized cell line or a cancer cell line mixed with immune cells is cultured in medium to which is added a test agent that binds LAIR1.
  • tumor cells are isolated from a patient sample such as, for example, a tissue biopsy, pleural effusion, or blood sample, mixed with immune cells (e.g., T-cells or myeloid cells), and cultured in medium to which is added a test agent that binds LAIR1.
  • the disclosure provides use of a LAIR1-binding agent described herein in the manufacture or preparation of a medicament for inhibiting growth of a tumor or a tumor cell.
  • the LAIR1-binding agent increases, promotes, and/or enhances the activity of effector immune cells. In some embodiments, the LAIR1-binding agent inhibits tumor cell growth.
  • a method of inhibiting tumor growth comprises contacting the tumor and/or tumor microenvironment with a LAIR1-binding agent described herein in vivo. In some embodiments, contacting a tumor and/or tumor microenvironment with the LAIR1-binding agent is undertaken in an animal model (e.g., a mouse model). In some embodiments, a test agent may be administered to mice that have tumors. In some embodiments, the test agent is a LAIR1-binding agent that binds mouse LAIR1.
  • the test agent is a surrogate antibody that binds mouse LAIR1.
  • the test agent is an anti- mouse LAIR1 antibody described herein.
  • the test agent is anti-mouse LAIR1 antibody 43H2.
  • the LAIR1-binding agent increases, promotes, and/or enhances the activity of immune cells in the mice.
  • the LAIR1- binding agent inhibits tumor growth.
  • the LAIR1-binding agent causes a tumor to regress.
  • the LAIR1-binding agent is administered at the same time or shortly after introduction of tumor cells into the animal to prevent tumor growth (“preventative model”).
  • the LAIR1-binding agent is administered after tumors have grown to a specified size or have become “established” for treatment (“therapeutic model”).
  • the LAIR1-binding agent is administered to a transgenic animal (e.g., a transgenic mouse) that expresses human LAIR1, wherein the transgenic animal has a tumor derived from human cells.
  • the LAIR1-binding agent is an anti-mouse LAIR1 antibody described herein.
  • the LAIR1-binding agent is anti-mouse LAIR1 antibody 43H2.
  • a method of inhibiting tumor growth in a subject comprises administering to the subject a therapeutically effective amount of a LAIR1-binding agent described herein.
  • a method of increasing or enhancing an immune response to a tumor or tumor cells in a subject comprises administering to the subject a therapeutically effective amount of a LAIR1-binding agent described herein.
  • a method of activating or enhancing a persistent or long-term immune response to a tumor or tumor cells in a subject comprises administering to the subject a therapeutically effective amount of a LAIR1-binding agent described herein.
  • a method of inhibiting tumor relapse or tumor regrowth in a subject comprises administering to the subject a therapeutically effective amount of a LAIR1-binding agent described herein.
  • a method of inducing a persistent or long-term immunity that inhibits tumor relapse or tumor regrowth in a subject comprises administering to the subject a therapeutically effective amount of a LAIR1-binding agent described herein.
  • the disclosure provides use of a LAIR1-binding agent described herein in the manufacture or preparation of a medicament for inhibiting growth of a tumor or tumor cell.
  • the tumor is a solid tumor.
  • the tumor is a pancreatic cancer, breast cancer, lung cancer (e.g., non-small cell lung cancer (NSCLC)), head and neck cancer (e.g., squamous cell carcinoma of the head and neck (SCCHN)), colorectal cancer (CRC), prostate cancer, skin cancer, melanoma, stomach cancer, gastric cancer, intestinal cancer, ovarian cancer, cervical and endocervical cancer, biliary cancer, uterine cancer, endometrial cancer, urinary bladder cancer, brain cancer, mesothelioma, esophageal cancer, liver cancer, kidney cancer (e.g., renal cell carcinoma (RCC)), testicular cancer, or cholangiocarcinoma.
  • NSCLC non-small cell lung cancer
  • SCCHN squamous cell carcinoma of the head and neck
  • CRCC colorectal cancer
  • prostate cancer skin cancer, melanoma
  • stomach cancer gastric cancer
  • intestinal cancer intestinal cancer
  • ovarian cancer ovarian
  • the tumor is a pancreatic tumor. In some embodiments, the tumor is an ovarian tumor. In some embodiments, the tumor is a breast tumor. In some embodiments, the tumor is a uterine tumor. In some embodiments, the subject has a tumor or the subject had a tumor that was at least partially removed. [00174]
  • the present disclosure provides methods of treating cancer.
  • a method of treating cancer in a subject comprises administering to the subject a therapeutically effective amount of a LAIR1-binding agent described herein. In some embodiments, the LAIR1-binding agent binds LAIR1 and inhibits or reduces growth of the cancer.
  • the LAIR1-binding agent binds LAIR1-expressing cells, enhances an immune response to a cancer, and inhibits or reduces growth of the cancer. In some embodiments, the LAIR1-binding agent binds LAIR1-expressing cells, activates myeloid cells, enhances an immune response to a cancer, and inhibits or reduces growth of the cancer. In some embodiments, the subject has a cancerous tumor. In some embodiments, the subject has had a tumor at least partially removed. [00175] In some embodiments, the disclosure provides use of a LAIR1-binding agent described herein in the manufacture or preparation of a medicament for the treatment of cancer.
  • the cancer is pancreatic cancer, breast cancer, lung cancer (e.g., non-small cell lung cancer (NSCLC)), head and neck cancer (e.g., squamous cell carcinoma of the head and neck (SCCHN)), colorectal cancer (CRC), prostate cancer, skin cancer, melanoma, stomach cancer, gastric cancer, intestinal cancer, ovarian cancer, cervical and endocervical cancer, biliary cancer, uterine cancer, endometrial cancer, urinary bladder cancer, brain cancer, mesothelioma, esophageal cancer, liver cancer, kidney cancer (e.g., renal cell carcinoma (RCC)), testicular cancer or cholangiocarcinoma.
  • NSCLC non-small cell lung cancer
  • SCCHN squamous cell carcinoma of the head and neck
  • CRCC colorectal cancer
  • prostate cancer skin cancer, melanoma
  • stomach cancer gastric cancer
  • intestinal cancer intestinal cancer
  • ovarian cancer ovarian cancer
  • the cancer is pancreatic cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is uterine cancer. [00177] In some embodiments, the cancer is a hematologic cancer. In some embodiments, the cancer is a myelogenous leukemia. In some embodiments, the myelogenous cancer is acute myeloid leukemia (AML). In some embodiments, the myelogenous cancer is a chronic myeloid leukemia. [00178] In some embodiments, the cancer is a myelodysplastic syndrome.
  • Myelodysplastic syndromes are a group of cancers in which immature blood cells in the bone marrow do not mature and therefore do not become healthy blood cells.
  • myelodysplastic syndrome develops into AML.
  • the disclosure provides methods of activating myeloid cells in the tumor microenvironment.
  • a method of activating myeloid cells in the tumor microenvironment in a subject with a tumor comprises administering to the subject a therapeutically effective amount of a LAIR1-binding agent described herein.
  • the myeloid cells are dendritic cells.
  • the myeloid cells are monocytes.
  • the myeloid cells are macrophages.
  • the myeloid cells are APCs.
  • the disclosure provides methods of activating T-cells in the tumor microenvironment.
  • a method of activating T-cells in the tumor microenvironment in a subject with a tumor comprises administering to the subject a therapeutically effective amount of a LAIR1-binding agent described herein.
  • the T-cells are CTLs.
  • the T-cells are tumor-associated T- cells.
  • a method is an in vitro method comprising contacting a cell with a LAIR-binding agent described herein.
  • a method is an in vivo method comprising administering a therapeutically effective amount of a LAIR1-binding agent described herein to a subject.
  • Amino acid (aa) sequences for human LAIR1 (UniProtKB No. Q6GTX8), cynomolgus monkey (“cyno”) LAIR1 (UniProtKB No. A0A2K5TN26), and mouse LAIR1 (UniProtKB No. Q8BG84) are provided herein as SEQ ID NO:1, SEQ ID NO:5, and SEQ ID NO:149, respectively.
  • reference to amino acid positions of LAIR1 refer to the numbering of amino acid sequences including the signal sequence.
  • LAIR1 is a single pass type I transmembrane protein with a predicted molecular weight of approximately 32 kDa.
  • human LAIR1 is a protein of 287 amino acids (aa) - the signal sequence is aa 1-21, the extracellular domain is aa 22-165, the transmembrane region is aa 166-186, and the cytoplasmic domain is aa 187-287.
  • the Ig-like C2-type domain is aa 29-117 and the “stem region” is aa 118-165.
  • ITIMs are positioned at aa 249-254 and 279- 284.
  • LAIR1 is expressed on almost all immune cells, including NK cells, T-cells, B-cells, monocytes, dendritic cells, eosinophils, basophils, and mast cells.
  • LAIR1 is characterized by an extracellular domain comprising one Ig-like C2 type domain, a transmembrane domain, and a cytoplasmic domain containing 2 ITIM domains (see, e.g., Meyaard et al., 1997, Immunity, 7:283-290; Meyaard et al., 2008, J. Leuk. Biol., 83:799-803).
  • LAIR1 is known to bind to multiple transmembrane and extracellular matrix collagens.
  • Cyno LAIR1 has an amino acid sequence identity to human LAIR1 of 88%. As characterized within UniProtKB, cyno LAIR1 is a protein of 287 amino acids and it is believed that the structural characteristics of cyno LAIR1 are similar to human LAIR1. Thus, for cyno LAIR1 the signal sequence is predicted to be aa 1-21, the extracellular domain is predicted to be aa 22-165, the transmembrane region is predicted to be aa 166-186, and the cytoplasmic domain is predicted to be aa 187-287.
  • Mouse LAIR1 has an amino acid sequence identity to human LAIR1 of 42%. As characterized within UniProtKB, mouse LAIR1 is a protein of 263 amino acids and has structural characteristics similar to human LAIR1. Thus, for mouse LAIR1 the signal sequence is aa 1-21, the extracellular domain is aa 22-144, the transmembrane region is aa 145-165, and the cytoplasmic domain is aa 166-263.
  • the Ig-like C2-type domain is aa 27-114 and the “stem region” is aa 115-144. Within the cytoplasmic domain, ITIMs are positioned at aa 226-231 and 255-260.
  • the LAIR1-binding agent binds LAIR1 or a fragment of LAIR1.
  • a fragment of LAIR1 comprises the extracellular domain.
  • a fragment of LAIR1 comprises the Ig-like C2 type domain (D1).
  • a fragment of LAIR1 comprises the Ig-like C2 type domain and the stem region (D1-stem).
  • the extracellular domain of human LAIR1 comprises amino acids 22-165 of SEQ ID NO:1.
  • D1 of human LAIR1 comprises amino acids 29-117 of SEQ ID NO:1.
  • D1-stem of human LAIR1 comprises amino acids 29-165 of SEQ ID NO:1.
  • a fragment of human LAIR1 comprises the amino acid sequence of SEQ ID NO:3.
  • a fragment of human LAIR1 comprises the amino acid sequence of SEQ ID NO:4.
  • the extracellular domain of cyno LAIR1 comprises amino acids 22-165 of SEQ ID NO:5.
  • D1 of cyno LAIR1 comprises amino acids 29-117 of SEQ ID NO:5.
  • D1-stem of cyno LAIR1 comprises amino acids 29-165 of SEQ ID NO:5. In some embodiments, a fragment of cyno LAIR1 comprises the amino acid sequence of SEQ ID NO:7. In some embodiments, a fragment of cyno LAIR1 comprises the amino acid sequence of SEQ ID NO:8. In some embodiments, the extracellular domain of mouse LAIR1 comprises amino acids 22-144 of SEQ ID NO:149. In some embodiments, D1 of mouse LAIR1 comprises amino acids 27-114 of SEQ ID NO:149. In some embodiments, D1-stem of mouse LAIR1 comprises amino acids 27-144 of SEQ ID NO:149.
  • a fragment of mouse LAIR1 comprises the amino acid sequence of SEQ ID NO:151. In some embodiments, a fragment of mouse LAIR1 comprises the amino acid sequence of SEQ ID NO:152.
  • LAIR1 e.g., human LAIR1, cyno LAIR1, or mouse LAIR1
  • the regions and/or domains of LAIR1 may be defined differently by those of skill in the art, therefore the N- terminal amino acids and the C-terminal amino acids of any LAIR1 domain or region may vary by 1, 2, 3, 4, 5, or more amino acid residues.
  • the present disclosure provides agents that bind LAIR1. In some embodiments, the LAIR1-binding agent binds a fragment of LAIR1.
  • the LAIR1-binding agent binds within a specific region of LAIR1. In some embodiments, the LAIR1-binding agent binds within the extracellular domain of LAIR1. In some embodiments, the LAIR1-binding agent binds within the D1 domain of LAIR1. In some embodiments, the LAIR1-binding agent binds within the D1-stem domain of LAIR1. In some embodiments, the LAIR1-binding agent binds an epitope on LAIR1. In some embodiments, the LAIR1-binding agent binds a conformational epitope on LAIR1. [00189] In some embodiments, the LAIR1-binding agent binds human LAIR1.
  • the LAIR1-binding agent binds cyno LAIR1. In some embodiments, the LAIR1- binding agent binds mouse LAIR1. In some embodiments, the LAIR1-binding agent binds human LAIR1 and cyno LAIR1. In some embodiments, the LAIR1-binding agent binds human LAIR1 and cyno LAIR1, but does not bind mouse LAIR1. In some embodiments, the LAIR1- binding agent binds SEQ ID NO:1. In some embodiments, the LAIR1-binding agent binds SEQ ID NO:2. In some embodiments, the LAIR1-binding agent binds within amino acids 22-165 of SEQ ID NO:1.
  • the LAIR1-binding agent binds within amino acids 29- 117 of SEQ ID NO:1. In some embodiments, the LAIR1-binding agent binds within amino acids 29-165 of SEQ ID NO:1. In some embodiments, the LAIR1-binding agent binds SEQ ID NO:3. In some embodiments, the LAIR1-binding agent binds SEQ ID NO:4. In some embodiments, the LAIR1-binding agent binds SEQ ID NO:5. In some embodiments, the LAIR1-binding agent binds SEQ ID NO:6. In some embodiments, the LAIR1-binding agent binds within amino acids 22-165 of SEQ ID NO:5.
  • the LAIR1-binding agent binds within amino acids 29-117 of SEQ ID NO:5. In some embodiments, the LAIR1- binding agent binds within amino acids 29-165 of SEQ ID NO:5. In some embodiments, the LAIR1-binding agent binds SEQ ID NO:7. In some embodiments, the LAIR1-binding agent binds SEQ ID NO:8. In some embodiments, the LAIR1-binding agent binds SEQ ID NO:149. In some embodiments, the LAIR1-binding agent binds SEQ ID NO:150. In some embodiments, the LAIR1-binding agent binds within amino acids 22-144 of SEQ ID NO:149.
  • the LAIR1-binding agent binds within amino acids 27-114 of SEQ ID NO:149. In some embodiments, the LAIR1-binding agent binds within amino acids 27-144 of SEQ ID NO:149. In some embodiments, the LAIR1-binding agent binds SEQ ID NO:151. In some embodiments, the LAIR1-binding agent binds SEQ ID NO:152. [00190] In some embodiments, the LAIR1-binding agent binds a polypeptide comprising the amino acid sequence of SEQ ID NO:2. In some embodiments, the LAIR1-binding agent binds a polypeptide comprising the amino acid sequence of SEQ ID NO:3.
  • the LAIR1-binding agent binds a polypeptide comprising the amino acid sequence of SEQ ID NO:4. In some embodiments, the LAIR1-binding agent binds a polypeptide comprising the amino acid sequence of SEQ ID NO:6. In some embodiments, the LAIR1-binding agent binds a polypeptide comprising the amino acid sequence of SEQ ID NO:7. In some embodiments, the LAIR1-binding agent binds a polypeptide comprising the amino acid sequence of SEQ ID NO:8. In some embodiments, the LAIR1-binding agent binds a polypeptide comprising the amino acid sequence of SEQ ID NO:150.
  • the LAIR1-binding agent binds a polypeptide comprising the amino acid sequence of SEQ ID NO:151. In some embodiments, the LAIR1-binding agent binds a polypeptide comprising the amino acid sequence of SEQ ID NO:152. [00191] In some embodiments, the LAIR1-binding agent binds an epitope comprising amino acids within SEQ ID NO:2. In some embodiments, the LAIR1-binding agent binds an epitope comprising amino acids within SEQ ID NO:3. In some embodiments, the LAIR1-binding agent binds an epitope comprising amino acids within SEQ ID NO:4.
  • the LAIR1-binding agent binds an epitope comprising at least one amino acid within amino acids 70-80 of SEQ ID NO:1. In some embodiments, the LAIR1-binding agent binds an epitope comprising at least one amino acid within amino acids 61-80 of SEQ ID NO:1. In some embodiments, the LAIR1-binding agent binds an epitope comprising amino acids within SEQ ID NO:6. In some embodiments, the LAIR1-binding agent binds an epitope comprising amino acids within SEQ ID NO:7. In some embodiments, the LAIR1-binding agent binds an epitope comprising amino acids within SEQ ID NO:8.
  • the LAIR1-binding agent binds an epitope comprising amino acids within SEQ ID NO:150. In some embodiments, the LAIR1-binding agent binds an epitope comprising amino acids within SEQ ID NO:151. In some embodiments, the LAIR1-binding agent binds an epitope comprising amino acids within SEQ ID NO:152. [00192] In some embodiments, the LAIR1-binding agent is an antibody. In some embodiments, the antibody is a recombinant antibody. In some embodiments, the antibody is a monoclonal antibody. In some embodiments, the antibody is a chimeric antibody. In some embodiments, the antibody is a humanized antibody. In some embodiments, the antibody is a human antibody.
  • the antibody is an IgG antibody. In some embodiments, the antibody is an IgG1 antibody. In some embodiments, the antibody is an IgG2 antibody. In some embodiments, the antibody is an IgG3 antibody. In some embodiments, the antibody is an IgG4 antibody. In some embodiments, the antibody comprises an IgG heavy chain. In some embodiments, the antibody comprises an IgG1 heavy chain. In some embodiments, the antibody comprises an IgG2 heavy chain. In some embodiments, the antibody comprises an IgG4 heavy chain. In some embodiments, the antibody comprises a human IgG1 heavy chain. In some embodiments, the antibody comprises a human IgG2 heavy chain. In some embodiments, the antibody comprises a human IgG4 heavy chain.
  • the antibody comprises a kappa light chain. In some embodiments, the antibody comprises a kappa light chain constant region. In some embodiments, the antibody comprises a human kappa light chain constant region. In some embodiments, the antibody comprises a lambda light chain. In some embodiments, the antibody comprises a lambda light chain constant region. In some embodiments, the antibody comprises a human lambda light chain constant region. In some embodiments, the human kappa light chain constant region comprises the amino acid sequence of SEQ ID NO:147. In some embodiments, the human lambda light chain constant region comprises the amino acid sequence of SEQ ID NO:148. [00193] In some embodiments, the antibody is an antibody fragment comprising an antigen- binding site.
  • the antibody is a scFv. In some embodiments, the antibody is a disulfide-linked scFv. In some embodiments, the antibody is a disulfide-linked sc(Fv)2. In some embodiments, the antibody is a Fab, Fab′, or a F(ab)2 antibody. In some embodiments, the antibody is a diabody. In some embodiments, the antibody is a nanobody. [00194] In some embodiments, the antibody is a monospecific antibody. In some embodiments, the antibody is a bispecific antibody. In some embodiments, the antibody is a multispecific antibody. In some embodiments, the antibody is a monovalent antibody. In some embodiments, the antibody is a bivalent antibody.
  • the antibody is a tetravalent antibody.
  • the antibody is isolated. In some embodiments, the antibody is substantially pure.
  • the LAIR1-binding agent is a polyclonal antibody.
  • Polyclonal antibodies can be prepared by any method known to those of skill in the art. In some embodiments, polyclonal antibodies are produced by immunizing an animal (e.g., a rabbit, rat, mouse, goat, donkey) with an antigen of interest (e.g., a purified peptide fragment, a recombinant protein, or a fusion protein) using multiple subcutaneous or intraperitoneal injections.
  • an animal e.g., a rabbit, rat, mouse, goat, donkey
  • an antigen of interest e.g., a purified peptide fragment, a recombinant protein, or a fusion protein
  • the antigen is conjugated to a carrier such as keyhole limpet hemocyanin (KLH), serum albumin, bovine thyroglobulin, or soybean trypsin inhibitor.
  • KLH keyhole limpet hemocyanin
  • serum albumin serum albumin
  • bovine thyroglobulin bovine thyroglobulin
  • soybean trypsin inhibitor e.g., soybean trypsin inhibitor
  • the antigen (with or without a carrier protein) is diluted in sterile saline and usually combined with an adjuvant (e.g., Complete or Incomplete Freund's Adjuvant) to form a stable emulsion. After a period of time, polyclonal antibodies are recovered from the immunized animal (e.g., from blood or ascites).
  • an adjuvant e.g., Complete or Incomplete Freund's Adjuvant
  • the polyclonal antibodies are purified from serum or ascites according to standard methods in the art including, but not limited to, affinity chromatography, ion-exchange chromatography, gel electrophoresis, and/or dialysis.
  • the LAIR1-binding agent is a monoclonal antibody.
  • Monoclonal antibodies can be prepared by any method known to those of skill in the art.
  • monoclonal antibodies are prepared using hybridoma methods known to one of skill in the art. For example, using a hybridoma method, a mouse, rat, rabbit, hamster, or other appropriate host animal, is immunized as described above.
  • lymphocytes are immunized in vitro.
  • the immunizing antigen is a human protein or a fragment thereof.
  • the immunizing antigen is a mouse protein or a fragment thereof.
  • the immunizing antigen is a cyno protein or a fragment thereof.
  • the immunizing antigen is a combination of two or more (e.g., 2, 3, 4) related proteins or fragments thereof. [00198] Following immunization, lymphocytes are isolated and fused with a suitable myeloma cell line using, for example, polyethylene glycol or electrofusion.
  • hybridoma cells are selected using specialized media as known in the art and unfused lymphocytes and myeloma cells do not survive the selection process.
  • Hybridomas that produce monoclonal antibodies directed specifically against a chosen antigen can be identified by a variety of methods including, but not limited to, immunoprecipitation, immunoblotting, and in vitro binding assays (e.g., flow cytometry, ELISA, SPR (e.g., Biacore), and radioimmunoassay).
  • the clones may be subcloned by limiting dilution techniques.
  • high-throughput methods are used to distribute single cell hybridoma cells into plates. In some embodiments, high-throughput methods are used to directly distribute single cells from original fusion into plates.
  • the hybridomas can be propagated either in in vitro culture using standard methods or in vivo as ascites tumors in an animal.
  • the monoclonal antibodies can be purified from the culture medium or ascites fluid according to standard methods in the art including, but not limited to, affinity chromatography, ion-exchange chromatography, gel electrophoresis, and dialysis. [00199] In some embodiments, monoclonal antibodies are made using recombinant DNA techniques as known to one skilled in the art.
  • the polynucleotides encoding an antibody are isolated from mature B-cells or hybridoma cells, such as by RT-PCR using oligonucleotide primers that specifically amplify the genes encoding the heavy and light chains of the antibody, and their sequence is determined using standard techniques.
  • the isolated polynucleotides encoding the heavy and light chains are then cloned into suitable expression vectors which produce the monoclonal antibodies when transfected into host cells such as E. coli, simian COS cells, Chinese hamster ovary (CHO) cells, or myeloma cells that do not otherwise produce immunoglobulin proteins.
  • recombinant monoclonal antibodies are isolated from phage display libraries expressing variable domains or CDRs of a desired species. Screening of phage libraries can be accomplished by various techniques known in the art.
  • a monoclonal antibody is modified by using recombinant DNA technology to generate alternative antibodies.
  • the constant domains of the light chain and heavy chain of a mouse monoclonal antibody are substituted for constant regions of a human antibody to generate a chimeric antibody.
  • the constant regions are truncated or removed to generate a desired antibody fragment of a monoclonal antibody.
  • the LAIR1-binding agent is a humanized antibody.
  • a humanized antibody comprises one or more amino acid residues that have been introduced into it from a source that is non-human.
  • humanization is performed by substituting one or more non-human CDR sequences for the corresponding CDR sequences of a human antibody.
  • the humanized antibodies are constructed by substituting all six CDRs of a non-human antibody (e.g., a mouse antibody) for the corresponding CDRs of a human antibody.
  • a non-human antibody e.g., a mouse antibody
  • the choice of which human heavy chain variable region and/or light chain variable region to use for generating humanized antibodies can be made based on a variety of factors and by a variety of methods known in the art.
  • the “best-fit” method is used where the sequence of the variable region of a non-human (e.g., rodent) antibody is screened against the entire library of known human variable region sequences. The human sequence that is most similar to that of the non-human sequence is selected as the human variable region framework for the humanized antibody.
  • variable region framework sequence is selected as the variable region framework.
  • variable region framework sequence is derived from the consensus sequences of the most abundant human subclasses.
  • human germline genes are used as the source of the variable region framework sequences.
  • LAIR1-binding agent is a human antibody.
  • Human antibodies can be prepared using various techniques known in the art. In some embodiments, human antibodies are generated from immortalized human B lymphocytes immunized in vitro.
  • human antibodies are generated from lymphocytes isolated from an immunized individual. In any case, cells that produce an antibody directed against a target antigen can be generated and isolated.
  • a human antibody is selected from a phage library, where that phage library expresses human antibodies.
  • phage display technology may be used to produce human antibodies and antibody fragments in vitro, from immunoglobulin variable region gene repertoires from unimmunized human donors. Techniques for the generation and use of antibody phage libraries are well known in the art. Once antibodies are identified, affinity maturation strategies known in the art, including but not limited to, chain shuffling and site-directed mutagenesis, may be employed to generate higher affinity human antibodies.
  • human antibodies are produced in transgenic mice that comprise human immunoglobulin loci. Upon immunization these mice are capable of producing the full repertoire of human antibodies in the absence of endogenous immunoglobulin production.
  • the LAIR1-binding agent is an antibody fragment. Examples of antibody fragments include, but are not limited to, Fab, Fab′, F(ab′) 2 , Fv, single chain antibody molecules, scFv, disulfide-linked scFv (dsscFv), nanobodies, diabodies, tribodies, tetrabodies, minibodies, dual variable domain antibodies (DVD), and single variable domain antibodies.
  • the LAIR1-binding agent is a scFv antibody.
  • the scFv is a disulfide-linked scFv (dsscFv).
  • DsscFv antibodies comprise an engineered disulfide bond between the light chain variable region and heavy chain variable region of the scFv.
  • the disulfide bond increases stability of the scFv molecule.
  • the disulfide bond increases thermostability of the scFv molecule.
  • the LAIR1-binding agent is a Fv.
  • the LAIR1-binding agent is a Fab.
  • the LAIR1-binding agent is a F(ab′)2. In some embodiments, the LAIR1-binding agent is a F(ab′).
  • Antibody fragments can be made by various techniques, including but not limited to proteolytic digestion of an intact antibody. In some embodiments, antibody fragments are produced using recombinant technologies known in the art (e.g., E.coli or phage expression).
  • the LAIR1-binding agent is a bispecific antibody. Bispecific antibodies are capable of recognizing and binding at least two different antigens or epitopes.
  • the different epitopes can either be within the same molecule (e.g., two epitopes on LAIR1) or on different molecules (e.g., one epitope on LAIR1 and one epitope on a different target).
  • a bispecific antibody has enhanced potency as compared to an individual antibody or to a combination of more than one antibody.
  • a bispecific antibody has reduced toxicity as compared to an individual antibody or to a combination of more than one antibody. It is known to those of skill in the art that any therapeutic agent may have unique pharmacokinetics (PK) (e.g., circulating half-life).
  • PK pharmacokinetics
  • a bispecific antibody has the ability to synchronize the PK of two active binding agents wherein the two individual binding agents have different PK profiles.
  • a bispecific antibody has the ability to concentrate the actions of two agents in a common area (e.g., tissue) in a subject.
  • a bispecific antibody has the ability to concentrate the actions of two agents to a common target (e.g., a specific cell type).
  • a bispecific antibody has the ability to target the actions of two agents to more than one biological pathway or function.
  • a bispecific antibody has the ability to target two different cells and bring them closer together. [00211] In some embodiments, a bispecific antibody has decreased toxicity and/or side effects.
  • a bispecific antibody has decreased toxicity and/or side effects as compared to a mixture of the two individual antibodies or the antibodies as single agents. In some embodiments, a bispecific antibody has an increased therapeutic index. In some embodiments, a bispecific antibody has an increased therapeutic index as compared to a mixture of the two individual antibodies or the antibodies as single agents. [00212] Many techniques for making bispecific antibodies are known to those skilled in the art. In some embodiments, a bispecific antibody comprises heavy chain constant regions with modifications in the amino acids that are part of the interface between the two heavy chains. These modifications are made to enhance heterodimer formation and generally reduce or eliminate homodimer formation. In some embodiments, the bispecific antibody is generated using a knobs-into-holes (KIH) strategy.
  • KIH knobs-into-holes
  • the bispecific antibody comprises variant hinge regions incapable of forming disulfide linkages between identical heavy chains (e.g., reduce homodimer formation). In some embodiments, the bispecific antibody comprises heavy chains with changes in amino acids that result in altered electrostatic interactions. In some embodiments, the bispecific antibodies comprise heavy chains with changes in amino acids that result in altered hydrophobic/hydrophilic interactions. [00213] Bispecific antibodies can be intact antibodies or antibody fragments comprising antigen-binding sites. [00214] In some embodiments, the LAIR1-binding agent is an antibody that binds LAIR1. In some embodiments, an anti-LAIR1 antibody binds human LAIR1. In some embodiments, an anti-LAIR1 antibody binds cyno LAIR1.
  • an anti-LAIR1 antibody binds mouse LAIR1. In some embodiments, an anti-LAIR1 antibody binds human LAIR1 and cyno LAIR1. In some embodiments, an anti-LAIR1 antibody binds human LAIR1 and cyno LAIR1, and does not bind mouse LAIR1. In some embodiments, an anti-LAIR1 antibody binds an LAIR1 epitope. In some embodiments, an anti-LAIR1 antibody binds an LAIR1 epitope within the extracellular domain of human LAIR1. In some embodiments, an anti-LAIR1 antibody binds an LAIR1 epitope within the extracellular domain of cyno LAIR1.
  • an anti-LAIR1 antibody binds an epitope comprising at least one amino acid (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9) within amino acids 22-165 of SEQ ID NO:1. In some embodiments, an anti-LAIR1 antibody binds an epitope comprising at least one amino acid within amino acids 22-117 of SEQ ID NO:1. In some embodiments, an anti-LAIR1 antibody binds an epitope comprising at least one amino acid within amino acids 29-117 of SEQ ID NO:1. In some embodiments, an anti-LAIR1 antibody binds an epitope comprising amino acids within SEQ ID NO:3.
  • an anti-LAIR1 antibody binds an epitope comprising amino acids within SEQ ID NO:4. [00216] In some embodiments, an anti-LAIR1 antibody binds an epitope comprising at least one amino acid (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9) within amino acids 22-165 of SEQ ID NO:5. In some embodiments, an anti-LAIR1 antibody binds an epitope comprising at least one amino acid within amino acids 22-117 of SEQ ID NO:5. In some embodiments, an anti-LAIR1 antibody binds an epitope comprising at least one amino acid within amino acids 29-117 of SEQ ID NO:5.
  • amino acid e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9
  • an anti-LAIR1 antibody binds an epitope comprising amino acids within SEQ ID NO:7. In some embodiments, an anti-LAIR1 antibody binds an epitope comprising amino acids within SEQ ID NO:8. [00217] In some embodiments, an anti-LAIR1 antibody binds an epitope comprising at least one amino acid (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9) within amino acids 22-144 of SEQ ID NO:149. In some embodiments, an anti-LAIR1 antibody binds an epitope comprising at least one amino acid within amino acids 22-114 of SEQ ID NO:149.
  • an anti-LAIR1 antibody binds an epitope comprising at least one amino acid within amino acids 27-114 of SEQ ID NO:149. In some embodiments, an anti-LAIR1 antibody binds an epitope comprising amino acids within SEQ ID NO:151. In some embodiments, an anti-LAIR1 antibody binds an epitope comprising amino acids within SEQ ID NO:152. [00218] In some embodiments, the epitope is a conformational epitope. In some embodiments, the epitope is a linear epitope. [00219] In some embodiments, an anti-LAIR1 antibody competes with a second agent for binding within the extracellular domain of human LAIR1.
  • an anti- LAIR1 antibody competes with a second agent for binding within the extracellular domain of cyno LAIR1. In some embodiments, an anti-LAIR1 antibody competes with a second agent for binding within amino acids 22-165 of SEQ ID NO:1. In some embodiments, an anti-LAIR1 antibody competes with a second agent for binding within amino acids 22-117 of SEQ ID NO:1. In some embodiments, an anti-LAIR1 antibody competes with a second agent for binding within amino acid sequence SEQ ID NO:3. In some embodiments, an anti-LAIR1 antibody competes with a second agent for binding within amino acid sequence SEQ ID NO:4.
  • the LAIR1-binding agent is an anti-LAIR1 antibody described herein. In some embodiments, the LAIR1-binding agent is a variant of an anti-LAIR1 antibody described herein. In some embodiments, a variant of an anti-LAIR1 antibody comprises one to thirty amino acid substitutions. In some embodiments, a variant of the anti-LAIR1 antibody comprises one to twenty-five amino acid substitutions. In some embodiments, a variant of the anti-LAIR1 antibody comprises one to twenty amino acid substitutions. In some embodiments, a variant of the anti-LAIR1 antibody comprises one to fifteen amino acid substitutions. In some embodiments, a variant of the anti-LAIR1 antibody comprises one to ten amino acid substitutions.
  • a variant of the anti-LAIR1 antibody comprises one to five amino acid substitutions. In some embodiments, the variant of the anti-LAIR1 antibody comprises one to three amino acid substitutions. In some embodiments, the amino acid substitution(s) is in a CDR of the antibody. In some embodiments, the amino acid substitution(s) is not in a CDR of the antibody. In some embodiments, the amino acid substitution(s) is in a framework region of the antibody. In some embodiments, the amino acid substitution(s) is a conservative amino acid substitution. [00221] CDRs of an antibody are defined using a variety of methods/systems by those skilled in the art.
  • the Kabat definition is based on sequence variability and is commonly used.
  • the Chothia definition is based on the location of the structural loop regions.
  • the IMGT system is based on sequence variability and location within the structure of the variable domain.
  • the AbM definition is a compromise between Kabat and Chothia.
  • the Contact definition is based on analyses of the available antibody crystal structures.
  • An Exemplary system is a combination of Kabat and Chothia.
  • Software programs e.g., abYsis
  • abYsis are available and known to those of skill in the art for analysis of antibody sequence and determination of CDRs.
  • an anti-LAIR1 antibody described herein comprises the six CDRs of antibody 47A1, 47H1, Hz47H1.v4, 57D12, 61H4, 62G10, 108D10, or 43H2 based on the Kabat definition.
  • an anti-LAIR1 antibody described herein comprises the six CDRs of antibody 47A1, 47H1, Hz47H1.v4, 57D12, 61H4, 62G10, 108D10, or 43H2 based on the Chothia definition. In some embodiments, an anti-LAIR1 antibody described herein comprises the six CDRs of antibody 47A1, 47H1, Hz47H1.v4, 57D12, 61H4, 62G10, 108D10, or 43H2 based on the AbM definition.
  • an anti-LAIR1 antibody described herein comprises the six CDRs of antibody 47A1, 47H1, Hz47H1.v4, 57D12, 61H4, 62G10, 108D10, or 43H2 based on the IMGT definition. In some embodiments, an anti-LAIR1 antibody described herein comprises the six CDRs of antibody 47A1, 47H1, Hz47H1.v4, 57D12, 61H4, 62G10, 108D10, or 43H2 based on the Contact definition.
  • an anti-LAIR1 antibody described herein comprises the six CDRs of antibody 47A1, 47H1, Hz47H1.v4, 57D12, 61H4, 62G10, 108D10, or 43H2 based on the Exemplary definition.
  • the LAIR1-binding agent is an anti-LAIR1 antibody that comprises one, two, three, four, five, and/or six CDRs of any one of the antibodies described herein.
  • an anti-LAIR1 antibody comprises (i) a heavy chain variable region comprising one, two, and/or three heavy chain variable region CDRs from Table 1, and/or (ii) a light chain variable region comprising one, two, and/or three light chain variable region CDRs from Table 1.
  • an anti-LAIR1 antibody comprises (i) a heavy chain variable region comprising one, two, and/or three heavy chain variable region CDRs from Table 2A, and/or (ii) a light chain variable region comprising one, two, and/or three light chain variable region CDRs from Table 2A.
  • an anti-LAIR1 antibody comprises (i) a heavy chain variable region comprising one, two, and/or three heavy chain variable region CDRs from Table 2B, and/or (ii) a light chain variable region comprising one, two, and/or three light chain variable region CDRs from Table 2B. In some embodiments, an anti-LAIR1 antibody comprises (i) a heavy chain variable region comprising one, two, and/or three heavy chain variable region CDRs from Table 3, and/or (ii) a light chain variable region comprising one, two, and/or three light chain variable region CDRs from Table 3.
  • an anti-LAIR1 antibody comprises (i) a heavy chain variable region comprising one, two, and/or three heavy chain variable region CDRs from Table 4, and/or (ii) a light chain variable region comprising one, two, and/or three light chain variable region CDRs from Table 4.
  • an anti-LAIR1 antibody comprises (i) a heavy chain variable region comprising one, two, and/or three heavy chain variable region CDRs from Table 5, and/or (ii) a light chain variable region comprising one, two, and/or three light chain variable region CDRs from Table 5.
  • an anti-LAIR1 antibody comprises (i) a heavy chain variable region comprising one, two, and/or three heavy chain variable region CDRs from Table 6, and/or (ii) a light chain variable region comprising one, two, and/or three light chain variable region CDRs from Table 6.
  • an anti-LAIR1 antibody comprises (i) a heavy chain variable region comprising one, two, and/or three heavy chain variable region CDRs from Table 7, and/or (ii) a light chain variable region comprising one, two, and/or three light chain variable region CDRs from Table 7.
  • an anti-LAIR1 antibody comprises (i) a heavy chain variable region comprising three heavy chain variable region CDRs from Table 1, and (ii) a light chain variable region comprising three light chain variable region CDRs from Table 1.
  • an anti-LAIR1 antibody comprises (i) a heavy chain variable region comprising three heavy chain variable region CDRs from Table 2A, and (ii) a light chain variable region comprising three light chain variable region CDRs from Table 2A.
  • an anti-LAIR1 antibody comprises (i) a heavy chain variable region comprising three heavy chain variable region CDRs from Table 2B, and (ii) a light chain variable region comprising three light chain variable region CDRs from Table 2B.
  • an anti-LAIR1 antibody comprises (i) a heavy chain variable region comprising three heavy chain variable region CDRs from Table 3, and (ii) a light chain variable region comprising three light chain variable region CDRs from Table 3. In some embodiments, an anti-LAIR1 antibody comprises (i) a heavy chain variable region comprising three heavy chain variable region CDRs from Table 4, and (ii) a light chain variable region comprising three light chain variable region CDRs from Table 4. In some embodiments, an anti-LAIR1 antibody comprises (i) a heavy chain variable region comprising three heavy chain variable region CDRs from Table 5, and (ii) a light chain variable region comprising three light chain variable region CDRs from Table 5.
  • an anti-LAIR1 antibody comprises (i) a heavy chain variable region comprising three heavy chain variable region CDRs from Table 6, and (ii) a light chain variable region comprising three light chain variable region CDRs from Table 6. In some embodiments, an anti- LAIR1 antibody comprises (i) a heavy chain variable region comprising three heavy chain variable region CDRs from Table 7, and (ii) a light chain variable region comprising three light chain variable region CDRs from Table 7.
  • the LAIR1-binding agent comprises a heavy chain variable region CDR1, CDR2, and CDR3 and/or a light chain variable region CDR1, CDR2, and CDR3 from an antibody described herein. In some embodiments, the LAIR1-binding agent comprises a heavy chain variable region CDR1, CDR2, and CDR3 and a light chain variable region CDR1, CDR2, and CDR3 from an antibody described herein. In some embodiments, the LAIR1- binding agent comprises: (a) a heavy chain variable region comprising a heavy chain variable region CDR1, CDR2, and CDR3; and (b) a light chain variable region comprising a light chain variable region CDR1, CDR2, and CDR3 from an antibody described herein.
  • the LAIR1-binding agent is a variant of a LAIR1-binding agent described herein.
  • the LAIR1-binding agent variant comprises amino acid substitutions in the heavy chain variable region and/or the light chain variable region as compared to a LAIR1-binding agent described herein.
  • the LAIR1- binding agent variant comprises amino acid substitutions in the heavy chain variable region CDR1, CDR2, and/or CDR3 and/or the light chain variable region CDR1, CDR2, and/or CDR3 as compared to a LAIR1-binding agent described herein.
  • the LAIR1- binding agent comprises one or more (e.g., 1, 2, 3, 4, etc.) amino acid substitutions in a CDR of an antibody described herein.
  • the amino acid substitutions are conservative substitutions.
  • a CDR comprises one amino acid substitution.
  • a CDR comprises two amino acid substitutions.
  • a CDR comprises three amino acid substitutions.
  • a CDR comprises four amino acid substitutions.
  • the CDR is a heavy chain variable region CDR1.
  • the CDR is a heavy chain variable region CDR2.
  • the CDR is a heavy chain variable region CDR3.
  • the CDR is a light chain variable region CDR1. In some embodiments, the CDR is a light chain variable region CDR2. In some embodiments, the CDR is a light chain variable region CDR3. In some embodiments, the substitutions are made as part of a humanization process. In some embodiments, the substitutions are made as part of a germline humanization process. In some embodiments, the substitutions are made as part of an affinity maturation process. In some embodiments, the substitutions are made as part of an optimization process. [00228] In some embodiments, the LAIR1-binding agent comprises one or more heavy chain variable region CDRs or light chain variable region CDRs that have been modified to reduce deamidation within the CDR sequence.
  • Deamidation is a chemical reaction in which an amide functional group in the side chain of the amino acids asparagine (Asn or N) or glutamine (Gln or Q) is removed or converted to another functional group.
  • asparagine is converted to aspartic acid or isoaspartic acid and glutamine is converted to glutamic acid or polyglutamic acid.
  • deamidation may change the structure, function, and/or stability of a polypeptide, potentially resulting in decreased biological activity.
  • the heavy chain variable region CDR1, CDR2, and/or CDR3 of an antibody described herein is modified to reduce deamidation.
  • the light chain variable region CDR1, CDR2, and/or CDR3 of an antibody described herein is modified to reduce deamidation.
  • the LAIR1-binding agent comprises one or more heavy chain variable region CDRs or light chain variable region CDRs that have been modified to reduce isomerization. Isomerization is a chemical process by which a compound is transformed into any of its isomeric forms, i.e., forms with the same chemical composition but with different structure or configuration and, potentially with different physical and chemical properties. Studies have shown that aspartate (Asp or D) isomerization within a CDR can impact antibody binding and/or stability.
  • the heavy chain variable region CDR1, CDR2, and/or CDR3 of an antibody described herein is modified to reduce isomerization.
  • the light chain variable region CDR1, CDR2, and/or CDR3 is modified to reduce isomerization.
  • the LAIR1-binding agent comprises one or more heavy chain variable region CDRs or light chain variable region CDRs that have been modified to reduce oxidation. Oxidation is a chemical process by which an oxygen is added to an atom, for example, methionine is converted to methionine sulfoxide by addition of an oxygen to the sulfur atom. Oxidation of one or more amino acids can potentially affect the physical and chemical properties of a protein.
  • the heavy chain variable region CDR1, CDR2, and/or CDR3 of an antibody described herein is modified to reduce oxidation.
  • the light chain variable region CDR1, CDR2, and/or CDR3 of an antibody described herein is modified to reduce oxidation.
  • the LAIR1-binding agent comprises a heavy chain variable region and/or a light chain variable region that comprises a modification within the amino acid sequence wherein the modification eliminates a glycosylation site.
  • the LAIR1-binding agent comprises one or more heavy chain variable region CDRs or light chain variable region CDRs that have been modified to eliminate a glycosylation site.
  • the consensus glycosylation site for N-linked glycans is N-X-S/T, wherein X can be any amino acid except proline.
  • a glycosylation site within a variable region and/or within a CDR will impact antibody structure, binding, and/or stability.
  • the LAIR1-binding agent comprises a heavy chain variable region CDR1, CDR2, and CDR3 and/or a light chain variable region CDR1, CDR2, and CDR3 from antibody 47A1, a humanized version thereof, or variants thereof.
  • the LAIR1-binding agent comprises a heavy chain variable region comprising a heavy chain variable region CDR1, a heavy chain variable region CDR2, and a heavy chain variable region CDR3 from antibody 47A1. In other embodiments, the LAIR1-binding agent comprises a light chain variable region comprising a light chain variable region CDR1, a light chain variable region CDR2, and a light chain variable region CDR3 from antibody 47A1.
  • the LAIR1-binding agent comprises: (a) a heavy chain variable region comprising a heavy chain variable region CDR1, a heavy chain variable region CDR2, a heavy chain variable region CDR3; and (b) a light chain variable region comprising a light chain variable region CDR1, a light chain variable region CDR2, and a light chain variable region CDR3 from antibody 47A1.
  • the LAIR1-binding agent comprises: (a) a heavy chain variable region CDR1 comprising the amino acid sequence GFTFNTYAIH (SEQ ID NO:9), a heavy chain variable region CDR2 comprising the amino acid sequence RIRSKSTNYATYYADSVKD (SEQ ID NO:10), a heavy chain variable region CDR3 comprising the amino acid sequence ENWYYYALDY (SEQ ID NO:11), a light chain variable region CDR1 comprising the amino acid sequence RASGNIHNYLT (SEQ ID NO:12), a light chain variable region CDR2 comprising the amino acid sequence NAKTLED (SEQ ID NO:13), and a light chain variable region CDR3 comprising the amino acid sequence QHFWSTPFT (SEQ ID NO:14); (b) a heavy chain variable region CDR1 comprising the amino acid sequence GFTFNTY (SEQ ID NO:15), a heavy chain variable region CDR2 comprising the amino acid sequence RSKSTNYA (SEQ ID NO:10), a heavy chain
  • the LAIR1-binding agent comprises: (a) a heavy chain variable region comprising a heavy chain variable region CDR1 comprising the amino acid sequence GFTFNTYAIH (SEQ ID NO:9), a heavy chain variable region CDR2 comprising the amino acid sequence RIRSKSTNYATYYADSVKD (SEQ ID NO:10), and a heavy chain variable region CDR3 comprising the amino acid sequence ENWYYYALDY (SEQ ID NO:11), and a light chain variable region comprising a light chain variable region CDR1 comprising the amino acid sequence RASGNIHNYLT (SEQ ID NO:12), a light chain variable region CDR2 comprising the amino acid sequence NAKTLED (SEQ ID NO:13), and a light chain variable region CDR3 comprising the amino acid sequence QHFWSTPFT (SEQ ID NO:14); (b) a heavy chain variable region comprising a heavy chain variable region CDR1 comprising the amino acid sequence GFTFNTY (SEQ ID NO:9), a heavy chain variable region
  • the LAIR1-binding agent comprises: (a) a heavy chain variable region comprising a heavy chain variable region CDR1 comprising the amino acid sequence GFTFNTYAIH (SEQ ID NO:9), a heavy chain variable region CDR2 comprising the amino acid sequence RIRSKSTNYATYYADSVKD (SEQ ID NO:10), and a heavy chain variable region CDR3 comprising the amino acid sequence ENWYYYALDY (SEQ ID NO:11), and/or (b) a light chain variable region comprising a light chain variable region CDR1 comprising the amino acid sequence RASGNIHNYLT (SEQ ID NO:12), a light chain variable region CDR2 comprising the amino acid sequence NAKTLED (SEQ ID NO:13), and a light chain variable region CDR3 comprising the amino acid sequence QHFWSTPFT (SEQ ID NO:14).
  • the LAIR1-binding agent comprises a heavy chain variable region comprising a heavy chain variable region CDR1 comprising the amino acid sequence GFTFNTYAIH (SEQ ID NO:9), a heavy chain variable region CDR2 comprising the amino acid sequence RIRSKSTNYATYYADSVKD (SEQ ID NO:10), and a heavy chain variable region CDR3 comprising the amino acid sequence ENWYYYALDY (SEQ ID NO:11).
  • the LAIR1-binding agent comprises a light chain variable region comprising a light chain variable region CDR1 comprising the amino acid sequence RASGNIHNYLT (SEQ ID NO:12), a light chain variable region CDR2 comprising the amino acid sequence NAKTLED (SEQ ID NO:13), and a light chain variable region CDR3 comprising the amino acid sequence QHFWSTPFT (SEQ ID NO:14).
  • the LAIR1-binding agent comprises (a) a heavy chain variable region comprising a heavy chain variable region CDR1 comprising the amino acid sequence GFTFNTYAIH (SEQ ID NO:9), a heavy chain variable region CDR2 comprising the amino acid sequence RIRSKSTNYATYYADSVKD (SEQ ID NO:10), and a heavy chain variable region CDR3 comprising the amino acid sequence ENWYYYALDY (SEQ ID NO:11), and (b) a light chain variable region comprising a light chain variable region CDR1 comprising the amino acid sequence RASGNIHNYLT (SEQ ID NO:12), a light chain variable region CDR2 comprising the amino acid sequence NAKTLED (SEQ ID NO:13), and a light chain variable region CDR3 comprising the amino acid sequence QHFWSTPFT (SEQ ID NO:14).
  • the LAIR1-binding agent comprises a heavy chain variable region having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity to the amino acid sequence of SEQ ID NO:115.
  • the LAIR1-binding agent comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO:115.
  • the LAIR1-binding agent comprises a light chain variable region having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity to the amino acid sequence of SEQ ID NO:116.
  • the LAIR1-binding agent comprises a light chain variable region comprising an amino acid sequence of SEQ ID NO:116.
  • the LAIR1-binding agent comprises a heavy chain variable region having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:115 and a light chain variable region having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:116.
  • the LAIR1-binding agent comprises a heavy chain variable region having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:115 and a light chain variable region having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:116.
  • the LAIR1-binding agent comprises a heavy chain variable region having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:115 and a light chain variable region having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:116. In some embodiments, the LAIR1-binding agent comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO:115 and a light chain variable region comprising an amino acid sequence of SEQ ID NO:116. [00238] In some embodiments, the LAIR1-binding agent is antibody 47A1. In some embodiments, the LAIR1-binding agent is a humanized version of antibody 47A1.
  • the LAIR1-binding agent is a variant of antibody 47A1 or a variant of a humanized version of 47A1.
  • the LAIR1-binding agent comprises a heavy chain variable region CDR1, CDR2, and CDR3 and/or a light chain variable region CDR1, CDR2, and CDR3 from antibody 47H1, a humanized version thereof, or variants thereof.
  • the LAIR1-binding agent comprises a heavy chain variable region comprising a heavy chain variable region CDR1, a heavy chain variable region CDR2, and a heavy chain variable region CDR3 from antibody 47H1.
  • the LAIR1-binding agent comprises a light chain variable region comprising a light chain variable region CDR1, a light chain variable region CDR2, and a light chain variable region CDR3 from antibody 47H1.
  • the LAIR1-binding agent comprises: (a) a heavy chain variable region comprising a heavy chain variable region CDR1, a heavy chain variable region CDR2, a heavy chain variable region CDR3; and (b) a light chain variable region comprising a light chain variable region CDR1, a light chain variable region CDR2, and a light chain variable region CDR3 from antibody 47H1.
  • the LAIR1-binding agent comprises a heavy chain variable region comprising a heavy chain variable region CDR1, a heavy chain variable region CDR2, and a heavy chain variable region CDR3 from antibody Hz47H1.v4. In other embodiments, the LAIR1-binding agent comprises a light chain variable region comprising a light chain variable region CDR1, a light chain variable region CDR2, and a light chain variable region CDR3 from antibody Hz47H1.v4.
  • the LAIR1-binding agent comprises: (a) a heavy chain variable region comprising a heavy chain variable region CDR1, a heavy chain variable region CDR2, a heavy chain variable region CDR3; and (b) a light chain variable region comprising a light chain variable region CDR1, a light chain variable region CDR2, and a light chain variable region CDR3 from antibody Hz47H1.v4.
  • the LAIR1-binding agent comprises: (a) a heavy chain variable region CDR1 comprising the amino acid sequence GFTFNINAMN (SEQ ID NO:25), a heavy chain variable region CDR2 comprising the amino acid sequence RIRTKNNNYATFYADSVKD (SEQ ID NO:26) or RIRTKNYNYATFYADSVKD (SEQ ID NO:41), a heavy chain variable region CDR3 comprising the amino acid sequence DRAGFFAY (SEQ ID NO:27), a light chain variable region CDR1 comprising the amino acid sequence LASQTIGTWLG (SEQ ID NO:28), a light chain variable region CDR2 comprising the amino acid sequence AATSLAD (SEQ ID NO:29) or AATSLAE (SEQ ID NO:42), and a light chain variable region CDR3 comprising the amino acid sequence QQLYSTPLT (SEQ ID NO:30); (b) a heavy chain variable region CDR1 comprising the amino acid sequence GFT
  • the LAIR1-binding agent comprises: (a) a heavy chain variable region comprising a heavy chain variable region CDR1 comprising the amino acid sequence GFTFNINAMN (SEQ ID NO:25), a heavy chain variable region CDR2 comprising the amino acid sequence RIRTKNNNYATFYADSVKD (SEQ ID NO:26) or RIRTKNYNYATFYADSVKD (SEQ ID NO:41), and a heavy chain variable region CDR3 comprising the amino acid sequence DRAGFFAY (SEQ ID NO:27), and a light chain variable region comprising a light chain variable region CDR1 comprising the amino acid sequence LASQTIGTWLG (SEQ ID NO:28), a light chain variable region CDR2 comprising the amino acid sequence AATSLAD (SEQ ID NO:29) or AATSLAE (SEQ ID NO:42), and a light chain variable region CDR3 comprising the amino acid sequence QQLYSTPLT (SEQ ID NO:30); (a) a heavy chain variable region compris
  • the LAIR1-binding agent comprises: (a) a heavy chain variable region comprising a heavy chain variable region CDR1 comprising the amino acid sequence GFTFNINAMN (SEQ ID NO:25), a heavy chain variable region CDR2 comprising the amino acid sequence RIRTKNNNYATFYADSVKD (SEQ ID NO:26) or RIRTKNYNYATFYADSVKD (SEQ ID NO:41), and a heavy chain variable region CDR3 comprising the amino acid sequence DRAGFFAY (SEQ ID NO:27), and/or (b) a light chain variable region comprising a light chain variable region CDR1 comprising the amino acid sequence LASQTIGTWLG (SEQ ID NO:28), a light chain variable region CDR2 comprising the amino acid sequence AATSLAD (SEQ ID NO:29) or AATSLAE (SEQ ID NO:42), and a light chain variable region CDR3 comprising the amino acid sequence QQLYSTPLT (SEQ ID NO:25), a heavy chain variable
  • the LAIR1-binding agent comprises a heavy chain variable region comprising a heavy chain variable region CDR1 comprising the amino acid sequence GFTFNINAMN (SEQ ID NO:25), a heavy chain variable region CDR2 comprising the amino acid sequence RIRTKNNNYATFYADSVKD (SEQ ID NO:26), and a heavy chain variable region CDR3 comprising the amino acid sequence DRAGFFAY (SEQ ID NO:27).
  • the LAIR1-binding agent comprises a heavy chain variable region comprising a heavy chain variable region CDR1 comprising the amino acid sequence GFTFNINAMN (SEQ ID NO:25), a heavy chain variable region CDR2 comprising the amino acid sequence RIRTKNYNYATFYADSVKD (SEQ ID NO:41), and a heavy chain variable region CDR3 comprising the amino acid sequence DRAGFFAY (SEQ ID NO:27).
  • the LAIR1-binding agent comprises a light chain variable region comprising a light chain variable region CDR1 comprising the amino acid sequence LASQTIGTWLG (SEQ ID NO:28), a light chain variable region CDR2 comprising the amino acid sequence AATSLAD (SEQ ID NO:29), and a light chain variable region CDR3 comprising the amino acid sequence QQLYSTPLT (SEQ ID NO:30).
  • the LAIR1-binding agent comprises a light chain variable region comprising a light chain variable region CDR1 comprising the amino acid sequence LASQTIGTWLG (SEQ ID NO:28), a light chain variable region CDR2 comprising the amino acid sequence AATSLAE (SEQ ID NO:42), and a light chain variable region CDR3 comprising the amino acid sequence QQLYSTPLT (SEQ ID NO:30).
  • the LAIR1-binding agent comprises: (a) a heavy chain variable region comprising a heavy chain variable region CDR1 comprising the amino acid sequence GFTFNINAMN (SEQ ID NO:25), a heavy chain variable region CDR2 comprising the amino acid sequence RIRTKNNNYATFYADSVKD (SEQ ID NO:26), and a heavy chain variable region CDR3 comprising the amino acid sequence DRAGFFAY (SEQ ID NO:27), and (b) a light chain variable region comprising a light chain variable region CDR1 comprising the amino acid sequence LASQTIGTWLG (SEQ ID NO:28), a light chain variable region CDR2 comprising the amino acid sequence AATSLAD (SEQ ID NO:29), and a light chain variable region CDR3 comprising the amino acid sequence QQLYSTPLT (SEQ ID NO:30).
  • the LAIR1-binding agent comprises: (a) a heavy chain variable region comprising a heavy chain variable region CDR1 comprising the amino acid sequence GFTFNINAMN (SEQ ID NO:25), a heavy chain variable region CDR2 comprising the amino acid sequence RIRTKNYNYATFYADSVKD (SEQ ID NO:41), and a heavy chain variable region CDR3 comprising the amino acid sequence DRAGFFAY (SEQ ID NO:27), and (b) a light chain variable region comprising a light chain variable region CDR1 comprising the amino acid sequence LASQTIGTWLG (SEQ ID NO:28), a light chain variable region CDR2 comprising the amino acid sequence AATSLAE (SEQ ID NO:42), and a light chain variable region CDR3 comprising the amino acid sequence QQLYSTPLT (SEQ ID NO:30).
  • the LAIR1-binding agent comprises: (a) a heavy chain variable region CDR1 comprising the amino acid sequence GFTFNINAMN (SEQ ID NO:25), or a variant thereof comprising 1, 2, 3, or 4 amino acid substitutions, a heavy chain variable region CDR2 comprising the amino acid sequence RIRTKNNNYATFYADSVKD (SEQ ID NO:26), RIRTKNYNYATFYADSVKD (SEQ ID NO:41), or a variant thereof comprising 1, 2, 3, or 4 amino acid substitutions, and a heavy chain variable region CDR3 comprising the amino acid sequence DRAGFFAY (SEQ ID NO:27), or a variant thereof comprising 1, 2, 3, or 4 amino acid substitutions; and (b) a light chain variable region CDR1 comprising the amino acid sequence LASQTIGTWLG (SEQ ID NO:28), or a variant thereof comprising 1, 2, 3, or 4 amino acid substitutions, a light chain variable region CDR2 comprising the amino acid sequence AATSLA
  • the LAIR1-binding agent comprises one or more heavy chain variable region CDRs or light chain variable region CDRs that have been modified to reduce deamidation within the CDR sequence. In some embodiments, the heavy chain variable region CDR2 of antibody 47H1 or Hz47H1 is modified to reduce deamidation. [00245] In some embodiments, the LAIR1-binding agent comprises one or more heavy chain variable region CDRs or light chain variable region CDRs that have been modified to reduce isomerization. In some embodiments, the light chain variable region CDR2 of antibody 47H1 or Hz47H1 is modified to reduce isomerization.
  • the LAIR1-binding agent comprises a heavy chain variable region having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity to the amino acid sequence of SEQ ID NO:117. In some embodiments, the LAIR1-binding agent comprises a light chain variable region having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity to the amino acid sequence of SEQ ID NO:118.
  • the LAIR1-binding agent comprises a heavy chain variable region having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity to the amino acid sequence of SEQ ID NO:119. In some embodiments, the LAIR1-binding agent comprises a light chain variable region having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity to the amino acid sequence of SEQ ID NO:120. [00247] In some embodiments, the LAIR1-binding agent comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO:117.
  • the LAIR1-binding agent comprises a light chain variable region comprising an amino acid sequence of SEQ ID NO:118. In some embodiments, the LAIR1-binding agent comprises a heavy chain variable region comprising an amino acid sequence of SEQ ID NO:119. In some embodiments, the LAIR1-binding agent comprises a light chain variable region comprising an amino acid sequence of SEQ ID NO:120. [00248] In some embodiments, the LAIR1-binding agent comprises a heavy chain variable region having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:117 and a light chain variable region having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:118.
  • the LAIR1-binding agent comprises a heavy chain variable region having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:117 and a light chain variable region having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:118. In some embodiments, the LAIR1-binding agent comprises a heavy chain variable region having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:117 and a light chain variable region having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:118.
  • the LAIR1-binding agent comprises a heavy chain variable region comprising an amino acid sequence of the amino acid sequence of SEQ ID NO:117 and a light chain variable region comprising an amino acid sequence of the amino acid sequence of SEQ ID NO:118. [00249] In some embodiments, the LAIR1-binding agent comprises a heavy chain variable region having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:119 and a light chain variable region having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:120.
  • the LAIR1-binding agent comprises a heavy chain variable region having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:119 and a light chain variable region having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:120. In some embodiments, the LAIR1-binding agent comprises a heavy chain variable region having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:119 and a light chain variable region having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:120. In some embodiments, the LAIR1-binding agent comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:119 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:120.
  • the LAIR1-binding agent comprises: (a) a heavy chain variable region comprising a heavy chain variable region CDR1 comprising the amino acid sequence GFTFNINAMN (SEQ ID NO:25), a heavy chain variable region CDR2 comprising the amino acid sequence RIRTKNNNYATFYADSVKD (SEQ ID NO:26), and a heavy chain variable region CDR3 comprising the amino acid sequence DRAGFFAY (SEQ ID NO:27), and (b) a light chain variable region comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO:118.
  • the LAIR1-binding agent comprises: (a) a heavy chain variable region comprising a heavy chain variable region CDR1 comprising the amino acid sequence GFTFNINAMN (SEQ ID NO:25), a heavy chain variable region CDR2 comprising the amino acid sequence RIRTKNNNYATFYADSVKD (SEQ ID NO:26), and a heavy chain variable region CDR3 comprising the amino acid sequence DRAGFFAY (SEQ ID NO:27), wherein the heavy chain variable region comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO:117, and (b) a light chain variable region comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO:118.
  • the LAIR1- binding agent comprises: (a) a heavy chain variable region comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO:117, and (b) a light chain variable region comprising a light chain variable region CDR1 comprising the amino acid sequence LASQTIGTWLG (SEQ ID NO:28), a light chain variable region CDR2 comprising the amino acid sequence AATSLAD (SEQ ID NO:29), and a light chain variable region CDR3 comprising the amino acid sequence QQLYSTPLT (SEQ ID NO:30).
  • the LAIR1-binding agent comprises: (a) a heavy chain variable region comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO:117, and (b) a light chain variable region comprising a light chain variable region CDR1 comprising the amino acid sequence LASQTIGTWLG (SEQ ID NO:28), a light chain variable region CDR2 comprising the amino acid sequence AATSLAD (SEQ ID NO:29), and a light chain variable region CDR3 comprising the amino acid sequence QQLYSTPLT (SEQ ID NO:30), wherein the light chain variable region comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO:118.
  • the LAIR1-binding agent comprises: (a) a heavy chain variable region comprising a heavy chain variable region CDR1 comprising the amino acid sequence GFTFNINAMN (SEQ ID NO:25), a heavy chain variable region CDR2 comprising the amino acid sequence RIRTKNYNYATFYADSVKD (SEQ ID NO:41), and a heavy chain variable region CDR3 comprising the amino acid sequence DRAGFFAY (SEQ ID NO:27), and (b) a light chain variable region comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO:120.
  • the LAIR1-binding agent comprises: (a) a heavy chain variable region comprising a heavy chain variable region CDR1 comprising the amino acid sequence GFTFNINAMN (SEQ ID NO:25), a heavy chain variable region CDR2 comprising the amino acid sequence RIRTKNYNYATFYADSVKD (SEQ ID NO:41), and a heavy chain variable region CDR3 comprising the amino acid sequence DRAGFFAY (SEQ ID NO:27), wherein the heavy chain variable region comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO:119, and (b) a light chain variable region comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO:120.
  • the LAIR1- binding agent comprises: (a) a heavy chain variable region comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO:119, and (b) a light chain variable region comprising a light chain variable region CDR1 comprising the amino acid sequence LASQTIGTWLG (SEQ ID NO:28), a light chain variable region CDR2 comprising the amino acid sequence AATSLAE (SEQ ID NO:42), and a light chain variable region CDR3 comprising the amino acid sequence QQLYSTPLT (SEQ ID NO:30).
  • the LAIR1-binding agent comprises: (a) a heavy chain variable region comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO:119, and (b) a light chain variable region comprising a light chain variable region CDR1 comprising the amino acid sequence LASQTIGTWLG (SEQ ID NO:28), a light chain variable region CDR2 comprising the amino acid sequence AATSLAE (SEQ ID NO:42), and a light chain variable region CDR3 comprising the amino acid sequence QQLYSTPLT (SEQ ID NO:30), wherein the light chain variable region comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, or at least 98% sequence identity to the amino acid sequence of SEQ ID NO:120.
  • the LAIR1-binding agent comprises: (a) a heavy chain comprising a heavy chain variable region CDR1 comprising the amino acid sequence GFTFNINAMN (SEQ ID NO:25), a heavy chain variable region CDR2 comprising the amino acid sequence RIRTKNYNYATFYADSVKD (SEQ ID NO:41), and a heavy chain variable region CDR3 comprising the amino acid sequence DRAGFFAY (SEQ ID NO:27), and (b) a light chain comprising a light chain variable region CDR1 comprising the amino acid sequence LASQTIGTWLG (SEQ ID NO:28), a light chain variable region CDR2 comprising the amino acid sequence AATSLAE (SEQ ID NO:42), and a light chain variable region CDR3 comprising the amino acid sequence QQLYSTPLT (SEQ ID NO:30), wherein the heavy chain comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at
  • the LAIR1-binding agent comprises: (a) a heavy chain comprising a heavy chain variable region CDR1 comprising the amino acid sequence GFTFNINAMN (SEQ ID NO:25), a heavy chain variable region CDR2 comprising the amino acid sequence RIRTKNYNYATFYADSVKD (SEQ ID NO:41), and a heavy chain variable region CDR3 comprising the amino acid sequence DRAGFFAY (SEQ ID NO:27), and (b) a light chain comprising a light chain variable region CDR1 comprising the amino acid sequence LASQTIGTWLG (SEQ ID NO:28), a light chain variable region CDR2 comprising the amino acid sequence AATSLAE (SEQ ID NO:42), and a light chain variable region CDR3 comprising the amino acid sequence QQLYSTPLT (SEQ ID NO:30), wherein the heavy chain comprises at least 95% sequence identity to the amino acid sequence of SEQ ID NO:134, and wherein the light chain comprises at least 95% sequence identity to the amino acid sequence of S
  • the LAIR1-binding agent comprises: (a) a heavy chain comprising the amino acid sequence of SEQ ID NO:134 and (b) a light chain comprising a light chain variable region CDR1 comprising the amino acid sequence LASQTIGTWLG (SEQ ID NO:28), a light chain variable region CDR2 comprising the amino acid sequence AATSLAE (SEQ ID NO:42), and a light chain variable region CDR3 comprising the amino acid sequence QQLYSTPLT (SEQ ID NO:30), wherein the light chain comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to the amino acid sequence of SEQ ID NO:136.
  • the LAIR1-binding agent comprises: (a) a heavy chain comprising a heavy chain variable region CDR1 comprising the amino acid sequence GFTFNINAMN (SEQ ID NO:25), a heavy chain variable region CDR2 comprising the amino acid sequence RIRTKNYNYATFYADSVKD (SEQ ID NO:41), and a heavy chain variable region CDR3 comprising the amino acid sequence DRAGFFAY (SEQ ID NO:27), wherein the heavy chain comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to the amino acid sequence of SEQ ID NO:134, and (b) a light chain comprising the amino acid sequence of SEQ ID NO:136.
  • the LAIR1- binding agent is an antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:134 and a light chain comprising the amino acid sequence of SEQ ID NO:136. [00253] In some embodiments, the LAIR1-binding agent is antibody 47H1. In some embodiments, the LAIR1-binding agent is a humanized version of antibody 47H1 (e.g., Hz47H1.v4). In some embodiments, the LAIR1-binding agent is a variant of antibody 47H1 or a variant of a humanized version of 47H1. In some embodiments, the LAIR1-binding agent is antibody Hz47H1.v4.
  • the LAIR1-binding agent comprises a heavy chain variable region CDR1, CDR2, and CDR3 and/or a light chain variable region CDR1, CDR2, and CDR3 from antibody 57D12, a humanized version thereof, or variants thereof.
  • the LAIR1-binding agent comprises a heavy chain variable region comprising a heavy chain variable region CDR1, a heavy chain variable region CDR2, and a heavy chain variable region CDR3 from antibody 57D12.
  • the LAIR1-binding agent comprises a light chain variable region comprising a light chain variable region CDR1, a light chain variable region CDR2, and a light chain variable region CDR3 from antibody 57D12.
  • the LAIR1-binding agent comprises: (a) a heavy chain variable region comprising a heavy chain variable region CDR1, a heavy chain variable region CDR2, a heavy chain variable region CDR3; and (b) a light chain variable region comprising a light chain variable region CDR1, a light chain variable region CDR2, and a light chain variable region CDR3 from antibody 57D12.
  • the LAIR1-binding agent comprises: (a) a heavy chain variable region CDR1 comprising the amino acid sequence GYSFTSFGIS (SEQ ID NO:46), a heavy chain variable region CDR2 comprising the amino acid sequence EIYPRSDNTFYNEKFKG (SEQ ID NO:47), a heavy chain variable region CDR3 comprising the amino acid sequence HFGSSSFDY (SEQ ID NO:48), a light chain variable region CDR1 comprising the amino acid sequence SASSSVSSIYFH (SEQ ID NO:49), a light chain variable region CDR2 comprising the amino acid sequence RASNLAS (SEQ ID NO:50), and a light chain variable region CDR3 comprising the amino acid sequence QQWSGYPLT (SEQ ID NO:51); (b) a heavy chain variable region CDR1 comprising the amino acid sequence GYSFTSF (SEQ ID NO:52), a heavy chain variable region CDR2 comprising the amino acid sequence YPRSDN (SEQ ID NO:47),
  • the LAIR1-binding agent comprises: (a) a heavy chain variable region comprising a heavy chain variable region CDR1 comprising the amino acid sequence GYSFTSFGIS (SEQ ID NO:46), a heavy chain variable region CDR2 comprising the amino acid sequence EIYPRSDNTFYNEKFKG (SEQ ID NO:47), and a heavy chain variable region CDR3 comprising the amino acid sequence HFGSSSFDY (SEQ ID NO:48), and a light chain variable region comprising a light chain variable region CDR1 comprising the amino acid sequence SASSSVSSIYFH (SEQ ID NO:49), a light chain variable region CDR2 comprising the amino acid sequence RASNLAS (SEQ ID NO:50), and a light chain variable region CDR3 comprising the amino acid sequence QQWSGYPLT (SEQ ID NO:51); (b) a heavy chain variable region comprising a heavy chain variable region CDR1 comprising the amino acid sequence GYSFTSF (SEQ ID NO:46), a heavy
  • the LAIR1-binding agent comprises: (a) a heavy chain variable region comprising a heavy chain variable region CDR1 comprising the amino acid sequence GYSFTSFGIS (SEQ ID NO:46), a heavy chain variable region CDR2 comprising the amino acid sequence EIYPRSDNTFYNEKFKG (SEQ ID NO:47), and a heavy chain variable region CDR3 comprising the amino acid sequence HFGSSSFDY (SEQ ID NO:48), and/or (b) a light chain variable region comprising a light chain variable region CDR1 comprising the amino acid sequence SASSSVSSIYFH (SEQ ID NO:49), a light chain variable region CDR2 comprising the amino acid sequence RASNLAS (SEQ ID NO:50), and a light chain variable region CDR3 comprising the amino acid sequence QQWSGYPLT (SEQ ID NO:51).
  • the LAIR1-binding agent comprises a heavy chain variable region comprising a heavy chain variable region CDR1 comprising the amino acid sequence GYSFTSFGIS (SEQ ID NO:46), a heavy chain variable region CDR2 comprising the amino acid sequence EIYPRSDNTFYNEKFKG (SEQ ID NO:47), and a heavy chain variable region CDR3 comprising the amino acid sequence HFGSSSFDY (SEQ ID NO:48).
  • the LAIR1-binding agent comprises a light chain variable region comprising a light chain variable region CDR1 comprising the amino acid sequence SASSSVSSIYFH (SEQ ID NO:49), a light chain variable region CDR2 comprising the amino acid sequence RASNLAS (SEQ ID NO:50), and a light chain variable region CDR3 comprising the amino acid sequence QQWSGYPLT (SEQ ID NO:51).
  • the LAIR1-binding agent comprises (a) a heavy chain variable region comprising a heavy chain variable region CDR1 comprising the amino acid sequence GYSFTSFGIS (SEQ ID NO:46), a heavy chain variable region CDR2 comprising the amino acid sequence EIYPRSDNTFYNEKFKG (SEQ ID NO:47), and a heavy chain variable region CDR3 comprising the amino acid sequence HFGSSSFDY (SEQ ID NO:48), and (b) a light chain variable region comprising a light chain variable region CDR1 comprising the amino acid sequence SASSSVSSIYFH (SEQ ID NO:49), a light chain variable region CDR2 comprising the amino acid sequence RASNLAS (SEQ ID NO:50), and a light chain variable region CDR3 comprising the amino acid sequence QQWSGYPLT (SEQ ID NO:51).
  • the LAIR1-binding agent comprises a heavy chain variable region having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:121.
  • the LAIR1-binding agent comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:121.
  • the LAIR1- binding agent comprises a light chain variable region having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:122.
  • the LAIR1-binding agent comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO:122.
  • the LAIR1-binding agent comprises a heavy chain variable region having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:121 and a light chain variable region having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:122.
  • the LAIR1-binding agent comprises a heavy chain variable region having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:121 and a light chain variable region having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:122.
  • the LAIR1-binding agent comprises a heavy chain variable region having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:121 and a light chain variable region having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:122. In some embodiments, the LAIR1-binding agent comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:121 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:122. [00260] In some embodiments, the LAIR1-binding agent is antibody 57D12. In some embodiments, the LAIR1-binding agent is a humanized version of antibody 57D12.
  • the LAIR1-binding agent is a variant of antibody 57D12 or a variant of a humanized version of antibody 57D12.
  • the LAIR1-binding agent comprises a heavy chain variable region CDR1, CDR2, and CDR3 and/or a light chain variable region CDR1, CDR2, and CDR3 from antibody 61H4, a humanized version thereof, or variants thereof.
  • the LAIR1-binding agent comprises a heavy chain variable region comprising a heavy chain variable region CDR1, a heavy chain variable region CDR2, and a heavy chain variable region CDR3 from antibody 61H4.
  • the LAIR1-binding agent comprises a light chain variable region comprising a light chain variable region CDR1, a light chain variable region CDR2, and a light chain variable region CDR3 from antibody 61H4.
  • the LAIR1-binding agent comprises: (a) a heavy chain variable region comprising a heavy chain variable region CDR1, a heavy chain variable region CDR2, a heavy chain variable region CDR3; and (b) a light chain variable region comprising a light chain variable region CDR1, a light chain variable region CDR2, and a light chain variable region CDR3 from antibody 61H4.
  • the LAIR1-binding agent comprises: (a) a heavy chain variable region CDR1 comprising the amino acid sequence GYTFTDYYYMN (SEQ ID NO:62), a heavy chain variable region CDR2 comprising the amino acid sequence YIYPNNGATSYNQKFKG (SEQ ID NO:63), a heavy chain variable region CDR3 comprising the amino acid sequence DGYSSNYYTMDY (SEQ ID NO:64), a light chain variable region CDR1 comprising the amino acid sequence QASQGTSINLN (SEQ ID NO:65), a light chain variable region CDR2 comprising the amino acid sequence GASNLED (SEQ ID NO:66), and a light chain variable region CDR3 comprising the amino acid sequence LQHTYLPYT (SEQ ID NO:67); (b) a heavy chain variable region CDR1 comprising the amino acid sequence GYTFTDYY (SEQ ID NO:68), a heavy chain variable region CDR2 comprising the amino acid sequence GYTFTDYY (
  • the LAIR1-binding agent comprises: (a) a heavy chain variable region comprising a heavy chain variable region CDR1 comprising the amino acid sequence GYTFTDYYYMN (SEQ ID NO:62), a heavy chain variable region CDR2 comprising the amino acid sequence YIYPNNGATSYNQKFKG (SEQ ID NO:63), and a heavy chain variable region CDR3 comprising the amino acid sequence DGYSSNYYTMDY (SEQ ID NO:64), and a light chain variable region comprising a light chain variable region CDR1 comprising the amino acid sequence QASQGTSINLN (SEQ ID NO:65), a light chain variable region CDR2 comprising the amino acid sequence GASNLED (SEQ ID NO:66), and a light chain variable region CDR3 comprising the amino acid sequence LQHTYLPYT (SEQ ID NO:67); (b) a heavy chain variable region comprising a heavy chain variable region CDR1 comprising the amino acid sequence G
  • the LAIR1-binding agent comprises: (a) a heavy chain variable region comprising a heavy chain variable region CDR1 comprising the amino acid sequence GYTFTDYYYMN (SEQ ID NO:62), a heavy chain variable region CDR2 comprising the amino acid sequence YIYPNNGATSYNQKFKG (SEQ ID NO:63), and a heavy chain variable region CDR3 comprising the amino acid sequence DGYSSNYYTMDY (SEQ ID NO:64), and/or (b) a light chain variable region comprising a light chain variable region CDR1 comprising the amino acid sequence QASQGTSINLN (SEQ ID NO:65), a light chain variable region CDR2 comprising the amino acid sequence GASNLED (SEQ ID NO:66), and a light chain variable region CDR3 comprising the amino acid sequence LQHTYLPYT (SEQ ID NO:67).
  • the LAIR1-binding agent comprises a heavy chain variable region comprising a heavy chain variable region CDR1 comprising the amino acid sequence GYTFTDYYYMN (SEQ ID NO:62), a heavy chain variable region CDR2 comprising the amino acid sequence YIYPNNGATSYNQKFKG (SEQ ID NO:63), and a heavy chain variable region CDR3 comprising the amino acid sequence DGYSSNYYTMDY (SEQ ID NO:64).
  • the LAIR1-binding agent comprises a light chain variable region comprising a light chain variable region CDR1 comprising the amino acid sequence QASQGTSINLN (SEQ ID NO:65), a light chain variable region CDR2 comprising the amino acid sequence GASNLED (SEQ ID NO:66), and a light chain variable region CDR3 comprising the amino acid sequence LQHTYLPYT (SEQ ID NO:67).
  • the LAIR1- binding agent comprises: (a) a heavy chain variable region comprising a heavy chain variable region CDR1 comprising the amino acid sequence GYTFTDYYYMN (SEQ ID NO:62), a heavy chain variable region CDR2 comprising the amino acid sequence YIYPNNGATSYNQKFKG (SEQ ID NO:63), and a heavy chain variable region CDR3 comprising the amino acid sequence DGYSSNYYTMDY (SEQ ID NO:64), and (b) a light chain variable region comprising a light chain variable region CDR1 comprising the amino acid sequence QASQGTSINLN (SEQ ID NO:65), a light chain variable region CDR2 comprising the amino acid sequence GASNLED (SEQ ID NO:66), and a light chain variable region CDR3 comprising the amino acid sequence LQHTYLPYT (SEQ ID NO:67).
  • the LAIR1-binding agent comprises a heavy chain variable region having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:123.
  • the LAIR1-binding agent comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:123.
  • the LAIR1- binding agent comprises a light chain variable region having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:124.
  • the LAIR1-binding agent comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO:124.
  • the LAIR1-binding agent comprises a heavy chain variable region having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:123 and a light chain variable region having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:124.
  • the LAIR1-binding agent comprises a heavy chain variable region having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:123 and a light chain variable region having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:124.
  • the LAIR1-binding agent comprises a heavy chain variable region having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:123 and a light chain variable region having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:124. In some embodiments, the LAIR1-binding agent comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:123 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:124. [00267] In some embodiments, the LAIR1-binding agent is antibody 61H4. In some embodiments, the LAIR1-binding agent is a humanized version of antibody 61H4.
  • the LAIR1-binding agent is a variant of antibody 61H4 or a variant of a humanized antibody 61H4.
  • the LAIR1-binding agent comprises a heavy chain variable region CDR1, CDR2, and CDR3 and/or a light chain variable region CDR1, CDR2, and CDR3 from antibody 62G10, a humanized version thereof, or variants thereof.
  • the LAIR1-binding agent comprises a heavy chain variable region comprising a heavy chain variable region CDR1, a heavy chain variable region CDR2, and a heavy chain variable region CDR3 from antibody 62G10.
  • the LAIR1-binding agent comprises a light chain variable region comprising a light chain variable region CDR1, a light chain variable region CDR2, and a light chain variable region CDR3 from antibody 62G10.
  • the LAIR1-binding agent comprises: (a) a heavy chain variable region comprising a heavy chain variable region CDR1, a heavy chain variable region CDR2, a heavy chain variable region CDR3; and (b) a light chain variable region comprising a light chain variable region CDR1, a light chain variable region CDR2, and a light chain variable region CDR3 from antibody 62G10.
  • the LAIR1-binding agent comprises: (a) a heavy chain variable region CDR1 comprising the amino acid sequence GFTFNINAMN (SEQ ID NO:25), a heavy chain variable region CDR2 comprising the amino acid sequence RIRTKNNNFATYYADSVKD (SEQ ID NO:78), a heavy chain variable region CDR3 comprising the amino acid sequence GPYFDY (SEQ ID NO:79), a light chain variable region CDR1 comprising the amino acid sequence LASQTIGTWLA (SEQ ID NO:80), a light chain variable region CDR2 comprising the amino acid sequence AATSLAD (SEQ ID NO:29), and a light chain variable region CDR3 comprising the amino acid sequence QQLYSTPYT (SEQ ID NO:81); (b) a heavy chain variable region CDR1 comprising the amino acid sequence GFTFNIN (SEQ ID NO:31), a heavy chain variable region CDR2 comprising the amino acid sequence RTKNNNFA (SEQ ID NO:31), a heavy
  • the LAIR1-binding agent comprises: (a) a heavy chain variable region comprising a heavy chain variable region CDR1 comprising the amino acid sequence GFTFNINAMN (SEQ ID NO:25), a heavy chain variable region CDR2 comprising the amino acid sequence RIRTKNNNFATYYADSVKD (SEQ ID NO:78), and a heavy chain variable region CDR3 comprising the amino acid sequence GPYFDY (SEQ ID NO:79), and a light chain variable region comprising a light chain variable region CDR1 comprising the amino acid sequence LASQTIGTWLA (SEQ ID NO:80), a light chain variable region CDR2 comprising the amino acid sequence AATSLAD (SEQ ID NO:29), and a light chain variable region CDR3 comprising the amino acid sequence QQLYSTPYT (SEQ ID NO:81); (b) a heavy chain variable region comprising a heavy chain variable region CDR1 comprising the amino acid sequence GFTFNIN (SEQ ID NO:25), a heavy chain variable
  • the LAIR1-binding agent comprises: (a) a heavy chain variable region comprising a heavy chain variable region CDR1 comprising the amino acid sequence GFTFNINAMN (SEQ ID NO:25), a heavy chain variable region CDR2 comprising the amino acid sequence RIRTKNNNFATYYADSVKD (SEQ ID NO:78), and a heavy chain variable region CDR3 comprising the amino acid sequence GPYFDY (SEQ ID NO:79), and/or (b) a light chain variable region comprising a light chain variable region CDR1 comprising the amino acid sequence LASQTIGTWLA (SEQ ID NO:80), a light chain variable region CDR2 comprising the amino acid sequence AATSLAD (SEQ ID NO:29), and a light chain variable region CDR3 comprising the amino acid sequence QQLYSTPYT (SEQ ID NO:81).
  • the LAIR1-binding agent comprises a heavy chain variable region comprising a heavy chain variable region CDR1 comprising the amino acid sequence GFTFNINAMN (SEQ ID NO:25), a heavy chain variable region CDR2 comprising the amino acid sequence RIRTKNNNFATYYADSVKD (SEQ ID NO:78), and a heavy chain variable region CDR3 comprising the amino acid sequence GPYFDY (SEQ ID NO:79).
  • the LAIR1-binding agent comprises a light chain variable region comprising a light chain variable region CDR1 comprising the amino acid sequence LASQTIGTWLA (SEQ ID NO:80), a light chain variable region CDR2 comprising the amino acid sequence AATSLAD (SEQ ID NO:29), and a light chain variable region CDR3 comprising the amino acid sequence QQLYSTPYT (SEQ ID NO:81).
  • the LAIR1-binding agent comprises: (a) a heavy chain variable region comprising a heavy chain variable region CDR1 comprising the amino acid sequence GFTFNINAMN (SEQ ID NO:25), a heavy chain variable region CDR2 comprising the amino acid sequence RIRTKNNNFATYYADSVKD (SEQ ID NO:78), and a heavy chain variable region CDR3 comprising the amino acid sequence GPYFDY (SEQ ID NO:79), and (b) a light chain variable region comprising a light chain variable region CDR1 comprising the amino acid sequence LASQTIGTWLA (SEQ ID NO:80), a light chain variable region CDR2 comprising the amino acid sequence AATSLAD (SEQ ID NO:29), and a light chain variable region CDR3 comprising the amino acid sequence QQLYSTPYT (SEQ ID NO:81).
  • the LAIR1-binding agent comprises a heavy chain variable region having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:125. In some embodiments, the LAIR1-binding agent comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:125. In some embodiments, the LAIR1- binding agent comprises a heavy chain variable region having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:127.
  • the LAIR1-binding agent comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:127. In some embodiments, the LAIR1-binding agent comprises a light chain variable region having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:126. In some embodiments, the LAIR1-binding agent comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO:126.
  • the LAIR1- binding agent comprises a light chain variable region having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:128.
  • the LAIR1-binding agent comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO:128.
  • the LAIR1-binding agent comprises a heavy chain variable region having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:125 and a light chain variable region having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:126.
  • the LAIR1-binding agent comprises a heavy chain variable region having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:125 and a light chain variable region having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:126. In some embodiments, the LAIR1-binding agent comprises a heavy chain variable region having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:125 and a light chain variable region having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:126. In some embodiments, the LAIR1-binding agent comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:125 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:126.
  • the LAIR1-binding agent comprises a heavy chain variable region having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:127 and a light chain variable region having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:128. In some embodiments, the LAIR1-binding agent comprises a heavy chain variable region having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:127 and a light chain variable region having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:128.
  • the LAIR1-binding agent comprises a heavy chain variable region having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:127 and a light chain variable region having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:128. In some embodiments, the LAIR1-binding agent comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:127 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:128.
  • the LAIR1-binding agent comprises: (a) a heavy chain comprising a heavy chain variable region CDR1 comprising the amino acid sequence GFTFNINAMN (SEQ ID NO:25), a heavy chain variable region CDR2 comprising the amino acid sequence RIRTKNNNFATYYADSVKD (SEQ ID NO:78), and a heavy chain variable region CDR3 comprising the amino acid sequence GPYFDY (SEQ ID NO:79), and (b) a light chain variable region comprising a light chain variable region CDR1 comprising the amino acid sequence LASQTIGTWLA (SEQ ID NO:80), a light chain variable region CDR2 comprising the amino acid sequence AATSLAD (SEQ ID NO:29), and a light chain variable region CDR3 comprising the amino acid sequence QQLYSTPYT (SEQ ID NO:81), wherein the heavy chain comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%
  • the LAIR1-binding agent comprises: (a) a heavy chain comprising a heavy chain variable region CDR1 comprising the amino acid sequence GFTFNINAMN (SEQ ID NO:25), a heavy chain variable region CDR2 comprising the amino acid sequence RIRTKNNNFATYYADSVKD (SEQ ID NO:78), and a heavy chain variable region CDR3 comprising the amino acid sequence GPYFDY (SEQ ID NO:79), and (b) a light chain variable region comprising a light chain variable region CDR1 comprising the amino acid sequence LASQTIGTWLA (SEQ ID NO:80), a light chain variable region CDR2 comprising the amino acid sequence AATSLAD (SEQ ID NO:29), and a light chain variable region CDR3 comprising the amino acid sequence QQLYSTPYT (SEQ ID NO:81), wherein the heavy chain comprises at least 95% sequence identity to the amino acid sequence of SEQ ID NO:138, and wherein the light chain comprises at least 95% sequence identity
  • the LAIR1- binding agent comprises: (a) a heavy chain comprising the amino acid sequence of SEQ ID NO:138 and (b) a light chain comprising a light chain variable region CDR1 comprising the amino acid sequence LASQTIGTWLA (SEQ ID NO:80), a light chain variable region CDR2 comprising the amino acid sequence AATSLAD (SEQ ID NO:29), and a light chain variable region CDR3 comprising the amino acid sequence QQLYSTPYT (SEQ ID NO:81), wherein the light chain comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to the amino acid sequence of SEQ ID NO:140.
  • the LAIR1-binding agent comprises: (a) a heavy chain comprising a heavy chain variable region CDR1 comprising the amino acid sequence GFTFNINAMN (SEQ ID NO:25), a heavy chain variable region CDR2 comprising the amino acid sequence RIRTKNNNFATYYADSVKD (SEQ ID NO:78), and a heavy chain variable region CDR3 comprising the amino acid sequence GPYFDY (SEQ ID NO:79), wherein the heavy chain comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 100% sequence identity to the amino acid sequence of SEQ ID NO:138, and (b) a light chain comprising the amino acid sequence of SEQ ID NO:140.
  • the LAIR1-binding agent is an antibody comprising a heavy chain comprising the amino acid sequence of SEQ ID NO:138 and a light chain comprising the amino acid sequence of SEQ ID NO:140.
  • the LAIR1-binding agent is antibody 62G10.
  • the LAIR1-binding agent is a humanized version of antibody 62G10 (e.g., Hz62G10.v1).
  • the LAIR1-binding agent is a variant of antibody 62G10 or a variant of humanized antibody 62G10.
  • the LAIR1-binding agent is antibody Hz62G10.v1.
  • the LAIR1-binding agent comprises a heavy chain variable region CDR1, CDR2, and CDR3 and/or a light chain variable region CDR1, CDR2, and CDR3 from antibody 108D10, a humanized version thereof, or variants thereof.
  • the LAIR1-binding agent comprises a heavy chain variable region comprising a heavy chain variable region CDR1, a heavy chain variable region CDR2, and a heavy chain variable region CDR3 from antibody 108D10.
  • the LAIR1-binding agent comprises a light chain variable region comprising a light chain variable region CDR1, a light chain variable region CDR2, and a light chain variable region CDR3 from antibody 108D10.
  • the LAIR1-binding agent comprises: (a) a heavy chain variable region comprising a heavy chain variable region CDR1, a heavy chain variable region CDR2, a heavy chain variable region CDR3; and (b) a light chain variable region comprising a light chain variable region CDR1, a light chain variable region CDR2, and a light chain variable region CDR3 from antibody 108D10.
  • the LAIR1-binding agent comprises: (a) a heavy chain variable region CDR1 comprising the amino acid sequence GFTFNINAMN (SEQ ID NO:25), a heavy chain variable region CDR2 comprising the amino acid sequence RIRTKNNNYATYYADSVKD (SEQ ID NO:88), a heavy chain variable region CDR3 comprising the amino acid sequence DRYGGAMAY (SEQ ID NO:89), a light chain variable region CDR1 comprising the amino acid sequence KASEDIYNRLA (SEQ ID NO:90), a light chain variable region CDR2 comprising the amino acid sequence SATSLET (SEQ ID NO:91), and a light chain variable region CDR3 comprising the amino acid sequence QQYWTIPYT (SEQ ID NO:92); (b) a heavy chain variable region CDR1 comprising the amino acid sequence GFTFNIN (SEQ ID NO:31), a heavy chain variable region CDR2 comprising the amino acid sequence RTKNNNYA (SEQ ID NO:31), a heavy
  • the LAIR1-binding agent comprises: (a) a heavy chain variable region comprising a heavy chain variable region CDR1 comprising the amino acid sequence GFTFNINAMN (SEQ ID NO:25), a heavy chain variable region CDR2 comprising the amino acid sequence RIRTKNNNYATYYADSVKD (SEQ ID NO:88), and a heavy chain variable region CDR3 comprising the amino acid sequence DRYGGAMAY (SEQ ID NO:89), and a light chain variable region comprising a light chain variable region CDR1 comprising the amino acid sequence KASEDIYNRLA (SEQ ID NO:90), a light chain variable region CDR2 comprising the amino acid sequence SATSLET (SEQ ID NO:91), and a light chain variable region CDR3 comprising the amino acid sequence QQYWTIPYT (SEQ ID NO:92); (b) a heavy chain variable region comprising a heavy chain variable region CDR1 comprising the amino acid sequence GFTFNIN (SEQ ID NO:25), a heavy chain variable
  • the LAIR1-binding agent comprises: (a) a heavy chain variable region comprising a heavy chain variable region CDR1 comprising the amino acid sequence GFTFNINAMN (SEQ ID NO:25), a heavy chain variable region CDR2 comprising the amino acid sequence RIRTKNNNYATYYADSVKD (SEQ ID NO:88), and a heavy chain variable region CDR3 comprising the amino acid sequence DRYGGAMAY (SEQ ID NO:89), and/or (b) a light chain variable region comprising a light chain variable region CDR1 comprising the amino acid sequence KASEDIYNRLA (SEQ ID NO:90), a light chain variable region CDR2 comprising the amino acid sequence SATSLET (SEQ ID NO:91), and a light chain variable region CDR3 comprising the amino acid sequence QQYWTIPYT (SEQ ID NO:92).
  • the LAIR1-binding agent comprises a heavy chain variable region comprising a heavy chain variable region CDR1 comprising the amino acid sequence GFTFNINAMN (SEQ ID NO:25), a heavy chain variable region CDR2 comprising the amino acid sequence RIRTKNNNYATYYADSVKD (SEQ ID NO:88), and a heavy chain variable region CDR3 comprising the amino acid sequence DRYGGAMAY (SEQ ID NO:89).
  • the LAIR1-binding agent comprises a light chain variable region comprising a light chain variable region CDR1 comprising the amino acid sequence KASEDIYNRLA (SEQ ID NO:90), a light chain variable region CDR2 comprising the amino acid sequence SATSLET (SEQ ID NO:91), and a light chain variable region CDR3 comprising the amino acid sequence QQYWTIPYT (SEQ ID NO:92).
  • the LAIR1-binding agent comprises: (a) a heavy chain variable region comprising a heavy chain variable region CDR1 comprising the amino acid sequence GFTFNINAMN (SEQ ID NO:25), a heavy chain variable region CDR2 comprising the amino acid sequence RIRTKNNNYATYYADSVKD (SEQ ID NO:88), and a heavy chain variable region CDR3 comprising the amino acid sequence DRYGGAMAY (SEQ ID NO:89), and (b) a light chain variable region comprising a light chain variable region CDR1 comprising the amino acid sequence KASEDIYNRLA (SEQ ID NO:90), a light chain variable region CDR2 comprising the amino acid sequence SATSLET (SEQ ID NO:91), and a light chain variable region CDR3 comprising the amino acid sequence QQYWTIPYT (SEQ ID NO:92).
  • the LAIR1-binding agent comprises a heavy chain variable region having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:129.
  • the LAIR1-binding agent comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:129.
  • the LAIR1- binding agent comprises a light chain variable region having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:130.
  • the LAIR1-binding agent comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO:130.
  • the LAIR1-binding agent comprises a heavy chain variable region having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:129 and a light chain variable region having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:130.
  • the LAIR1-binding agent comprises a heavy chain variable region having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:129 and a light chain variable region having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:130.
  • the LAIR1-binding agent comprises a heavy chain variable region having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:129 and a light chain variable region having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:130. In some embodiments, the LAIR1-binding agent comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:129 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:130. [00283] In some embodiments, the LAIR1-binding agent is antibody 108D10. In some embodiments, the LAIR1-binding agent is a humanized version of antibody 108D10.
  • the LAIR1-binding agent is a variant of antibody 108D10 or a variant of humanized antibody 108D10.
  • a LAIR1-binding agent binds mouse LAIR1.
  • the LAIR1-binding agent comprises a heavy chain variable region CDR1, CDR2, and CDR3 and/or a light chain variable region CDR1, CDR2, and CDR3 from antibody 43H2 or variants thereof.
  • the LAIR1-binding agent comprises a heavy chain variable region comprising a heavy chain variable region CDR1, a heavy chain variable region CDR2, and a heavy chain variable region CDR3 from antibody 43H2.
  • the LAIR1-binding agent comprises a light chain variable region comprising a light chain variable region CDR1, a light chain variable region CDR2, and a light chain variable region CDR3 from antibody 43H2.
  • the LAIR1-binding agent comprises: (a) a heavy chain variable region comprising a heavy chain variable region CDR1, a heavy chain variable region CDR2, a heavy chain variable region CDR3; and (b) a light chain variable region comprising a light chain variable region CDR1, a light chain variable region CDR2, and a light chain variable region CDR3 from antibody 43H2.
  • the LAIR1-binding agent comprises: (a) a heavy chain variable region CDR1 comprising the amino acid sequence GFTFSNYGIH (SEQ ID NO:99), a heavy chain variable region CDR2 comprising the amino acid sequence SISPSGRSTYFRDSVKG (SEQ ID NO:100), a heavy chain variable region CDR3 comprising the amino acid sequence GINYSSFDY (SEQ ID NO:101), a light chain variable region CDR1 comprising the amino acid sequence KASQNVGSHVD (SEQ ID NO:102), a light chain variable region CDR2 comprising the amino acid sequence TASNRYT (SEQ ID NO:103), and a light chain variable region CDR3 comprising the amino acid sequence MQSNSYPPT (SEQ ID NO:104); (b) a heavy chain variable region CDR1 comprising the amino acid sequence GFTFSNY (SEQ ID NO:105), a heavy chain variable region CDR2 comprising the amino acid sequence SPSGRS (SEQ ID NO:
  • the LAIR1-binding agent comprises: (a) a heavy chain variable region comprising a heavy chain variable region CDR1 comprising the amino acid sequence GFTFSNYGIH (SEQ ID NO:99), a heavy chain variable region CDR2 comprising the amino acid sequence SISPSGRSTYFRDSVKG (SEQ ID NO:100), and a heavy chain variable region CDR3 comprising the amino acid sequence GINYSSFDY (SEQ ID NO:101), and a light chain variable region comprising a light chain variable region CDR1 comprising the amino acid sequence KASQNVGSHVD (SEQ ID NO:102), a light chain variable region CDR2 comprising the amino acid sequence TASNRYT (SEQ ID NO:103), and a light chain variable region CDR3 comprising the amino acid sequence MQSNSYPPT (SEQ ID NO:104); (b) a heavy chain variable region comprising a heavy chain variable region CDR1 comprising the amino acid sequence GFTFSNY (SEQ ID NO:99), a heavy chain
  • the LAIR1-binding agent comprises: (a) a heavy chain variable region comprising a heavy chain variable region CDR1 comprising the amino acid sequence GFTFSNYGIH (SEQ ID NO:99), a heavy chain variable region CDR2 comprising the amino acid sequence SISPSGRSTYFRDSVKG (SEQ ID NO:100), and a heavy chain variable region CDR3 comprising the amino acid sequence GINYSSFDY (SEQ ID NO:101), and/or (b) a light chain variable region comprising a light chain variable region CDR1 comprising the amino acid sequence KASQNVGSHVD (SEQ ID NO:102), a light chain variable region CDR2 comprising the amino acid sequence TASNRYT (SEQ ID NO:103), and a light chain variable region CDR3 comprising the amino acid sequence MQSNSYPPT (SEQ ID NO:104).
  • the LAIR1-binding agent comprises a heavy chain variable region comprising a heavy chain variable region comprising a heavy chain variable region CDR1 comprising the amino acid sequence GFTFSNYGIH (SEQ ID NO:99), a heavy chain variable region CDR2 comprising the amino acid sequence SISPSGRSTYFRDSVKG (SEQ ID NO:100), and a heavy chain variable region CDR3 comprising the amino acid sequence GINYSSFDY (SEQ ID NO:101).
  • the LAIR1-binding agent comprises a light chain variable region comprising a light chain variable region CDR1 comprising the amino acid sequence KASQNVGSHVD (SEQ ID NO:102), a light chain variable region CDR2 comprising the amino acid sequence TASNRYT (SEQ ID NO:103), and a light chain variable region CDR3 comprising the amino acid sequence MQSNSYPPT (SEQ ID NO:104).
  • the LAIR1-binding agent comprises: (a) a heavy chain variable region comprising a heavy chain variable region CDR1 comprising the amino acid sequence GFTFSNYGIH (SEQ ID NO:99), a heavy chain variable region CDR2 comprising the amino acid sequence SISPSGRSTYFRDSVKG (SEQ ID NO:100), and a heavy chain variable region CDR3 comprising the amino acid sequence GINYSSFDY (SEQ ID NO:101), and (b) a light chain variable region comprising a light chain variable region CDR1 comprising the amino acid sequence KASQNVGSHVD (SEQ ID NO:102), a light chain variable region CDR2 comprising the amino acid sequence TASNRYT (SEQ ID NO:103), and a light chain variable region CDR3 comprising the amino acid sequence MQSNSYPPT (SEQ ID NO:104).
  • the LAIR1-binding agent comprises a heavy chain variable region having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:131.
  • the LAIR1-binding agent comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:131.
  • the LAIR1- binding agent comprises a light chain variable region having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:132.
  • the LAIR1-binding agent comprises a light chain variable region comprising the amino acid sequence of SEQ ID NO:132.
  • the LAIR1-binding agent comprises a heavy chain variable region having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:131 and a light chain variable region having at least 80% sequence identity to the amino acid sequence of SEQ ID NO:132.
  • the LAIR1-binding agent comprises a heavy chain variable region having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:131 and a light chain variable region having at least 90% sequence identity to the amino acid sequence of SEQ ID NO:132.
  • the LAIR1-binding agent comprises a heavy chain variable region having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:131 and a light chain variable region having at least 95% sequence identity to the amino acid sequence of SEQ ID NO:132. In some embodiments, the LAIR1-binding agent comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:131 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:132. [00290] In some embodiments, the LAIR1-binding agent is antibody 43H2. In some embodiments, the LAIR1-binding agent is a humanized version of antibody 43H2.
  • the LAIR1-binding agent is a variant of antibody 43H2 or a variant of humanized antibody 43H2.
  • an agent competes with one or more of the binding agents described herein for binding to LAIR1.
  • an agent competes with one or more of the binding agents described herein for binding to human LAIR1.
  • an agent that competes with one or more of the binding agents described herein is an antibody.
  • an agent binds the same epitope as one of the LAIR1-binding agents described herein.
  • an agent binds an epitope overlapping with an epitope bound by one of the LAIR1-binding agents described herein.
  • Antibodies and antigen-binding fragments that compete with or bind the same epitope as the LAIR1-binding agents described herein are expected to show similar functional properties.
  • an agent competes for binding to human LAIR1 with a reference antibody
  • the reference antibody comprises: (a) a heavy chain variable region comprising a heavy chain variable region CDR1 comprising the amino acid sequence GFTFNINAMN (SEQ ID NO:25), a heavy chain variable region CDR2 comprising the amino acid sequence RIRTKNNNYATFYADSVKD (SEQ ID NO:26) or RIRTKNYNYATFYADSVKD (SEQ ID NO:41), and a heavy chain variable region CDR3 comprising the amino acid sequence DRAGFFAY (SEQ ID NO:27), and a light chain variable region comprising a light chain variable region CDR1 comprising the amino acid sequence LASQTIGTWLG (SEQ ID NO:28), a light chain variable region CDR2 comprising the amino acid sequence AATSLAD (SEQ ID NO:29) or AATSLAE (SEQ ID NO:42), and a light chain variable region CDR3 comprising the amino acid sequence Q
  • the reference antibody is antibody 47H1 or Hz47H1.v4.
  • an agent competes for binding to human LAIR1 with a reference antibody, wherein the reference antibody comprises: (a) a heavy chain variable region comprising a heavy chain variable region CDR1 comprising the amino acid sequence GFTFNTYAIH (SEQ ID NO:9), a heavy chain variable region CDR2 comprising the amino acid sequence RIRSKSTNYATYYADSVKD (SEQ ID NO:10), and a heavy chain variable region CDR3 comprising the amino acid sequence ENWYYYALDY (SEQ ID NO:11), and a light chain variable region comprising a light chain variable region CDR1 comprising the amino acid sequence RASGNIHNYLT (SEQ ID NO:12), a light chain variable region CDR2 comprising the amino acid sequence NAKTLED (SEQ ID NO:13), and a light chain variable region CDR3 comprising the amino acid sequence QHFWSTPFT (SEQ ID NO:14).
  • the reference antibody is antibody 47A1.
  • the LAIR1-binding agent described herein comprises an antibody in which at least one or more of the constant regions of the antibody has been modified or deleted.
  • an antibody comprises one or more modifications to one or more of the heavy chain constant regions (CH1, CH2, CH3, or CH4) and/or to the light chain constant region (CL).
  • an antibody comprises one or more modifications to the hinge region.
  • the heavy chain constant region of the modified antibody comprises at least one human constant region. In some embodiments, the heavy chain constant region of the modified antibody comprises more than one human constant region.
  • modifications to the constant region comprise additions, deletions, or substitutions of one or more amino acids in one or more regions.
  • one or more regions are partially or entirely deleted from the constant regions of a modified antibody.
  • the entire CH2 domain has been removed from an antibody ( ⁇ CH2 constructs).
  • one or more regions are partially or entirely deleted from the hinge region of a modified antibody.
  • a deleted constant region is replaced by a short amino acid spacer that provides some of the molecular flexibility typically imparted by the absent constant region.
  • a deleted hinge region is replaced by a short amino acid spacer that provides some of the molecular flexibility typically imparted by the absent hinge region.
  • a modified antibody comprises a CH3 domain directly fused to the hinge region of the antibody. In some embodiments, a modified antibody comprises a peptide spacer inserted between the hinge region and modified CH2 and/or CH3 domains.
  • the constant region(s) of an antibody mediates several effector functions and these effector functions can vary depending on the isotype of the antibody. For example, binding of the C1q component of complement to the Fc region of IgG or IgM antibodies when the antibodies are bound to antigen activates the complement system. Activation of complement is important in the opsonization and lysis of cell pathogens. The activation of complement also stimulates the inflammatory immune response and can be involved in autoimmune hypersensitivity.
  • the Fc region of an antibody can bind a cell expressing a Fc receptor (FcR).
  • FcR Fc receptor
  • Fc receptors There are a number of Fc receptors that are specific for different classes of antibody, including IgG (gamma receptors), IgE (epsilon receptors), IgA (alpha receptors) and IgM (mu receptors). Binding of antibody to Fc receptors on cell surfaces triggers a number of important and diverse biological responses including, but not limited to, engulfment and destruction of antibody-coated particles, clearance of immune complexes, lysis of antibody-coated target cells by killer cells (i.e., antibody-dependent cell cytotoxicity or ADCC), release of inflammatory mediators, placental transfer, and control of immunoglobulin production.
  • killer cells i.e., antibody-dependent cell cytotoxicity or ADCC
  • the LAIR1-binding agent comprises a variant constant region or Fc region.
  • the amino acid sequences of the constant region or Fc region of human IgG1, IgG2, IgG3, and IgG4 are known to those of ordinary skill in the art (e.g., a representative human IgG1 constant region is SEQ ID NO:141).
  • constant regions or Fc regions with amino acid variations have been identified in native antibodies.
  • a variant constant region or Fc region is engineered with substitutions at specific amino acid positions as compared to a native constant region or Fc region.
  • a modified antibody provides for altered effector functions that, in turn, affect the biological profile of the antibody.
  • the deletion or inactivation (through point mutations or other means) of a constant region reduces binding of a modified antibody to a Fc receptor.
  • constant region modifications increase the serum half-life of an antibody.
  • constant region modifications reduce the serum half-life of an antibody.
  • constant region modifications decrease or remove ADCC and/or complement-dependent cytotoxicity (CDC) of an antibody.
  • a human IgG1 Fc region with specific amino acid substitutions corresponding to IgG2 or IgG4 residues reduce effector functions (e.g., ADCC and CDC) in a modified antibody.
  • a modified antibody does not have one or more effector functions.
  • a modified antibody has no ADCC activity and/or no CDC activity.
  • a modified antibody does not bind an Fc receptor and/or complement factors.
  • a modified antibody does not have any detectable effector functions (e.g., an “effectorless” antibody).
  • constant region modifications increase or enhance ADCC and/or CDC of an antibody.
  • the constant region is modified to eliminate disulfide linkages or oligosaccharide moieties.
  • the constant region is modified to add/substitute one or more amino acids to provide one or more cytotoxin, oligosaccharide, or carbohydrate attachment sites.
  • Modifications to the constant region of antibodies described herein may be made using well-known biochemical or molecular engineering techniques.
  • antibody variants are prepared by introducing appropriate nucleotide changes into the encoding DNA, and/or by synthesis of the desired antibody or polypeptide.
  • the present disclosure further embraces additional variants and equivalents that are substantially homologous to the recombinant, monoclonal, chimeric, humanized, and human antibodies, or antibody fragments thereof, described herein. In some embodiments, it is desirable to improve the binding affinity of the antibody. In some embodiments, it is desirable to modulate biological properties of the antibody, including but not limited to, specificity, thermostability, expression level, effector function(s), glycosylation, immunogenicity, and/or solubility.
  • amino acid changes may alter post- translational processes of an antibody, such as changing the number or position of glycosylation sites or altering membrane anchoring characteristics.
  • Variations may be a substitution, deletion, or insertion of one or more nucleotides encoding the antibody or polypeptide that results in a change in the amino acid sequence as compared with the native antibody or polypeptide sequence.
  • amino acid substitutions are the result of replacing one amino acid with another amino acid having similar structural and/or chemical properties, such as the replacement of a leucine with a serine (i.e., conservative amino acid replacements).
  • the substitution, deletion, or insertion includes less than 25 amino acid substitutions, less than 20 amino acid substitutions, less than 15 amino acid substitutions, less than 10 amino acid substitutions, less than 5 amino acid substitutions, less than 4 amino acid substitutions, less than 3 amino acid substitutions, or less than 2 amino acid substitutions relative to the parent molecule.
  • variations in the amino acid sequence that are biologically useful and/or relevant are determined by systematically making insertions, deletions, or substitutions in the sequence and testing the resulting variant proteins for activity as compared to the parental antibody.
  • variants may include addition of amino acid residues at the amino- and/or carboxyl-terminal end of the antibody or polypeptide.
  • a variant comprises an N-terminal methionyl residue.
  • the variant comprises an additional polypeptide/protein to create a fusion protein.
  • a variant is engineered to be detectable and may comprise a detectable label and/or protein (e.g., a fluorescent tag, a fluorescent protein, or an enzyme).
  • a cysteine residue not involved in maintaining the proper conformation of an antibody is substituted or deleted to modulate the antibody’s characteristics, for example, to improve oxidative stability and/or prevent aberrant disulfide crosslinking.
  • an antibody of the present disclosure is “deimmunized”.
  • the deimmunization of antibodies generally consists of introducing specific amino acid mutations (e.g., substitutions, deletions, additions) that result in removal of T-cell epitopes (known or predicted) without significantly reducing the binding affinity or other desired activities of the antibody.
  • the variant antibodies or polypeptides described herein may be generated using methods known in the art, including but not limited to, site-directed mutagenesis, alanine scanning mutagenesis, and PCR mutagenesis.
  • the LAIR1-binding agent described herein is chemically modified.
  • the LAIR1-binding agent is an anti-LAIR1 antibody that is chemically modified by glycosylation, acetylation, pegylation, phosphorylation, amidation, derivatization by known protecting/blocking groups, proteolytic cleavage, and/or linkage to a cellular ligand or other protein. Any of numerous chemical modifications may be carried out by known techniques.
  • the LAIR1-binding agent is attached (either directly or indirectly) to a half-life extending moiety including, but not limited to, polyethylene glycol (PEG), a PEG mimetic, XTEN®, serum albumin, polysialic acid, N-(2- hydroxypropyl)methacrylamide, or dextran.
  • the LAIR1-binding agent is an antibody, wherein the antibody is attached (either directly or indirectly) to a half-life extending moiety including, but not limited to, polyethylene glycol (PEG), a PEG mimetic, XTEN®, serum albumin, polysialic acid, N-(2-hydroxypropyl)methacrylamide, or dextran.
  • the LAIR1-binding agent is an antibody fragment (e.g., scFv, Fv, Fab, F(ab′) 2 , or F(ab′)), wherein the antibody fragment is attached (either directly or indirectly) to a half-life extending moiety including, but not limited to, polyethylene glycol (PEG), a PEG mimetic, XTEN®, serum albumin, polysialic acid, N-(2-hydroxypropyl)methacrylamide, or dextran.
  • PEG polyethylene glycol
  • the present disclosure encompasses LAIR1-binding agents built upon non- immunoglobulin backbones, wherein the agents bind the same epitope or essentially the same epitope as an anti-LAIR1 antibody disclosed herein.
  • a non- immunoglobulin-based binding agent is an agent that competes with a LAIR1-binding agent described herein in a competitive binding assay.
  • alternative LAIR1- binding agents comprise a scaffold protein.
  • scaffold proteins can be assigned to one of three groups based on the architecture of their backbone (1) scaffolds consisting of ⁇ -helices; (2) small scaffolds with few secondary structures or an irregular architecture of ⁇ -helices and ⁇ - sheets; and (3) scaffolds consisting of predominantly ⁇ -sheets.
  • Scaffold proteins include, but are not limited to, (i) anticalins, which are based upon the lipocalin scaffold; (ii) adnectins, which are based on the 10 th domain of human fibronectin type 3; (iii) affibodies, which are based on the B-domain in the Ig-binding region of Staphylococcus aureus protein A; (iv) darpins, which are based on ankyrin repeat domain proteins; (v) fynomers, which are based on the SH3 domain of the human Fyn protein kinase; (vi) affitins, which are based on Sac7d from Sulfolobus acidocaldarius; (vii) affilins, which are based on human ⁇ -B-crystallin or human ubiquitin; (viii) avimers, which are based on the A-domains of membrane receptor proteins; (ix) knottins (cysteine knot mini
  • the LAIR1-binding agent comprises an engineered scaffold protein comprising a heavy chain variable region CDR1, CDR2, and CDR3 and a light chain variable region CDR1, CDR2, and CDR3 shown in Table 1.
  • the LAIR1- binding agent comprises an engineered scaffold protein comprising a heavy chain variable region CDR1 comprising the amino acid sequence GFTFNTYAIH (SEQ ID NO:9), a heavy chain variable region CDR2 comprising the amino acid sequence RIRSKSTNYATYYADSVKD (SEQ ID NO:10), a heavy chain variable region CDR3 comprising the amino acid sequence ENWYYYALDY (SEQ ID NO:11), a light chain variable region CDR1 comprising the amino acid sequence RASGNIHNYLT (SEQ ID NO:12), a light chain variable region CDR2 comprising the amino acid sequence NAKTLED (SEQ ID NO:13), and a light chain variable region CDR3 comprising the amino acid sequence QHFWSTPFT (SEQ ID NO:9), a heavy chain variable
  • the LAIR1-binding agent comprises an engineered scaffold protein comprising a heavy chain variable region CDR1, CDR2, and CDR3 and a light chain variable region CDR1, CDR2, and CDR3 from antibody 47A1.
  • the LAIR1-binding agent comprises an engineered scaffold protein comprising a heavy chain variable region CDR1, CDR2, and CDR3 and a light chain variable region CDR1, CDR2, and CDR3 shown in Table 2A or 2B.
  • the LAIR1-binding agent comprises an engineered scaffold protein comprising a heavy chain variable region CDR1 comprising the amino acid sequence GFTFNINAMN (SEQ ID NO:25), a heavy chain variable region CDR2 comprising the amino acid sequence RIRTKNNNYATFYADSVKD (SEQ ID NO:26) or RIRTKNYNYATFYADSVKD (SEQ ID NO:41), a heavy chain variable region CDR3 comprising the amino acid sequence DRAGFFAY (SEQ ID NO:27), a light chain variable region CDR1 comprising the amino acid sequence LASQTIGTWLG (SEQ ID NO:28), a light chain variable region CDR2 comprising the amino acid sequence AATSLAD (SEQ ID NO:29) or AATSLAE (SEQ ID NO:42), and a light chain variable region CDR3 comprising the amino acid sequence QQLYSTPLT (SEQ ID NO:30).
  • a heavy chain variable region CDR1 comprising the amino acid sequence GFTFNINAMN (S
  • the LAIR1-binding agent comprises an engineered scaffold protein comprising a heavy chain variable region CDR1, CDR2, and CDR3 and a light chain variable region CDR1, CDR2, and CDR3 from antibody 47H1 or Hz47H1.v4.
  • the LAIR1-binding agent comprises an engineered scaffold protein comprising a heavy chain variable region CDR1, CDR2, and CDR3 and a light chain variable region CDR1, CDR2, and CDR3 shown in Table 3.
  • the LAIR1- binding agent comprises an engineered scaffold protein comprising a heavy chain variable region CDR1 comprising the amino acid sequence GYSFTSFGIS (SEQ ID NO:46), a heavy chain variable region CDR2 comprising the amino acid sequence EIYPRSDNTFYNEKFKG (SEQ ID NO:47), a heavy chain variable region CDR3 comprising the amino acid sequence HFGSSSFDY (SEQ ID NO:48), a light chain variable region CDR1 comprising the amino acid sequence SASSSVSSIYFH (SEQ ID NO:49), a light chain variable region CDR2 comprising the amino acid sequence RASNLAS (SEQ ID NO:50), and a light chain variable region CDR3 comprising the amino acid sequence QQWSGYPLT (SEQ ID NO:51).
  • the LAIR1-binding agent comprises an engineered scaffold protein comprising a heavy chain variable region CDR1, CDR2, and CDR3 and a light chain variable region CDR1, CDR2, and CDR3 from antibody 57D12. [00310] In some embodiments, the LAIR1-binding agent comprises an engineered scaffold protein comprising a heavy chain variable region CDR1, CDR2, and CDR3 and a light chain variable region CDR1, CDR2, and CDR3 shown in Table 4.
  • the LAIR1- binding agent comprises an engineered scaffold protein comprising a heavy chain variable region CDR1 comprising the amino acid sequence GYTFTDYYYMN (SEQ ID NO:62), a heavy chain variable region CDR2 comprising the amino acid sequence YIYPNNGATSYNQKFKG (SEQ ID NO:63), a heavy chain variable region CDR3 comprising the amino acid sequence DGYSSNYYTMDY (SEQ ID NO:64), a light chain variable region CDR1 comprising the amino acid sequence QASQGTSINLN (SEQ ID NO:65), a light chain variable region CDR2 comprising the amino acid sequence GASNLED (SEQ ID NO:66), and a light chain variable region CDR3 comprising the amino acid sequence LQHTYLPYT (SEQ ID NO:67).
  • a heavy chain variable region CDR1 comprising the amino acid sequence GYTFTDYYYMN
  • a heavy chain variable region CDR2 comprising the amino acid sequence YIYPNNGATSYN
  • the LAIR1-binding agent comprises an engineered scaffold protein comprising a heavy chain variable region CDR1, CDR2, and CDR3 and a light chain variable region CDR1, CDR2, and CDR3 from antibody 61H4. [00311] In some embodiments, the LAIR1-binding agent comprises an engineered scaffold protein comprising a heavy chain variable region CDR1, CDR2, and CDR3 and a light chain variable region CDR1, CDR2, and CDR3 shown in Table 5.
  • the LAIR1- binding agent comprises an engineered scaffold protein comprising a heavy chain variable region CDR1 comprising the amino acid sequence GFTFNINAMN (SEQ ID NO:25), a heavy chain variable region CDR2 comprising the amino acid sequence RIRTKNNNFATYYADSVKD (SEQ ID NO:78), a heavy chain variable region CDR3 comprising the amino acid sequence GPYFDY (SEQ ID NO:79), a light chain variable region CDR1 comprising the amino acid sequence LASQTIGTWLA (SEQ ID NO:80), a light chain variable region CDR2 comprising the amino acid sequence AATSLAD (SEQ ID NO:29), and a light chain variable region CDR3 comprising the amino acid sequence QQLYSTPYT (SEQ ID NO:81).
  • the LAIR1-binding agent comprises an engineered scaffold protein comprising a heavy chain variable region CDR1, CDR2, and CDR3 and a light chain variable region CDR1, CDR2, and CDR3 from antibody 62G10 or Hz62G10.v1.
  • the LAIR1-binding agent comprises an engineered scaffold protein comprising a heavy chain variable region CDR1, CDR2, and CDR3 and a light chain variable region CDR1, CDR2, and CDR3 shown in Table 6.
  • the LAIR1- binding agent comprises an engineered scaffold protein comprising a heavy chain variable region CDR1 comprising the amino acid sequence GFTFNINAMN (SEQ ID NO:25), a heavy chain variable region CDR2 comprising the amino acid sequence RIRTKNNNYATYYADSVKD (SEQ ID NO:88), a heavy chain variable region CDR3 comprising the amino acid sequence DRYGGAMAY (SEQ ID NO:89), a light chain variable region CDR1 comprising the amino acid sequence KASEDIYNRLA (SEQ ID NO:90), a light chain variable region CDR2 comprising the amino acid sequence SATSLET (SEQ ID NO:91), and a light chain variable region CDR3 comprising the amino acid sequence QQYWTIPYT (SEQ ID NO:92).
  • the LAIR1-binding agent comprises an engineered scaffold protein comprising a heavy chain variable region CDR1, CDR2, and CDR3 and a light chain variable region CDR1, CDR2, and CDR3 from antibody 108D10.
  • a composition comprises the LAIR1-binding agent described herein.
  • a composition comprises an anti-LAIR1 antibody described herein.
  • a composition comprises a monoclonal anti-LAIR1 antibody described herein.
  • a composition comprises an antibody selected from the group consisting of: antibody 47A1, antibody 47H1, antibody 57D12, antibody 61H4, antibody 62G10, or antibody 108D10, or humanized versions thereof.
  • a composition comprises the antibody 47A1, antibody 47H1, antibody Hz47H1.v4, antibody 57D12, antibody 61H4, antibody 62G10, antibody Hz62G10.v1, or antibody 108D10. [00314]
  • a pharmaceutical composition comprises the LAIR1-binding agent described herein and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprises an anti-LAIR1 antibody described herein and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprises a monoclonal anti-LAIR1 antibody described herein and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprises an antibody selected from the group consisting of: antibody 47A1, antibody 47H1, antibody 57D12, antibody 61H4, antibody 62G10, or antibody 108D10, or humanized versions thereof and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprises the antibody 47A1, antibody 47H1, antibody Hz47H1.v4, antibody 57D12, antibody 61H4, antibody 62G10, antibody Hz62G10.v1, or antibody 108D10 and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprises antibody Hz47H1.v4 and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition comprises antibody Hz62G10.v1 and a pharmaceutically acceptable carrier.
  • the LAIR1-binding agent is isolated. In some embodiments, the LAIR1-binding agent is substantially pure.
  • antigen-antibody interactions are non-covalent and reversible, formed by a combination of hydrogen bonds, hydrophobic interactions, electrostatic and van der Waals forces. When describing the strength of an antigen-antibody complex, the terms affinity and/or avidity are commonly used. The binding of an antibody to its antigen is a reversible process, and the affinity of the binding is typically reported as an equilibrium dissociation constant (K D ).
  • K D is the ratio of an antibody dissociation rate (koff) (how quickly it dissociates from its antigen) to the antibody association rate (k on ) (how quickly it binds to its antigen).
  • K D values are determined by measuring the k on and k off rates of a specific antibody/antigen interaction and then using a ratio of these values to calculate the K D value.
  • K D values may be used to evaluate and rank order the strength of individual antibody/antigen interactions. The lower the K D of an antibody, the higher the affinity of the antibody for its target.
  • affinity is measured using SPR technology in a Biacore system. Avidity gives a measure of the overall strength of an antibody-antigen complex.
  • the LAIR1-binding agent binds LAIR1 with a dissociation constant (K D ) of 1 ⁇ M or less, 100 nM or less, 40 nM or less, 20 nM or less, 10 nM or less, 1 nM or less, 0.1 nM or less, 50 pM or less, 10 pM or less, or 1 pM or less. In some embodiments, the LAIR1-binding agent binds LAIR1 with a K D of about 20 nM or less.
  • the LAIR1-binding agent binds LAIR1 with a K D of 10 nM or less. In some embodiments, the LAIR1-binding agent binds LAIR1 with a K D of 5 nM or less. In some embodiments, the LAIR1-binding agent binds LAIR1 with a K D of 3 nM or less. In some embodiments, the LAIR1-binding agent binds LAIR1 with a K D of 2 nM or less. In some embodiments, the LAIR1-binding agent binds LAIR1 with a K D of 1 nM or less.
  • the LAIR1-binding agent binds LAIR1 with a K D of 0.5 nM or less. In some embodiments, the LAIR1-binding agent binds LAIR1 with a K D of 0.1 nM or less. In some embodiments, the LAIR1-binding agent binds LAIR1 with a K D of 50 pM or less. In some embodiments, the LAIR1-binding agent binds LAIR1 with a K D of 25 pM or less. In some embodiments, the LAIR1-binding agent binds LAIR1 with a K D of 10 pM or less.
  • the LAIR1-binding agent binds LAIR1 with a K D of 1 pM or less. In some embodiments, the LAIR1-binding agent binds LAIR1 with a K D of 0.01 nM to 2.5 nM. In some embodiments, the LAIR1-binding agent binds LAIR1 with a K D of 0.1 nM to 5 nM. In some embodiments, the LAIR1-binding agent binds LAIR1 with a K D of 1 nM to 5 nM. In some embodiments, the dissociation constant of the binding agent for LAIR1 is the dissociation constant determined using an LAIR1 protein immobilized on a Biacore chip and the binding agent flowed over the chip.
  • the dissociation constant of the binding agent for LAIR1 is the dissociation constant determined using the binding agent captured by an anti-human IgG antibody on a Biacore chip and soluble LAIR1 flowed over the chip.
  • the LAIR1-binding agent binds LAIR1 with a half maximal effective concentration (EC50) of 1 ⁇ M or less, 100 nM or less, 40 nM or less, 20 nM or less, 10 nM or less, 1 nM or less, or 0.1 nM or less.
  • the LAIR1-binding agent binds human LAIR1 with an EC50 of 1 ⁇ M or less, 100 nM or less, 40 nM or less, 20 nM or less, 10 nM or less, 1 nM or less, or 0.1 nM or less. In some embodiments, the LAIR1-binding agent binds cyno LAIR1 and/or human LAIR1 with an EC50 of 40 nM or less, 20 nM or less, 10 nM or less, 1 nM or less or 0.1 nM or less.
  • the LAIR1-binding agent binds LAIR1 with an EC50 of 0.1 nM to about 3 nM, 0.1 nM to 2 nM, 0.1 nM to 1 nM, 0.5 nM to 3 nM, 0.5 nM to 2 nM, or 0.5 nM to 1 nM.
  • the LAIR1-binding agent has at least one or more of the following properties: (i) binds human LAIR1; (ii) binds cyno LAIR1; (iii) does not bind mouse LAIR1; (iv) does not bind human LAIR-2; (v) is a LAIR1 antagonist; (vi) inhibits LAIR1 activity; (vii) inhibits LAIR1 signaling in cells that express LAIR1; (viii) inhibits binding of LAIR1 to collagen; (ix) inhibits LAIR1-induced suppression of myeloid cells; (x) inhibits LAIR1-induced suppression of myeloid cell activity; (xi) restores FcR activation in myeloid cells; (xii) restores cytokine and/or chemokine production in myeloid cells; (xiii) inhibits LAIR1-induced suppression of NK cells; (xiv) inhibits LAIR1-induced suppression of NK activity; (xv) inhibits LAIR1-induced suppression of
  • the myeloid cells are monocytes. In some embodiments, the myeloid cells are macrophages. In some embodiments, the myeloid cells are dendritic cells. In some embodiments, the myeloid cells are antigen-presenting cells (APCs).
  • APCs antigen-presenting cells
  • the LAIR1-binding agents described herein can be produced by any suitable method known in the art. Such methods range from direct protein synthesis methods to constructing a DNA sequence encoding polypeptide sequences and expressing those sequences in a suitable host. In some embodiments, a DNA sequence is constructed using recombinant technology by isolating or synthesizing a DNA sequence encoding a wild-type protein of interest.
  • the sequence can be mutagenized by site-specific mutagenesis to provide functional variants thereof.
  • a DNA sequence encoding a polypeptide of interest is constructed by chemical synthesis using an oligonucleotide synthesizer. Oligonucleotides can be designed based on the amino acid sequence of the desired polypeptide and selecting those codons that are favored in the host cell in which the recombinant polypeptide of interest will be produced. Standard methods can be applied to synthesize a polynucleotide sequence encoding an isolated polypeptide of interest. For example, a complete amino acid sequence can be used to construct a back-translated gene.
  • a DNA oligomer containing a nucleotide sequence coding for the particular isolated polypeptide can be synthesized. For example, several oligonucleotides coding for portions of the desired polypeptide can be synthesized and then ligated. The individual oligonucleotides typically comprise 5′ or 3′ overhangs for complementary assembly. [00321] Once assembled (by synthesis, site-directed mutagenesis, or another method), the polynucleotide sequences encoding a particular polypeptide of interest can be inserted into an expression vector and operatively linked to an expression control sequence appropriate for expression of the protein in a desired host.
  • recombinant expression vectors are used to amplify and express DNA encoding the LAIR1-binding agents described herein.
  • recombinant expression vectors can be replicable DNA constructs which have synthetic or cDNA-derived DNA fragments encoding a polypeptide chain of a LAIR1-binding agent, such as an anti-LAIR1 antibody, or antigen-binding fragment thereof, operatively linked to suitable transcriptional and/or translational regulatory elements derived from mammalian, microbial, viral or insect genes.
  • a transcriptional unit generally comprises an assembly of (i) a genetic element or elements having a regulatory role in gene expression, for example, transcriptional promoters or enhancers, (ii) a structural or coding sequence that is transcribed into mRNA and translated into protein, and (iii) appropriate transcription and translation initiation and termination sequences.
  • Regulatory elements can include an operator sequence to control transcription.
  • the ability to replicate in a host, usually conferred by an origin of replication, and a selection gene to facilitate recognition of transformants can additionally be incorporated.
  • DNA regions are “operatively linked” when they are functionally related to each other.
  • DNA for a signal peptide is operatively linked to DNA for a polypeptide if it is expressed as a precursor that participates in the secretion of the polypeptide; a promoter is operatively linked to a coding sequence if it controls the transcription of the sequence; or a ribosome binding site is operatively linked to a coding sequence if it is positioned so as to permit translation.
  • structural elements intended for use in yeast expression systems include a leader sequence enabling extracellular secretion of translated protein by a host cell.
  • a polypeptide may include an N-terminal methionine residue.
  • This residue can optionally be subsequently cleaved from the expressed recombinant protein to provide a final product.
  • the choice of an expression control sequence and an expression vector generally depends upon the choice of host. A wide variety of expression host/vector combinations can be employed.
  • Useful expression vectors for eukaryotic hosts include, for example, vectors comprising expression control sequences from SV40, bovine papilloma virus, adenovirus, and cytomegalovirus.
  • Useful expression vectors for bacterial hosts include known bacterial plasmids, such as plasmids from E.
  • Suitable host cells for expression of a LAIR1-binding agent or a LAIR1 protein or fragment thereof to use as an antigen or immunogen include prokaryotes, yeast cells, insect cells, or higher eukaryotic cells under the control of appropriate promoters.
  • Prokaryotes include gram-negative or gram-positive organisms, for example E. coli or Bacillus.
  • Higher eukaryotic cells include established cell lines of mammalian origin as described herein. Cell-free translation systems may also be employed.
  • cloning vectors and expression vectors for use with bacterial, fungal, yeast, and mammalian cellular hosts, as well as methods of protein production, including antibody production are well known in the art.
  • Various mammalian culture systems may be used to express recombinant polypeptides. Expression of recombinant proteins in mammalian cells may be desirable because these proteins are generally correctly folded, appropriately modified, and biologically functional.
  • suitable mammalian host cell lines include, but are not limited to, COS-7 (monkey kidney-derived), L-929 (murine fibroblast-derived), C127 (murine mammary tumor-derived), 3T3 (murine fibroblast-derived), CHO (Chinese hamster ovary-derived), HeLa (human cervical cancer-derived), BHK (hamster kidney fibroblast-derived), HEK-293 (human embryonic kidney-derived) cell lines and variants thereof.
  • Mammalian expression vectors can comprise non-transcribed elements such as an origin of replication, a suitable promoter and enhancer linked to the gene to be expressed, and other 5′ or 3′ flanking non-transcribed sequences, and 5′ or 3′ non-translated sequences, such as necessary ribosome binding sites, a polyadenylation site, splice donor and acceptor sites, and transcriptional termination sequences.
  • non-transcribed elements such as an origin of replication, a suitable promoter and enhancer linked to the gene to be expressed, and other 5′ or 3′ flanking non-transcribed sequences, and 5′ or 3′ non-translated sequences, such as necessary ribosome binding sites, a polyadenylation site, splice donor and acceptor sites, and transcriptional termination sequences.
  • expression of recombinant proteins in insect cell culture systems e.g., baculovirus
  • Baculovirus systems for production of heterologous proteins in insect cells are well-known to those of skill in the art.
  • Proteins produced by a host cell can be purified according to any suitable method.
  • Standard methods include chromatography (e.g., ion exchange, affinity, and sizing column chromatography), centrifugation, differential solubility, or by any other standard technique for protein purification.
  • Affinity tags such as hexahistidine (His6; SEQ ID NO:153), maltose binding domain, influenza coat sequence, and glutathione-S-transferase can be attached to the protein to allow easy purification by passage over an appropriate affinity column.
  • Affinity chromatography methods used for purifying immunoglobulins can include, but are not limited to, Protein A, Protein G, and Protein L chromatography.
  • Isolated proteins can be physically characterized using techniques that include, but are not limited to, proteolysis, size exclusion chromatography (SEC), mass spectrometry (MS), nuclear magnetic resonance (NMR), isoelectric focusing (IEF), high performance liquid chromatography (HPLC), and x-ray crystallography.
  • SEC size exclusion chromatography
  • MS mass spectrometry
  • NMR nuclear magnetic resonance
  • IEF isoelectric focusing
  • HPLC high performance liquid chromatography
  • x-ray crystallography x-ray crystallography
  • supernatants from expression systems that secrete recombinant protein into culture media are first concentrated using a commercially available protein concentration filter, for example, an Amicon® or Millipore Pellicon® ultrafiltration unit. Following the concentration step, the concentrate can be applied to a suitable purification matrix.
  • a suitable purification matrix for example, an anion exchange resin is employed, for example, a matrix or substrate having pendant diethylaminoethyl (DEAE) groups.
  • the matrices can be acrylamide, agarose, dextran, cellulose, or other types commonly employed in protein purification.
  • a cation exchange step is employed.
  • Suitable cation exchangers include various insoluble matrices comprising sulfopropyl or carboxymethyl groups.
  • a hydroxyapatite media is employed, including but not limited to, ceramic hydroxyapatite (CHT).
  • CHT ceramic hydroxyapatite
  • one or more reverse-phase HPLC steps employing hydrophobic RP- HPLC media, e.g., silica gel having pendant methyl or other aliphatic groups, are employed to further purify a recombinant protein.
  • hydrophobic interaction chromatography HIC is used to separate recombinant proteins based on their hydrophobicity.
  • LAIR1-binding agents of the present disclosure may be analyzed for their physical/chemical properties and/or biological activities by various assays known in the art. In some embodiments, the LAIR1-binding agent is tested for its ability to bind LAIR1. Binding assays include, but are not limited to, SPR (e.g., Biacore), ELISA, and flow cytometry.
  • the LAIR1-binding agent is tested for its ability to inhibit, reduce, or block binding to collagen.
  • binding agents may be evaluated for solubility, stability, thermostability, viscosity, expression levels, expression quality, and/or purification efficiency.
  • monoclonal antibodies generated against LAIR1 are grouped based upon the epitope each individual antibody recognizes, a process known as “epitope binning”. Generally, antibodies are tested in a pairwise combinatorial manner and antibodies that compete with each other are grouped together into bins.
  • a first antibody is immobilized on a surface and a premixed solution of a second antibody and antigen is flowed over the immobilized first antibody.
  • the antigen is immobilized on a surface and the two antibodies are flowed over the immobilized antigen and compete to bind.
  • antibodies that block one another can be identified.
  • a competitive blocking profile is created for each antibody relative to the other antibodies. The blocking results determine which bin each antibody is placed in.
  • High-throughput methods of epitope binning are known in the art and allow for screening and characterization of large numbers of antibodies within a short period of time. Antibodies that bind similar epitopes often share similar functions and/or capabilities.
  • an epitope bin comprises at least one antibody from the group consisting of: 47A1, 47H1, 57D12, 61H4, 62G10, and 108D10. In some embodiments, an epitope bin comprises at least antibodies 47A1, 57D12, and 61H4. In some embodiments, an epitope bin comprises antibodies 47A1, 57D12, and 61H4. In some embodiments, an epitope bin comprises at least antibodies 47H1, 62G10, and 108D10. In some embodiments, an epitope bin comprises antibodies 47H1, 62G10, and 108D10.
  • Epitope mapping is the process of identifying the binding site, or epitope on a target protein/antigen where an antibody (or other binding agent) binds.
  • a variety of methods are known in the art for mapping epitopes on target proteins. These methods include (i) mutagenesis, including but not limited to, shotgun mutagenesis, site-directed mutagenesis, and alanine scanning; (ii) domain or fragment scanning; (iii) peptide scanning (e.g., Pepscan technology); (iv) display methods, including but not limited to, phage display, microbial display, and ribosome/mRNA display; (v) methods involving proteolysis and mass spectroscopy; (vi) methods involving amide hydrogen/deuterium exchange; and (vii) structural determination, including but not limited to, x-ray crystallography and NMR.
  • purified anti-LAIR1 antibodies are characterized by assays including, but not limited to, N-terminal sequencing, amino acid analysis, HPLC, mass spectrometry, differential scanning fluorimetry (DSF), nanoDSF, capillary isoelectric focusing (cIEF), ion exchange chromatography, and papain digestion.
  • assays are provided for identifying LAIR1-binding agents that affect LAIR1 activity.
  • assays are provided for identifying an anti-LAIR1 antibody that affects LAIR1 activity.
  • These assays may include, but are not limited to, cell activation assays (e.g., cell proliferation assays), cytotoxic T-cell (CTL) assays, NK cell assays, mixed lymphocyte reaction (MLR) assays, cytokine/chemokine production assays, FcR binding assays, and cell migration assays.
  • cell activation assays e.g., cell proliferation assays
  • CTL cytotoxic T-cell
  • NK cell assays e.g., NK cell assays
  • MLR mixed lymphocyte reaction
  • cytokine/chemokine production assays cytokine/chemokine production assays
  • FcR binding assays e.g., FcR binding assays
  • cell migration assays e.g., cell migration assays.
  • Affect or affecting LAIR1 activity may include, for example, inhibiting, reducing, blocking, antagonizing, suppressing, and/or inter
  • LAIR1 generally acts a negative regulator/inhibitory molecule, in some embodiments, inhibiting, reducing, blocking, antagonizing, suppressing, and/or interfering with LAIR1 activity results in a release of LAIR1-induced suppression of a biological function (e.g., an activation signal).
  • LAIR1 is expressed on T-cells, B-cells, NK cells, and myeloid cells.
  • Myeloid cells include, but may not be limited to, monocytes, macrophages, dendritic cells, and APCs.
  • LAIR1 activity or LAIR1 signaling activity includes, but is not limited to, suppression of myeloid cells, suppression of myeloid cell activity, suppression of tumor-associated myeloid cells, suppression of NK cells, suppression of NK cell activity, suppression of T-cells, and suppression of T-cell activity.
  • inhibiting, reducing, blocking, antagonizing, suppressing, and/or interfering with LAIR1 activity results in a release of LAIR1-induced suppression of an activation signal.
  • an anti- LAIR1 antibody inhibits LAIR1 signaling.
  • an anti-LAIR1 antibody inhibits LAIR1 signaling thereby reversing an LAIR1-induced suppressive effect.
  • an anti-LAIR1 antibody inhibits an LAIR1-induced extinction signal.
  • an anti-LAIR1 antibody disrupts the LAIR1 signaling pathway.
  • an anti-LAIR1 antibody disrupts the LAIR1 signaling pathway and activates myeloid cells.
  • an anti-LAIR1 antibody disrupts the LAIR1 signaling pathway and activates APCs.
  • an anti-LAIR1 antibody disrupts the LAIR1 signaling pathway and activates dendritic cells.
  • an anti- LAIR1 antibody disrupts the LAIR1 signaling pathway and activates NK cells.
  • an anti-LAIR1 antibody disrupts the LAIR1 signaling pathway and activates T- cells. In some embodiments, an anti-LAIR1 antibody disrupts the LAIR1 signaling pathway and activates CTLs. In some embodiments, an anti-LAIR1 antibody disrupts the LAIR1 signaling pathway and activates tumor-associated T-cells. [00336] In some embodiments, the terms “inhibiting”, “reducing”, “blocking”, “antagonizing”, “suppressing”, and “interfering” are relative to levels and/or activity in the absence of treatment with the LAIR1-binding agent.
  • the terms “inhibiting”, “reducing”, “blocking”, “antagonizing”, “suppressing”, and “interfering” are relative to levels and/or activity prior to treatment with the LAIR1-binding agent.
  • the LAIR1-binding agent inhibits human LAIR1 activity.
  • an anti-LAIR1 antibody inhibits human LAIR1 activity.
  • an anti-LAIR1 antibody that inhibits human LAIR1 activity is antibody 47A1.
  • an anti-LAIR1 antibody that inhibits human LAIR1 activity is antibody 47H1.
  • an anti-LAIR1 antibody that inhibits human LAIR1 activity is antibody Hz47H1.v4.
  • an anti-LAIR1 antibody that inhibits human LAIR1 activity is antibody 57D12. In some embodiments, an anti-LAIR1 antibody that inhibits human LAIR1 activity is antibody 61H4. In some embodiments, an anti-LAIR1 antibody that inhibits human LAIR1 activity is antibody 62G10. In some embodiments, an anti-LAIR1 antibody that inhibits human LAIR1 activity is antibody Hz62H10.v1. In some embodiments, an anti-LAIR1 antibody that inhibits human LAIR1 activity is antibody 108D10. [00338] In some embodiments, the LAIR1-binding agent inhibits mouse LAIR1 activity. In some embodiments, an anti-LAIR1 antibody inhibits mouse LAIR1 activity.
  • an anti-LAIR1 antibody that inhibits mouse LAIR1 activity is antibody 43H2.
  • the present disclosure also provides conjugates comprising the LAIR1-binding agent described herein.
  • a conjugate comprises an anti-LAIR1 antibody described herein.
  • the antibody is attached to a second molecule.
  • the antibody is conjugated to a cytotoxic agent or moiety.
  • the antibody is conjugated to a cytotoxic agent to form an antibody-drug conjugate (ADC).
  • ADC antibody-drug conjugate
  • the cytotoxic agent is a chemotherapeutic agent including, but not limited to, methotrexate, adriamycin/doxorubicin, melphalan, mitomycin C, chlorambucil, duocarmycin, daunorubicin, pyrrolobenzodiazepines (PBDs), or other intercalating agents.
  • the cytotoxic agent is a microtubule inhibitor including, but not limited to, auristatins, maytansinoids (e.g., DM1 and DM4), and tubulysins.
  • the cytotoxic agent is an enzymatically active toxin of bacterial, fungal, plant, or animal origin, or fragments thereof, including, but not limited to, diphtheria A chain, non-binding active fragments of diphtheria toxin, exotoxin A chain, ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, Aleurites fordii proteins, dianthin proteins, Phytolaca americana proteins (PAPI, PAPII, and PAP-S), Momordica charantia inhibitor, curcin, crotin, Sapaonaria officinalis inhibitor, gelonin, mitogellin, restrictocin, phenomycin, enomycin, and the tricothecenes.
  • diphtheria A chain non-binding active fragments of diphtheria toxin
  • exotoxin A chain exotoxin A chain
  • ricin A chain abrin A chain
  • modeccin A chain
  • an antibody is conjugated to one or more small molecule toxins, such as calicheamicins, maytansinoids, trichothenes, and CC1065.
  • a derivative of any one of these toxins may be used as long as the derivative retains the cytotoxic activity of the parent molecule.
  • Conjugates comprising a LAIR1-binding agent disclosed herein (e.g., an anti-LAIR1 antibody described herein) may be made using any suitable method known in the art.
  • conjugates are made using a variety of bifunctional protein-coupling agents such as N-succinimidyl-3-(2-pyridyidithiol) propionate (SPDP), iminothiolane (IT), bifunctional derivatives of imidoesters (such as dimethyl adipimidate HCl), active esters (such as disuccinimidyl suberate), aldehydes (such as glutaraldehyde), bis-azido compounds (such as bis(p-azidobenzoyl) hexanediamine), bis-diazonium derivatives (such as bis-(p- diazoniumbenzoyl)-ethylenediamine), diisocyanates (such as toluene 2,6-diisocyanate), and bis- active fluorine compounds (such as 1,5-difluoro-2,4-dinitrobenzene).
  • SPDP N-succinimidyl-3-(2-pyridyidithi
  • the LAIR1-binding agent described herein is conjugated to a detectable substance or molecule that allows the agent to be used for diagnosis and/or detection.
  • an anti-LAIR1 antibody described herein is conjugated to a detectable substance or molecule that allows the antibody to be used for diagnosis and/or detection.
  • a labeled anti-LAIR1 antibody is used to monitor immune cells in a tumor or in the microenvironment of a tumor.
  • a labeled anti-LAIR1 antibody is used to monitor immune cells in a tumor or in the microenvironment of a tumor after treatment.
  • a detectable substance can include but is not limited to, enzymes, such as horseradish peroxidase, alkaline phosphatase, beta-galactosidase, and acetylcholinesterase; prosthetic groups, such as biotin and flavine(s); fluorescent materials, such as, umbelliferone, fluorescein, fluorescein isothiocyanate (FITC), rhodamine, tetramethylrhodamine isothiocyanate (TRITC), dichlorotriazinylamine fluorescein, dansyl chloride, cyanine (Cy3), and phycoerythrin; bioluminescent materials, such as luciferase; radioactive materials, such as 212 Bi, 14 C, 57 Co, 51 Cr, 67 Cu, 18 F, 68 Ga, 67 Ga, 153 Gd, 159 Gd, 68 Ge, 3 H, 166 Ho, 131 I, 125 I, 123 I, 121 I,
  • An anti-LAIR1 antibody described herein can also be conjugated to a second antibody to form an antibody heteroconjugate.
  • a LAIR1-binding agent as described herein may be attached to a solid support.
  • an anti-LAIR1 antibody as described herein is attached to a solid support.
  • Such solid supports include, but are not limited to, glass, cellulose, polyacrylamide, nylon, polystyrene, polyvinyl chloride, or polypropylene.
  • an immobilized anti- LAIR1 antibody is used in an immunoassay.
  • an immobilized anti-LAIR1 antibody is used in purification of the target antigen.
  • an anti-LAIR1 antibody described herein is used in an immunoassay.
  • Immunoassays are known to those of skill in the art and include, but are not limited to, ELISA, SPR (e.g., Biacore), flow cytometry, and immunohistochemistry (IHC).
  • an anti-LAIR1 antibody described herein is used on a tissue sample or a tumor sample.
  • OSCAR-binding agents e.g., anti-OSCAR antibodies
  • OSCAR e.g., human OSCAR
  • the OSCAR-binding agent is an antibody.
  • the antibody is a recombinant antibody.
  • the antibody is a monoclonal antibody.
  • the antibody is a polyclonal antibody.
  • the antibody is a chimeric antibody.
  • the antibody is a humanized antibody.
  • the antibody is a human antibody.
  • the antibody is an IgG antibody.
  • the antibody is an IgG1 antibody.
  • the antibody is an IgG2 antibody.
  • the antibody is an IgG3 antibody. In some embodiments, the antibody is an IgG4 antibody. In some embodiments, the antibody comprises an IgG heavy chain. In some embodiments, the antibody comprises an IgG1 heavy chain. In some embodiments, the antibody comprises an IgG2 heavy chain. In some embodiments, the antibody comprises an IgG4 heavy chain. In some embodiments, the antibody comprises a human IgG1 heavy chain. In some embodiments, the antibody comprises a human IgG2 heavy chain. In some embodiments, the antibody comprises a human IgG4 heavy chain. In some embodiments, the antibody comprises a kappa light chain. In some embodiments, the antibody comprises a kappa light chain constant region.
  • the antibody comprises a human kappa light chain constant region. In some embodiments, the antibody comprises a lambda light chain. In some embodiments, the antibody comprises a lambda light chain constant region. In some embodiments, the antibody comprises a human lambda light chain constant region. In some embodiments, the human kappa light chain constant region comprises the amino acid sequence of SEQ ID NO:147. In some embodiments, the human lambda light chain constant region comprises the amino acid sequence of SEQ ID NO:148. [00347] In some embodiments, the antibody is an antibody fragment comprising an antigen- binding site. In some embodiments, the antibody is a scFv. In some embodiments, the antibody is a disulfide-linked scFv.
  • the antibody is a disulfide-linked sc(Fv) 2 .
  • the antibody is a Fab, Fab′, or a F(ab)2 antibody.
  • the antibody is a diabody.
  • the antibody is a nanobody.
  • the antibody is a monospecific antibody.
  • the antibody is a bispecific antibody.
  • the antibody is a multispecific antibody.
  • the antibody is a monovalent antibody.
  • the antibody is a bivalent antibody.
  • the antibody is a tetravalent antibody.
  • the antibody is isolated.
  • the antibody is substantially pure.
  • the OSCAR-binding agent is an anti-OSCAR antibody described herein. In some embodiments, the OSCAR-binding agent is a variant of an anti- OSCAR antibody described herein. In some embodiments, a variant of an anti-OSCAR antibody comprises one to thirty amino acid substitutions. In some embodiments, a variant of the anti-OSCAR antibody comprises one to twenty-five amino acid substitutions. In some embodiments, a variant of the anti-OSCAR antibody comprises one to twenty amino acid substitutions. In some embodiments, a variant of the anti-OSCAR antibody comprises one to fifteen amino acid substitutions.
  • a variant of the anti-OSCAR antibody comprises one to ten amino acid substitutions. In some embodiments, a variant of the anti- OSCAR antibody comprises one to five amino acid substitutions. In some embodiments, the variant of the anti-OSCAR antibody comprises one to three amino acid substitutions. In some embodiments, the amino acid substitution(s) is in a CDR of the antibody. In some embodiments, the amino acid substitution(s) is not in a CDR of the antibody. In some embodiments, the amino acid substitution(s) is in a framework region of the antibody. In some embodiments, the amino acid substitution(s) is a conservative amino acid substitution.
  • an anti-OSCAR antibody described herein comprises the six CDRs of antibody 1G9, 4E3, 4F11, 14G11.1, 14G11.2, 18B12, or 18D12. In some embodiments, an anti-OSCAR antibody described herein comprises the six CDRs of antibody 1G9, 4E3, 4F11, 14G11.1, 14G11.2, 18B12, or 18D12 based on the Kabat definition. In some embodiments, an anti-OSCAR antibody described herein comprises the six CDRs of antibody 1G9, 4E3, 4F11, 14G11.1, 14G11.2, 18B12, or 18D12 based on the Chothia definition.
  • an anti-OSCAR antibody described herein comprises the six CDRs of antibody 1G9, 4E3, 4F11, 14G11.1, 14G11.2, 18B12, or 18D12 based on the AbM definition. In some embodiments, an anti-OSCAR antibody described herein comprises the six CDRs of antibody 1G9, 4E3, 4F11, 14G11.1, 14G11.2, 18B12, or 18D12 based on the IMGT definition. In some embodiments, an anti-OSCAR antibody described herein comprises the six CDRs of antibody 1G9, 4E3, 4F11, 14G11.1, 14G11.2, 18B12, or 18D12 based on the Contact definition.
  • an anti-OSCAR antibody described herein comprises the six CDRs of antibody 1G9, 4E3, 4F11, 14G11.1, 14G11.2, 18B12, or 18D12 based on the Exemplary definition.
  • the OSCAR-binding agent is an anti-OSCAR antibody that comprises one, two, three, four, five, and/or six CDRs of any one of the antibodies described herein.
  • an anti-OSCAR antibody comprises (i) a heavy chain variable region comprising one, two, and/or three heavy chain variable region CDRs from Table 8, and/or (ii) a light chain variable region comprising one, two, and/or three light chain variable region CDRs from Table 8.
  • an anti-OSCAR antibody comprises (i) a heavy chain variable region comprising one, two, and/or three heavy chain variable region CDRs from Table 9, and/or (ii) a light chain variable region comprising one, two, and/or three light chain variable region CDRs from Table 9.
  • an anti-OSCAR antibody comprises (i) a heavy chain variable region comprising one, two, and/or three heavy chain variable region CDRs from Table 10, and/or (ii) a light chain variable region comprising one, two, and/or three light chain variable region CDRs from Table 10.
  • an anti-OSCAR antibody comprises (i) a heavy chain variable region comprising one, two, and/or three heavy chain variable region CDRs from Table 11, and/or (ii) a light chain variable region comprising one, two, and/or three light chain variable region CDRs from Table 11.
  • an anti-OSCAR antibody comprises (i) a heavy chain variable region comprising one, two, and/or three heavy chain variable region CDRs from Table 12, and/or (ii) a light chain variable region comprising one, two, and/or three light chain variable region CDRs from Table 12.
  • an anti-OSCAR antibody comprises (i) a heavy chain variable region comprising one, two, and/or three heavy chain variable region CDRs from Table 13, and/or (ii) a light chain variable region comprising one, two, and/or three light chain variable region CDRs from Table 13.
  • an anti-OSCAR antibody comprises (i) a heavy chain variable region comprising one, two, and/or three heavy chain variable region CDRs from Table 14, and/or (ii) a light chain variable region comprising one, two, and/or three light chain variable region CDRs from Table 14.
  • an anti-OSCAR antibody comprises (i) a heavy chain variable region comprising three heavy chain variable region CDRs from Table 8, and (ii) a light chain variable region comprising three light chain variable region CDRs from Table 8. In some embodiments, an anti-OSCAR antibody comprises (i) a heavy chain variable region comprising three heavy chain variable region CDRs from Table 9, and (ii) a light chain variable region comprising three light chain variable region CDRs from Table 9. In some embodiments, an anti- OSCAR antibody comprises (i) a heavy chain variable region comprising three heavy chain variable region CDRs from Table 10, and (ii) a light chain variable region comprising three light chain variable region CDRs from Table 10.
  • an anti-OSCAR antibody comprises (i) a heavy chain variable region comprising three heavy chain variable region CDRs from Table 11, and (ii) a light chain variable region comprising three light chain variable region CDRs from Table 11. In some embodiments, an anti-OSCAR antibody comprises (i) a heavy chain variable region comprising three heavy chain variable region CDRs from Table 12, and (ii) a light chain variable region comprising three light chain variable region CDRs from Table 12. In some embodiments, an anti-OSCAR antibody comprises (i) a heavy chain variable region comprising three heavy chain variable region CDRs from Table 13, and (ii) a light chain variable region comprising three light chain variable region CDRs from Table 13.
  • an anti-OSCAR antibody comprises (i) a heavy chain variable region comprising three heavy chain variable region CDRs from Table 14, and (ii) a light chain variable region comprising three light chain variable region CDRs from Table 14.
  • the specific CDR sequences defined in Tables 8-14 are based on Kabat definition. CDR sequences are underlined within the VH and VL sequences listed in Tables 8-14, in the order of CDR1, CDR2, and CDR3 from N terminus to C terminus.
  • the OSCAR-binding agent (e.g., an antibody) comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3; and/or a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 from antibody 1G9 (Table 8), a humanized version thereof, or variants thereof.
  • the OSCAR-binding agent (e.g., antibody) comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 from antibody 1G9 (Table 8).
  • the OSCAR-binding agent comprises a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 from antibody 1G9 (Table 8).
  • the OSCAR-binding agent e.g., an antibody
  • the OSCAR-binding agent comprises: (a) a VH comprising a VH CDR1, a VH CDR2, a VH CDR3; and (b) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 from antibody 1G9 (Table 8).
  • the OSCAR-binding agent provided herein comprises a VH CDR1, a VH CDR2, and/or a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:196; and/or a VL CDR1, a VL CDR2, and/or a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:197.
  • the OSCAR-binding agent provided herein comprises a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:196; and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:197.
  • CDR sequences can be determined according to well-known numbering systems or a combination thereof. In certain embodiments, the CDRs are determined according to Kabat numbering.
  • the OSCAR-binding agent (e.g., an antibody) comprises (a) a VH comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:154, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:155, and a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:156; and/or (b) a VL comprising a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:157, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:158, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:159.
  • the OSCAR- binding agent (e.g., an antibody) comprises (a) a VH comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:154, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:155, and a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:156; and (b) a VL comprising a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:157, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:158, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:159.
  • the OSCAR-binding agent (e.g., an antibody) comprises a VH having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:196; and/or a VL having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:197.
  • the binding of the OSCAR-binding agent (e.g., an antibody) thereof to OSCAR is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%).
  • the OSCAR-binding agent e.g., an antibody
  • the OSCAR-binding agent comprises a VH comprising an amino acid sequence of SEQ ID NO:196 and/or a VL comprising an amino acid sequence of SEQ ID NO:197.
  • the OSCAR-binding agent (e.g., an antibody) comprises a VH comprising an amino acid sequence of SEQ ID NO:196 and a VL comprising an amino acid sequence of SEQ ID NO:197.
  • the OSCAR-binding agent is antibody 1G9 (Table 8).
  • the OSCAR-binding agent is a humanized version of antibody 1G9 (Table 8).
  • the OSCAR-binding agent is a variant of antibody 1G9 (Table 8) or a variant of a humanized version of 1G9.
  • the OSCAR-binding agent (e.g., an antibody) comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3; and/or a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 from antibody 4E3 (Table 9), a humanized version thereof, or variants thereof.
  • the OSCAR-binding agent (e.g., antibody) comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 from antibody 4E3 (Table 9).
  • the OSCAR-binding agent comprises a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 from antibody 4E3 (Table 9).
  • the OSCAR-binding agent e.g., an antibody
  • the OSCAR-binding agent comprises: (a) a VH comprising a VH CDR1, a VH CDR2, a VH CDR3; and (b) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 from antibody 4E3 (Table 9).
  • the OSCAR-binding agent provided herein comprises a VH CDR1, a VH CDR2, and/or a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:198; and/or a VL CDR1, a VL CDR2, and/or a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:199.
  • the OSCAR-binding agent provided herein comprises a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:198; and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:199.
  • CDR sequences can be determined according to well-known numbering systems or a combination thereof. In certain embodiments, the CDRs are according to Kabat numbering.
  • the OSCAR-binding agent (e.g., an antibody) comprises (a) a VH comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:160, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:161, and a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:162; and/or (b) a VL comprising a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:163, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:164, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:165.
  • the OSCAR- binding agent (e.g., an antibody) comprises (a) a VH comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:160, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:161, and a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:162; and (b) a VL comprising a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:163, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:164, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:165.
  • the OSCAR-binding agent (e.g., an antibody) comprises a VH having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:198; and/or a VL having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:199.
  • the binding of the OSCAR-binding agent (e.g., an antibody) thereof to OSCAR is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%).
  • the OSCAR-binding agent e.g., an antibody
  • the OSCAR-binding agent comprises a VH comprising an amino acid sequence of SEQ ID NO:198 and/or a VL comprising an amino acid sequence of SEQ ID NO:199.
  • the OSCAR-binding agent (e.g., an antibody) comprises a VH comprising an amino acid sequence of SEQ ID NO:198 and a VL comprising an amino acid sequence of SEQ ID NO:199.
  • the OSCAR-binding agent is antibody 4E3 (Table 9).
  • the OSCAR-binding agent is a humanized version of antibody 4E3 (Table 9).
  • the OSCAR-binding agent is a variant of antibody 4E3 (Table 9) or a variant of a humanized version of 4E3.
  • the OSCAR-binding agent (e.g., an antibody) comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3; and/or a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 from antibody 4F11 (Table 10), a humanized version thereof, or variants thereof.
  • the OSCAR-binding agent (e.g., antibody) comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 from antibody 4F11 (Table 10).
  • the OSCAR-binding agent comprises a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 from antibody 4F11 (Table 10).
  • the OSCAR-binding agent e.g., an antibody
  • the OSCAR-binding agent comprises: (a) a VH comprising a VH CDR1, a VH CDR2, a VH CDR3; and (b) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 from antibody 4F11 (Table 10).
  • the OSCAR-binding agent provided herein comprises a VH CDR1, a VH CDR2, and/or a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:200; and/or a VL CDR1, a VL CDR2, and/or a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:201.
  • the OSCAR-binding agent provided herein comprises a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:200; and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:201.
  • CDR sequences can be determined according to well-known numbering systems or a combination thereof. In certain embodiments, the CDRs are according to Kabat numbering.
  • the OSCAR-binding agent (e.g., an antibody) comprises (a) a VH comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:166, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:167, and a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:168; and/or (b) a VL comprising a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:169, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:170, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:171.
  • the OSCAR- binding agent (e.g., an antibody) comprises (a) a VH comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:166, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:167, and a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:168; and (b) a VL comprising a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:169, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:170, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:171.
  • the OSCAR-binding agent (e.g., an antibody) comprises a VH having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:200; and/or a VL having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:201.
  • the binding of the OSCAR-binding agent (e.g., an antibody) thereof to OSCAR is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%).
  • the OSCAR-binding agent e.g., an antibody
  • the OSCAR-binding agent comprises a VH comprising an amino acid sequence of SEQ ID NO:200 and/or a VL comprising an amino acid sequence of SEQ ID NO:201.
  • the OSCAR-binding agent (e.g., an antibody) comprises a VH comprising an amino acid sequence of SEQ ID NO:200 and a VL comprising an amino acid sequence of SEQ ID NO:201.
  • the OSCAR-binding agent is antibody 4F11 (Table 10).
  • the OSCAR-binding agent is a humanized version of antibody 4F11 (Table 10).
  • the OSCAR-binding agent is a variant of antibody 4F11 (Table 10) or a variant of a humanized version of 4F11.
  • the OSCAR-binding agent (e.g., an antibody) comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3; and/or a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 from antibody 14G11.1 (Table 11), a humanized version thereof, or variants thereof.
  • the OSCAR-binding agent (e.g., antibody) comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 from antibody 14G11.1 (Table 11).
  • the OSCAR-binding agent comprises a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 from antibody 14G11.1 (Table 11).
  • the OSCAR-binding agent e.g., an antibody
  • the OSCAR-binding agent comprises: (a) a VH comprising a VH CDR1, a VH CDR2, a VH CDR3; and (b) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 from antibody 14G11.1 (Table 11).
  • the OSCAR-binding agent provided herein comprises a VH CDR1, a VH CDR2, and/or a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:202; and/or a VL CDR1, a VL CDR2, and/or a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:203.
  • the OSCAR-binding agent provided herein comprises a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:202; and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:203.
  • CDR sequences can be determined according to well-known numbering systems or a combination thereof. In certain embodiments, the CDRs are according to Kabat numbering.
  • the OSCAR-binding agent (e.g., an antibody) comprises (a) a VH comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:172, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:173, and a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:174; and/or (b) a VL comprising a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:175, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:176, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:177.
  • the OSCAR- binding agent (e.g., an antibody) comprises (a) a VH comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:172, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:173, and a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:174; and (b) a VL comprising a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:175, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:176, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:177.
  • the OSCAR-binding agent (e.g., an antibody) comprises a VH having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:202; and/or a VL having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:203.
  • the binding of the OSCAR-binding agent (e.g., an antibody) thereof to OSCAR is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%).
  • the OSCAR-binding agent e.g., an antibody
  • the OSCAR-binding agent comprises a VH comprising an amino acid sequence of SEQ ID NO:202 and/or a VL comprising an amino acid sequence of SEQ ID NO:203.
  • the OSCAR-binding agent (e.g., an antibody) comprises a VH comprising an amino acid sequence of SEQ ID NO:202 and a VL comprising an amino acid sequence of SEQ ID NO:203.
  • the OSCAR-binding agent is antibody 14G11.1 (Table 11).
  • the OSCAR-binding agent is a humanized version of antibody 14G11.1 (Table 11).
  • the OSCAR-binding agent is a variant of antibody 14G11.1 (Table 11) or a variant of a humanized version of 14G11.1.
  • the OSCAR-binding agent (e.g., an antibody) comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3; and/or a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 from antibody 14G11.2 (Table 12), a humanized version thereof, or variants thereof.
  • the OSCAR-binding agent (e.g., antibody) comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 from antibody 14G11.2 (Table 12).
  • the OSCAR-binding agent comprises a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 from antibody 14G11.2 (Table 12).
  • the OSCAR-binding agent e.g., an antibody
  • the OSCAR-binding agent comprises: (a) a VH comprising a VH CDR1, a VH CDR2, a VH CDR3; and (b) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 from antibody 14G11.2 (Table 12).
  • the OSCAR-binding agent provided herein comprises a VH CDR1, a VH CDR2, and/or a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:204; and/or a VL CDR1, a VL CDR2, and/or a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:205.
  • the OSCAR-binding agent provided herein comprises a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:204; and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:205.
  • CDR sequences can be determined according to well-known numbering systems or a combination thereof. In certain embodiments, the CDRs are according to Kabat numbering.
  • the OSCAR-binding agent (e.g., an antibody) comprises (a) a VH comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:178, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:179, and a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:180; and/or (b) a VL comprising a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:181, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:182, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:183.
  • the OSCAR- binding agent (e.g., an antibody) comprises (a) a VH comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:178, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:179, and a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:180; and (b) a VL comprising a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:181, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:182, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:183.
  • the OSCAR-binding agent (e.g., an antibody) comprises a VH having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:204; and/or a VL having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:205.
  • the binding of the OSCAR-binding agent (e.g., an antibody) thereof to OSCAR is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%).
  • the OSCAR-binding agent e.g., an antibody
  • the OSCAR-binding agent comprises a VH comprising an amino acid sequence of SEQ ID NO:204 and/or a VL comprising an amino acid sequence of SEQ ID NO:205.
  • the OSCAR-binding agent (e.g., an antibody) comprises a VH comprising an amino acid sequence of SEQ ID NO:204 and a VL comprising an amino acid sequence of SEQ ID NO:205.
  • the OSCAR-binding agent is antibody 14G11.2 (Table 12).
  • the OSCAR-binding agent is a humanized version of antibody 14G11.2 (Table 12).
  • the OSCAR-binding agent is a variant of antibody 14G11.2 (Table 12) or a variant of a humanized version of 14G11.2.
  • the OSCAR-binding agent (e.g., an antibody) comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3; and/or a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 from antibody 18B12 (Table 13), a humanized version thereof, or variants thereof.
  • the OSCAR-binding agent (e.g., antibody) comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 from antibody 18B12 (Table 13).
  • the OSCAR-binding agent comprises a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 from antibody 18B12 (Table 13).
  • the OSCAR-binding agent e.g., an antibody
  • the OSCAR-binding agent comprises: (a) a VH comprising a VH CDR1, a VH CDR2, a VH CDR3; and (b) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 from antibody 18B12 (Table 13).
  • the OSCAR-binding agent provided herein comprises a VH CDR1, a VH CDR2, and/or a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:206; and/or a VL CDR1, a VL CDR2, and/or a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:207.
  • the OSCAR-binding agent provided herein comprises a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:206; and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:207.
  • CDR sequences can be determined according to well-known numbering systems or a combination thereof. In certain embodiments, the CDRs are according to Kabat numbering.
  • the OSCAR-binding agent (e.g., an antibody) comprises (a) a VH comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:184, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:185, and a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:186; and/or (b) a VL comprising a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:187, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:188, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:189.
  • the OSCAR- binding agent (e.g., an antibody) comprises (a) a VH comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:184, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:185, and a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:186; and (b) a VL comprising a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:187, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:188, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:189.
  • the OSCAR-binding agent (e.g., an antibody) comprises a VH having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:206; and/or a VL having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:207.
  • the binding of the OSCAR-binding agent (e.g., an antibody) thereof to OSCAR is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%).
  • the OSCAR-binding agent e.g., an antibody
  • the OSCAR-binding agent comprises a VH comprising an amino acid sequence of SEQ ID NO:206 and/or a VL comprising an amino acid sequence of SEQ ID NO:207.
  • the OSCAR-binding agent (e.g., an antibody) comprises a VH comprising an amino acid sequence of SEQ ID NO:206 and a VL comprising an amino acid sequence of SEQ ID NO:207.
  • the OSCAR-binding agent is antibody 18B12 (Table 13).
  • the OSCAR-binding agent is a humanized version of antibody 18B12 (Table 13).
  • the OSCAR-binding agent is a variant of antibody 18B12 (Table 13) or a variant of a humanized version of 18B12.
  • the OSCAR-binding agent (e.g., an antibody) comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3; and/or a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 from antibody 18D12 (Table 14), a humanized version thereof, or variants thereof.
  • the OSCAR-binding agent (e.g., antibody) comprises a VH comprising a VH CDR1, a VH CDR2, and a VH CDR3 from antibody 18D12 (Table 14).
  • the OSCAR-binding agent comprises a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 from antibody 18D12 (Table 14).
  • the OSCAR-binding agent e.g., an antibody
  • the OSCAR-binding agent comprises: (a) a VH comprising a VH CDR1, a VH CDR2, a VH CDR3; and (b) a VL comprising a VL CDR1, a VL CDR2, and a VL CDR3 from antibody 18D12 (Table 14).
  • the OSCAR-binding agent provided herein comprises a VH CDR1, a VH CDR2, and/or a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:208; and/or a VL CDR1, a VL CDR2, and/or a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:209.
  • the OSCAR-binding agent provided herein comprises a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:208; and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:209.
  • CDR sequences can be determined according to well-known numbering systems or a combination thereof. In certain embodiments, the CDRs are according to Kabat numbering.
  • the OSCAR-binding agent (e.g., an antibody) comprises (a) a VH comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:190, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:191, and a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:192; and/or (b) a VL comprising a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:193, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:194, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:195.
  • the OSCAR- binding agent (e.g., an antibody) comprises (a) a VH comprising a VH CDR1 comprising the amino acid sequence set forth in SEQ ID NO:190, a VH CDR2 comprising the amino acid sequence set forth in SEQ ID NO:191, and a VH CDR3 comprising the amino acid sequence set forth in SEQ ID NO:192; and (b) a VL comprising a VL CDR1 comprising the amino acid sequence set forth in SEQ ID NO:193, a VL CDR2 comprising the amino acid sequence set forth in SEQ ID NO:194, and a VL CDR3 comprising the amino acid sequence set forth in SEQ ID NO:195 [00395]
  • the OSCAR-binding agent (e.g., an antibody) comprises a VH having at least 75%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 9
  • the binding of the OSCAR-binding agent (e.g., an antibody) thereof to OSCAR is maintained (e.g., substantially maintained, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%).
  • the OSCAR-binding agent e.g., an antibody
  • the OSCAR-binding agent comprises a VH comprising an amino acid sequence of SEQ ID NO:208 and/or a VL comprising an amino acid sequence of SEQ ID NO:209.
  • the OSCAR-binding agent (e.g., an antibody) comprises a VH comprising an amino acid sequence of SEQ ID NO:208 and a VL comprising an amino acid sequence of SEQ ID NO:209. [00396]
  • the OSCAR-binding agent is antibody 18D12 (Table 14).
  • the OSCAR-binding agent is a humanized version of antibody 18D12 (Table 14).
  • the OSCAR-binding agent is a variant of antibody 18D12 (Table 14) or a variant of a humanized version of 18D12.
  • OSCAR-binding agents that compete with one or more of the OSCAR-binding agents described herein for binding to OSCAR.
  • the OSCAR-binding agent competes with one or more of the binding OSCAR-binding agents described herein for binding to human OSCAR.
  • the OSCAR-binding agent that competes with one or more of the OSCAR-binding agents described herein is an antibody.
  • the OSCAR-binding agent provided herein specifically binds to OSCAR (e.g., human OSCAR) competitively with an anti- OSCAR antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:196 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:197.
  • OSCAR e.g., human OSCAR
  • an anti- OSCAR antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:196 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:197.
  • the OSCAR-binding agent provided herein specifically binds to OSCAR (e.g., human OSCAR) competitively with an anti-OSCAR antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:196, and a VL comprising the amino acid sequence of SEQ ID NO:197.
  • the OSCAR-binding agent provided herein specifically binds to OSCAR (e.g., human OSCAR) competitively with an anti- OSCAR antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:198 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:199.
  • OSCAR e.g., human OSCAR
  • an anti- OSCAR antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:198 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:199.
  • the OSCAR-binding agent provided herein specifically binds to OSCAR (e.g., human OSCAR) competitively with an anti-OSCAR antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:198, and a VL comprising the amino acid sequence of SEQ ID NO:199.
  • the OSCAR-binding agent provided herein specifically binds to OSCAR (e.g., human OSCAR) competitively with an anti- OSCAR antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:200 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:201.
  • OSCAR e.g., human OSCAR
  • an anti- OSCAR antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:200 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:201.
  • the OSCAR-binding agent provided herein specifically binds to OSCAR (e.g., human OSCAR) competitively with an anti-OSCAR antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:200, and a VL comprising the amino acid sequence of SEQ ID NO:201.
  • the OSCAR-binding agent provided herein specifically binds to OSCAR (e.g., human OSCAR) competitively with an anti- OSCAR antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:202 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:203.
  • OSCAR e.g., human OSCAR
  • an anti- OSCAR antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:202 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:203.
  • the OSCAR-binding agent provided herein specifically binds to OSCAR (e.g., human OSCAR) competitively with an anti-OSCAR antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:202, and a VL comprising the amino acid sequence of SEQ ID NO:203.
  • the OSCAR-binding agent provided herein specifically binds to OSCAR (e.g., human OSCAR) competitively with an anti- OSCAR antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:204 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:205.
  • OSCAR e.g., human OSCAR
  • an anti- OSCAR antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:204 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:205.
  • the OSCAR-binding agent provided herein specifically binds to OSCAR (e.g., human OSCAR) competitively with an anti-OSCAR antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:204, and a VL comprising the amino acid sequence of SEQ ID NO:205.
  • the OSCAR-binding agent provided herein specifically binds to OSCAR (e.g., human OSCAR) competitively with an anti- OSCAR antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:206 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:207.
  • OSCAR e.g., human OSCAR
  • an anti- OSCAR antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:206 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:207.
  • the OSCAR-binding agent provided herein specifically binds to OSCAR (e.g., human OSCAR) competitively with an anti-OSCAR antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:206, and a VL comprising the amino acid sequence of SEQ ID NO:207.
  • the OSCAR-binding agent provided herein specifically binds to OSCAR (e.g., human OSCAR) competitively with an anti- OSCAR antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:208 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:209.
  • OSCAR e.g., human OSCAR
  • an anti- OSCAR antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:208 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:209.
  • the OSCAR-binding agent provided herein specifically binds to OSCAR (e.g., human OSCAR) competitively with an anti-OSCAR antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:208, and a VL comprising the amino acid sequence of SEQ ID NO:209.
  • OSCAR e.g., human OSCAR
  • an anti-OSCAR antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:208, and a VL comprising the amino acid sequence of SEQ ID NO:209.
  • functional epitopes can be mapped, e.g., by combinatorial alanine scanning, to identify amino acids in the OSCAR protein that are necessary for interaction with OSCAR-binding agents (such as antibodies) provided herein.
  • conformational and crystal structure of OSCAR-binding agents (such as antibodies) bound to OSCAR may be employed to identify the epitopes.
  • the present disclosure provides an antibody that specifically binds to the same epitope as any of the OSCAR-binding agents (such as antibodies or fragments thereof) provided herein.
  • the OSCAR-binding agent provided herein binds to the same epitope as an anti-OSCAR antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:196 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:197.
  • the OSCAR- binding agent provided herein binds to the same epitope as an anti-OSCAR antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:196, and a VL comprising the amino acid sequence of SEQ ID NO:197.
  • the OSCAR-binding agent provided herein binds to the same epitope as an anti-OSCAR antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:198 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:199.
  • the OSCAR-binding agent provided herein binds to the same epitope as an anti-OSCAR antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:198, and a VL comprising the amino acid sequence of SEQ ID NO:199.
  • the OSCAR-binding agent provided herein binds to the same epitope as an anti-OSCAR antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:200 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:201.
  • the OSCAR-binding agent provided herein binds to the same epitope as an anti-OSCAR antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:200, and a VL comprising the amino acid sequence of SEQ ID NO:201.
  • the OSCAR-binding agent provided herein binds to the same epitope as an anti-OSCAR antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:202 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:203.
  • the OSCAR-binding agent provided herein binds to the same epitope as an anti-OSCAR antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:202, and a VL comprising the amino acid sequence of SEQ ID NO:203.
  • the OSCAR-binding agent provided herein binds to the same epitope as an anti-OSCAR antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:204 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:205.
  • the OSCAR-binding agent provided herein binds to the same epitope as an anti-OSCAR antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:204, and a VL comprising the amino acid sequence of SEQ ID NO:205.
  • the OSCAR-binding agent provided herein binds to the same epitope as an anti-OSCAR antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:206 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:207.
  • the OSCAR-binding agent provided herein binds to the same epitope as an anti-OSCAR antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:206, and a VL comprising the amino acid sequence of SEQ ID NO:207.
  • the OSCAR-binding agent provided herein binds to the same epitope as an anti-OSCAR antibody comprising a VH CDR1, a VH CDR2, and a VH CDR3 as set forth in a VH comprising the amino acid sequence of SEQ ID NO:208 and a VL CDR1, a VL CDR2, and a VL CDR3 as set forth in a VL comprising the amino acid sequence of SEQ ID NO:209.
  • the OSCAR-binding agent provided herein binds to the same epitope as an anti-OSCAR antibody comprising a VH comprising the amino acid sequence of SEQ ID NO:208, and a VL comprising the amino acid sequence of SEQ ID NO:209.
  • the OSCAR-binding agent described herein comprises an antibody in which at least one or more of the constant regions of the antibody has been modified or deleted.
  • an antibody comprises one or more modifications to one or more of the heavy chain constant regions (CH1, CH2, CH3, or CH4) and/or to the light chain constant region (CL).
  • an antibody comprises one or more modifications to the hinge region.
  • the heavy chain constant region of the modified antibody comprises at least one human constant region. In certain embodiments, the heavy chain constant region of the modified antibody comprises more than one human constant region. In certain embodiments, modifications to the constant region comprise additions, deletions, or substitutions of one or more amino acids in one or more regions. In certain embodiments, one or more regions are partially or entirely deleted from the constant regions of a modified antibody. In certain embodiments, the entire CH2 domain has been removed from an antibody ( ⁇ CH2 constructs). In certain embodiments, one or more regions are partially or entirely deleted from the hinge region of a modified antibody. In certain embodiments, a deleted constant region is replaced by a short amino acid spacer that provides some of the molecular flexibility typically imparted by the absent constant region.
  • a deleted hinge region is replaced by a short amino acid spacer that provides some of the molecular flexibility typically imparted by the absent hinge region.
  • a modified antibody comprises a CH3 domain directly fused to the hinge region of the antibody.
  • a modified antibody comprises a peptide spacer inserted between the hinge region and modified CH2 and/or CH3 domains.
  • Fc region of an antibody can bind a cell expressing a Fc receptor (FcR).
  • Fc receptors There are a number of Fc receptors that are specific for different classes of antibody, including IgG (gamma receptors), IgE (epsilon receptors), IgA (alpha receptors) and IgM (mu receptors).
  • the OSCAR-binding agent e.g., an antibody
  • the OSCAR-binding agent comprises a variant constant region or Fc region.
  • amino acid sequences of the constant region or Fc region of human IgG1, IgG2, IgG3, and IgG4 are known to those of ordinary skill in the art (e.g., a representative human IgG1 constant region is SEQ ID NO:141).
  • constant regions or Fc regions with amino acid variations have been identified in native antibodies.
  • a variant constant region or Fc region is engineered with substitutions at specific amino acid positions as compared to a native constant region or Fc region.
  • a modified antibody provides for altered effector functions that, in turn, affect the biological profile of the antibody.
  • the deletion or inactivation (through point mutations or other means) of a constant region reduces binding of a modified antibody to a Fc receptor.
  • constant region modifications increase the serum half-life of an antibody.
  • constant region modifications reduce the serum half-life of an antibody.
  • constant region modifications decrease or remove ADCC and/or complement- dependent cytotoxicity (CDC) of an antibody.
  • a human IgG1 Fc region with specific amino acid substitutions corresponding to IgG2 or IgG4 residues reduce effector functions (e.g., ADCC and CDC) in a modified antibody.
  • a modified antibody does not have one or more effector functions.
  • a modified antibody has no ADCC activity and/or no CDC activity.
  • a modified antibody does not bind an Fc receptor and/or complement factors.
  • a modified antibody does not have any detectable effector functions (e.g., an “effectorless” antibody).
  • constant region modifications increase or enhance ADCC and/or CDC of an antibody.
  • the constant region is modified to eliminate disulfide linkages or oligosaccharide moieties.
  • the constant region is modified to add/substitute one or more amino acids to provide one or more cytotoxin, oligosaccharide, or carbohydrate attachment sites.
  • Modifications to the constant region of antibodies described herein may be made using well-known biochemical or molecular engineering techniques.
  • antibody variants are prepared by introducing appropriate nucleotide changes into the encoding DNA, and/or by synthesis of the desired antibody or polypeptide.
  • the present disclosure further embraces additional variants and equivalents that are substantially homologous to the recombinant, monoclonal, chimeric, humanized, and human antibodies, or antibody fragments thereof, described herein.
  • it is desirable to improve the binding affinity of the antibody.
  • it is desirable to modulate biological properties of the antibody, including but not limited to, specificity, thermostability, expression level, effector function(s), glycosylation, immunogenicity, and/or solubility.
  • amino acid changes may alter post- translational processes of an antibody, such as changing the number or position of glycosylation sites or altering membrane anchoring characteristics.
  • Variations may be a substitution, deletion, or insertion of one or more nucleotides encoding the antibody or polypeptide that results in a change in the amino acid sequence as compared with the native antibody or polypeptide sequence.
  • amino acid substitutions are the result of replacing one amino acid with another amino acid having similar structural and/or chemical properties, such as the replacement of a leucine with a serine (i.e., conservative amino acid replacements).
  • the substitution, deletion, or insertion includes less than 25 amino acid substitutions, less than 20 amino acid substitutions, less than 15 amino acid substitutions, less than 10 amino acid substitutions, less than 5 amino acid substitutions, less than 4 amino acid substitutions, less than 3 amino acid substitutions, or less than 2 amino acid substitutions relative to the parent molecule.
  • variations in the amino acid sequence that are biologically useful and/or relevant are determined by systematically making insertions, deletions, or substitutions in the sequence and testing the resulting variant proteins for activity as compared to the parental antibody.
  • variants may include addition of amino acid residues at the amino- and/or carboxyl-terminal end of the antibody or polypeptide.
  • a variant comprises an N-terminal methionyl residue.
  • the variant comprises an additional polypeptide/protein to create a fusion protein.
  • a variant is engineered to be detectable and may comprise a detectable label and/or protein (e.g., a fluorescent tag, a fluorescent protein, or an enzyme).
  • a cysteine residue not involved in maintaining the proper conformation of an antibody is substituted or deleted to modulate the antibody’s characteristics, for example, to improve oxidative stability and/or prevent aberrant disulfide crosslinking.
  • an antibody of the present disclosure is “deimmunized”.
  • the deimmunization of antibodies generally consists of introducing specific amino acid mutations (e.g., substitutions, deletions, additions) that result in removal of T-cell epitopes (known or predicted) without significantly reducing the binding affinity or other desired activities of the antibody.
  • the variant antibodies or polypeptides described herein may be generated using methods known in the art, including but not limited to, site-directed mutagenesis, alanine scanning mutagenesis, and PCR mutagenesis.
  • the OSCAR-binding agent described herein is chemically modified.
  • the OSCAR-binding agent is the anti-OSCAR antibody that is chemically modified by glycosylation, acetylation, pegylation, phosphorylation, amidation, derivatization by known protecting/blocking groups, proteolytic cleavage, and/or linkage to a cellular ligand or other protein. Any of numerous chemical modifications may be carried out by known techniques.
  • the OSCAR-binding agent is attached (either directly or indirectly) to a half-life extending moiety including, but not limited to, polyethylene glycol (PEG), a PEG mimetic, XTEN®, serum albumin, polysialic acid, N-(2- hydroxypropyl)methacrylamide, or dextran.
  • the OSCAR-binding agent is an antibody, wherein the antibody is attached (either directly or indirectly) to a half-life extending moiety including, but not limited to, polyethylene glycol (PEG), a PEG mimetic, XTEN®, serum albumin, polysialic acid, N-(2-hydroxypropyl)methacrylamide, or dextran.
  • the OSCAR-binding agent is an antibody fragment (e.g., scFv, Fv, Fab, F(ab′)2, or F(ab′)), wherein the antibody fragment is attached (either directly or indirectly) to a half-life extending moiety including, but not limited to, polyethylene glycol (PEG), a PEG mimetic, XTEN®, serum albumin, polysialic acid, N-(2-hydroxypropyl)methacrylamide, or dextran.
  • PEG polyethylene glycol
  • PEG mimetic e.g., a PEG mimetic
  • XTEN® e.g., serum albumin
  • polysialic acid e.g., N-(2-hydroxypropyl)methacrylamide
  • dextran e.g., dextran.
  • the composition comprises a monoclonal anti-OSCAR antibody described herein.
  • the present disclosure further provides a pharmaceutical composition comprises a OSCAR-binding agent (e.g., an antibody) described herein and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition comprises an anti-OSCAR antibody described herein and a pharmaceutically acceptable carrier.
  • the pharmaceutical composition comprises a monoclonal anti-OSCAR antibody described herein and a pharmaceutically acceptable carrier.
  • the OSCAR-binding agent e.g., an antibody
  • the OSCAR-binding agent is isolated.
  • the OSCAR-binding agent e.g., an antibody
  • the OSCAR-binding agents described herein can be produced by any suitable method known in the art, for example, the methods disclosed in paragraphs [0320]-[0330] of the present disclosure.
  • the present disclosure also provides conjugates comprising the OSCAR-binding agent described herein.
  • a conjugate comprises the anti-OSCAR antibody described herein.
  • the antibody is attached to a second molecule.
  • the antibody is conjugated to a cytotoxic agent or moiety.
  • the antibody is conjugated to a cytotoxic agent to form an antibody-drug conjugate (ADC).
  • ADC antibody-drug conjugate
  • the cytotoxic agent is a chemotherapeutic agent including, but not limited to, methotrexate, adriamycin/doxorubicin, melphalan, mitomycin C, chlorambucil, duocarmycin, daunorubicin, pyrrolobenzodiazepines (PBDs), or other intercalating agents.
  • the cytotoxic agent is a microtubule inhibitor including, but not limited to, auristatins, maytansinoids (e.g., DM1 and DM4), and tubulysins.
  • the cytotoxic agent is an enzymatically active toxin of bacterial, fungal, plant, or animal origin, or fragments thereof, including, but not limited to, diphtheria A chain, non-binding active fragments of diphtheria toxin, exotoxin A chain, ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, Aleurites fordii proteins, dianthin proteins, Phytolaca americana proteins (PAPI, PAPII, and PAP-S), Momordica charantia inhibitor, curcin, crotin, Sapaonaria officinalis inhibitor, gelonin, mitogellin, restrictocin, phenomycin, enomycin, and the tricothecenes.
  • diphtheria A chain non-binding active fragments of diphtheria toxin
  • exotoxin A chain exotoxin A chain
  • ricin A chain abrin A chain
  • modeccin A chain
  • an antibody is conjugated to one or more small molecule toxins, such as calicheamicins, maytansinoids, trichothenes, and CC1065.
  • small molecule toxins such as calicheamicins, maytansinoids, trichothenes, and CC1065.
  • a derivative of any one of these toxins may be used as long as the derivative retains the cytotoxic activity of the parent molecule.
  • Conjugates comprising the OSCAR-binding agent e.g., the anti-OSCAR antibody described herein
  • conjugates are made using a variety of bifunctional protein-coupling agents such as N-succinimidyl-3-(2-pyridyidithiol) propionate (SPDP), iminothiolane (IT), bifunctional derivatives of imidoesters (such as dimethyl adipimidate HCl), active esters (such as disuccinimidyl suberate), aldehydes (such as glutaraldehyde), bis-azido compounds (such as bis(p-azidobenzoyl) hexanediamine), bis-diazonium derivatives (such as bis-(p- diazoniumbenzoyl)-ethylenediamine), diisocyanates (such as toluene 2,6-diisocyanate), and bis- active fluorine compounds (such as 1,5-difluoro-2,4-dinitrobenzene).
  • SPDP N-succinimidyl-3-(2-pyridyidithi
  • the OSCAR-binding agent described herein is conjugated to a detectable substance or molecule that allows the agent to be used for diagnosis and/or detection.
  • the anti-OSCAR antibody described herein is conjugated to a detectable substance or molecule that allows the antibody to be used for diagnosis and/or detection.
  • a labeled anti-OSCAR antibody is used to monitor immune cells in a tumor or in the microenvironment of a tumor.
  • a labeled anti- OSCAR antibody is used to monitor immune cells in a tumor or in the microenvironment of a tumor after treatment.
  • a detectable substance can include but is not limited to, enzymes, such as horseradish peroxidase, alkaline phosphatase, beta-galactosidase, and acetylcholinesterase; prosthetic groups, such as biotin and flavine(s); fluorescent materials, such as, umbelliferone, fluorescein, fluorescein isothiocyanate (FITC), rhodamine, tetramethylrhodamine isothiocyanate (TRITC), dichlorotriazinylamine fluorescein, dansyl chloride, cyanine (Cy3), and phycoerythrin; bioluminescent materials, such as luciferase; radioactive materials, such as 212 Bi, 14 C, 57 Co, 51 Cr, 67 Cu, 18 F, 68 Ga, 67 Ga, 153 Gd, 159 Gd, 68 Ge, 3 H, 166 Ho, 131 I, 125 I, 123 I, 121 I,
  • the anti-OSCAR antibody described herein can also be conjugated to a second antibody to form an antibody heteroconjugate.
  • the OSCAR-binding agent as described herein may be attached to a solid support.
  • the anti-OSCAR antibody as described herein is attached to a solid support.
  • Such solid supports include, but are not limited to, glass, cellulose, polyacrylamide, nylon, polystyrene, polyvinyl chloride, or polypropylene.
  • an immobilized anti-OSCAR antibody is used in an immunoassay.
  • an immobilized anti-OSCAR antibody is used in purification of the target antigen.
  • the anti-OSCAR antibody described herein is used in an immunoassay.
  • Immunoassays are known to those of skill in the art and include, but are not limited to, ELISA, SPR (e.g., Biacore), FACS, and immunohistochemistry (IHC).
  • the anti-OSCAR antibody described herein is used on a tissue sample or a tumor sample.
  • a OSCAR-binding agent described herein comprises a detectable moiety. Detectable moieties, also referred to as detectable labels or detectable tags, are known to those of skill in the art.
  • the detectable moiety is a fluorescent label, a bioluminescent label, a chemiluminescent label, an enzyme, a small molecule, a radioisotope, or colloidal gold. In some embodiments, the detectable moiety is a fluorescent label.
  • the OSCAR-binding agents described herein are used in methods for detecting OSCAR in a biological sample. In some embodiments, a method of detecting OSCAR in a biological sample comprises: (a) contacting the biological sample with a OSCAR-binding agent described herein; and (b) detecting the binding between the binding agent and OSCAR in the sample.
  • the method uses flow cytometry, immunohistochemistry (IHC), western blot analysis, ELISA, or mass spectrometry.
  • the sample is a fresh sample, a frozen sample, or a formalin-fixed paraffin- embedded sample.
  • the sample is a tissue sample, a tissue biopsy, a cell pellet, a blood sample, or a pleural effusion.
  • the OSCAR-binding agents described herein are used for the methods for identifying a subject for treatment, predicting response to treatment, and/or treating a cancer or a tumor as disclosed in Section 5.2.
  • the OSCAR-binding agents described herein are used for the kits disclosed in Section 5.7.
  • compositions which include a peptide sequence (or sequences) provided herein, including subsequences, variants and modified forms of the exemplified peptide sequences (e.g., sequences listed in the Sequence Listing or Tables 1- 14), and one or more pharmaceutically acceptable or physiologically acceptable diluents, carriers or excipients; in combination with, or separate from, one or more additional agents for the treatment of a cancer or a tumor, or a composition comprising such one or more additional agents and one or more pharmaceutically acceptable or physiologically acceptable diluents, carriers or excipients.
  • a peptide sequence or sequences and an additional agent(s) are present in a therapeutically acceptable amount.
  • the pharmaceutical compositions may be used in accordance with the methods and uses provided herein.
  • the pharmaceutical compositions can be administered ex vivo or in vivo to a subject in order to practice treatment methods and uses provided herein.
  • Pharmaceutical compositions provided herein can be formulated to be compatible with the intended method or route of administration.
  • a LAIR1-binding agent of the present disclosure depends on the disorder or disease to be treated, the severity and course of the disorder or disease, the responsiveness of the disorder or disease, whether the agent is administered for therapeutic or preventative purposes, previous therapy, the patient's clinical history, and so on.
  • a LAIR1-binding agent can be administered one time or over a series of treatments lasting from several days to several months, or until a cure is effected or a diminution of the disease state is achieved.
  • dosage of a LAIR1-binding agent disclosed herein is from about 0.01 ⁇ g/kg to about 100 mg/kg of body weight, from about 0.1 ⁇ g/kg to about 100 mg/kg of body weight, from about 1 ⁇ g/kg to about 100 mg/kg of body weight, from about 1 mg/kg to about 100 mg/kg of body weight, from about 1 mg/kg to about 80 mg/kg of body weight, from about 1 mg/kg to about 50 mg/kg of body weight, from about 1 mg/kg to 25 mg/kg of body weight, from 1 mg/kg to 15 mg/kg of body weight, from 10 mg/kg to 100 mg/kg of body weight, from 10 mg/kg to 75 mg/kg of body weight, or from 10 mg/kg to 50 mg/kg of body weight.
  • dosage of the LAIR1-binding agent is from about 0.1 mg to about 20 mg/kg of body weight. In some embodiments, dosage of the LAIR1-binding agent is about 0.5 mg/kg of body weight. In some embodiments, dosage of the LAIR1-binding agent is about 1 mg/kg of body weight. In some embodiments, dosage of the LAIR1-binding agent is about 1.5 mg/kg of body weight. In some embodiments, dosage of the LAIR1-binding agent is about 2 mg/kg of body weight. In some embodiments, dosage of the LAIR1-binding agent is about 2.5 mg/kg of body weight. In some embodiments, dosage of the LAIR1-binding agent is about 5 mg/kg of body weight.
  • dosage of the LAIR1-binding agent is about 7.5 mg/kg of body weight. In some embodiments, dosage of the LAIR1-binding agent is about 10 mg/kg of body weight. In some embodiments, dosage of the LAIR1-binding agent is about 12.5 mg/kg of body weight. In some embodiments, dosage of the LAIR1-binding agent is about 15 mg/kg of body weight. [00440] In some embodiments, the LAIR1-binding agent is dosed once or more daily, weekly, monthly, or yearly. In some embodiments, the LAIR1-binding agent is dosed once every week, once every two weeks, once every three weeks, or once every four weeks. In some embodiments, the LAIR1-binding agent is dosed once a week.
  • the LAIR1-binding agent is dosed once every two weeks. In some embodiments, the LAIR1- binding agent is dosed once every three weeks. In some embodiments, the LAIR1-binding agent is dosed once every four weeks. [00441] In some embodiments of the methods described herein, a method comprises administering a LAIR1-binding agent described herein in combination with at least one additional therapeutic agent or therapeutic therapy. Treatment with two or more therapeutic agents often uses agents that work by different mechanisms of action, although this is not required. Combination therapy using agents with different mechanisms of action may result in additive or synergetic effects.
  • Combination therapy may allow for a lower dose of each agent than is used in monotherapy, thereby reducing toxic side effects and/or increasing the therapeutic index of the agent(s). Combination therapy may decrease the likelihood that resistance to an agent will develop.
  • the combination of a LAIR1- binding agent described herein and at least one additional therapeutic agent results in additive or synergistic results.
  • the combination therapy results in an increase in the therapeutic index of the LAIR1-binding agent.
  • the combination therapy results in an increase in the therapeutic index of the additional therapeutic agent(s).
  • the combination therapy results in a decrease in the toxicity and/or side effects of the LAIR1-binding agent.
  • combination therapy results in a decrease in the toxicity and/or side effects of the additional therapeutic agent(s).
  • combination therapy comprises a therapeutic agent that affects the immune response (e.g., enhances or activates the response) and a therapeutic agent that affects (e.g., inhibits or kills) the tumor/cancer cells.
  • a combination treatment comprises one additional therapeutic agent. In some embodiments of the methods described herein, a combination treatment comprises two or more additional therapeutic agents.
  • Useful classes of therapeutic agents include, but are not limited to, anti-tubulin agents, auristatins, DNA minor groove binders, DNA replication inhibitors, alkylating agents (e.g., platinum complexes such as cisplatin, mono(platinum), bis(platinum) and tri-nuclear platinum complexes and carboplatin), anthracyclines, antibiotics, anti-folates, anti-metabolites, chemotherapy sensitizers, duocarmycins, etoposides, fluorinated pyrimidines, ionophores, lexitropsins, nitrosoureas, platinols, purine antimetabolites, puromycins, radiation sensitizers, steroids, taxanes, topoisomerase inhibitors, vinca alkaloids, or the like.
  • alkylating agents e.g., platinum complexes such as cisplatin, mono(platinum), bis(platinum) and tri-nucle
  • the second therapeutic agent is an alkylating agent, an antimetabolite, an antimitotic, a topoisomerase inhibitor, or an angiogenesis inhibitor.
  • Therapeutic agents that may be administered in combination with the LAIR1-binding agents described herein include chemotherapeutic agents.
  • the method or treatment involves the administration of a LAIR1-binding agent of the present disclosure in combination with a chemotherapeutic agent or in combination with a cocktail of chemotherapeutic agents.
  • Chemotherapeutic agents useful in the present disclosure include, but are not limited to, alkylating agents such as thiotepa and cyclophosphamide (CYTOXAN); alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethylenethiophosphaoramide and trimethylolomelamime; nitrogen mustards such as chlorambucil, chlornaphazine, cholophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil
  • paclitaxel TAXOL
  • docetaxel TAXOTERE
  • chlorambucil gemcitabine
  • 6- thioguanine mercaptopurine
  • platinum analogs such as cisplatin and carboplatin
  • vinblastine platinum
  • etoposide VP-16
  • ifosfamide mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; ibandronate; CPT 11; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoic acid; esperamicins; capecitabine (XELODA); and pharmaceutically acceptable salts, acids or derivatives of any of the above.
  • DMFO difluoromethylornithine
  • XELODA retinoic acid
  • esperamicins capecitabine
  • Chemotherapeutic agents also include anti-hormonal agents that act to regulate or inhibit hormone action on tumors such as anti-estrogens including for example tamoxifen, raloxifene, aromatase inhibiting 4(5)-imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and toremifene (FARESTON); and anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; and pharmaceutically acceptable salts, acids or derivatives of any of the above.
  • anti-estrogens including for example tamoxifen, raloxifene, aromatase inhibiting 4(5)-imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and toremifene (FARESTON); and anti-androgen
  • the chemotherapeutic agent is a topoisomerase inhibitor.
  • Topoisomerase inhibitors are chemotherapy agents that interfere with the action of a topoisomerase enzyme (e.g., topoisomerase I or II).
  • Topoisomerase inhibitors include, but are not limited to, doxorubicin HC1, daunorubicin citrate, mitoxantrone HC1, actinomycin D, etoposide, topotecan HC1, teniposide (VM-26), and irinotecan, as well as pharmaceutically acceptable salts, acids, or derivatives of any of these.
  • the additional therapeutic agent is irinotecan.
  • the chemotherapeutic agent is an anti-metabolite.
  • An anti- metabolite is a chemical with a structure that is similar to a metabolite required for normal biochemical reactions, yet different enough to interfere with one or more normal functions of cells, such as cell division.
  • Anti-metabolites include, but are not limited to, gemcitabine, fluorouracil, capecitabine, methotrexate sodium, ralitrexed, pemetrexed, tegafur, cytosine arabinoside, thioguanine, 5-azacytidine, 6-mercaptopurine, azathioprine, 6-thioguanine, pentostatin, fludarabine phosphate, and cladribine, as well as pharmaceutically acceptable salts, acids, or derivatives of any of these.
  • the additional therapeutic agent is gemcitabine.
  • the chemotherapeutic agent is an antimitotic agent, including, but not limited to, agents that bind tubulin.
  • the agent is a taxane.
  • the agent is paclitaxel or docetaxel, or a pharmaceutically acceptable salt, acid, or derivative of paclitaxel or docetaxel.
  • the agent is paclitaxel (TAXOL), docetaxel (TAXOTERE), albumin-bound paclitaxel (nab-paclitaxel; ABRAXANE), DHA-paclitaxel, or PG-paclitaxel.
  • the antimitotic agent comprises a vinca alkaloid, such as vincristine, vinblastine, vinorelbine, or vindesine, or pharmaceutically acceptable salts, acids, or derivatives thereof.
  • the antimitotic agent is an inhibitor of kinesin Eg5 or an inhibitor of a mitotic kinase such as Aurora A or Plkl.
  • the additional therapeutic agent is paclitaxel.
  • the additional therapeutic agent is nab-paclitaxel.
  • an additional therapeutic agent comprises an agent such as a small molecule.
  • treatment can involve the combined administration of a LAIR1-binding agent of the present disclosure with a small molecule that acts as an inhibitor against tumor-associated antigens including, but not limited to, EGFR, HER2 (ErbB2), and/or VEGF.
  • a LAIR1-binding agent of the present disclosure with a small molecule that acts as an inhibitor against tumor-associated antigens including, but not limited to, EGFR, HER2 (ErbB2), and/or VEGF.
  • a LAIR1-binding agent of the present disclosure is administered in combination with a protein kinase inhibitor selected from the group consisting of: gefitinib (IRESSA), erlotinib (TARCEVA), sunitinib (SUTENT), lapatanib, vandetanib (ZACTIMA), AEE788, CI-1033, cediranib (RECENTIN), sorafenib (NEXAVAR), and pazopanib (GW786034B).
  • IRESSA gefitinib
  • TARCEVA sunitinib
  • ZACTIMA ZACTIMA
  • AEE788, CI-1033 cediranib
  • sorafenib NEXAVAR
  • GW786034B pazopanib
  • an additional therapeutic agent comprises an mTOR inhibitor.
  • an additional therapeutic agent comprises a biological molecule, such as an antibody.
  • treatment can involve the combined administration of a LAIR1-binding agent of the present disclosure with antibodies against tumor-associated antigens including, but not limited to, antibodies that bind EGFR, HER2/ErbB2, and/or VEGF.
  • the additional therapeutic agent is an antibody that is an angiogenesis inhibitor (e.g., an anti-VEGF or VEGF receptor antibody).
  • the additional therapeutic agent is bevacizumab (AVASTIN), ramucirumab, trastuzumab (HERCEPTIN), pertuzumab (OMNITARG), panitumumab (VECTIBIX), nimotuzumab, zalutumumab, or cetuximab (ERBITUX).
  • the additional therapeutic agent is an antibody that modulates the immune response.
  • the additional therapeutic agent is an anti-PD-1 antibody, an anti-PD-Ll antibody, an anti-PD-L2 antibody, an anti-CTLA-4 antibody, or an anti-TIGIT antibody.
  • the additional therapeutic agent is an ILT3 antibody.
  • U.S. Provisional Application No.63/265,824 which is hereby incorporated by reference in its entirety, provides various descriptions and uses of the ILT3 antibodies provided herein.
  • any of the ILT-3 antibodies disclosed in U.S. Provisional Application No.63/265,824 can be used in any of the methods disclosed herein.
  • the anti-ILT3 antibody and the anti-LAIR1 antibody are formulated into two separate pharmaceutical compositions for use.
  • the anti-ILT3 antibody and the anti-LAIR1 antibody are formulated into the same pharmaceutical composition for use.
  • an anti-ILT3 antibody includes a VH including a VH CDR1, a VH CDR2, a VH CDR3, and a VL including a VL CDR1, a VL CDR2, and a VL CDR3, wherein the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2 and VL CDR3 are from any one of the VH and VL sequences of the antibodies described in U.S. Provisional Application No. 63/265,824 (e.g., 3A3, 5A7, 12A12, 16C5, 45G10, 48A6, 53F10, or Hz5A7.v5).
  • the anti-ILT3 antibody is a humanized version of an antibody described herein, (e.g., 3A3, 5A7, 12A12, 16C5, 45G10, 48A6, 53F10).
  • treatment with a LAIR1-binding agent described herein can include combination treatment with other biologic molecules, such as one or more cytokines (e.g., lymphokines, interleukins, tumor necrosis factors, and/or growth factors) or can be accompanied by surgical removal of tumors, removal of cancer cells, or any other therapy deemed necessary by a treating physician.
  • the additional therapeutic agent is an immunotherapeutic agent.
  • the LAIR1-binding agent is combined with a growth factor selected from the group consisting of: adrenomedullin (AM), angiopoietin (Ang), BMPs, BDNF, EGF, erythropoietin (EPO), FGF, GDNF, G-CSF, GM-CSF, GDF9, HGF, HDGF, IGF, migration-stimulating factor, myostatin (GDF-8), NGF, neurotrophins, PDGF, thrombopoietin, TGF-a, TGF- ⁇ , TNF-a, VEGF, PIGF, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-12, IL-15, and IL-18.
  • a growth factor selected from the group consisting of: adrenomedullin (AM), angiopoietin (Ang), BMPs, BDNF, EGF, erythropo
  • the additional therapeutic agent is an immunotherapeutic agent.
  • the immunotherapeutic agent is selected from the group consisting of granulocyte-macrophage colony stimulating factor (GM- CSF), macrophage colony stimulating factor (M-CSF), granulocyte colony stimulating factor (G-CSF), interleukin 3 (IL- 3), interleukin 12 (IL-12), interleukin 1 (IL-1), interleukin 2 (IL-2), B7-1 (CD80), B7-2 (CD86), 4- 1BB ligand, anti-CD3 antibody, anti-CTLA-4 antibody, anti- TIGIT antibody, anti-PD-1 antibody, anti-PD-Ll antibody, anti-LAG-3 antibody, and anti-TIM-3 antibody.
  • GM- CSF granulocyte-macrophage colony stimulating factor
  • M-CSF macrophage colony stimulating factor
  • G-CSF granulocyte colony stimulating factor
  • IL- 3 interleukin 12
  • IL-1 interleukin 1
  • IL-2 inter
  • an immunotherapeutic agent is selected from the group consisting of: a modulator of PD-1 activity, a modulator of PD-L1 activity, a modulator of PD-L2 activity, a modulator of CTLA-4 activity, a modulator of CD28 activity, a modulator of CD80 activity, a modulator of CD86 activity, a modulator of 4-1BB activity, an modulator of OX40 activity, a modulator of KIR activity, a modulator of Tim-3 activity, a modulator of LAG3 activity, a modulator of CD27 activity, a modulator of CD40 activity, a modulator of GITR activity, a modulator of TIGIT activity, a modulator of CD20 activity, a modulator of CD96 activity, a modulator of IDO1 activity, a cytokine, a chemokine, an interferon, an interleukin, a lymphokine, a member of the tumor necrosis factor (
  • an immunotherapeutic agent is selected from the group consisting of: a PD-1 antagonist, a PD-L1 antagonist, a PD-L2 antagonist, a CTLA-4 antagonist, a CD80 antagonist, a CD86 antagonist, a KIR antagonist, a Tim-3 antagonist, a LAG3 antagonist, a TIGIT antagonist, a CD20 antagonist, a CD96 antagonist, and/or an IDO1 antagonist.
  • the PD-1 antagonist is an antibody that specifically binds PD-1.
  • the antibody that binds PD-1 is pembrolizumab (KEYTRUDA, MK-3475), pidilizumab (CT-011), nivolumab (OPDIVO, BMS- 936558, MDX-1106), MEDI0680 (AMP-514), REGN2810, BGB-A317, PDR-001, or STI- A1110.
  • the antibody that binds PD-1 is described in PCT Publication WO 2014/179664, for example, an antibody identified as APE2058, APE1922, APE1923, APE1924, APE 1950, or APE1963, or an antibody containing the CDR regions of any of these antibodies.
  • the PD-1 antagonist is a fusion protein that includes PD-L2, for example, AMP-224. In other embodiments, the PD-1 antagonist is a peptide inhibitor, for example, AU P-12. [00463] In some embodiments, the PD-L1 antagonist is an antibody that specifically binds PD-L1.
  • the antibody that binds PD-L1 is atezolizumab (TECENTRIQ, RG7446, MPDL3280A), MEDI4736, BMS-936559 (MDX-1105), avelumab (BAVENCIO, MSB0010718C), durvalumab (IMFINZI), KD033, the antibody portion of KD033, or STI- A1014.
  • the antibody that binds PD-L1 is described in PCT Publication WO 2014/055897, for example, Ab-14, Ab-16, Ab-30, Ab-31, Ab-42, Ab-50, Ab-52, or Ab-55, or an antibody that comprises the CDR regions of any of these antibodies.
  • the CTLA-4 antagonist is an antibody that specifically binds CTLA-4.
  • the antibody that binds CTLA-4 is ipilimumab (YERVOY) or tremelimumab (CP-675,206).
  • the CTLA-4 antagonist a CTLA-4 fusion protein, for example, KAHR-102.
  • the LAG3 antagonist is an antibody that specifically binds LAG3.
  • the antibody that binds LAG3 is I ⁇ 701, IMP731, BMS- 986016, LAG525, and GSK2831781.
  • the LAG3 antagonist includes a soluble LAG3 receptor, for example, IMP321.
  • the KIR antagonist is an antibody that specifically binds KIR.
  • the antibody that binds KIR is lirilumab.
  • an immunotherapeutic agent is selected from the group consisting of: a CD28 agonist, a 4-1BB agonist, an OX40 agonist, a CD27 agonist, a CD80 agonist, a CD86 agonist, a CD40 agonist, and a GITR agonist.
  • the OX40 agonist includes OX40 ligand, or an OX40-binding portion thereof.
  • the OX40 agonist may be MEDI6383.
  • the OX40 agonist is an antibody that specifically binds OX40.
  • the antibody that binds OX40 is MEDI6469, MEDI0562, or MOXR0916 (RG7888).
  • the OX40 agonist is a vector (e.g., an expression vector or virus, such as an adenovirus) capable of expressing OX40 ligand.
  • the OX40-expressing vector is tasadenoturev (DNX-2401).
  • the 4-1BB (CD137) agonist is a binding molecule, such as an anticalin.
  • the anticalin is PRS-343.
  • the 4-1BB agonist is an antibody that specifically binds 4-1BB.
  • antibody that binds 4-1BB is PF-2566 (PF-05082566) or urelumab (BMS-663513).
  • the CD27 agonist is an antibody that specifically binds CD27.
  • the antibody that binds CD27 is varlilumab (CDX-1127).
  • the GITR agonist comprises a GITR ligand or a GITR- binding portion thereof.
  • the GITR agonist is an antibody that specifically binds GITR.
  • the antibody that binds GITR is TRX518, MK-4166, or INBRX-110.
  • immunotherapeutic agents include, but are not limited to, cytokines such as chemokines, interferons, interleukins, lymphokines, and members of the tumor necrosis factor (TNF) family.
  • immunotherapeutic agents include immunostimulatory oligonucleotides, such as CpG dinucleotides.
  • an immunotherapeutic agent includes, but is not limited to, anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-PD-L2 antibodies, anti-CTLA-4 antibodies, anti-CD28 antibodies, anti-CD80 antibodies, anti-CD86 antibodies, anti-4-1BB antibodies, anti- OX40 antibodies, anti-KIR antibodies, anti-Tim-3 antibodies, anti-LAG3 antibodies, anti-CD27 antibodies, anti-CD40 antibodies, anti-GITR antibodies, anti-TIGIT antibodies, anti-CD20 antibodies, anti-CD96 antibodies, or anti-IDO1 antibodies.
  • a LAIR1-binding agent described herein and at least one additional therapeutic agent may be administered in any order or concurrently.
  • the LAIR1-binding agent is administered to subjects that have previously undergone treatment with a therapeutic agent.
  • the LAIR1-binding agent and a second therapeutic agent are administered substantially simultaneously or concurrently.
  • a subject may be given the LAIR1-binding agent while undergoing a course of treatment with a second therapeutic agent (e.g., a chemotherapeutic agent).
  • the LAIR1-binding agent is administered within 1 year of the treatment with a second therapeutic agent.
  • the LAIR1-binding agent is administered within 10, 8, 6, 4, or 2 months of any treatment with a second therapeutic agent.
  • the LAIR1-binding agent is administered within 4, 3, 2, or 1 weeks of any treatment with a second therapeutic agent. In some embodiments, the LAIR1-binding agent is administered within 5, 4, 3, 2, or 1 days of any treatment with a second therapeutic agent. It will further be appreciated that the two (or more) agents or treatments can be administered to the subject within a matter of hours or minutes (i.e., substantially simultaneously). [00475] In some embodiments, treatment with a LAIR1-binding agent disclosed herein can occur prior to, concurrently with, or subsequent to administration of the additional therapeutic agents.
  • compositions comprising a LAIR1-binding agent described herein.
  • a composition comprises an antibody selected from the group consisting of 47A1, 47H1, Hz47H1.v4, 57D11, 61H4, 62G10, Hz62G10.v1, 108D10, and 43H2.
  • a composition comprises antibody Hz47H1.v4.
  • a composition comprises antibody Hz62G10.v1.
  • the present disclosure provides pharmaceutical compositions comprising a LAIR1- binding agent described herein and a pharmaceutically acceptable vehicle.
  • a pharmaceutical composition comprises an antibody selected from the group consisting of 47A1, 47H1, Hz47H1.v4, 57D11, 61H4, 62G10, Hz62G10.v1, 108D10, and 43H2 and a pharmaceutically acceptable vehicle.
  • a pharmaceutical composition comprises antibody Hz47H1.v4 and a pharmaceutically acceptable vehicle.
  • a pharmaceutical composition comprises antibody Hz62G10.v1 and a pharmaceutically acceptable vehicle.
  • Formulations are prepared for storage and use by combining a purified antibody or agent of the present disclosure with a pharmaceutically acceptable vehicle (e.g., a carrier or excipient).
  • a pharmaceutically acceptable vehicle e.g., a carrier or excipient.
  • pharmaceutically acceptable carriers, excipients, and/or stabilizers to be inactive ingredients of a formulation or pharmaceutical composition.
  • Suitable pharmaceutically acceptable vehicles include, but are not limited to, nontoxic buffers such as phosphate, citrate, and other organic acids; salts such as sodium chloride; antioxidants including ascorbic acid and methionine; preservatives such as octadecyldimethylbenzyl ammonium chloride, hexamethonium chloride, benzalkonium chloride, benzethonium chloride, phenol, butyl or benzyl alcohol, alkyl parabens, such as methyl or propyl paraben, catechol, resorcinol, cyclohexanol, 3-pentanol, and m-cresol; low molecular weight polypeptides; proteins such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine;
  • the formulation is in the form of an aqueous solution. In some embodiments, the formulation is stored in a lyophilized or in an alternative dried form.
  • the binding agents of the present disclosure can be formulated in any suitable form for delivery to a target cell/tissue.
  • the LAIR1-binding agent can be formulated as a liposome, microparticle, microcapsule, albumin microsphere, microemulsion, nanoparticle, nanocapsule, or macroemulsion.
  • the LAIR1-binding agent is formulated with liposomes.
  • the LAIR1-binding agent is formulated as a sustained-release preparation.
  • sustained-release preparations include semi-permeable matrices of solid hydrophobic polymers containing an agent, where the matrices are in the form of shaped articles (e.g., films or microcapsules).
  • Sustained-release matrices include but are not limited to polyesters, hydrogels such as poly(2-hydroxyethyl-methacrylate) or poly(vinyl alcohol), polylactides, copolymers of L-glutamic acid and 7 ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOTTM (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), sucrose acetate isobutyrate, and poly-D-(-)-3-hydroxybutyric acid.
  • polyesters such as poly(2-hydroxyethyl-methacrylate) or poly(vinyl alcohol), polylactides, copolymers of L-glutamic acid and 7 ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-
  • kits for performing any one of the methods disclosed herein.
  • a kit of identifying a subject having or suspected of having a cancer or a tumor who is likely to be responsive to a binding agent comprises an agent for determining the expression level of OSCAR in a sample of the subject.
  • the kit further comprises a tool for obtaining the sample from the subject.
  • the kit further comprises an instruction (for example in the format of a manual or a label) that describes identifying a subject as likely to be responsive to said binding agent if the expression level of said OSCAR in said sample is higher than a reference expression level of OSCAR, wherein said binding agent is a LAIR1-binding agent.
  • the kit further comprises an instruction (for example in the format of a manual or a label) that describes identifying a subject as not likely to be responsive to said binding agent if the expression level of said OSCAR in said sample is not higher than a reference expression level of OSCAR, wherein said binding agent is a LAIR1-binding agent.
  • the kit further comprises agents for determining a reference expression level of OSCAR or otherwise provide a pre-determined expression level of OSCAR as a reference expression level, for example, in the instruction.
  • the reference expression level of OSCAR can be a pre- determined expression level of OSCAR, for example, an expression level of OSCAR determined based on a database (e.g., eGTex (gtexportal.org)).
  • the reference expression level of OSCAR is determined based on the OSCAR expression level in a subject or a cohort of subjects non-responsive to the treatment with the LAIR1-binding agent (such as the anti-LAIR1 antibodies provided herein).
  • the reference expression level of OSCAR is a minimal expression level of OSCAR required to be responsive to the treatment with a LAIR1-binding agent (such as the anti-LAIR1 antibodies provided herein).
  • the reference expression level of OSCAR is an OSCAR expression level in a corresponding normal tissue.
  • the reference expression level of OSCAR is an OSCAR expression level in a corresponding normal tissue from a subject or a cohort of subjects who are different from the subject from whom the sample is obtained (i.e., a different subject or a cohort of different subjects).
  • the reference expression level of OSCAR is an OSCAR expression level measured in a neighboring non-cancerous tissue in the same subject from whom the sample is obtained.
  • the reference expression level of OSCAR is an OSCAR expression level in a corresponding tissue measured in a cohort of healthy subjects.
  • the reference expression level of OSCAR is the OSCAR expression levels measured in a cohort of subjects (e.g., a cohort of different subjects, a cohort of non-responsive subjects to the treatment with the LAIR1-binding agent, a cohort of heathy subjects)
  • the reference expression level of OSCAR is a mean or a median value of the OSCAR expression levels measured in the cohort of subjects.
  • the kit comprises an agent for determining the expression level of OSCAR in a sample of the subject. In certain embodiments, the kit further comprises a tool for obtaining the sample from the subject. In certain embodiments, the kit further comprises an instruction (for example in the format of a manual or a label) that describes identifying a subject as likely to be responsive to said binding agent if the expression level of said OSCAR in said sample is higher than a reference expression level of OSCAR, wherein said binding agent is a LAIR1-binding agent. In certain embodiments, the kit comprises agents for determining a reference expression level of OSCAR or otherwise provide a pre-determined expression level of OSCAR as a reference expression level, for example, in the instruction.
  • the reference expression level of OSCAR can be a pre- determined expression level of OSCAR, for example, an expression level of OSCAR determined based on a database (e.g., eGTex (gtexportal.org)). In some embodiments, the reference expression level of OSCAR is determined based on the OSCAR expression level in a subject or a cohort of subjects non-responsive to the treatment with the LAIR1-binding agent (such as the anti-LAIR1 antibodies provided herein). In some embodiments, the reference expression level of OSCAR is a minimal expression level of OSCAR required to be responsive to the treatment with a LAIR1-binding agent (such as the anti-LAIR1 antibodies provided herein).
  • the reference expression level of OSCAR is an OSCAR expression level in a corresponding normal tissue. In other embodiments, the reference expression level of OSCAR is an OSCAR expression level in a corresponding normal tissue from a subject or a cohort of subjects who are different from the subject from whom the sample is obtained (i.e., a different subject or a cohort of different subjects). In other embodiments, the reference expression level of OSCAR is an OSCAR expression level measured in a neighboring non-cancerous tissue in the same subject from whom the sample is obtained. In yet other embodiments, the reference expression level of OSCAR is an OSCAR expression level in a corresponding tissue measured in a cohort of healthy subjects.
  • the reference expression level of OSCAR when the reference expression level of OSCAR is the OSCAR expression levels measured in a cohort of subjects (e.g., a cohort of different subjects, a cohort of non-responsive subjects to the treatment with the LAIR1-binding agent, a cohort of heathy subjects), the reference expression level of OSCAR is a mean or a median value of the OSCAR expression levels measured in the cohort of subjects.
  • the expression level of OSCAR in the subject’s sample is higher than the reference expression level of OSCAR, the subject is predicted to be responsive to a binding agent.
  • treatment with a binding agent is effective.
  • higher means that the reference expression level of OSCAR is higher (e.g., statistically significantly higher) than the reference expression level of OSCAR according to an assay (including those assays disclosed herein).
  • the kit comprises an agent for determining the percentage of cells that express both OSCAR and LAIR1 (OSCAR + /LAIR1 + cells) in a sample of the subject.
  • the kit further comprises a tool for obtaining the sample from the subject.
  • the kit further comprises an instruction (for example in the format of a manual or a label) that describes identifying said subject as likely to be responsive to said binding agent if the percentage of OSCAR + /LAIR1 + cells in said sample of said subject is higher than a reference percentage of OSCAR + /LAIR1 + cells, wherein said binding agent is a LAIR1- binding agent.
  • the kit further comprises agents for determining a reference percentage of OSCAR + /LAIR1 + cells or otherwise provide a pre-determined percentage of OSCAR + /LAIR1 + cells as a reference percentage, for example, in the instruction.
  • the reference percentage of OSCAR + /LAIR1 + cells can be a pre-determined percentage of OSCAR + /LAIR1 + cells, for example, a percentage of OSCAR + /LAIR1 + cells obtained is based on a certain database.
  • the reference percentage of OSCAR + /LAIR1 + cells can be a pre-determined percentage of OSCAR + /LAIR1 + cells, for example, a percentage of OSCAR + /LAIR1 + cells obtained is based on a certain database.
  • the reference percentage of OSCAR + /LAIR1 + cells is determined based on the percentage of OSCAR + /LAIR1 + cells in a subject or a cohort of subjects non-responsive to the treatment with the LAIR1-binding agent (such as the anti-LAIR1 antibodies provided herein). In some embodiments, the reference percentage of OSCAR + /LAIR1 + cells is a minimal percentage of OSCAR + /LAIR1 + cells required to be responsive to the treatment with a LAIR1-binding agent (such as the anti-LAIR1 antibodies provided herein). In other embodiments, the reference percentage of OSCAR + /LAIR1 + cells is a percentage of OSCAR + /LAIR1 + cells in a corresponding normal tissue.
  • the reference percentage of OSCAR + /LAIR1 + cells is a percentage of OSCAR + /LAIR1 + cells in a corresponding normal tissue from a subject or a cohort of subjects who are different from the subject from whom the sample is obtained (i.e., a different subject or a cohort of different subjects).
  • the reference percentage of OSCAR + /LAIR1 + cells is a percentage of OSCAR + /LAIR1 + cells measured in a neighboring non-cancerous tissue in the same subject.
  • the reference percentage of OSCAR + /LAIR1 + cells is a percentage of OSCAR + /LAIR1 + cells in a corresponding tissue measured in a cohort of healthy subjects.
  • the reference percentage of OSCAR + /LAIR1 + cells is the percentage of OSCAR + /LAIR1 + cells measured in a cohort of subjects (e.g., a cohort of different subjects, a cohort of non-responsive subjects to the treatment with the LAIR1-binding agent, a cohort of heathy subjects)
  • the reference percentage of OSCAR + /LAIR1 + cells is a mean or median value of the percentages of OSCAR + /LAIR1 + cells measured in the cohort of subjects.
  • the kit comprises an agent for determining the percentage of cells that express both OSCAR and LAIR1 (OSCAR + /LAIR1 + cells) in a sample of the subject.
  • the kit further comprises a tool for obtaining the sample from the subject.
  • the kit further comprises an instruction (for example in the format of a manual or a label) that describes identifying said subject as likely to be responsive to said binding agent if the percentage of OSCAR + /LAIR1 + cells in said sample of said subject is higher than a reference percentage, wherein said binding agent is a LAIR1-binding agent.
  • the kit comprises agents for determining a reference percentage of OSCAR + /LAIR1 + cells or otherwise provide a pre-determined percentage of OSCAR + /LAIR1 + cells as a reference percentage, for example, in the instruction.
  • the reference percentage of OSCAR + /LAIR1 + cells can be a pre-determined percentage of OSCAR + /LAIR1 + cells, for example, a percentage of OSCAR + /LAIR1 + cells obtained is based on a certain database.
  • the reference percentage of OSCAR + /LAIR1 + cells is determined based on the percentage of OSCAR + /LAIR1 + cells in a subject or a cohort of subjects non-responsive to the treatment with the LAIR1-binding agent (such as the anti-LAIR1 antibodies provided herein). In some embodiments, the reference percentage of OSCAR + /LAIR1 + cells is a minimal percentage of OSCAR + /LAIR1 + cells required to be responsive to the treatment with a LAIR1-binding agent (such as the anti-LAIR1 antibodies provided herein). In other embodiments, the reference percentage of OSCAR + /LAIR1 + cells is a percentage of OSCAR + /LAIR1 + cells in a corresponding normal tissue.
  • the reference percentage of OSCAR + /LAIR1 + cells is a percentage of OSCAR + /LAIR1 + cells in a corresponding normal tissue from a subject or a cohort of subjects who are different from the subject from whom the sample is obtained (i.e., a different subject or a cohort of different subjects).
  • the reference percentage of OSCAR + /LAIR1 + cells is a percentage of OSCAR + /LAIR1 + cells measured in a neighboring non-cancerous tissue in the same subject.
  • the reference percentage of OSCAR + /LAIR1 + cells is a percentage of OSCAR + /LAIR1 + cells in a corresponding tissue measured in a cohort of healthy subjects.
  • the reference percentage of OSCAR + /LAIR1 + cells is the percentage of OSCAR + /LAIR1 + cells measured in a cohort of subjects (e.g., a cohort of different subjects, a cohort of non-responsive subjects to the treatment with the LAIR1-binding agent, a cohort of heathy subjects)
  • the reference percentage of OSCAR + /LAIR1 + cells is a mean or median value of the percentages of OSCAR + /LAIR1 + cells measured in the cohort of subjects.
  • the OSCAR + /LAIR1 + cells comprise myeloid cells.
  • the myeloid cells comprise megakaryocytes, erythrocytes, mast cells, or myelobasts. In some embodiments, the myeloid cells comprise basophils, neutrophils, eosinophils, monocytes, macrophages, and dendritic cells. [00494] In some embodiments, the percentage of OSCAR + /LAIR1 + cells is determined by using an immunoassay. In some embodiments, the immunoassay comprises flow cytometry, or double immunocytochemical labeling.
  • the subject when the percentage of OSCAR + /LAIR1 + cells in the subject’s sample is higher than the reference percentage of OSCAR + /LAIR1 + cells, the subject is predicted to be responsive to a binding agent. In some embodiments, when the percentage of OSCAR + /LAIR1 + cells in the subject’s sample is higher than the reference percentage of OSCAR + /LAIR1 + cells, treatment with a binding agent is effective. In certain embodiments, higher means that the percentage of OSCAR + /LAIR1 + cells is higher (e.g., statistically significantly higher) than the reference percentage of OSCAR + /LAIR1 + cells according to an assay (including those assays disclosed herein).
  • the percentage of OSCAR + /LAIR1 + cells in the subject is higher than the reference percentage of OSCAR + /LAIR1 + cells. In some embodiments, when the percentage of OSCAR + /LAIR1 + cells in the subject is higher than the reference percentage of OSCAR + /LAIR1 + cells, the subject is identified as likely to be responsive to a binding agent. In some embodiments, once a subject is identified as likely to be responsive to a binding agent provided herein, administration of the binding agent can be performed. Thus, in some embodiments, the methods provided herein further comprise administering the binding agent to the subject identified as likely to be responsive to a binding agent. [00496] In some embodiments, the sample comprises a tumor biopsy.
  • the sample comprises whole blood.
  • the tumor biopsy or whole blood comprises myeloid cells.
  • the myeloid cells comprise one or more cell types selected from the group consisting of monocytes, macrophages, neutrophils and dendritic cells.
  • the sample comprises one or more cell types selected from the group consisting of monocytes, macrophages, neutrophils and dendritic cells.
  • the sample comprises monocytes.
  • the sample comprises macrophages.
  • the sample comprises neutrophils.
  • the sample comprises dendritic cells.
  • the sample comprises a solid tissue. In some embodiments, the sample comprises a liquid.
  • the solid tissue comprises a non-diseased tissue. In some embodiments, the solid tissue comprises a diseased tissue. In some embodiments, the diseased tissue comprises a tumor biopsy. In some embodiments, the tumor biopsy comprises myeloid cells. In some embodiments, the myeloid cells comprise one or more cell types selected from the group consisting of monocytes, macrophages, neutrophils and dendritic cells. In some embodiments, the sample comprises one or more cell types selected from the group consisting of monocytes, macrophages, neutrophils and dendritic cells. In some embodiments, the sample comprises monocytes. In some embodiments, the sample comprises macrophages. In some embodiments, the sample comprises neutrophils.
  • the sample comprises dendritic cells. [00498] In some embodiments, the sample comprises cells. In some embodiments, the cells comprise non-diseased cells. In some embodiments, the cells comprise diseased cells. In some embodiments, the diseased cells comprise cancer cells. [00499] In some embodiments, the sample comprises a liquid. In some embodiments, the liquid is obtained from a diseased subject. In some embodiments, the liquid is obtained from a non-diseased subject. In some embodiments, the liquid comprises whole blood. [00500] In some embodiments, the cancer is a solid tumor (e.g., an advanced solid tumor).
  • a solid tumor e.g., an advanced solid tumor
  • the cancer is pancreatic cancer, breast cancer, lung cancer (e.g., non-small cell lung cancer (NSCLC)), head and neck cancer (e.g., squamous cell carcinoma of the head and neck (SCCHN)), colorectal cancer (CRC), prostate cancer, skin cancer, melanoma, stomach cancer, gastric cancer, intestinal cancer, ovarian cancer, cervical and endocervical cancer, biliary cancer, uterine cancer, endometrial cancer, urinary bladder cancer, brain cancer, mesothelioma, esophageal cancer, liver cancer, kidney cancer (e.g., renal cell carcinoma (RCC)),testicular cancer, or cholangiocarcinoma.
  • NSCLC non-small cell lung cancer
  • SCCHN squamous cell carcinoma of the head and neck
  • CRCC colorectal cancer
  • prostate cancer skin cancer, melanoma
  • stomach cancer gastric cancer
  • intestinal cancer intestinal cancer
  • ovarian cancer ovarian cancer
  • the cancer is gastric cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is insensitive to treatment with an immune-checkpoint inhibitor (e.g., an anti-PD-1 antibody). In some embodiments, the cancer has become resistant to treatment with an immune-checkpoint inhibitor (e.g., an anti-PD-1 antibody).
  • an agent for determining the expression level of OSCAR can be an anti-OSCAR antibody (e.g., an anti-OSCAR antibody disclosed in Section 5.5).
  • an agent for determining the expression level of OSCAR can be a nucleic acid that hybridizes to OSCAR mRNA or cDNA. Detection and/or quantification of LAIR1 and/or OSCAR may further comprise an assay that utilizes a capture agent.
  • the capture agent can be a binding agent, an antibody, antibody fragment, or nucleic acid that is detectable using any existing, available or conventional separation, detection and quantification agents/methods to measure the presence or absence (e.g., readout being present vs. absent; or detectable amount vs.
  • a capture agent can be a labeled antibody, wherein the label has fluorescent (e.g., fluorophore), colorimetric or chemiluminescent properties.
  • the expression level of OSCAR is determined by measuring the nucleic acid expression level of OSCAR.
  • Nucleic acid which can also be referred to herein as a gene, polynucleotide, nucleotide sequence, primer, oligonucleotide or probe, refers to natural or modified purine- and pyrimidine-containing polymers of any length, either polyribonucleotides or polydeoxyribonucleotides or mixed polyribo-polydeoxyribo nucleotides and ⁇ -anomeric forms thereof.
  • the two or more purine- and pyrimidine-containing polymers are typically linked by a phosphoester bond or analog thereof.
  • the terms can be used interchangeably to refer to all forms of nucleic acid, including deoxyribonucleic acid (DNA) and ribonucleic acid (RNA).
  • the nucleic acids can be single strand, double, or triplex, linear or circular. Nucleic acids include genomic DNA and cDNA. RNA nucleic acid can be spliced or unspliced mRNA, rRNA, tRNA or antisense. Nucleic acids include naturally occurring, synthetic, as well as nucleotide analogs and derivatives. [00503] In some embodiments, the mRNA expression level of OSCAR is determined. In some embodiments, the mRNA expression level of OSCAR is determined by using quantitative reverse-transcriptase PCR (RT-qPCR), microarray, Northern blot or RNA sequencing. [00504] In other embodiments, the expression level of OSCAR is determined by measuring the protein expression level of OSCAR.
  • RT-qPCR quantitative reverse-transcriptase PCR
  • the expression level of OSCAR is determined by measuring the protein expression level of OSCAR.
  • Protein which can also be referred to herein as a peptide or polypeptide, refers to natural or modified amino acid polymers of any length.
  • the terms can be used interchangeably to refer to all forms of protein including antibodies, enzymes, contractile proteins, hormonal proteins, structural proteins, storage proteins and transport proteins. Proteins include naturally occurring, synthetic, as well as protein analogs and derivatives.
  • the protein expression level of OSCAR is determined by using an immunoassay.
  • the immunoassay comprises Western blots, enzyme-linked immunosorbent assay (ELISA), immunoprecipitation, immunohistochemistry, immunofluorescence, radioimmunoassay (RIA), dot blotting, and flow cytometry.
  • the ELISA is direct ELISA (enzyme-linked immunosorbent assay), indirect ELISA, sandwich ELISA, competitive ELISA, multiplex ELISA, ELISPOT technologies, and other similar techniques known in the art.
  • the protein expression level of OSCAR is determined by using mass spectrometry (MS).
  • MS comprises liquid chromatography- tandem mass spectrometry (LC MS/MS), liquid chromatography-mass spectrometry (LC-MS), multiple reaction monitoring (MRM), selected reaction monitoring (SRM), affinity-capture MS (AC-MS), matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) MS, MALDI-TOF post-source-decay (PSD), MALDI- TOF/TOF, surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF) MS, electrospray ionization mass spectrometry (ESI-MS), ESI-MS/MS, ESI-MS/(MS)n (n is an integer greater than zero), ESI 3D or linear (2D) ion trap MS, ESI triple quadrupole MS, ESI quadrupole orthogonal TOF (Q-TOF), ESI Fourier transform MS systems, desorption/
  • the percentage of OSCAR + /LAIR1 + cells in the sample can be determined by any currently available methods for measuring co-expression of two proteins on cells in the art.
  • the percentage of OSCAR + /LAIR1 + cells is determined by using an immunoassay.
  • the immunoassay comprises flow cytometry or double immunocytochemical labeling.
  • the immunoassay uses an OSCAR- binding agent (e.g., an anti-OSCAR antibody disclosed in Section 5.5) to detect the presence of OSCAR in the sample.
  • Kits provided herein can additionally include other components. Each component of the kit can be enclosed within an individual container and all of the various containers can be within a single packaging material.
  • packaging material refers to a physical structure housing the components of the kit.
  • the packaging material can maintain the components sterilely, and can be made of material commonly used for such purposes (e.g., paper, corrugated fiber, glass, plastic, foil, ampules, vials, tubes, etc.).
  • kits are designed for cold storage. Kits provided herein can further be designed to comprise peptide sequences provided herein, or that comprise nucleic acids encoding peptide sequences.
  • Kits provided herein can also be designed to comprise, either separately or in combination with the peptide sequences provided herein, one or more additional agents useful in the treatment or prevention of a cancer or a tumor. Any cells in the kit can be maintained under appropriate storage conditions until ready to use.
  • Kits provided herein can include labels or inserts. Labels or inserts include “printed matter,” e.g., paper or cardboard, separate or affixed to a component, a kit or packing material (e.g., a box), or attached to, for example, an ampule, tube or vial containing a kit component.
  • Labels or inserts can additionally include a computer readable medium, such as a disk (e.g., hard disk, card, memory disk), optical disk such as CD- or DVD-ROM/RAM, DVD, MP3, magnetic tape, or an electrical storage media such as RAM and ROM or hybrids of these such as magnetic/optical storage media, FLASH media or memory type cards.
  • the instructions recite a method provided herein.
  • Labels or inserts can include, among other things, identifying information of one or more components therein, dosing parameters, and/or information on the clinical pharmacology of the active ingredient(s), including mechanism of action, pharmacokinetics and pharmacodynamics. Labels or inserts can include information identifying manufacturer information, lot numbers, manufacturer location and date.
  • Labels or inserts can include information on a condition, disorder, disease or symptom for which a kit component may be used.
  • Labels or inserts can include instructions for the clinician or for a subject for using one or more of the kit components in a method, treatment protocol or therapeutic regimen. Instructions can include dosage amounts, frequency or duration, and instructions for practicing any of the methods, treatment protocols or therapeutic regimens set forth herein. Exemplary instructions include instructions for treatment or use of a peptide sequence as set forth herein and/or the use of an additional agent or treatment modality useful in treating a cancer or a tumor. Kits provided herein therefore can additionally include labels or instructions for practicing any of the methods and uses provided herein, including treatment methods and uses.
  • Labels or inserts can include information on any benefit that a component may provide, such as a prophylactic or therapeutic benefit. Labels or inserts can include information on potential adverse side effects, such as warnings to the subject or clinician regarding situations where it would not be appropriate to use a particular composition. Adverse effects could also occur when the subject has, will be, or is currently taking one or more other medications that may be incompatible with the composition, or the subject has, will be, or is currently undergoing another treatment protocol or therapeutic regimen which would be incompatible with the composition and, therefore, instructions could include information regarding such incompatibilities. [00513] In case of conflict, the specification, including definitions, will control.
  • reference to a range of 90-100% includes 91-99%, 92-98%, 93-95%, 91-98%, 91-97%, 91-96%, 91-95%, 91-94%, 91-93%, and so forth.
  • Reference to a range of 90-100% also includes 91%, 92%, 93%, 94%, 95%, 96%, 97%, etc., as well as 91.1%, 91.2%, 91.3%, 91.4%, 91.5%, etc., 92.1%, 92.2%, 92.3%, 92.4%, 92.5%, etc., and so forth.
  • reference to a range of 1-3, 3-5, 5-10, 10-20, 20-30, 30-40, 40-50, 50-60, 60-70, 70-80, 80-90, 90-100, 100-110, 110-120, 120-130, 130-140, 140-150, 150-160, 160-170, 170-180, 180-190, 190-200, 200-225, 225-250 includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, etc.
  • reference to a range of 25-250, 250-500, 500-1000, 1000-2500, 2500-5000, 5000- 25,000, or 5000-50,000 includes any numerical value or range within or encompassing such values, e.g., 25, 26, 27, 28, 29...250, 251, 252, 253, 254....500, 501, 502, 503, 504..., etc.
  • the use of a series of ranges includes combinations of the upper and lower ranges to provide another range. This construction applies regardless of the breadth of the range and in all contexts throughout this patent document.
  • ranges such as 5- 10, 10-20, 20-30, 30-40, 40-50, 50-75, 75-100, 100-150, includes ranges such as 5-20, 5-30, 5- 40, 5-50, 5-75, 5-100, 5-150, and 10-30, 10-40, 10-50, 10-75, 10-100, 10-150, and 20-40, 20-50, 20-75, 20-100, 20-150, and so forth.
  • ranges such as 5-20, 5-30, 5- 40, 5-50, 5-75, 5-100, 5-150, and 10-30, 10-40, 10-50, 10-75, 10-100, 10-150, and 20-40, 20-50, 20-75, 20-100, 20-150, and so forth.
  • certain abbreviations are used herein.
  • One example is the single letter abbreviation to represent amino acid residues.
  • amino acids and their corresponding three letter and single letter abbreviations are as follows: alanine Ala (A) arginine Arg (R) asparagine Asn (N) aspartic acid Asp (D) cysteine Cys (C) glutamic acid Glu (E) glutamine Gln (Q) glycine Gly (G) histidine His (H) isoleucine Ile (I) leucine Leu (L) lysine Lys (K) methionine Met (M) phenylalanine Phe (F) proline Pro (P) serine Ser (S) threonine Thr (T) tryptophan Trp (W) tyrosine Tyr (Y) valine Val (V) [00517] The invention is generally disclosed herein using affirmative language to describe the numerous embodiments.
  • the invention also specifically includes embodiments in which particular subject matter is excluded, in full or in part, such as substances or materials, method steps and conditions, protocols, procedures, assays or analysis. Thus, even though the invention is generally not expressed herein in terms of what the invention does not include, aspects that are not expressly included in the invention are nevertheless disclosed herein. [00518] Particular embodiments of this invention are described herein, including the best mode known to the inventors for carrying out the invention. Upon reading the foregoing description, variations of the disclosed embodiments may become apparent to individuals working in the art, and it is expected that those skilled artisans may employ such variations as appropriate.
  • a method of identifying a subject having or suspected of having a cancer or a tumor as likely or not likely to be responsive to a LAIR1-binding agent comprising: (a) determining the expression level of OSCAR in a sample from the subject; and (b) identifying the subject as likely to be responsive to the LAIR1-binding agent if the expression level of the OSCAR in the sample is higher than a reference expression level of OSCAR, and identifying the subject as not likely to be responsive to the LAIR1-binding agent if the expression level of the OSCAR in the sample is not higher than a reference expression level of OSCAR; optionally wherein the method further comprises obtaining the sample from the subject. 2.
  • a method of predicting the responsiveness of a subject having or suspected of having a cancer or a tumor to a LAIR1-binding agent comprising: (a) determining the expression level of OSCAR in a sample from the subject; and (b) predicting the subject as likely to be responsive to the LAIR1-binding agent if the expression level of the OSCAR in the sample is higher than a reference expression level of OSCAR; optionally wherein the method further comprises obtaining the sample from the subject. 3.
  • a method of selectively treating a cancer or a tumor comprising administering a therapeutically effective amount of a LAIR1-binding agent to a subject identified as likely to be responsive to the LAIR1-binding agent according to a method comprising: (a) determining the expression level of OSCAR in a sample from the subject; and (b) identifying the subject as likely to be responsive to the LAIR1-binding agent if the expression level of the OSCAR in the sample of the subject is higher than a reference expression level of OSCAR; optionally wherein the method further comprises obtaining the sample from the subject. 4.
  • a method of selectively treating a cancer or a tumor in a subject identified as having a higher expression level of OSCAR than a reference expression level of OSCAR comprising administering a therapeutically effective amount of a LAIR1-binding agent to the subject.
  • a method of selectively treating a cancer or a tumor in a subject with a LAIR1-binding agent comprising: (a) determining the expression level of OSCAR in a sample from the subject; (b) identifying the subject as likely to be responsive to the LAIR1-binding agent if the expression level of the OSCAR in the sample of the subject is higher than a reference expression level of OSCAR; and (c) administering a therapeutically effective amount of the LAIR1-binding agent to the subject identified as likely to be responsive to the LAIR1-binding agent; optionally wherein the method further comprises obtaining the sample from the subject. 6.
  • the reference expression level of OSCAR is: (a) a predetermined expression level of OSCAR; (b) an OSCAR expression level in a corresponding normal tissue; (c) an OSCAR expression level measured in a neighboring non-cancerous tissue in the same subject; or (d) an OSCAR expression level in a corresponding tissue measured in a cohort of healthy subjects.
  • the expression level of OSCAR is the mRNA expression level of OSCAR.
  • the mRNA expression level of OSCAR is determined by quantitative reverse-transcriptase PCR (RT-qPCR), microarray, Northern blot, and/or RNA sequencing. 9.
  • the expression level of OSCAR is the protein expression level of OSCAR.
  • the method of embodiment 9, wherein the protein expression level of OSCAR is determined by mass spectrometry (MS).
  • MS mass spectrometry
  • the MS comprises liquid chromatography- tandem mass spectrometry (LC MS/MS).
  • the protein expression level of OSCAR is determined by an immunoassay.
  • the immunoassay comprises flow cytometry, immunohistochemistry, western blot, or enzyme-linked immunosorbent assay (ELISA).
  • ELISA enzyme-linked immunosorbent assay
  • the anti-OSCAR antibody comprises: (i) a VH comprising a VH-CDR1, a VH-CDR2 and a VH-CDR3 from SEQ ID NO:196, and a VL comprising a VL-CDR1, a VL-CDR2 and a VL-CDR3 from SEQ ID NO:197; (ii) a VH comprising a VH-CDR1, a VH-CDR2 and a VH-CDR3 from SEQ ID NO:198, and a VL comprising a VL-CDR1, a VL-CDR2 and a VL-CDR3 from SEQ ID NO:199; (iii) a VH comprising a VH-CDR1, a VH-CDR2 and a VH-CDR3 from SEQ ID NO:200, and a VL comprising a VL-CDR1, a VL-CDR2 and a VL-CDR3 from SEQ ID
  • the VH comprises the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:154, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:155, and the VH- CDR3 comprising the amino acid sequence of SEQ ID NO:156; and the VL comprises the VL- CDR1 comprising the amino acid sequence of SEQ ID NO:157, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO:158, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO:159; (ii) the VH comprises the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:160, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:161, and the VH- CDR3 comprising the amino acid sequence of SEQ ID NO:162; and the VL comprises the VL- CDR1 comprising the amino acid sequence of SEQ ID NO:163, the VL-CDR2
  • a method of identifying a subject having or suspected of having a cancer or a tumor as likely or not likely to be responsive to a LAIR1-binding agent comprising: (a) determining the percentage of cells that express both OSCAR and LAIR1 (OSCAR + /LAIR1 + cells) in a sample from the subject; and (b) identifying the subject as likely to be responsive to the LAIR1-binding agent if the percentage of OSCAR + /LAIR1 + cells in the sample is higher than a reference percentage of OSCAR + /LAIR1 + cells; optionally wherein the method further comprises obtaining the sample from the subject. 19.
  • a method of predicting the responsiveness of a subject having or suspected of having a cancer or a tumor to a LAIR1-binding agent comprising: (a) determining the percentage of cells that express both OSCAR and LAIR1 (OSCAR + /LAIR1 + cells) in a sample from the subject; and (b) predicting the subject as likely to be responsive to the LAIR1-binding agent if the percentage of OSCAR + /LAIR1 + cells in the sample of the subject is higher than a reference percentage of OSCAR + /LAIR1 + cells; optionally wherein the method further comprises obtaining the sample from the subject.
  • a method of selectively treating a cancer or a tumor comprising administering a therapeutically effective amount of a LAIR1-binding agent to a subject identified as likely to be responsive to the LAIR1-binding agent according to a method comprising: (a) determining the percentage of cells that express both OSCAR and LAIR1 (OSCAR + /LAIR1 + cells) in a sample from the subject; and (b) identifying the subject as likely to be responsive to the binding agent if the percentage of OSCAR + /LAIR1 + cells in the sample of the subject is higher than a reference percentage of OSCAR + /LAIR1 + cells, optionally wherein the method further comprises obtaining the sample from the subject. 21.
  • a method of selectively treating a cancer or a tumor in a subject identified to have a higher percentage of cells that express both OSCAR and LAIR1 (OSCAR + /LAIR1 + cells) than a reference percentage of OSCAR + /LAIR1 + cells comprising administering a therapeutically effective amount of a LAIR1-binding agent to the subject.
  • a method of selectively treating a cancer or a tumor in a subject with a LAIR1-binding agent comprising: (a) determining the percentage of cells that express both OSCAR and LAIR1 in a sample from the subject; (b) identifying the subject as likely to be responsive to the LAIR1-binding agent if the percentage of OSCAR + /LAIR1 + cells in the sample of the subject is higher than a reference percentage of OSCAR + /LAIR1 + cells; and (c) administering a therapeutically effective amount of the LAIR1-binding agent to the subject identified as likely to be responsive to the LAIR1-binding agent, optionally wherein the method further comprises obtaining the sample from the subject.
  • the OSCAR + /LAIR1 + cells comprise myeloid cells.
  • the myeloid cells comprise at least one of monocytes, macrophages, neutrophils, and dendritic cells; optionally wherein the monocytes comprise classical monocytes, non-classical monocytes, or a combination thereof.
  • the percentage of OSCAR + /LAIR1 + cells is determined by flow cytometry. 26. The method of embodiment 25, wherein the flow cytometry comprises detecting OSCAR using an anti-OSCAR antibody. 27.
  • the anti-OSCAR antibody comprises: (i) a VH comprising a VH-CDR1, a VH-CDR2 and a VH-CDR3 from SEQ ID NO:196, and a VL comprising a VL-CDR1, a VL-CDR2 and a VL-CDR3 from SEQ ID NO:197; (ii) a VH comprising a VH-CDR1, a VH-CDR2 and a VH-CDR3 from SEQ ID NO:198, and a VL comprising a VL-CDR1, a VL-CDR2 and a VL-CDR3 from SEQ ID NO:199; (iii) a VH comprising a VH-CDR1, a VH-CDR2 and a VH-CDR3 from SEQ ID NO:200, and a VL comprising a VL-CDR1, a VL-CDR2 and a VL-CDR3 from SEQ ID
  • the VH comprises the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:154, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:155, and the VH- CDR3 comprising the amino acid sequence of SEQ ID NO:156; and the VL comprises the VL- CDR1 comprising the amino acid sequence of SEQ ID NO:157, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO:158, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO:159; (ii) the VH comprises the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:160, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:161, and the VH- CDR3 comprising the amino acid sequence of SEQ ID NO:162; and the VL comprises the VL- CDR1 comprising the amino acid sequence of SEQ ID NO:163, the VL-CDR
  • the reference percentage of OSCAR + /LAIR1 + cells is: (a) a predetermined percentage of OSCAR + /LAIR1 + cells; (b) a percentage of OSCAR + /LAIR1 + cells in a corresponding normal tissue; (c) a percentage of OSCAR + /LAIR1 + cells in a neighboring non-cancerous tissue in the same subject; or (d) a percentage of OSCAR + /LAIR1 + cells in a corresponding tissue measured in a cohort of healthy subjects.
  • the LAIR1-binding agent is an antibody comprising: (a) a heavy chain variable region (VH) comprising a VH-complementarity determining region (CDR)1, a VH-CDR2 and a VH-CDR3 from SEQ ID NO:117, and a light chain variable region (VL) comprising a VL-CDR1, a VL-CDR2 and a VL-CDR3 from SEQ ID NO:118; (b) a VH comprising a VH-CDR1, a VH-CDR2 and a VH-CDR3 from SEQ ID NO:119, and a VL comprising a VL-CDR1, a VL-CDR2 and a VL-CDR3 from SEQ ID NO:120; (c) a VH comprising a VH-CDR1, a VH-CDR2 and a VH-CDR3 from SEQ ID NO:115, and
  • the VH comprises the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:25, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:26, and the VH-CDR3 comprising the amino acid sequence of SEQ ID NO:27; and the VL comprises the VL-CDR1 comprising the amino acid sequence of SEQ ID NO:28, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO:29, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO:30; (2) the VH comprises the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:31, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:32, and the VH- CDR3 comprising the amino acid sequence of SEQ ID NO:27; and the VL comprises the VL- CDR1 comprising the amino acid sequence of SEQ ID NO:28, the VL-CDR2 compris
  • the LAIR1 antibody further comprises: (a) a heavy chain comprising an amino acid sequence having 80% sequence identity to the sequence of SEQ ID NO:134 and/or a light chain comprising an amino acid sequence having 80% sequence identity to the sequence of SEQ ID NO:136; (b) a heavy chain comprising an amino acid sequence having 80% sequence identity to the sequence of SEQ ID NO:138 and/or a light chain comprising an amino acid sequence having 80% sequence identity to the sequence of SEQ ID NO:140; (c) a heavy chain comprising the amino acid sequence of SEQ ID NO:134 and/or a light chain comprising the amino acid sequence of SEQ ID NO:136; or (d) a heavy chain comprising the amino acid sequence of SEQ ID NO:138 and/or a light chain comprising the amino acid sequence of SEQ ID NO:140.
  • the sample comprises a tumor biopsy.
  • the sample comprises whole blood.
  • the tumor biopsy or whole blood comprises myeloid cells.
  • the myeloid cells comprise at least one of monocytes, macrophages, neutrophils, and dendritic cells; optionally wherein the monocytes comprise classical monocytes, non-classical monocytes, or a combination thereof. 42.
  • the cancer or tumor is osteosarcoma, pancreatic cancer, breast cancer, mesothelioma, gastric cancer, non-small cell lung cancer (NSCLC), cervical and endocervical cancer, biliary duct cancer, squamous cell carcinoma of head and neck (SCCHN), bladder cancer, urothelial cancer, colorectal cancer (CRC), esophageal cancer, ovarian cancer, renal cell carcinoma (RCC), prostate cancer, melanoma, or cholangiocarcinoma.
  • NSCLC non-small cell lung cancer
  • SCCHN squamous cell carcinoma of head and neck
  • bladder cancer urothelial cancer
  • CRCC colorectal cancer
  • esophageal cancer ovarian cancer
  • RRCC renal cell carcinoma
  • prostate cancer melanoma
  • cholangiocarcinoma cholangiocarcinoma
  • kits for identifying a subject having or suspected of having a cancer or a tumor who is likely to be responsive to a LAIR1-binding agent comprising an agent for determining the expression level of OSCAR in a sample of the subject.
  • the kit further comprises an instruction of identifying the subject as likely to be responsive to the LAIR1-binding agent if the expression level of the OSCAR in the sample is higher than a reference expression level of OSCAR, and/or identifying the subject as not likely to be responsive to the LAIR1-binding agent if the expression level of the OSCAR in the sample is not higher as compared to a reference expression level of OSCAR. 46.
  • a kit for predicting the responsiveness of a subject having or suspected of having a cancer or a tumor to a LAIR1-binding agent comprising an agent for determining the expression level of OSCAR in a sample of the subject. 47.
  • the kit provides a pre-determined level of OSCAR as a reference expression level.
  • kit further comprises an instruction of identifying the subject as likely to be responsive to the LAIR1-binding agent if the percentage of OSCAR + /LAIR1 + cells in the sample of the subject is higher than a reference percentage of OSCAR + /LAIR1 + cells, or identifying the subject as not likely to be responsive to the LAIR1- binding agent if the percentage of OSCAR + /LAIR1 + cells in the sample of the subject is not higher as compared to a reference percentage of OSCAR + /LAIR1 + cells. 53.
  • a kit for predicting the responsiveness of a subject having or suspected of having a cancer or a tumor to a LAIR1-binding agent comprising an agent for determining the percentage of cells that express both OSCAR and LAIR1 (OSCAR + /LAIR1 + cells) in a sample of the subject. 54.
  • kit further comprises an instruction of predicting the subject as likely to be responsive to the LAIR1-binding agent if the percentage of OSCAR + /LAIR1 + cells in the sample of the subject is higher than a reference percentage of OSCAR + /LAIR1 + cells, or predicting the subject as not likely to be responsive to the LAIR1- binding agent if the percentage of OSCAR + /LAIR1 + cells in the sample of the subject is lower as compared to a reference percentage of OSCAR + /LAIR1 + cells.
  • the kit further comprises a tool for obtaining the sample from the subject.
  • kit of any one of embodiments 51 to 55 wherein the kit further comprises an agent for determining the reference percentage of OSCAR+/LAIR1+ cells.
  • kit further comprises an agent for determining the reference percentage of OSCAR+/LAIR1+ cells.
  • kit provides a pre-determined percentage of OSCAR + /LAIR1 + cells as the reference percentage.
  • a binding agent that specifically binds OSCAR comprises: (i) a VH comprising a VH-CDR1, a VH-CDR2 and a VH-CDR3 from SEQ ID NO:196, and a VL comprising a VL-CDR1, a VL-CDR2 and a VL-CDR3 from SEQ ID NO:197; (ii) a VH comprising a VH-CDR1, a VH-CDR2 and a VH-CDR3 from SEQ ID NO:198, and a VL comprising a VL-CDR1, a VL-CDR2 and a VL-CDR3 from SEQ ID NO:199; (iii) a VH comprising a VH-CDR1, a VH-CDR2 and a VH-CDR3 from SEQ ID NO:200, and a VL comprising a VL-CDR1, a VL-CDR2 and a VL
  • the VH comprises the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:154, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:155, and the VH- CDR3 comprising the amino acid sequence of SEQ ID NO:156; and the VL comprises the VL- CDR1 comprising the amino acid sequence of SEQ ID NO:157, the VL-CDR2 comprising the amino acid sequence of SEQ ID NO:158, and the VL-CDR3 comprising the amino acid sequence of SEQ ID NO:159; (ii) the VH comprises the VH-CDR1 comprising the amino acid sequence of SEQ ID NO:160, the VH-CDR2 comprising the amino acid sequence of SEQ ID NO:161, and the VH- CDR3 comprising the amino acid sequence of SEQ ID NO:162; and the VL comprises the VL- CDR1 comprising the amino acid sequence of SEQ ID NO:163, the V
  • 65. The binding agent of any one of embodiments 61-64, which is an antigen-binding fragment.
  • 66. The binding agent of embodiment 65, wherein the antigen-binding fragment is a Fab, Fab′, F(ab′)2, Fv, scFv, (scFv)2, single chain antibody, dual variable region antibody, diabody, or nanobody.
  • the binding agent of any one of embodiments 58-66 which comprises a detectable moiety. 68.
  • the binding agent of embodiment 67 wherein the detectable moiety is a fluorescent label, a bioluminescent label, a chemiluminescent label, an enzyme, a small molecule, a radioisotope, or colloidal gold.
  • a pharmaceutical composition comprising the binding agent of any one of embodiments 58-68, and a pharmaceutically acceptable carrier.
  • 70. An isolated polynucleotide or polynucleotides encoding the binding agent of any one of embodiments 58-68.
  • a vector or vectors comprising the polynucleotide or polynucleotides of embodiment 70. 72.
  • An isolated cell comprising the polynucleotide or polynucleotides of embodiment 70 or the vector or vectors of embodiment 71. 73.
  • An isolated cell producing the binding agent of any one of embodiments 58-68.
  • a method of making the binding agent of any one of embodiments 58-68, comprising: (a) culturing the cell of embodiment 72 or 73, and (b) isolating the binding agent.
  • a method of detecting OSCAR in a biological sample comprising: (a) contacting the biological sample with the binding agent of any one of embodiments 58-68; and (b) detecting the binding between the binding agent and OSCAR in the sample. 76.
  • LAIR1 is expressed on myeloid cells.
  • an acute myeloid leukemia cell line (OCI-AML6 cells) was used as the experimental system. Briefly, 24 hours prior to assay initiation, 96 well tissue culture plates were coated with 5 ⁇ g/mL human collagen 1, fibronectin, or PBS. On day 1, plates were aspirated and washed. OCI-AML6 cells were then added at 200,000 cells per well, and an anti-LAIR1 antibody was added at 10 ⁇ g/mL. Cells were incubated at 37 o C for 72 hours.
  • LAIR1-blockade by an anti-LAIR1 antibody e.g., Hz47H1.v4
  • IL1RA IL1RA
  • CCL3 IL1RA
  • CCL4 inflammatory cytokine secretion from OCI-AML6 cells
  • This inflammatory response and cytokine secretion of OCI- AML6 cells were driven by collagen, as the anti-LAIR1 antibody had no impact on cytokine secretion in the absence of an extracellular matrix substrate or in the presence of immobilized fibronectin (FIG.1A).
  • a CRISPR/Cas9-based screening approach was then used to identify protein(s) that transduce collagen-induced inflammatory response and cytokine secretion in response to LAIR1-blockade (e.g., by an anti-LAIR1 antibody) in myeloid cells.
  • OSCAR was identified. Knockout of OSCAR in OCI-AML6 cells inhibited the inflammatory cytokine secretion induced by an anti-LAIR1 antibody. As show in FIG.1B, the anti-LAIR1 antibody induced secretion of CCL3, CCL4, and IL-8 was inhibited in OCI-AML6 cells when OSCAR was knocked out.
  • Example 2 OSCAR Transduced Collagen-Induced Inflammatory Response and Cytokine Secretion in Response to LAIR1-blockade in Primary Myeloid Lineage Cells
  • Primary monocyte-derived dendritic cells (moDC) were prepared from human peripheral blood mononuclear cells (PBMCs). Human PBMCs were isolated from freshly drawn leukopacks (AllCells) by centrifugation over a Ficoll density gradient (GE Healthcare), resuspended in CryoStor cell freezing medium (StemCell Technologies), and stored in liquid nitrogen until use.
  • PBMCs 100 million frozen PBMCs were thawed and suspended in 10 mL pre-warmed X-VIVO 15 media (Lonza). Cells were spun down at 1200 RPM for 10 minutes at room temperature and resuspended in 400 ul Miltenyi MACS buffer. Monocytes were isolated using Miltenyi Pan Monocyte Isolation Kit (Miltenyi, 130-096-537 The monocytes were plated at 2 x 10 6 cells/mL in X-Vivo 15 media containing 50 ng/mL recombinant human GM-CSF and 50 ng/mL recombinant human IL-4 (both from Peprotech) and cultured for 5-7 days to generate monocyte- derived DCs (moDCs).
  • Miltenyi Pan Monocyte Isolation Kit Miltenyi Pan Monocyte Isolation Kit
  • FIG.2A shows that both OSCAR and LAIR1 were expressed by moDCs across a set of 10 donors. Average numbers of OSCAR and LAIR1 per cell was estimated in the 10 donors based on the flow cytometry data. The level of OSCAR expression was more uniform across all the donors compared to the level of LAIR1 expression (FIG.2B).
  • OSCAR was knockout out individually in moDCs by CRISPR/Cas9 technology.
  • a selection of signaling receptors known to engage the ECM and collagen including ITGB1, ITGB2, ITGB3, OSCAR, DDR1, and DDR2 was also knockout out individually in moDCs by CRISPR/Cas9 technology as a comparison with OSCAR.
  • 24 hours prior to assay initiation 96 well tissue culture plates were coated with 5 ⁇ g/mL human collagen 1 (Millipore CC050) or PBS. MoDCs were then added at 100,000 cells per well, and each antibody was added at 10 ⁇ g/mL. Cells were incubated at 37 o C for 72 hours.
  • the plates were washed and moDCs were added to the plates at 2,000,000 cells/mL in ice-chilled X-VIVO 15 media containing 10 ⁇ g/mL of mouse anti- OSCAR antibody or control mouse anti-KLH antibody. After 30 minutes of incubation, the cells were centrifuged and resuspended in fresh X-VIVO 15 media at 100,000 to 200,000 cells per well. After 72 hours of incubation at 37 o C, the supernatant was collected at 24, 48, and 72 hours and the secreted factors were assessed using magnetic Luminex assays.
  • the plates were washed and moDCs were added to the plates at 2,000,000 cells/mL in ice-chilled X-VIVO 15 media containing 10 ⁇ g/mL of mouse anti-ITGB1 antibody and/or mouse anti-ITGB2 antibody. After 30 minutes of incubation, the cells were centrifuged and resuspended in fresh X-VIVO 15 media at 100,000 to 200,000 cells per well. After 72 hours of incubation at 37 o C, the supernatant was collected, and the secreted factors were assessed using magnetic Luminex assays.
  • genes regulated by LAIR1 and sensitive to OSCAR- blockade were identified (FIG.6A). 1325 genes were induced upon LAIR1 blockage (i.e., comparing gene expression upon treatment of anti-LAIR1 + anti-KLH antibodies vs. gene expression upon treatment of anti-KLH antibody). Among those gene, the induction of 712 genes was repressed by blockage of OSCAR (i.e., comparing gene expression upon the treatment of anti-LAIR1 + anti-OSCAR antibodies vs.
  • the 712 genes induced by LAIR1 blockage (e.g., an anti-LAIR1 antibody) that is dependent on OSCAR activity include inflammatory signaling molecules such as TNFSF14, IL1RA, CCL22, CCL5, CCL17, IL1B, CCL3, and CCL19; and ECM-degrading enzymes such as MMP1, MMP19, MMP7, MMP10, MMP9, and MMP14.
  • the 540 genes repressed by LAIR1 blockage (e.g., an anti-LAIR1 antibody) that is dependent on OSCAR activity include IL-10, MARCO, CD163, and F13A1, all of which are M2 phenotypic markers.
  • RNAseq data uncovered 128 genes that were (1) up-regulated in moDCs upon LAIR1 blockage (i.e., comparing cells treated with an anti-LAIR1 and anti- KLH with cells treated with anti-KLH using the criteria of log2 ratio > log2(1.5) and adjusted P- value ⁇ 0.05), (2) down-regulated upon blockage of OSCAR (i.e., comparing cells treated with an anti-LAIR1 and anti-OSCAR with cells treated with anti-LAIR1 and anti-KLH using the criteria of log2 ratio ⁇ -log2(1.5) and adjusted P-value ⁇ 0.05), and (3) not up-regulated upon blockage of both LAIR1 and OSCAR (i.e., comparing cells treated with anti-LAIR1 and anti- OSCAR with cells treated with anti-KLH using the criteria of log2 ratio ⁇ log2(1.5) (FIG.8A).
  • IPA Ingenuity Pathway Analysis
  • Top 20 canonical pathways, top 20 upstream regulators, top 20 causal networks, and top 20 disease and biological functions were shown FIG. 8B.
  • pathways including phagosome formation, upstream regulators including NFkB and IFNG, causal networks including TLR agonists and LTBR, and disease and biological functions including cell motility were involved in OSCAR dependent collagen- induced activation of myeloid cells in response to LAIR1 blockade (e.g., by an anti-LAIR1 antibody).
  • Example 5 LAIR1 Blockage Induced Myeloid Cell Activity Promoted T Cell Proliferation in OSCAR-dependent Manner
  • MLR mixed lymphocyte reaction
  • the MLR is a classic immunological assay used to investigate interactions between MHC-mismatched immune cells. Briefly, moDCs were generated as described herein. Allogeneic MHC-mismatched human T-cells were purified from PBMCs using a human pan T isolation kit (Miltenyi). Donor cells were pre-screened for MLR compatibility/incompatibility and collagen-responsiveness.
  • 96 well tissue culture plates were coated with 5 ⁇ g/mL human collagen 1 in PBS overnight at 4° C. On day 1, the plates were washed, and 2.5 x 10 4 dendritic cells and 1 ⁇ 10 5 T-cells were added to each well.
  • an anti-KLH control antibody, an anti-LAIR1 antibody Hz47H1.v4, or an anti- OSCAR antibody was added to a final concentration of 10 ⁇ g/mL. The plates were incubated for 5 days at 37° C.
  • fresh media containing tritiated thymidine 3 H- thymidine; Perkin-Elmer
  • RNAseq data uncovered 128 genes that were (1) up-regulated in moDCs upon LAIR1 blockage (i.e., comparing cells treated with an anti-LAIR1 and anti- KLH with cells treated with anti-KLH using the criteria of log2 ratio > log2(1.5) and adjusted P- value ⁇ 0.05), (2) down-regulated upon blockage of OSCAR (i.e., comparing cells treated with an anti-LAIR1 and anti-OSCAR with cells treated with anti-LAIR1 and anti-KLH using the criteria of log2 ratio ⁇ -log2(1.5) and adjusted P-value ⁇ 0.05), and (3) not up-regulated upon blockage of both LAIR1 and OSCAR (i.e., comparing cells treated with anti-
  • IPA Ingenuity Pathway Analysis
  • Top 20 canonical pathways, top 20 upstream regulators, top 20 causal networks, and top 20 disease and biological functions were shown FIG. 8B.
  • pathways including phagosome formation, upstream regulators including NFkB and IFNG, causal networks including TLR agonists and LTBR, and disease and biological functions including cell motility were involved in OSCAR dependent collagen- induced activation of myeloid cells in response to LAIR1 blockade (e.g., by an anti-LAIR1 antibody).
  • Table 15 Subject Information [00540] Briefly, the PBMCs were stained with a panel of fluorophore-conjugated antibodies recognizing OSCAR, LAIR1, CD123, CD33, CD45, CD3, CD4, CD8, CD19, CD56, HLA-DR, or CD14, and assayed by multi-color spectral flow cytometry.
  • CD4 + T cells were defined as CD45 + CD3 + CD56- CD4 + CD8-; CD8 + T cells were defined as CD45 + CD3 + CD56- CD4- CD8 + ; double negative T cells (DN T cells) were defined as CD45 + CD3 + CD56- CD4- CD8-; B cells were defined as CD45 + CD3 not CD33- CD19 + ; natural killer cells (NK cells) were defined as CD45 + CD3 not CD19 not CD56 + CD14-; plasmacytoid dendritic cells (pDCs) were defined as CD45 + CD3 not CD19 not CD56 not CD123 high HLA-DR + , classical monocytes (C monos) were defined as CD45 + CD3 not CD19 not CD56 not CD123 low HLA-DR + CD33 high CD14 high ; dendritic cells (DCs) were defined as CD45 + CD3 not CD19 not CD56 not CD123 low HLA-DR + CD33 high CD14 low/neg ; non-classical monocytes (NC
  • PBMCs from the CPI-treated patients as described in Example 6 were cultured in the presence or absence of collagen and treated with anti-LAIR1 antibody or combination of anti-LAIR1 antibody and anti-OSCAR antibody.
  • IL1RA secretion was assayed by ProcartPlex Simplex Kit (Thermo Fisher), and used as a readout for myeloid cell activity.
  • Figure 11A PBMCs from CPI-treated patients responded to anti- LAIR1 antibody, and the response was dependent on both collagen and OSCAR ( Figure 11A). However, not all nine patients responded equally.
  • OSCAR expression in subsets of immune cells was associated with a patient’s response to anti- LAIR1 therapy.
  • a high OSCAR expression level could serve as a marker for selecting cancer patients for treatment with anti-LAIR1 therapy as well as a marker for predicting response to anti-LAIR1 therapy in a cancer patient.
  • an anti-human OSCAR monoclonal antibody (clone 18D12, see e.g., Table 14) was developed.

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Abstract

L'invention concerne des méthodes de prédiction de la sensibilité clinique à un traitement d'un cancer ou d'une tumeur avec des agents qui se lient au récepteur 1 de type immunoglobuline associé aux leucocytes (LAIR1), tels que des anticorps LAIR1 ou certains de leurs fragments fonctionnels.
PCT/US2023/064145 2022-03-11 2023-03-10 Récepteur de type ig associé aux ostéoclastes (oscar) et ses méthodes d'utilisation WO2023173091A1 (fr)

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