WO2022208505A1 - Enhanced anti-hvem antibodies and use thereof - Google Patents

Enhanced anti-hvem antibodies and use thereof Download PDF

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Publication number
WO2022208505A1
WO2022208505A1 PCT/IL2022/050348 IL2022050348W WO2022208505A1 WO 2022208505 A1 WO2022208505 A1 WO 2022208505A1 IL 2022050348 W IL2022050348 W IL 2022050348W WO 2022208505 A1 WO2022208505 A1 WO 2022208505A1
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seq
antibody
amino acid
cdr
acid sequence
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French (fr)
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WO2022208505A9 (en
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Eyal Greenberg
Gilli GALORE-HASKEL
Efrat MERHAVI-SHOHAM
Gal Markel
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4C Biomed Ltd
Tel HaShomer Medical Research Infrastructure and Services Ltd
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4C Biomed Ltd
Tel HaShomer Medical Research Infrastructure and Services Ltd
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Priority to JP2023561005A priority Critical patent/JP2024514255A/ja
Priority to IL307407A priority patent/IL307407A/en
Priority to CA3213956A priority patent/CA3213956A1/en
Priority to CN202280039545.6A priority patent/CN117412990A/zh
Priority to KR1020237037195A priority patent/KR20240047954A/ko
Priority to EP22779311.4A priority patent/EP4320162A4/en
Application filed by 4C Biomed Ltd, Tel HaShomer Medical Research Infrastructure and Services Ltd filed Critical 4C Biomed Ltd
Priority to AU2022251320A priority patent/AU2022251320A1/en
Publication of WO2022208505A1 publication Critical patent/WO2022208505A1/en
Anticipated expiration legal-status Critical
Priority to US18/375,657 priority patent/US20240067742A1/en
Publication of WO2022208505A9 publication Critical patent/WO2022208505A9/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2878—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IG], 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
    • C07K16/2818—Immunoglobulins [IG], 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 against CD28 or CD152
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2803—Immunoglobulins [IG], 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
    • C07K16/2827—Immunoglobulins [IG], 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 against B7 molecules, e.g. CD80, CD86
    • 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
    • G01N33/575—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/5758—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumours, cancers or neoplasias, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides or metabolites
    • 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
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6863—Cytokines, i.e. immune system proteins modifying a biological response such as cell growth proliferation or differentiation, e.g. TNF, CNF, GM-CSF, lymphotoxin, MIF or their receptors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/40—Immunoglobulins specific features characterized by post-translational modification
    • C07K2317/41—Glycosylation, sialylation, or fucosylation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]
    • 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
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
    • 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
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
    • 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 present invention is in the field of immunotherapy.
  • Immunotherapies designed to enhance an immune response are considered activating immunotherapies and are at the forefront of cancer treatment.
  • immune checkpoint blockade therapy is successfully being used for treatment of advanced non- small cell lung cancers (NSCLC), metastatic melanoma, advanced renal cell carcinoma (RCC) metastatic urothelial carcinoma, head and neck squamous cell carcinoma (HNSCC), MSI-high tumors, Merkel cell carcinoma and many others.
  • NSCLC non- small cell lung cancers
  • RRCC advanced renal cell carcinoma
  • HNSCC head and neck squamous cell carcinoma
  • MSI-high tumors Merkel cell carcinoma and many others.
  • a few such drugs, developed and manufactured by different companies have shown great promise in different cancer types and have been FDA approved, including antibodies to the immune checkpoints programmed cell death protein 1 receptor (PD1), programmed cell death protein 1 ligand (PDL1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4).
  • PD1 programmed cell death protein 1 receptor
  • PDL1 programmed
  • Patient response rate is still not optimal, as only 10% - 40% of treated patients usually benefit, and at the same time patients may suffer from Post Immunotherapy Treatments Side-Effects.
  • treatment with these antibodies or antigen binding fragments thereof may induce resistance through upregulation of additional immune checkpoints.
  • Combination of anti-PDl and anti-CTLA- 4 therapy in melanoma patients has demonstrated higher response rate (60%) as compared to single antibody or antigen binding fragment thereof, however this combination therapy involves also severe treatment-related adverse effects.
  • HVEM Herpesvirus entry mediator
  • HVEM-mediated signaling network which can be involved in positive or negative immunological reactions under different contexts. Dysregulation of this network is involved in the pathogenesis of autoimmune diseases, inflammatory diseases as well as cancer, making HVEM a target for immunotherapy. Antibodies or antigen binding fragments thereof that can block HVEM inhibitory signaling, particularly through BTLA interaction, while preserving activating signaling are greatly needed.
  • the present invention provides antibodies or antigen binding fragments thereof that bind HVEM, inhibit HVEM-BTLA interaction, and inhibit downstream BTLA signaling. Methods of treating disease with these antibodies or antigen binding fragments thereof, nucleic acid molecules encoding these antibodies or antigen binding fragments thereof and kits comprising these antibodies or antigen binding fragments thereof are also provided.
  • an antibody or antigen binding fragment thereof comprises three heavy chain CDRs (CDR-H) and three light chain CDRs (CDR-L), wherein: CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 1 (SYAMS), CDR-H2 comprises the amino acid sequence as set forth in SEQ ID NO: 49 (X1IX2X3X4X5X18X7X19YYADSVX20G) wherein Xi is A, G or N, X 2 is S, N, G or Y, X 3 is G or S, X4 is S, N or P, X5 is G or P, Xis is any amino acid other than C, X?
  • CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 1 (SYAMS)
  • CDR-H2 comprises the amino acid sequence as set forth in SEQ ID NO: 49 (X1IX2X3X4X5X18X7X19YYADSVX20G) wherein Xi is A,
  • CDR-H3 comprises the amino acid sequence as set forth in SEQ ID NO: 18 (AX9X10X11X12X13X14YX15DY) wherein X9 is P or S, X10 is G or Y, Xu is D or R, X12 is Y, N, P or S, X13 is T or Y, X14 is A or N and X15 is F, G or Y, CDR-L1 comprises the amino acid sequence as set forth in SEQ ID NO: 4 (RASQSVSSYLA), CDR-L2 comprises the amino acid sequence as set forth in SEQ ID NO: 5 (GASSRAT), and CDR-L3 comprises the amino acid sequence as set forth in SEQ ID NO: 19 (QQYGSXiePPXnT) wherein Xi6 is S or Y and X17 is Y or L; and wherein the antibody or
  • composition comprising an antibody or antigen binding fragment of the invention and a pharmaceutically acceptable carrier, excipient or adjuvant.
  • a method of treating a disease or condition characterized by HVEM positive cells in a subject in need thereof comprising administering to the subject the pharmaceutical composition of the invention or an antibody or antigen binding fragment of the invention, thereby treating the disease or condition.
  • a method of determining suitability of a subject to be treated by a method of the invention comprising obtaining a disease sample from the subject and determining HVEM levels in the sample, wherein positive expression of HVEM indicates the subject is suitable for a method of treatment of the invention.
  • a method of detecting HVEM in a sample comprising contacting the sample with an antibody or antigen binding fragment of the invention, thereby detecting HVEM.
  • nucleic acid molecule encoding an antibody or antigen binding fragment of the invention.
  • kits comprising, a pharmaceutical composition of the invention and at least one of: a. an anti-PD-l/PD-Ll based immunotherapy; b. a label stating the pharmaceutical composition of the invention is for use with an anti-PD-l/PD-Ll based immunotherapy; and c. a secondary detection molecule for detecting at least one antibody or antigen binding fragment thereof of the invention.
  • CDR-H2 comprises the amino acid sequence as set forth in SEQ ID NO: 17 (X1IX2X3X4X5X6X7X21YYADSVX8G) wherein Xi is A, G or N, X 2 is S, N, G or Y, X 3 is G or S, X 4 is S, N or P, X 5 is G or P, X 6 is G, D, S, E, Q or N, X 7 is S, Y, G or R, X21 is T, A, E, G or N and X 8 is E or K.
  • SEQ ID NO: 17 X1IX2X3X4X5X6X7X21YYADSVX8G
  • X20 is any amino acid other than C or S.
  • X20 is any non-positively charged amino acid.
  • X20 is K or E. PCT/IL2022/050348
  • CDR-H2 comprises an amino acid sequence selected from: SEQ ID NO: 2, SEQ ID NO: 20 (GINGNGDYTYYADSVKG), SEQ ID NO:
  • SEQ ID NO: 58 (NIYSNPERTYYADSVEG), SEQ ID NO: 59
  • SEQ ID NO: 65 (NIYSNPNRNYYADSVEG).
  • CDR-H3 comprises an amino acid sequence selected from: SEQ ID NO: 3, SEQ ID NO: 24 (ASYRNYNYGDY), SEQ ID NO: 25 (ASYDPTNYYDY) and SEQ ID NO: 26 (ASYRSTNYFDY).
  • CDR-L3 comprises an amino acid sequence selected from: SEQ ID NO: 6 and SEQ ID NO: 27 (QQYGSYPPLT).
  • CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 1
  • CDR-H2 comprises an amino acid sequence selected from SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 47, SEQ ID NO: 48, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64 and SEQ ID NO: 65
  • CDR-H3 comprises the amino acid sequence as set forth in SEQ ID NO: 3
  • CDR-L1 comprises the amino acid sequence as set forth in SEQ ID NO: 4
  • CDR-L2 comprises the amino acid sequence as set forth in SEQ ID NO: 5
  • CDR-L3 comprises the amino acid sequence as set forth in SEQ ID NO: 6.
  • CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 1
  • CDR-H2 comprises the amino acid sequence set forth in SEQ ID NO: 2
  • CDR-H3 comprises an amino acid sequence selected from SEQ ID NO: 24, SEQ ID NO: 25 and SEQ ID NO: 26
  • CDR-L1 comprises the amino acid sequence as set forth in SEQ ID NO: 4
  • CDR-L2 comprises the amino acid sequence as set forth in SEQ ID NO: 5
  • CDR-L3 comprises the amino acid sequence as set forth in SEQ ID NO: 6.
  • CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 1
  • CDR-H2 comprises the amino acid sequence set forth in SEQ ID ⁇ 022/208505 ⁇ 2 comprises the amino acid sequence set forth in SE ⁇ JZPi32?. 2 (9, 5 £?A?v-Ll comprises the amino acid sequence as set forth in SEQ ID NO: 4, CDR-L2 comprises the amino acid sequence as set forth in SEQ ID NO: 5, and CDR-L3 comprises the amino acid sequence as set forth in SEQ ID NO: 27.
  • the antibody or antigen binding fragment of the invention comprises aa heavy chain comprising aa sequence selected from QVQLVQSGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGS
  • the antibody or antigen binding fragment of the invention comprises aa light chain comprising a sequence selected from: ELVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYGASSRAT
  • the antibody or antigen binding fragment of the invention comprises a heavy chain comprising an amino acid sequence selected from SEQ ID NO: 85-103.
  • the antibody or antigen binding fragment of the invention comprises a light chain comprising an amino acid sequence selected from SEQ ID NO: 104 and SEQ ID NO: 105.
  • the antibody or antigen binding fragment thereof of the invention comprises a heavy chain comprising SEQ ID NO: 97 and a light chain comprising SEQ ID NO: 104.
  • the method of the invention further comprises inhibition or blockade of a non-HVEM immune checkpoint protein.
  • the method of the invention further comprises administering an anti-PD-l/PD-Ll based immunotherapy.
  • the method of the invention further comprises administering adoptive cell therapy.
  • the adoptive cell therapy comprises adoptive TIL therapy.
  • the adoptive cell therapy comprises administering a chimeric antigen receptor (CAR) expressing immune cell, wherein the CAR targets a non- HVEM protein on a surface of the HVEM expressing cells.
  • CAR chimeric antigen receptor
  • the disease or condition is an HVEM positive cancer or precancerous lesion.
  • the disease or condition is an infectious disease and wherein the infected cells comprise HVEM expression.
  • positive expression of HVEM comprises an elevated HVEM level as compared to a healthy sample or predetermined threshold.
  • Figure 1 Photograph of SDS-PAGE of various purified antibodies in non-reducing and reducing conditions.
  • the heavy chain band of the H4 antibody runs high due to glycosylation, which is lost in the three variant antibodies in which the NXS/T glycosylation site is removed.
  • Figure 2 Bar graph of binding to hHVEM coated plates by two antibodies of the invention (H4 and Par-K64E), as well as isotype control as the negative control and Parental as the positive control.
  • FIGS 3A-3D (A-3B) Biacore (3A) multi-cycle kinetic and (3B) single-cycle kinetic raw sensorgrams and fitted curves with a 1 : 1 model for the binding to hHVEM of (3A) SEC purified antibodies H4, H4 T57A, H4 T57G, H4 T57N and parent antibody and (3B) supernatants of H4 N55G, H4 N55S, H4 N55D, H4 N55Q, H4N55E, H4T57E and parent antibody. (3C) A histogram overlay of binding of the 4 antibodies to hHVEM of the surface of CHO cells. (3D) Bar graph of hHVEM expression on CHO cells as detected by flow cytometry using the parental or H4 T57A antibodies at various concentrations.
  • Figures 4A-4H Bar charts of absorbance read at 450 nm and 570 nm of ELISA on (4A-4E) recombinant hHVEM coated plates in the presence of (4A) parental, H4 T57A, H4 T57G and H4 T57N anti-HVEM antibodies, (4B) parental, H4 T57A, H4 T57G and H4 T57N anti-HVEM antibodies and recombinant hBTLA, (4C) parental, H4 T57A, H4 T57G and H4 T57N anti-HVEM antibodies and recombinant hLIGHT, (4D) parental, H4 and Par- K64E anti-HVEM antibodies and recombinant hBTLA, (4E) parental, H4 and Par-K64E anti-HVEM antibodies and recombinant hLIGHT, or (4F-4G) recombinant cHVEM coated plates in the presence of (4F) parental, H4 T57A,
  • Figures 7A-7B Line graphs of specific cell killing of primary ovary cancer cells cocultured with autologous PBMCs in the presence of (7A) the anti-HVEM antibodies or anti-PDl antibody, or (7B) the anti-HVEM antibodies in combination with an anti-PD-1 antibody.
  • Figure 8 Micrographs (Magnification X63, Zoom 1.5.) of FFPE CHO cells overexpressing hHVEM stained fluorescently with the parental antibody (left) or the H4 T57A antibody (right) and a secondary Cy3 antibody (red fluorescence). Nuclei are counterstained blue with DAPI.
  • the present invention in some embodiments, provides antibodies or antigen binding fragments thereof that bind HVEM, inhibit HVEM-BTLA interaction, and do not significantly inhibit HVEM-LIGHT interaction.
  • the present invention further concerns methods of treating HVEM positive disease in a subject in need thereof by administering these antibodies or antigen binding fragments thereof, nucleic acid molecules encoding these antibodies or antigen binding fragments thereof and kits comprising these antibodies or antigen binding fragments thereof.
  • HVEM positive cancers can avoid immune surveillance by binding BTLA on the surface of immune cells. Engagement of BTLA produces an inhibitory signal within the immune cell, which reduces T cell activation and increases cancer survival. Inhibiting this signaling with antibodies that bind HVEM or antibodies that bind BTLA is known.
  • International Patent Publication WO2020222235 herein incorporated by reference in its entirety, provides antibodies that specifically bind HVEM and do not inhibit the binding of other HVEM ligands such as LIGHT. HVEM is also expressed on the surface of immune cells where it plays both an inhibitory and activating role, depending on the context.
  • Those antibodies not only block the HVEM-BTLA interaction by binding HVEM on 'p2i?i?4 ⁇ ?i?v 5 vvils thus freeing immune cells from inhibition, but alscPSKj ⁇ AAVi ⁇ S ⁇ bind activating ligands (e.g., LIGHT).
  • the instant invention is based on the finding of antibodies that are superior to those presented in WO2020222235.
  • the antibodies of the invention bind to HVEM with greater strength (lower KD) than do the already known anti-HVEM antibodies.
  • an antibody or antigen binding fragment thereof comprising three heavy chain CDRs (CDR-H) and three light chain CDRs (CDR-L), wherein: CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 1 (SYAMS), CDR-H2 comprises the amino acid sequence as set forth in SEQ ID NO: 17 (X1IX2X3X4X5X6X7X21YYADSVX8G) wherein Xi is A, G or N, X 2 is S, N, G or Y, X 3 is G or S, X 4 is S, N or P, X 5 is G or P, X 6 is G, D, S, E, Q or N, X 7 is S, Y, G or R, X21 is T, A, E, G or N and Xs is E or K, CDR-H3 comprises the amino acid sequence as set forth in SEQ ID NO: 18 (AX9X10X11X12X
  • an antibody or antigen binding fragment thereof comprising three heavy chain CDRs (CDR-H) and three light chain CDRs (CDR-L), wherein: CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 1 (SYAMS), CDR-H2 comprises the amino acid sequence as set forth in SEQ ID NO: 49 (X1IX2X3X4X5X18X7X19YYADSVX20G) wherein Xi is A, G or N, X 2 is S, N, G or Y, X 3 is G or S, X4 is S, N or P, X5 is G or P, Xis is any amino acid other than C, X?
  • CDR-H3 comprises the amino acid sequence as set forth in SEQ ID NO: 18 (AX9X10X11X12X13X14YX15DY) wherein X9 is P or S, X10 is G or Y, Xu is D or R, X12 is Y, N, P or S, X13 is T or Y, X14 is
  • a or N and X15 is F, G or Y
  • CDR-L1 comprises the amino acid sequence as set forth in SEQ ID NO: 4 (RASQSVSSYLA)
  • CDR-L2 comprises the amino acid sequence as set forth in SEQ ID NO: 5 (GASSRAT)
  • CDR-L3 comprises the amino acid sequence as set forth in SEQ ID NO: 19 (QQYGSXI 6 PPXI 7 T) wherein X 16 is S or Y and X17 is Y or L.
  • the antibody or antigen binding fragment thereof binds to HVEM. In some embodiments, the antibody or antigen binding fragment thereof has superior HVEM binding as compared to an antibody known in the art. In some embodiments, 'YiQ. 2 J?i? ⁇ i?S ⁇ °Rnown in the art is the parental antibody.
  • an antibody comprises three heavy chain CDRs (CDR-H) and three light chain CDRs (CDR-L), wherein: CDR-H 1 comprises the amino acid sequence set forth in SEQ ID NO: 1 (SYAMS), CDR-H2 comprises the amino acid sequence as set forth in SEQ ID NO: 2 (AISGSGGSTYYADSVKG), CDR-H3 comprises the amino acid sequence as set forth in SEQ ID NO: 3 (APGDYTAYFDY), CDR-L1 comprises the amino acid sequence as set forth in SEQ ID NO: 4 (RASQSVSSYLA), CDR-L2 comprises the amino acid sequence as set forth in SEQ ID NO: 5 (GASSRAT), and CDR-L3 comprises the amino acid sequence as set forth in SEQ ID NO: 6 (QQYGSSPPYT).
  • CDR-H 1 comprises the amino acid sequence set forth in SEQ ID NO: 1 (SYAMS)
  • CDR-H2 comprises the amino acid sequence as set forth in SEQ ID NO: 2 (AISGSGGSTY
  • CDR- H1 comprises the amino acid sequence set forth in SEQ ID NO: 11 (GFTFSSYA)
  • CDR-H2 comprises the amino acid sequence as set forth in SEQ ID NO: 12 (ISGSGGST)
  • CDR-H3 comprises the amino acid sequence as set forth in SEQ ID NO: 13 (AKAPGDYTAYFDY)
  • CDR-L1 comprises the amino acid sequence as set forth in SEQ ID NO: 14 (QSVSSY)
  • CDR-L2 comprises the amino acid sequence as set forth in SEQ ID NO: 15 (GAS)
  • CDR-L3 comprises the amino acid sequence as set forth in SEQ ID NO: 16 (QQYGSSPPYT).
  • Heavy chain CDRS of SEQ ID NO: 11-13 and light chain CDRs of SEQ ID NO: 14-16 are according to the IMGT numbering system.
  • the antibody known in the art is an antibody comprises a heavy chain variable region comprising or consisting of SEQ ID NO: 7 and a light chain variable region comprising or consisting of SEQ ID NO: 8.
  • the antibody known in the art is an antibody with a heavy chain of SEQ ID NO: 9 and a light chain of SEQ ID NO: 10.
  • superior binding is stronger binding. In some embodiments, superior binding is binding with greater affinity. In some embodiments, superior binding is binding with a lower RD.
  • the antibody is an anti-HVEM antibody. In some embodiments, the antibody or antigen binding fragment thereof is an HVEM blocking antibody. In some embodiments, the antibody or antigen binding fragment thereof blocks interaction between HVEM and BTLA. In some embodiments, the antibody or antigen binding fragment thereof, has superior blocking as compared to an antibody known in the art. In some embodiments, superior is stronger. In some embodiments, superior is longer lasting. In some embodiments, superior is more specific. In some embodiments, the antibody or antigen binding fragment thereof activates downstream signaling through HVEM.
  • the antibody or antigen binding fragment thereof In 'Y9n?2 ⁇ ?X?SSu ⁇ l?iients, the antibody or antigen binding fragment thereof, ®i 2 i ⁇ 0 ⁇ A 8 ating as compared to an antibody known in the art. In some embodiments, the antibody or antigen binding fragment thereof inhibits downstream signaling through BTLA. In some embodiments, the antibody or antigen binding fragment thereof, has superior inhibition as compared to an antibody known in the art. In some embodiments, the antibody or antigen binding fragment thereof activates downstream signaling through the HVEM and inhibits downstream signaling through the BTLA. In some embodiments, inhibiting interaction between the HVEM and BTLA inhibits downstream signaling through the BTLA.
  • HVEM is mammalian HVEM. In some embodiments, HVEM is rodent HVEM. In some embodiments, HVEM is monkey HVEM. In some embodiments, HVEM is human HVEM. In some embodiments, HVEM is any one of mouse, monkey and human HVEM. In some embodiments, HVEM is membrane bound HVEM. In some embodiments, HVEM is HVEM on a cell. In some embodiments, HVEM is HVEM on a cell surface. In some embodiments, HVEM is soluble HVEM.
  • the cell is a pathogenic cell. In some embodiments, the cell is a cancerous cell. In some embodiments, the cell is a cell of a pathogen. In some embodiments, the cell is a bacterial cell. In some embodiments, the cell is a fungal cell. In some embodiments, the cell is a eukaryotic cell infected by a pathogen. In some embodiments, the cell is a cell infected by a bacterium. In some embodiments, the cell is a cell infected by a virus. In some embodiments, a pathogen is selected from a bacterium, a virus and a fungus.
  • the cell is an immune cell. In some embodiments, the cell is a hematopoietic cell. In some embodiments, the immune cell is a T-cell. In some embodiments, the T-cell is a CDS positive T-cell. In some embodiments, the T-cell is a cytotoxic CDS positive T-cell. In some embodiments, the T-cell is a CD4 positive T-cell. In some embodiments, the T-cell is a CD4 positive helper T-cell. In some embodiments, the T- cell is selected from a CDS positive and a CD4 positive T-cell. In some embodiments, the T-cell is a CDS positive T-cell, a CD4 positive T-cell or both.
  • the immune cell is a gamma/delta T cell. In some embodiments, the immune cell is a tumor infiltrating lymphocyte (TIL). In some embodiments, the immune cell is not a peripheral blood immune cell. In some embodiments, the immune cell is a B-cell. In some embodiments, the immune cell is a natural killer (NK) cell. In some embodiments, the immune cell is a neutrophil. In some embodiments, the immune cell is a dendritic cell. In some embodiments, the immune cell is a macrophage. In some embodiments, the immune 'Y9i. 2 !9?/?, , ! ⁇ 9. , v2id derived suppressor cell (MDSC).
  • TIL tumor infiltrating lymphocyte
  • the immune cell is not a peripheral blood immune cell.
  • the immune cell is a B-cell.
  • the immune cell is a natural killer (NK) cell.
  • the immune cell is a neutrophil.
  • the immune cell is a dendritic cell.
  • the cell is selected from a T-cell, a B-cell, an NK cell, a neutrophil, a dendritic cell, and a macrophage.
  • the immune cell is a chimeric antigen receptor (CAR) expressing immune cell.
  • the CAR is a CAR-T cell.
  • the CAR is a CAR-NK cell.
  • CAR refers to an engineered receptor which has specificity for at least one protein of interest (for example a protein expressed by an HVEM expressing cell) and is grafted onto an immune effector cell (such as a T cell or NK cell).
  • the CAR-T cell has the specificity of a monoclonal antibody grafted onto a T-cell.
  • the CAR-NK cell has the specificity of a monoclonal antibody grafted onto a NK-cell.
  • the T cell is selected from a cytotoxic T lymphocyte and a regulatory T cell.
  • MARTI is an example of a target protein co-expressed with HVEM on target cells.
  • the CAR targets a protein expressed by the HVEM expressing cells.
  • the protein is not HVEM.
  • the CAR targets a protein on the surface of the HVEM expressing cells.
  • the protein is an antibody.
  • the CAR targets an antibody.
  • the CAR targets an antibody of the invention.
  • the CAR targets a cytotoxic antibody. In some embodiments, the CAR targets an antibody constant domain. In some embodiments, the CAR targets an Fc domain. In some embodiments, the CAR therapy further comprises administering an antibody that targets the HVEM expressing cells. In some embodiments, embodiments, the antibody targeted by the CAR is not the antibody of the invention.
  • CAR-T and CAR-NK cells and their vectors are well known in the art. Such cells target and are cytotoxic to the protein for which the receptor binds.
  • a CAR-T or CAR-NK cell targets at least one cancer protein.
  • a CAR- T or CAR-NK cell targets a plurality of cancer proteins.
  • CAR-T cells Construction of CAR-T cells is well known in the art.
  • a monoclonal antibody to a cancer protein can be made and then a vector coding for the antibody will be constructed.
  • the vector will also comprise a costimulatory signal region.
  • the costimulatory signal region comprises the intracellular domain of a known T cell or NK cell stimulatory molecule.
  • the intracellular domain is selected from at least one of the following: CD3Z, CD27, CD28, 4-1BB, 0X40, CD30, CD40, PD- 1, ICOS, lymphocyte function-associated antigen- 1 (LFA- 1), CD2, CD WO 2fi ⁇ /?Q 85 P, 5 KG2C, B7- H3, and a ligand that specifically binds p CT/IL2022/05 ⁇ ? 48 ome embodiments, the vector also comprises a CD3Z signaling domain. This vector is then transfected, for example by lentiviral infection, into a T-cell.
  • HVEM is Tumor necrosis factor receptor superfamily member 14 (TNFRSF14). In some embodiments, HVEM is CD270. In some embodiments, HVEM is a receptor of BTLA. In some embodiments, HVEM is a ligand of BTLA. In some embodiments, BTLA is CD272. In some embodiments, HVEM is a receptor of Tumor necrosis factor superfamily member 14 (TNFSF14). In some embodiments, HVEM is a ligand of TNFSF14. In some embodiments, the TNFSF14 is LIGHT. In some embodiments, TNFSF14 is CD258. In some embodiments, HVEM is a receptor of CD160.
  • HVEM is a ligand of CD 160. In some embodiments, HVEM is a receptor of lymphotoxin alpha (LT a). In some embodiments, HVEM is a ligand of LTa. In some embodiments, LTa is TNF-p. In some embodiments, HVEM is a receptor of SALMS. In some embodiments, HVEM is a ligand of SALMS.
  • the antibody or antigen binding fragment thereof specifically binds to HVEM. In some embodiments, the antibody or antigen binding fragment thereof binds no other protein other than HVEM. In some embodiments, the antibody or antigen binding fragment thereof binds an extracellular domain of HVEM. In some embodiments, the antibody or antigen binding fragment thereof binds in a ligand binding domain of HVEM. In some embodiments, the antibody or antigen binding fragment thereof binds in a BTLA binding domain of HVEM. In some embodiments, the antibody or antigen binding fragment thereof occludes a BTLA binding domain of HVEM. In some embodiments, the antibody or antigen binding fragment thereof inhibits interaction between HVEM and BTLA.
  • the antibody or antigen binding fragment thereof blocks interaction between HVEM and BTLA. In some embodiments, the antibody or antigen binding fragment thereof inhibits HVEM mediated, BTLA induced immune suppression. In some embodiments, the antibody or antigen binding fragment thereof binds HVEM and prohibits the bound HVEM from further binding BTLA. In some embodiments, the antibody or antigen binding fragment thereof inhibits downstream signaling through BTLA. In some embodiments, the antibody or antigen binding fragment thereof reduced downstream signaling through BTLA.
  • the antibody or antigen binding fragment thereof does not inhibit interaction between HVEM and TNFSF14. In some embodiments, the antibody or antigen binding fragment thereof inhibits interaction between HVEM and TNFSF14. In some embodiments, the TNFSF14 is membranal TNFSF14 (mTNFS14). In some the TNFSF14 is soluble TNFSF14 (sTNFS14). In so ⁇ SJ ⁇ Ii? ⁇ ! 5 ! ⁇ , the antibody or antigen binding fragment thereof does not inhibit interaction between HVEM and one of mTNFS14 and sTNFS14 but does inhibit interaction with the other. In some embodiments, the antibody or antigen binding fragment thereof does not inhibit interaction between both of mTNFS14 and sTNFS14 and HVEM. In some embodiments, inhibition is substantial inhibition. In some embodiments, inhibition is at least a 5, 10, 15, 20, 25, 30, 40,
  • the antibody or antigen binding fragment thereof does not block interaction between HVEM and TNFSF14. In some embodiments, the antibody or antigen binding fragment thereof does not substantially block interaction between HVEM and TNFSF14. In some embodiments, the antibody or antigen binding fragment thereof does not block/inhibit TNFSF14 mediated signaling. In some embodiments, the antibody or antigen binding fragment thereof does not block/inhibit TNFSF14 mediated cell survival.
  • the antibody or antigen binding fragment thereof activates signaling through HVEM.
  • the antibody or antigen binding fragment thereof induces superior activation as compared to an antibody known in the art.
  • the antibody or antigen binding fragment thereof is an HVEM agonist.
  • the antibody or antigen binding fragment thereof is a superior agonist as compared to an antibody known in the art.
  • the antibody or antigen binding fragment thereof induces signaling though HVEM.
  • signaling through HVEM is HVEM downstream signaling.
  • the antibody or antigen binding fragment thereof binds HVEM on a cell and activates/induces HVEM signaling in the cell.
  • HVEM signaling comprises activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) signaling.
  • NF-kB signaling comprises control of genes with an NF-kB response element in their promoter.
  • the signaling comprises increased cytotoxicity of a cell.
  • the signaling comprises increased cytotoxicity of a cell expressing HVEM contacted by the antibody or antigen binding fragment thereof.
  • increased cytotoxicity comprises increased secretion of a proinflammatory cytokine.
  • the proinflammatory cytokine is selected from IL-1, IL- IB, IL-4, IL-6, TNFa, IFNy, MCP1, IL- 12, IL- 18, IL-23 and CM-CSF. In some embodiments, the proinflammatory cytokine is IFNy. In some embodiments, the increase is as compared to a cell not contacted by the antibody or antigen binding fragment thereof of the invention. In 'Y9i 2 2 2 3/i 2 2? ⁇ ?i?nents, the increase is at least a 10, 20, 25, 30, 40, 50, , 2 9 22 ⁇ uv9 3 ⁇ , 95,
  • the cell is an immune cell and the signaling comprises immune activation.
  • the immune cell is a lymphocyte.
  • the immune cell is a T cell.
  • the immune cell is a CD8+
  • the immune cell is a CD4+ T cell. In some embodiments, the immune cell is not a gamma/delta T cell. In some embodiments, the immune cell is a gamma/delta T cell. In some embodiments, the immune cell is an NK cell. In some embodiments, activating HVEM signaling comprises activating the immune cell. In some embodiments, immune activation comprises increased proliferation. In some embodiments, immune activation comprises increased cytotoxicity. In some embodiments, immune activation comprises increased migration. In some embodiments, immune activation comprises increased homing. In some embodiments, immune activation comprises increased cell clustering. In some embodiments, immune activation is T cell activation.
  • immune activation comprises an increase in the number of Thl T cells. In some embodiments, the increase is a relative increase as compared to Th2 T cells. In some embodiments, immune activation comprises an increase in CD8+ T cells. In some embodiments, immune activation comprises a decrease in T regulatory cells. In some embodiments, immune activation comprises an increase in the expression of a marker selected from: 41BB, CD69, CD25, CD107a, HLA-DR and secretion of a cytokine. In some embodiments, the cytokine is a proinflammatory cytokine. In some embodiments, T cell activation comprises increased T cell clustering.
  • cell is a cancerous cell and the signaling comprises an antitumor effect.
  • the anti-tumor effect comprises increased apoptosis.
  • the anti-tumor effect comprises decreased proliferation.
  • the anti-tumor effect comprises increased chemotherapeutic sensitivity.
  • the anti-tumor effect comprises decreases motility.
  • the anti-tumor effect comprises decreases invasion.
  • the anti-tumor effect comprises decreased metastasis.
  • the anti-tumor effect comprises decreased self-renewal.
  • the effect is as compared to a cancer cell than was not contacted by the antibody or antigen binding fragment thereof of the invention.
  • the decrease is at least a 10, 20, 25, 30, 40, 50, 60, 70, 97, 99 or 100% decrease. Each possibility represents ⁇ J ⁇ S j2 S?Ji?5?wd?ment of the invention.
  • the antibody or antigen binding fragment thereof does not induce apoptosis.
  • inducing apoptosis is directly inducing apoptosis.
  • the antibody or antigen binding fragment thereof does not directly induce apoptosis.
  • direct induction refers to a result that occurs as an immediate result of binding of the antibody or antigen binding fragment thereof and does not feature downstream signaling within the bound cell.
  • the antibody or antigen binding fragment thereof is not cytotoxic.
  • the antibody or antigen binding fragment thereof is not cytotoxic in and of itself.
  • the antibody or antigen binding fragment thereof does not induce antibody-directed cell cytotoxicity (ADCC).
  • ADCC antibody-directed cell cytotoxicity
  • the antibody or antigen binding fragment thereof does not induce complement dependent cytotoxicity (CDC). In some embodiments, the antibody or antigen binding fragment thereof does not comprise a cytotoxic moiety. In some embodiments, the antibody or antigen binding fragment thereof does not induce apoptosis of a cell expressing HVEM upon binding of the HVEM expressed by the cell. In some embodiments, the antibody or antigen binding fragment thereof does not induce apoptosis via interaction with another cell. In some embodiments, the antibody or antigen binding fragment thereof does not directly induce killing of a cell expressing HVEM. In some embodiments, the antibody or antigen binding fragment thereof does not target a cell for killing. In some embodiments, the antibody or antigen binding fragment thereof does induce indirect apoptosis.
  • CDC complement dependent cytotoxicity
  • indirect apoptosis is apoptosis induced by downstream signaling through the HVEM receptor that leads to apoptosis. In some embodiments, indirect apoptosis is apoptosis that requires signal transduction. In some embodiments, indirect apoptosis is apoptosis that does not require the involvement of a second cell. In some embodiments, the antibody or antigen binding fragment thereof does not induce apoptosis in an immune cell. In some embodiments, the antibody or antigen binding fragment thereof induces apoptosis in a cancer cell.
  • the antibody or antigen binding fragment thereof inhibits interaction between HVEM and CD160. In some embodiments, the antibody or antigen binding fragment thereof, induces superior inhibition as compared to an antibody known in the art. In some embodiments, the antibody or antigen binding fragment thereof inhibits interaction between HVEM and LTa. In some embodiments, the antibody or antigen binding fragment thereof inhibits interaction between HVEM and herpes simplex virus type 1 WO 20, 22/208505) (HSVl-gD). In some embodiments, the antibody or thereof inhibits interaction between HVEM and at least two of CD160, HSVl-gD and LTa. In some embodiments, the antibody or antigen binding fragment thereof blocks interaction between HVEM and CD160.
  • the antibody or antigen binding fragment thereof blocks interaction between HVEM and LTa. In some embodiments, the antibody or antigen binding fragment thereof blocks interaction between HVEM and HSVl- gD. In some embodiments, the antibody or antigen binding fragment thereof blocks interaction between HVEM and at least two of CD 160, HSVl-gD and LTa. In some embodiments, the antibody or antigen binding fragment thereof inhibits/blocks interaction between HVEM and all of CD160, HSVl-gD and LTa. In some embodiments, the antibody or antigen binding fragment thereof does not inhibit or block interaction between HVEM and at least one of CD 160, HSVl-gD and LTa.
  • the antibody or fragment thereof is a fab fragment. In some embodiments, the antibody or fragment thereof is a single chain antibody (scFv). In some embodiments, the antibody or fragment thereof is a single domain antibody. In some embodiments, the antibody is a human antibody. In some embodiments, the antibody is a humanized antibody. In some embodiments, the antibody is a monoclonal antibody. In some embodiments, the antibody is a blocking antibody. In some embodiments, the antibody is an affinity matured antibody.
  • an antibody refers to a polypeptide or group of polypeptides that include at least one binding domain that is formed from the folding of polypeptide chains having three-dimensional binding spaces with internal surface shapes and charge distributions complementary to the features of an antigenic determinant of an antigen.
  • An antibody typically has a tetrameric form, comprising two identical pairs of polypeptide chains, each pair having one "light” and one "heavy” chain. The variable regions of each light/heavy chain pair form an antibody binding site.
  • An antibody may be oligoclonal, polyclonal, monoclonal, chimeric, camelised, CDR-grafted, multi- specific, bi-specific, catalytic, humanized, fully human, anti- idiotypic and antibodies that can be labeled in soluble or bound form as well as fragments, including epitope-binding fragments, variants or derivatives thereof, either alone or in combination with other amino acid sequences.
  • An antibody may be from any species.
  • the term antibody also includes binding fragments, including, but not limited to Fv, Fab, Fab', F(ab')2 single stranded antibody (svFC), dimeric variable region (Diabody) and disulphide-linked variable region (dsFv).
  • antibodies include immunoglobulin molecules and immunologically active fragments of 'YSi?Pui?4glw 5 uuiin molecules, i.e., molecules that contain an antigen J£u(??g 2, l??v? ⁇ Q?it?oody fragments may or may not be fused to another immunoglobulin domain including but not limited to, an Fc region or fragment thereof.
  • fusion products may be generated including but not limited to, scFv- Fc fusions, variable region (e.g., VE and VH) ⁇ Fc fusions and scFv-scFv-Fc fusions.
  • Immunoglobulin molecules can be of any type (e.g., IgG, IgE, IgM, IgD, IgA and IgY), class (e.g., IgGl, IgG2, IgG3, IgG4, IgAl and IgA2) or subclass.
  • the antibody comprises IgG2 or IgG4.
  • the antibody comprises IgG2.
  • the antibody comprises IgG4.
  • the antibody comprises IgGl.
  • the antibody comprises IgG3.
  • the antibody comprises a modified IgGl or IgG3 with reduced toxicity.
  • the basic unit of the naturally occurring antibody structure is a heterotetrameric glycoprotein complex of about 150,000 Daltons, composed of two identical light (L) chains and two identical heavy (H) chains, linked together by both noncovalent associations and by disulfide bonds. Each heavy and light chain also has regularly spaced intra-chain disulfide bridges.
  • Five human antibody classes (IgG, IgA, IgM, IgD and IgE) exist, and within these classes, various subclasses, are recognized based on structural differences, such as the number of immunoglobulin units in a single antibody molecule, the disulfide bridge structure of the individual units, and differences in chain length and sequence.
  • the class and subclass of an antibody is its isotype.
  • variable domains The amino terminal regions of the heavy and light chains are more diverse in sequence than the carboxy terminal regions, and hence are termed the variable domains.
  • This part of the antibody structure confers the antigen-binding specificity of the antibody.
  • a heavy variable (VH) domain and a light variable (VL) domain together form a single antigenbinding site, thus, the basic immunoglobulin unit has two antigen-binding sites.
  • Particular amino acid residues are believed to form an interface between the light and heavy chain variable domains (Chothia et al., J. Mol. Biol. 186, 651-63 (1985); Novotny and Haber, (1985) Proc. Natl. Acad. Sci. USA 82 4592-4596).
  • the carboxy terminal portion of the heavy and light chains form the constant domains i.e., CHI, CH2, CH3, CL. While there is much less diversity in these domains, there are differences from one animal species to another, and further, within the same individual there are several different isotypes of antibody, each having a different function.
  • L U5vVil rr mII n l “framework region” or “FR” refers to the amin ⁇ ?CT/IL2022/(£0348i the variable domain of an antibody, which are other than the hypervariable region amino acid residues as herein defined.
  • hypervariable region refers to the amino acid residues in the variable domain of an antibody, which are responsible for antigen binding.
  • the hypervariable region comprises amino acid residues from a “complementarity determining region” or “CDR”.
  • CDRs are primarily responsible for binding to an epitope of an antigen.
  • the extent of FRs and CDRs has been precisely defined (see, Kabat et al.).
  • CDR positions are determined by the Kabat numbering system.
  • CDR positions are determined by the EU numbering system.
  • Immunoglobulin variable domains can also be analyzed using the IMGT information system (www://imgt. cines.fr/) (IMGT®/V-Quest) to identify variable region segments, including CDRs. See, e.g., Brochet, X. et al, Nucl. Acids Res. J6:W503-508 (2008).
  • humanized antibody refers to an antibody from a nonhuman species whose protein sequences have been modified to increase similarity to human antibodies.
  • a humanized antibody may be produced by production of recombinant DNA coding for the CDRs of the non-human antibody surrounded by sequences that resemble a human antibody.
  • the humanized antibody is a chimeric antibody.
  • humanizing comprises insertion of the CDRs of the invention into a human antibody scaffold or backbone. Humanized antibodies are well known in the art and any method of producing them that retains the CDRs of the invention may be employed.
  • the term "monoclonal antibody” or “mAb” as used herein refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical and/or bind the same epitope, except for possible variants that may arise during production of the monoclonal antibody, such variants generally being present in minor amounts.
  • each monoclonal antibody is directed against a single determinant on the antigen.
  • the monoclonal antibodies are advantageous in that they are uncontaminated by other immunoglobulins.
  • the modifier "monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies and is not to be construed as produced by any specific preparation method.
  • Monoclonal antibodies to be used in accordance with the methods provided herein may be made by the hybridoma method first described by Kohler et al, Nature 256:495 (1975), or may be made by recombinant DNA methods (see, e.g., U.S. Patent No. 4,816,567).
  • the ⁇ antibodies may also be isolated from phage antiboE ⁇ V ⁇ I Ji?S?3Z 0 uQ,?A
  • the mAb of the present invention may be of any immunoglobulin class including IgG, IgM, IgD, IgE or IgA.
  • a hybridoma producing a mAb may be cultivated in vitro or in vivo. High titers of mAbs can be obtained in vivo production where cells from the individual hybridomas are injected intraperitoneally into pristine -primed Balb/c mice to produce ascites fluid containing high concentrations of the desired mAbs.
  • mAbs of isotype IgM or IgG may be purified from such ascites fluids, or from culture supernatants, using column chromatography methods well known to those of skill in the art.
  • Antibody fragments comprise a portion of an intact antibody, preferably comprising the antigen binding region thereof.
  • antibody fragments include Fab, Fab', F(ab')2, and Fv fragments; diabodies; tandem diabodies (taDb), linear antibodies (e.g., U.S. Patent No. 5,641,870, Example 2; Zapata et al, Protein Eng.
  • Papain digestion of antibodies produces two identical antigen-binding fragments, called “Fab” fragments, each with a single antigen-binding site, and a residual "Fc” fragment, whose name reflects its ability to crystallize readily.
  • Pepsin treatment yields an
  • F(ab')2 fragment that has two antigen-binding sites and is still capable of cross-linking antigen.
  • Fv is the minimum antibody fragment that contains a complete antigen-recognition and antigen-binding site. This region consists of a dimer of one heavy chain and one light chain variable domain in tight, non-covalent association. It is in this configuration that the three surfaces of the VH-VL dimer. Collectively, the six hypervariable regions confer antigen-binding specificity to the antibody. However, even a single variable domain (or half of an Fv comprising only three hypervariable regions specific for an antigen) has the ability to recognize and bind antigen, although at a lower affinity than the entire binding site.
  • the Fab fragment also contains the constant domain of the light chain and the first constant domain (CHI) of the heavy chain.
  • Fab' fragments differ from Fab fragments by the addition of a few residues at the carboxy terminus of the heavy chain CHI domain including 'Y,2v 2 S? 2 /i?8?5Q?ysteines from the antibody hinge region.
  • Fab'-SH is f or Fab' in which the cysteine residue(s) of the constant domains bear at least one free thiol group.
  • F(ab')2 antibody fragments originally were produced as pairs of Fab' fragments that have hinge cysteines between them. Other chemical couplings of antibody fragments are also known.
  • the "light chains" of antibodies (immunoglobulins) from any vertebrate species can be assigned to one of two clearly distinct types, called kappa and lambda, based on the amino acid sequences of their constant domains.
  • antibodies can be assigned to different classes. There are five major classes of intact antibodies: IgA, IgD, IgE, IgG, and IgM, and several of these may be further divided into subclasses (isotypes), e.g., IgGl, IgG2, IgG3, IgG4, IgA, and IgA2.
  • the heavy chain constant domains that correspond to the different classes of antibodies are called a, delta, e, gamma, and micro, respectively.
  • the subunit structures and three-dimensional configurations of different classes of immunoglobulins are well known.
  • Single-chain Fv or “scFv” antibody fragments comprise the VH and VL domains of antibody, wherein these domains are present in a single polypeptide chain.
  • the Fv polypeptide further comprises a polypeptide linker between the VH and VL domains that enables the scFv to form the desired structure for antigen binding.
  • diabodies refers to small antibody fragments with two antigen-binding sites, which fragments comprise a heavy chain variable domain (VH) connected to a light chain variable domain (VL) in the same polypeptide chain (VH - VL).
  • VH heavy chain variable domain
  • VL light chain variable domain
  • the monoclonal antibodies of the invention may be prepared using methods well known in the art. Examples include various techniques, such as those in Kohler, G. and Milstein, C, Nature 256: 495-497 (1975); Kozbor et al, Immunology Today 4: 72 (1983); Cole et al, pg. 77-96 in MONOCLONAL ANTIBODIES AND CANCER THERAPY, Alan R. Liss, Inc. (1985). [vo" j—'jSv'Ji’dds the conventional method of raising antibodies in viv ⁇ PHiJ ⁇ J/Sv ⁇ d ⁇ n be generated in vitro using phage display technology.
  • recombinant antibodies Such a production of recombinant antibodies is much faster compared to conventional antibody production and they can be generated against an eennoorrmmoouuss number of antigens. Furthermore, when using the conventional method, many antigens prove to be non-immunogenic or extremely toxic, and therefore cannot be used to generate antibodies in animals. Moreover, affinity maturation (i.e., increasing the affinity and specificity) of recombinant antibodies is very simple and relatively fast. Finally, large numbers of different antibodies against a specific antigen can be generated in one selection procedure. To generate recombinant monoclonal antibodies, one can use various methods all based on display libraries to generate a large pool of antibodies with different antigen recognition sites.
  • Such a library can be made in several ways: One can generate a synthetic repertoire by cloning synthetic CDR3 regions in a pool of heavy chain germline genes and thus generating a large antibody repertoire, from which recombinant antibody fragments with various specificities can be selected.
  • antibodies and portions thereof include but are not limited to: antibodies, fragments of antibodies, Fab and F(ab')2, single-domain antigen-binding recombinant fragments and natural nanobodies.
  • the antigen binding fragment is selected from the group consisting of a Fv, Fab, F(ab')2, scFv, scFv2 or a scFv4 fragment.
  • the present invention provides nucleic acid sequences encoding the antibodies or antigen binding portions of the present invention.
  • the polynucleotide may encode an entire immunoglobulin molecule chain, such as a light chain or a heavy chain.
  • a complete heavy chain includes not only a heavy chain variable region (VH) but also a heavy chain constant region (CH), which typically will comprise three constant domains: CHI, CH2 and CH3; and a "hinge" region.
  • VH heavy chain variable region
  • CH heavy chain constant region
  • the presence of a constant region is desirable.
  • polypeptides which may be encoded by the polynucle?£u(J I i2 i 022/p50348g en _ binding antibody fragments such as single domain antibodies (“dAbs"), Fv, scFv, Fab' and CHI and CK or CL domain has been excised.
  • dAbs single domain antibodies
  • minibodies are smaller than conventional antibodies they should achieve better tissue penetration in clinical/diagnostic use but being bivalent they should retain higher binding affinity than monovalent antibody fragments, such as dAbs.
  • antibody as used herein encompasses not only whole antibody molecules, but also antigen-binding antibody fragments of the type discussed above.
  • Each framework region present in the encoded polypeptide may comprise at least one amino acid substitution relative to the corresponding human acceptor framework.
  • the framework regions may comprise, in total, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or fifteen amino acid substitutions relative to the acceptor framework regions.
  • Amino acid substitutions i.e., "conservative substitutions,” may be made, for instance, on the basis of similarity in polarity, charge, solubility, hydrophobicity, hydrophilicity, and/or the amphipathic nature of the residues involved.
  • the polynucleotides described herein may be isolated and/or purified.
  • the polynucleotides are isolated polynucleotides.
  • non-naturally occurring substance, composition, entity, and/or any combination of substances, compositions, or entities, or any grammatical variants thereof is a conditional term that explicitly excludes, but only excludes, those forms of the substance, composition, entity, and/or any combination of substances, compositions, or entities that are well-understood by persons of ordinary skill in the art as being “naturally- occurring," or that are, or might be at any time, determined or interpreted by a judge or an administrative or judicial body to be, "naturally-occurring".
  • the antibody comprises an IgG4. In some embodiments, the antibody comprises an IgG2. In some embodiments, the antibody comprises an IgG2 or an IgG4. In some embodiments, the antibody comprises an IgGl, IgG2, IgG3 or IgG4. In some embodiments, the antibody does not comprise an IgGl. In some embodiments, the antibody does not comprise an IgG3. In some embodiments, the antibody does not comprise an IgGl or IgG3. In some embodiments, the antibody comprises a mutated IgGl and/or IgG3, wherein the mutation inhibits induction of ADCC, CDC or both. In some embodiments, the mutation is in the FcRgamma binding motif.
  • the antibody or antigen binding fragSS ⁇ J ⁇ P/JZP ⁇ IPot an antibody present in WO2020222235.
  • the antibody or antigen binding fragment thereof does not comprise all of a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 1 (SYAMS), a CDR-H2 comprising the amino acid sequence as set forth in SEQ ID NO: 2 (AISGSGGSTYYADSVKG), a CDR-H3 comprising the amino acid sequence as set forth in SEQ ID NO: 3 (APGDYTAYFDY), a CDR-L1 comprising the amino acid sequence as set forth in SEQ ID NO: 4 (RASQSVSSYLA), a CDR-L2 comprising the amino acid sequence as set forth in SEQ ID NO: 5 (GASSRAT), and a CORLS comprising the amino acid sequence as set forth in SEQ ID NO: 6 (QQYGS), a CDR-H2 comprising the amino acid sequence as set forth in SEQ ID NO: 2 (AISGSGG
  • the antibody or antigen binding fragment thereof does not comprise all of a CDR-H2 comprising the amino acid sequence as set forth in SEQ ID NO: 2, a CDR-H3 comprising the amino acid sequence as set forth in SEQ ID NO: 3 and a CDR-L3 comprising the amino acid sequence as set forth in SEQ ID NO: 6. In some embodiments, the antibody or antigen binding fragment thereof does not comprise both of a CDR-H2 comprising the amino acid sequence as set forth in SEQ ID NO: 2, and a CDR-H3 comprising the amino acid sequence as set forth in SEQ ID NO: 3. In some embodiments, the antibody or antigen binding fragment thereof does not comprise a CDR-H2 comprising the amino acid sequence as set forth in SEQ ID NO: 2.
  • the antibody or antigen binding fragment thereof does not comprise a CDR-H3 comprising the amino acid sequence as set forth in SEQ ID NO: 3. In some embodiments, the antibody or antigen binding fragment thereof does not comprise a CDR-L3 comprising the amino acid sequence as set forth in SEQ ID NO: 6.
  • the antibody or antigen binding fragment thereof does not comprise all of a CDR-H1 consisting of the amino acid sequence set forth in SEQ ID NO: 1 (SYAMS), a CDR-H2 consisting of the amino acid sequence as set forth in SEQ ID NO: 2 (AISGSGGSTYYADSVKG), a CDR-H3 consisting of the amino acid sequence as set forth in SEQ ID NO: 3 (APGDYTAYFDY), a CDR-L1 consisting of the amino acid sequence as set forth in SEQ ID NO: 4 (RASQSVSSYLA), a CDR-L2 consisting of the amino acid sequence as set forth in SEQ ID NO: 5 (GASSRAT), and a CDR-L3 consisting of the amino acid sequence as set forth in SEQ ID NO: 6 (QQYGSSPPYT).
  • SYAMS CDR-H1 consisting of the amino acid sequence set forth in SEQ ID NO: 1
  • CDR-H2 consisting of the amino acid sequence as set forth in SEQ ID NO
  • the antibody or antigen binding fragment thereof does not comprise all of a CDR-H2 consisting of the amino acid sequence as set forth in SEQ ID NO: 2, a CDR-H3 consisting of the amino acid sequence as set forth in SEQ ID NO: 3 and a CDR-L3 consisting of the amino acid sequence as set forth in SEQ ID NO: 6.
  • the antibody or antigen binding fragment thereof does not comprise both of a CDR-H2 consisting of the amino acid sequence as set forth in SEQ ID NO: 2, and a CDR-H3 consisting of the amino WO 20 ⁇ 208505 as se [ forth in SEQ ID NO: 3.
  • ( P ICVT CL/lIlLLl2U0W22l ⁇ y/0 U5013 a4.l8ll :lgVll binding fragment thereof does not comprise a CDR-H2 consisting of the amino acid sequence as set forth in SEQ ID NO: 2.
  • the antibody or antigen binding fragment thereof does not comprise a CDR-H3 consisting of the amino acid sequence as set forth in SEQ ID NO: 3.
  • tthhee aannttiibbooddyy or antigen binding fragment thereof does not comprise a CDR-L3 consisting of the amino acid sequence as set forth in SEQ ID NO: 6.
  • CDR-H2 comprises the amino acid sequence as set forth in SEQ ID NO: 17 (X1IX2X3X4X5X6X7X21YYADSVX8G) wherein Xi is A, G or N, X 2 is S, N, G or Y, X 3 is G or S, X 4 is S, N or P, X 5 is G or P, X 6 is G, D, S, E, Q or N, X 7 is S, Y, G or R, X21 is T, A, E, G or N and Xs is E or K.
  • CDR-H2 comprises the amino acid sequence as set forth in SEQ ID NO: 49 (X1IX2X3X4X5X18X7X19YYADSVX20G) wherein Xi is A, G or N, X2 is S, N, G or Y, X3 is G or S, X4 is S, N or P, X5 is G or P, Xis is any amino acid other than C, X 7 is S, Y, G or R, X19 is any amino acid other than S or C, and X20 is any amino acid.
  • Xis is any amino acid other than C. In some embodiments, Xis is selected from any amino acid other than C. In some embodiments, Xis is Xe. In some embodiments, Xis is G, D, S, or N. In some embodiments, Xis is any amino acid other than G. In some embodiments, Xis is selected from any amino acid other than G.
  • X19 is any amino acid other than C. In some embodiments, X19 is selected from any amino acid other than C. In some embodiments, X19 is any amino acid other than S. In some embodiments, X19 is selected from any amino acid other than S. In some embodiments, X19 is any amino acid other than C or S. In some embodiments, X19 is selected from any amino acid other than C and S. In some embodiments, X19 is any amino acid other than T. In some embodiments, X19 is selected from any amino acid other than T. In some embodiments, X19 is T.
  • X20 is any amino acid. In some embodiments, X20 is selected from any amino acid. In some embodiments, X20 is an amino acid other than K. In some embodiments, X20 is any amino acid other than C or S. In some embodiments, X20 is an amino acid other than K, C or S. In some embodiments, X20 is a non-positively charged amino acid. In some embodiments, a positively charged amino acid is K, R or H. In some embodiments, a positively charged amino acid is any one of K, R and H. In some embodiments, charged is charged at pH 7.0.
  • charged is charged at W 11OV U 2L01 C2L12/2 U0 ⁇ 8 ⁇ .50 ⁇ 511
  • charged is comprising a charge?£TJL v ⁇ /S ⁇ J ⁇ ome
  • X20 is a negatively charged amino acid.
  • a negatively charged amino acid is E or D.
  • a negatively charged amino acid is selected from E and D.
  • X20 is K or E.
  • X20 is selected from K and E.
  • X20 is a negatively charged amino acid or a polar amino acid.
  • X20 is selected from a negatively charged amino acid and a polar amino acid.
  • a polar amino acid is Y, S, T, N or Q. In some embodiments, a polar amino acid is selected from Y, S, T, N and Q. In some embodiments, X20 is K. In some embodiments, X20 is E.
  • Xi is A, G or N. In some embodiments, Xi is selected from
  • X2 is S, N, G or Y. In some embodiments, X2 is selected from S, N, G and Y. In some embodiments, X3 is G or S. In some embodiments, X3 is selected from G and S. In some embodiments, X4 is S, N or P. In some embodiments, X4 is selected from S, N and P. In some embodiments, X5 is G or P. In some embodiments, X5 is selected from G and P. In some embodiments, Xe is G, D, S, or N. In some embodiments, Xe is selected from G, D, S, and N. In some embodiments, X? is S, Y, G or R. In some embodiments, X? is selected from S, Y, G and R. In some embodiments, Xs is E or K. In some embodiments, Xs is selected from E and K.
  • CDR-H2 comprises an amino acid sequence selected from:
  • SEQ ID NO: 2 SEQ ID NO: 20 (GINGNGDYTYYADSVKG), SEQ ID NO: 21
  • SEQ ID NO: 60 (NIYSNPQRTYYADSVEG), SEQ ID NO: 61
  • CDR-H2 comprises SEQ ID NO: 65 (NIYSNPNRNYYADSVEG).
  • CDR-H2 comprises SEQ ID NO: 65 (NIYSNPNRNYYADSVEG).
  • CDR-H2 consists of SEQ ID NO: 2. In some embodiments,
  • CDR-H2 comprises SEQ ID NO: 20. In some embodiments, CDR-H2 consists of SEQ ID NO: 20. In some embodiments, CDR-H2 comprises SEQ ID NO: 21. In some embodiments, CDR-H2 consists of SEQ ID NO: 21. In some embodiments, CDR-H2 comprises SEQ ID NO: 22. In some embodiments, CDR-H2 consists of SEQ ID NO: 22. In some embodiments,
  • CDR-H2 comprises SEQ ID NO: 23. In some embodiments, CDR-H2 consists of SEQ ID ⁇ 2022/208505 ⁇ embodiments, CDR-H2 is SEQ ID NO: 17. In somE ⁇ I/lW ⁇ P ⁇ DR- H2 comprises SEQ ID NO: 17. In some embodiments, CDR-H2 consists of SEQ ID NO: 17. In some embodiments, CDR-H2 comprises SEQ ID NO: 47. In some embodiments, CDR- H2 consists of SEQ ID NO: 47. In some embodiments, CDR-H2 comprises SEQ ID NO: 48. In some embodiments, CDR-H2 consists of SEQ ID NO: 48. In some embodiments, CDR- H2 comprises SEQ ID NO: 57.
  • CDR-H2 consists of SEQ ID NO: 57. In some embodiments, CDR-H2 comprises SEQ ID NO: 58. In some embodiments, CDR- H2 consists of SEQ ID NO: 58. In some embodiments, CDR-H2 comprises SEQ ID NO: 59. In some embodiments, CDR-H2 consists of SEQ ID NO: 59. In some embodiments, CDR- H2 comprises SEQ ID NO: 60. In some embodiments, CDR-H2 consists of SEQ ID NO: 60. In some embodiments, CDR-H2 comprises SEQ ID NO: 61. In some embodiments, CDR- H2 consists of SEQ ID NO: 61.
  • CDR-H2 comprises SEQ ID NO: 62. In some embodiments, CDR-H2 consists of SEQ ID NO: 62. In some embodiments, CDR- H2 comprises SEQ ID NO: 63. In some embodiments, CDR-H2 consists of SEQ ID NO: 63. In some embodiments, CDR-H2 comprises SEQ ID NO: 64. In some embodiments, CDR- H2 consists of SEQ ID NO: 64. In some embodiments, CDR-H2 comprises SEQ ID NO: 65. In some embodiments, CDR-H2 consists of SEQ ID NO: 65.
  • CDR-H3 comprises an amino acid sequence selected from: SEQ ID NO: 3, SEQ ID NO: 24 (ASYRNYNYGDY), SEQ ID NO: 25 (ASYDPTNYYDY) and SEQ ID NO: 26 (ASYRSTNYFDY).
  • CDR-H3 comprises SEQ ID NO: 3.
  • CDR-H3 consists of SEQ ID NO: 3.
  • CDR-H3 comprises SEQ ID NO: 24.
  • CDR-H3 consists of SEQ ID NO: 24.
  • CDR-H3 comprises SEQ ID NO: 25.
  • CDR-H3 consists of SEQ ID NO: 25.
  • CDR-H3 comprises SEQ ID NO: 26. In some embodiments, CDR-H3 consists of SEQ ID NO: 26. In some embodiments, CDR-H3 is SEQ ID NO: 18. In some embodiments, CDR-H2 comprises SEQ ID NO: 18. In some embodiments, CDR-H2 consists of SEQ ID NO: 18.
  • CDR-L3 comprises an amino acid sequence selected from: SEQ ID NO: 6 and SEQ ID NO: 27 (QQYGSYPPLT). In some embodiments, CDR-L3 comprises SEQ ID NO: 6. In some embodiments, CDR-L3 consists of SEQ ID NO: 6. In some embodiments, CDR-L3 comprises SEQ ID NO: 27. In some embodiments, CDR-L3 consists of SEQ ID NO: 27. In some embodiments, CDR-L3 is SEQ ID NO: 19. In some embodiments, CDR-H2 comprises SEQ ID NO: 19. In some embodiments, CDR-H2 consists of SEQ ID NO: 19.
  • a CDR is devoid of a labile liability.
  • EPJ ⁇ I?i3Q?i?i2uu ⁇ ents the CDRs are devoid of a labile liability.
  • the labile liability is an acid labile liability.
  • the liability is liability to degradation.
  • the liability is liability to cleavage.
  • the liability is a DP di-amino acid.
  • the X11X12 is not DP. In some embodiments, if Xu is
  • the liability is a liability to aspartate isomerization. In some embodiments, the liability is a DG di-amino acid. In some embodiments, the liability is a DT di-amino acid. In some embodiments, the liability is a DS di-amino acid. In some embodiments, the liability is a DD di-amino acid. In some embodiments, the liability is a DH di-amino acid. In some embodiments, the liability is a liability to deamination. In some embodiments, the liability is a NG di-amino acid.
  • the liability is a NS di-amino acid. In some embodiments, the liability is a NT di-amino acid. In some embodiments, the liability is a NH di-amino acid. In some embodiments, the liability is a NN di-amino acid. In some embodiments, the liability is a liability to N-linked glycosylation. In some embodiments, the liability is NXS/T (SEQ ID NO: 84). In some embodiments, the liability is NXS. In some embodiments, the liability is NXT. It will be understood that the X in these liability sequences may be any amino acid. In some embodiments, the liability is a free cysteine residue.
  • all CDRs are devoid of a free cysteine residue.
  • the liability is an oxidation liability.
  • the liability is a surface exposed methionine or tryptophan residue.
  • the liability is a surface exposed methionine residue.
  • the liability is a surface exposed tryptophan residue.
  • the CDR comprises a single amino acid change to abolish the liability.
  • the CDR comprises a single amino acid change to abolish the di-amino acid sequence.
  • CDR-H2 is devoid of an N-glycosylation site.
  • an N-glycosylation site comprises NXS/T wherein X is any amino acid and wherein the third amino acid is S or T.
  • CDR-H2 comprises SEQ ID NO: 106 (NIYSNPNRX22YYADSVEG).
  • X22 is any amino acid other than S and T.
  • CDR-H2 comprises SEQ ID NO: 107 (NIYSNPNRX23YYADSVEG).
  • X23 is any amino acid other than S, T and C.
  • CDR-H2 consists of SEQ ID NO: 106.
  • CDR-H2 consists of SEQ ID NO: 107. In some embodiments, CDR-H2 comprises SEQ ID NO: 112 (NIYSNPX24RTYYADSVEG). In some embodiments, X 24 is other than N. In some embodiments, CDR-H2 compFiot ⁇ S ⁇ v 2 ⁇ 5 ® ⁇ H3 (NIYSNPX25RTYYADSVEG). In some embodiments, X25 is any amino acid other than N and C. In some embodiments, CDR-H2 comprises SEQ ID NO: 114 (NIYSNPX 26 RTYYADSVEG). In some embodiments, X 26 is G, D, S, E, Q or N. In some embodiments, CDR-H2 consists of SEQ ID NO: 112. In some embodiments, CDR-H2 consists of SEQ ID NO: 113. In some embodiments, CDR-H2 consists of SEQ ID NO: 114.
  • CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 1
  • CDR-H2 comprises an amino acid sequence selected from SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 47, SEQ ID NO: 48, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64 and SEQ ID NO: 65
  • CDR-H3 comprises the amino acid sequence as set forth in SEQ ID NO: 3
  • CDR-L1 comprises the amino acid sequence as set forth in SEQ ID NO: 4
  • CDR-L2 comprises the amino acid sequence as set forth in SEQ ID NO: 5
  • CDR-L3 comprises the amino acid sequence as set forth in SEQ ID NO: 6.
  • CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 1
  • CDR-H2 comprises the amino acid sequence set forth in SEQ ID NO: 20
  • CDR-H3 comprises the amino acid sequence as set forth in SEQ ID NO: 3
  • CDR-L1 comprises the amino acid sequence as set forth in SEQ ID NO: 4
  • CDR-L2 comprises the amino acid sequence as set forth in SEQ ID NO: 5
  • CDR-L3 comprises the amino acid sequence as set forth in SEQ ID NO: 6.
  • CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 1
  • CDR-H2 comprises the amino acid sequence set forth in SEQ ID NO: 21
  • CDR-H3 comprises the amino acid sequence as set forth in SEQ ID NO: 3
  • CDR-L1 comprises the amino acid sequence as set forth in SEQ ID NO: 4
  • CDR-L2 comprises the amino acid sequence as set forth in SEQ ID NO: 5
  • CDR-L3 comprises the amino acid sequence as set forth in SEQ ID NO: 6.
  • CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 1
  • CDR-H2 comprises the amino acid sequence set forth in SEQ ID NO: 22
  • CDR-H3 comprises the amino acid sequence as set forth in SEQ ID NO: 3
  • CDR-L1 comprises the amino acid sequence as set forth in SEQ ID NO: 4
  • CDR-L2 comprises the amino acid sequence as set forth in SEQ ID NO: 5
  • CDR-L3 comprises the amino acid sequence as set forth in SEQ ID NO: 6.
  • CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 1
  • CDR- H2 comprises the amino acid sequence set forth in SEQ ID NO: 23
  • CDR-H3 comprises the amino acid sequence as set forth in SEQ ID NO: 3
  • CDR-L1 comprises the amino acid sequence as set forth in SEQ ID NO: 4
  • CDR-L2 comprises the amino acid sequence as set NO: 5
  • CDR-L3 comprises the amino acid sequeEStFa ⁇ v ⁇ Q ⁇ iQ ⁇ SEQ ID NO: 6.
  • CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 1
  • CDR-H2 comprises the amino acid sequence set forth in SEQ ID NO: 47
  • CDR-H3 comprises the amino acid sequence as set forth in SEQ ID NO: 3
  • CDR-L1 comprises the amino acid sequence as set forth in SEQ ID NO: 4
  • CDR-L2 comprises the amino acid sequence as set forth in SEQ ID NO: 5
  • CDR-L3 comprises the amino acid sequence as set forth in SEQ ID NO: 6.
  • CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 1
  • CDR-H2 comprises the amino acid sequence set forth in SEQ ID NO: 48
  • CDR-H3 comprises the amino acid sequence as set forth in SEQ ID NO: 3
  • CDR-L1 comprises the amino acid sequence as set forth in SEQ ID NO: 4
  • CDR- L2 comprises the amino acid sequence as set forth in SEQ ID NO: 5
  • CDR-L3 comprises the amino acid sequence as set forth in SEQ ID NO: 6.
  • CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 1
  • CDR-H2 comprises the amino acid sequence set forth in SEQ ID NO: 57
  • CDR-H3 comprises the amino acid sequence as set forth in SEQ ID NO: 3
  • CDR-L1 comprises the amino acid sequence as set forth in SEQ ID NO: 4
  • CDR-L2 comprises the amino acid sequence as set forth in SEQ ID NO: 5
  • CDR-L3 comprises the amino acid sequence as set forth in SEQ ID NO: 6.
  • CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 1
  • CDR- H2 comprises the amino acid sequence set forth in SEQ ID NO: 58
  • CDR-H3 comprises the amino acid sequence as set forth in SEQ ID NO: 3
  • CDR-L1 comprises the amino acid sequence as set forth in SEQ ID NO: 4
  • CDR-L2 comprises the amino acid sequence as set forth in SEQ ID NO: 5
  • CDR-L3 comprises the amino acid sequence as set forth in SEQ ID NO: 6.
  • CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 1
  • CDR-H2 comprises the amino acid sequence set forth in SEQ ID NO: 59
  • CDR-H3 comprises the amino acid sequence as set forth in SEQ ID NO: 3
  • CDR-L1 comprises the amino acid sequence as set forth in SEQ ID NO: 4
  • CDR-L2 comprises the amino acid sequence as set forth in SEQ ID NO: 5
  • CDR-L3 comprises the amino acid sequence as set forth in SEQ ID NO: 6.
  • CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 1
  • CDR-H2 comprises the amino acid sequence set forth in SEQ ID NO: 60
  • CDR-H3 comprises the amino acid sequence as set forth in SEQ ID NO: 3
  • CDR-L1 comprises the amino acid sequence as set forth in SEQ ID NO: 4
  • CDR- L2 comprises the amino acid sequence as set forth in SEQ ID NO: 5
  • CDR-L3 comprises the amino acid sequence as set forth in SEQ ID NO: 6.
  • CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 1
  • CDR-H2 comprises the amino acid sequence set forth in SEQ ID NO: 61
  • CDR-H3 comprises the amino acid sequence as 'Yft 2022/208505Q jp [xfO: 3
  • CDR-L1 comprises the amino acid sequeJ£L T Zl L ; ⁇
  • CDR-L2 comprises the amino acid sequence as set forth in SEQ ID NO: 5
  • CDR-L3 comprises the amino acid sequence as set forth in SEQ ID NO: 6.
  • CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 1
  • CDR- H2 comprises the amino acid sequence set forth in SEQ ID NO: 62
  • CDR-H3 comprises the amino acid sequence as set forth in SEQ ID NO: 3
  • CDR-L1 comprises the amino acid sequence as set forth in SEQ ID NO: 4
  • CDR-L2 comprises the amino acid sequence as set forth in SEQ ID NO: 5
  • CDR-L3 comprises the amino acid sequence as set forth in SEQ ID NO: 6.
  • CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 1
  • CDR-H2 comprises the amino acid sequence set forth in SEQ ID NO: 63
  • CDR-H3 comprises the amino acid sequence as set forth in SEQ ID NO: 3
  • CDR-L1 comprises the amino acid sequence as set forth in SEQ ID NO: 4
  • CDR-L2 comprises the amino acid sequence as set forth in SEQ ID NO: 5
  • CDR-L3 comprises the amino acid sequence as set forth in SEQ ID NO: 6.
  • CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 1
  • CDR-H2 comprises the amino acid sequence set forth in SEQ ID NO: 64
  • CDR-H3 comprises the amino acid sequence as set forth in SEQ ID NO: 3
  • CDR-L1 comprises the amino acid sequence as set forth in SEQ ID NO: 4
  • CDR- L2 comprises the amino acid sequence as set forth in SEQ ID NO: 5
  • CDR-L3 comprises the amino acid sequence as set forth in SEQ ID NO: 6.
  • CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 1
  • CDR-H2 comprises the amino acid sequence set forth in SEQ ID NO: 65
  • CDR-H3 comprises the amino acid sequence as set forth in SEQ ID NO: 3
  • CDR-L1 comprises the amino acid sequence as set forth in SEQ ID NO: 4
  • CDR-L2 comprises the amino acid sequence as set forth in SEQ ID NO: 5
  • CDR-L3 comprises the amino acid sequence as set forth in SEQ ID NO: 6.
  • CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 1
  • CDR-H2 comprises the amino acid sequence set forth in SEQ ID NO: 2
  • CDR- H3 comprises an amino acid sequence selected from SEQ ID NO: 24, SEQ ID NO: 25 and SEQ ID NO: 26
  • CDR-L1 comprises the amino acid sequence as set forth in SEQ ID NO: 4
  • CDR-L2 comprises the amino acid sequence as set forth in SEQ ID NO: 5
  • CDR-L3 comprises the amino acid sequence as set forth in SEQ ID NO: 6.
  • CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 1
  • CDR-H2 comprises the amino acid sequence set forth in SEQ ID NO: 2
  • CDR-H3 comprises the amino acid sequence set forth in SEQ ID NO: 24
  • CDR-L1 comprises the amino acid sequence as set forth in SEQ ID NO: 4
  • CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 1
  • CDR-H2 comprises the amino acid sequence set forth in SEQ ID NO: 2
  • CDR-H3 comprises the amino acid sequence set forth in SEQ ID NO: 25
  • CDR-L1 comprises the amino acid sequence as set forth in SEQ ID NO: 4
  • CDR-L2 comprises the amino acid sequence as set forth in SEQ ID NO: 5
  • CDR-L3 comprises the amino acid sequence as set forth in SEQ ID NO: 6.
  • CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 1
  • CDR-H2 comprises the amino acid sequence set forth in SEQ ID NO: 2
  • CDR-H3 comprises the amino acid sequence set forth in SEQ ID NO: 26
  • CDR-L1 comprises the amino acid sequence as set forth in SEQ ID NO: 4
  • CDR-L2 comprises the amino acid sequence as set forth in SEQ ID NO: 5
  • CDR-L3 comprises the amino acid sequence as set forth in SEQ ID NO: 6.
  • CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 1
  • CDR-H2 comprises the amino acid sequence set forth in SEQ ID NO: 2
  • CDR- H3 comprises the amino acid sequence set forth in SEQ ID NO: 3
  • CDR-L1 comprises the amino acid sequence as set forth in SEQ ID NO: 4
  • CDR-L2 comprises the amino acid sequence as set forth in SEQ ID NO: 5
  • CDR-L3 comprises the amino acid sequence as set forth in SEQ ID NO: 27.
  • CDR-H1 comprises the amino acid sequence set forth in SEQ ID NO: 1
  • CDR-H2 comprises an amino acid sequence selected from SEQ ID NO: 2
  • CDR-H3 comprises an amino acid sequence selected from SEQ ID NO: 3
  • SEQ ID NO: 24 SEQ ID NO: 25 and SEQ ID NO: 26
  • CDR-L1 comprises the amino acid sequence as set forth in SEQ ID NO: 4
  • CDR-L2 comprises the amino acid sequence as set forth in SEQ ID NO: 5
  • CDR-L3 comprises an amino acid sequence selected from SEQ ID NO: 6 and SEQ ID NO: 27.
  • the antibody or antigen binding fragment thereof does not comprise a heavy chain comprising
  • the antibody or antigen binding fragment thereof does not comprise a heavy chain variable region comprising or consisting of SEQ ID NO: 7.
  • the antibody or antigen binding fragment thereof comprises a heavy chain comprising SEQ ID NO:7 and a light chain comprising a CDR-L3 comprising SEQ ID NO: 27. 'YS > ⁇ 2 P?j 2 4?P ⁇ 5?5e embodiments, the antibody or antigen binding fragmSitl/Biv® ⁇ 2 /®5P ⁇ jl?ses a heavy chain comprising
  • the antibody or antigen binding fragment thereof comprises aa heavy chain comprising QVQLVQSGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAIGGS
  • the antibody or antigen binding fragment thereof comprises aa heavy chain comprising QVQLVQSGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSNIYSN
  • the antibody or antigen binding fragment thereof comprises aa heavy chain comprising QVQLVQSGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSNINGP
  • the antibody or antigen binding fragment thereof comprises aa heavy chain comprising QVQLVQSGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSNIYSN
  • the antibody or antigen binding fragment thereof comprises aa heavy chain comprising QVQLVQSGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGS
  • the antibody or antigen binding fragment thereof comprises aa heavy chain comprising QVQLVQSGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSNIYSN
  • the antibody or antigen binding fragment thereof comprises aa heavy chain comprising QVQLVQSGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSNIYSN
  • the antibody or antigen binding fragment thereof comprises aa heavy chain comprising QVQLVQSGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSNIYSN WO 2022/208505, VEGRFTISRDNSKNTLYLQMNSLRAEDTAVYYC ⁇ I ⁇ B ⁇ A ⁇ FD YWGQGTLVTVSS (SEQ ID NO: 68).
  • the antibody or antigen binding fragment thereof comprises aa heavy chain comprising QVQLVQSGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSNIYSN PQRTYYADSVEGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKAPGDYTAYFD YWGQGTLVTVSS (SEQ ID NO: 69).
  • the antibody or antigen binding fragment thereof comprises aa heavy chain comprising QVQLVQSGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSNIYSN PSRTYYADSVEGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKAPGDYTAYFDY WGQGTLVTVSS (SEQ ID NO: 70).
  • the antibody or antigen binding fragment thereof comprises aa heavy chain comprising QVQLVQSGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSNIYSN PNRAYYADSVEGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKAPGDYTAYFD YWGQGTLVTVSS (SEQ ID NO: 71).
  • the antibody or antigen binding fragment thereof comprises aa heavy chain comprising QVQLVQSGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSNIYSN PNREYYADSVEGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKAPGDYTAYFD YWGQGTLVTVSS (SEQ ID NO: 72).
  • the antibody or antigen binding fragment thereof comprises aa heavy chain comprising QVQLVQSGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSNIYSN PNRGYYADSVEGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKAPGDYTAYFD YWGQGTLVTVSS (SEQ ID NO: 73).
  • the antibody or antigen binding fragment thereof comprises aa heavy chain comprising QVQLVQSGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSNIYSN PNRNYYADSVEGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKAPGDYTAYFD YWGQGTLVTVSS (SEQ ID NO: 74).
  • the antibody or antigen binding fragment thereof comprises aa heavy chain comprising QVQLVQSGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGS GGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKASYRNYNYGD YWGQGTLVTVSS (SEQ ID NO: 32).
  • the antibody or antigen binding fragment thereof comprises aa heavy chain comprising QVQLVQSGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGS GGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKASYDPTNYYD YWGQGTLVTVSS (SEQ ID NO: 33).
  • the antibody or antigen binding fragment thereof comprises aa heavy chain comprising ⁇ y 2 ⁇ 2 J( 2 ⁇ PGGLVQPGGSLRLSCAASGFTFSSYAM
  • the antibody or antigen binding fragment comprises a heavy chain comprising a sequence selected from SEQ ID NO: 28-34, 50-51 and 66-74. In some embodiments, the antibody or antigen binding fragment comprises a heavy chain comprising a sequence selected from SEQ ID NO: 7, 28- 34, 50-51 and 66-74. In some embodiments, the antibody or antigen binding fragment comprises a heavy chain variable region comprising a sequence selected from SEQ ID NO: 28-34, 50-51 and 66-74.
  • the antibody or antigen binding fragment comprises a heavy chain variable region comprising a sequence selected from SEQ ID NO: 7, 28-34, 50-51 and 66-74. In some embodiments, the antibody or antigen binding fragment comprises a heavy chain variable region consisting of a sequence selected from SEQ ID NO: 28-34, 50-51 and 66-74. In some embodiments, the antibody or antigen binding fragment comprises a heavy chain variable region consisting of a sequence selected from SEQ ID NO: 7, 28-34, 50-51 and 66-74.
  • the antibody or antigen binding fragment comprises a light chain comprising a sequence selected from
  • the antibody or antigen binding fragment comprises a light chain variable region comprising or consisting of a sequence selected from SEQ ID NO: 8 and SEQ ID NO: 35. In some embodiments, the antibody or antigen binding fragment comprises a light chain comprising SEQ ID NO: 8. In some embodiments, the antibody or antigen binding fragment comprises a light chain comprising SEQ ID NO: 35.
  • the antibody or antigen binding fragment comprises a light chain comprising a sequence selected from SEQ ID NO: 8 and 35. In some embodiments, the antibody or antigen binding fragment comprises a light chain variable region comprising SEQ ID NO: 35. In some embodiments, the antibody or antigen binding fragment comprises a light chain variable region comprising a sequence selected from SEQ ID NO: 8 and 35. In some embodiments, the antibody or antigen binding fragment comprises a light chain variable region consisting of SEQ ID NO: 35. In some embodiments, the antibody or antigen binding 'YSgS?3/i2Q?v?S?prises a light chain variable region consisting of a sequeEv J ⁇ 3S?3u 0 AQ?A 8 SEQ
  • the heavy chain comprises an N-terminal peptide comprising MGWSCIILFLVATATGVHS (SEQ ID NO: 36). In some embodiments, the heavy chain comprises an N-terminal peptide consisting of SEQ ID NO: 36. In some embodiments, the heavy chain comprises an amino acid sequence of SEQ ID NO: 36.
  • the heavy chain comprises an amino acid sequence of SEQ ID NO: 36 N-terminal to any one of SEQ ID NO: 7, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73 and SEQ ID NO: 74.
  • the N- terminal peptide is a signal peptide.
  • the heavy chain comprises a signal peptide. In some embodiments, the heavy chain is devoid of a signal peptide. In some embodiments, the heavy chain lacks a signal peptide. In some embodiments, the heavy chain comprises a signal peptide when first expressed in a cell and the signal peptide is cleaved and the secreted heavy chain lacks the signal peptide.
  • Signal peptides are well known in the art and any signal peptide that is functional to lead to secretion of the antibody chains may be used.
  • the heavy chain comprises a C-terminal peptide comprising
  • the heavy chain comprises a C-terminal peptide consisting of SEQ ID NO: 37.
  • the C-terminal peptide is a heavy chain constant region.
  • the heavy chain comprises an amino acid sequence of SEQ ID NO: 37.
  • the heavy chain comprises an amino acid sequence of SEQ ID NO: 37 C-terminal to any one of SEQ ID NO: 7, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73 and SEQ ID NO: 74.
  • the C-terminal peptide is an IgG backbone.
  • the antigen binding fragment lacks a C-termin£P T /Sp 2 ?u? ⁇ 05 Pi? 48 ome embodiments, the antigen binding fragment is devoid of a C-terminal peptide. In some embodiments, the C-terminal peptide is not cytotoxic. In some embodiments, the C-terminal peptide is mutated to reduce cytotoxicity. In some embodiments, the C-terminal peptide comprises an antibody hinge domain. It will be understood by a skilled artisan that the disulfide bridges present in the hinge domain of the heavy chains are sufficient for heavy chain dimerization.
  • the C-terminal peptide comprises a CHI domain. It will be understood by a skilled artisan that the disulfide bridge that forms between the CHI domain of the heavy chain and the CL domain of the light chain are sufficient for heavy chain-light chain dimerization and formation of a function antibody or antigen binding fragment.
  • the C-terminal peptide comprises a dimerization domain. In some embodiments, the dimerization domain is sufficient to induce dimerization between the two heavy chains. In some embodiments, the dimerization domain is sufficient to induce dimerization between the heavy chain and the light chain.
  • the C- terminal peptide comprises two dimerization domains, a first dimerization domain that is sufficient to induce dimerization between the two heavy chains and a second dimerization domain that is sufficient to induce dimerization between the heavy and light chain.
  • dimerizing is forming a disulfide bond.
  • the antibody or antigen binding fragment thereof comprises a heavy chain comprising
  • the heavy chain consists of the sequence of SEQ ID NO: 9. It will be understood that SEQ ID NO: 9 can also lack the signal peptide (SEQ ID NO: 36) which produces
  • LSLSLGK (SEQ ID NO: 85) or can contain a different signal peptide.
  • the antibody or antigen binding fragment thereof comprises a heavy chain comprising
  • the heavy chain consists of the sequence of SEQ ID NO: 54. It will be understood that SEQ ID NO: 54 can also include the signal peptide of the invention (SEQ ID NO: 36) or contain a different signal peptide.
  • the antibody or antigen binding fragment thereof comprises a heavy chain comprising
  • the heavy chain consists of the sequence of SEQ ID NO: 55. It will be understood that SEQ ID NO: 55 can also include the signal peptide of the invention (SEQ ID NO: 36) or contain a different signal peptide. 'YS > ⁇ 2 P? J 2 4?P ⁇ u?5e embodiments, the antibody or antigen binding fragm££T/Si 2 w? 2 vw?Pipl?ses a heavy chain comprising
  • HYTQKSLSLSLGK (SEQ ID NO: 56).
  • the heavy chain consists of the sequence of SEQ ID NO: 56. It will be understood that SEQ ID NO: 56 can also include the signal peptide of the invention (SEQ ID NO: 36) or contain a different signal peptide.
  • the antibody or antigen binding fragment thereof comprises a heavy chain comprising
  • SEQ ID NO: 86 can also include the signal peptide of the invention (SEQ ID NO: 36) producing SEQ ID NO: 39 or contain a different signal peptide.
  • the antibody or antigen binding fragment thereof comprises a heavy chain consisting of SEQ ID NO: 86 or 39.
  • the antibody or antigen binding fragment thereof comprises a heavy chain comprising QVQLVQSGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAIGGS
  • SEQ ID NO: 87 can also include the signal peptide of the invention (SEQ ID NO: 36) producing SEQ ID NO: 40 or contain a different signal peptide.
  • the antibody or antigen binding fragment thereof comprises a heavy chain consisting of SEQ ID NO: 87 or 40.
  • the antibody or antigen binding fragment thereof comprises a heavy chain comprising QVQLVQSGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSNIYSN
  • SEQ ID NO: 88 can also include the signal peptide of the invention (SEQ ID NO: 36) producing SEQ ID NO: 41 or contain a different signal peptide.
  • the antibody or antigen binding fragment thereof comprises a heavy chain consisting of SEQ ID NO: 88 or 41.
  • the antibody or antigen binding fragment thereof comprises a heavy chain comprising QVQLVQSGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSNINGP
  • SEQ ID NO: 89 can also include the signal peptide of the invention (SEQ ID NO: 36) producing SEQ ID NO: 42 or contain a different signal peptide.
  • the antibody or antigen binding fragment thereof comprises a heavy chain consisting of SEQ ID NO: 89 or 42.
  • the antibody or antigen binding fragment thereof comprises a heavy chain comprising QVQLVQSGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSNIYSN
  • SEQ ID NO: 90 can also include the signal peptide of the invention (SEQ ID NO: 36) producing SEQ ID NO: 52 or contain a different signal peptide.
  • the antibody or antigen binding fragment thereof comprises a heavy chain consisting of SEQ ID NO: 90 or 52.
  • the antibody or antigen binding fragment thereof comprises a heavy chain comprising QVQLVQSGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGS
  • SEQ ID NO: 91 can also include the signal peptide of the invention (SEQ ID NO: 36) producing SEQ ID NO: 53 or contain a different signal peptide.
  • the antibody or antigen binding fragment thereof comprises a heavy chain consisting of SEQ ID NO: 91 or 53.
  • the antibody or antigen binding fragment thereof comprises a heavy chain comprising QVQLVQSGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSNIYSN
  • SEQ ID NO: 92 can also include the signal peptide of the invention (SEQ ID NO: 36) producing SEQ ID NO: 75 or contain a different signal peptide.
  • EflZSlv ⁇ uiS ⁇ fSents, the antibody or antigen binding fragment thereof comprises a heavy chain comprising QVQLVQSGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSNIYSN
  • SEQ ID NO: 93 can also include the signal peptide of the invention (SEQ ID NO: 36) producing SEQ ID NO: 76 or contain a different signal peptide.
  • the antibody or antigen binding fragment thereof comprises a heavy chain consisting of SEQ ID NO: 93 or 76.
  • the antibody or antigen binding fragment thereof comprises a heavy chain comprising QVQLVQSGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSNIYSN
  • SEQ ID NO: 94 can also include the signal peptide of the invention (SEQ ID NO: 36) producing SEQ ID NO: 77 or contain a different signal peptide.
  • the antibody or antigen binding fragment thereof comprises a heavy chain consisting of SEQ ID NO: 94 or 77.
  • the antibody or antigen binding fragment thereof comprises a heavy chain comprising QVQLVQSGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSNIYSN
  • SEQ ID NO: 95 can also include the signal peptide of the invention (SEQ ID NO: 36) producing SEQ ID NO: 78 or contain a different signal peptide.
  • the antibody or antigen binding fragment thereof comprises a heavy chain consisting of SEQ ID NO: 95 or 78.
  • the antibody or antigen binding fragment thereof comprises a heavy chain comprising QVQLVQSGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSNIYSN
  • SEQ ID NO: 96 can also include the signal peptide of the invention (SEQ ID NO: 36) producing SEQ ID NO: 79 or contain a different signal peptide.
  • the antibody or antigen binding fragment thereof comprises a heavy chain consisting of SEQ ID NO: 96 or 79.
  • the antibody or antigen binding fragment thereof comprises a heavy chain comprising QVQLVQSGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSNIYSN
  • SEQ ID NO: 97 can also include the signal peptide of the invention (SEQ ID NO: 36) producing SEQ ID NO: 80 or contain a different signal peptide.
  • the antibody or antigen binding fragment thereof comprises a heavy chain consisting of SEQ ID NO: 97 or 80.
  • the antibody or antigen binding fragment thereof comprises a heavy chain comprising QVQLVQSGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSNIYSN
  • SEQ ID NO: 98 can also include the signal peptide of the invention (SEQ ID NO: 36) producing SEQ ID NO: 81 or contain a different signal peptide.
  • the antibody or antigen binding fragment thereof comprises a heavy chain consisting of SEQ ID NO: 98 or 81.
  • the antibody or antigen binding fragment thereof comprises a heavy chain comprising QVQLVQSGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSNIYSN
  • SEQ ID NO: 99 can also include the signal peptide of the invention (SEQ ID NO: 36) producing SEQ ID NO: 82 or contain a different signal peptide.
  • the antibody or antigen binding fragment thereof comprises a heavy chain consisting of SEQ ID NO: 99 or 82.
  • the antibody or antigen binding fragment thereof comprises a heavy chain comprising QVQLVQSGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSNIYSN
  • SEQ ID NO: 100 can also include the signal peptide of the invention (SEQ ID NO: 36) producing SEQ ID NO: 83 or contain a different signal peptide.
  • the antibody or antigen binding fragment thereof comprises a heavy chain consisting of SEQ ID NO: 100 or 83. 'Yft 2 o 22 4?P ⁇ u?5e embodiments, the antibody or antigen binding fragm££T/Si! 2 w? 2 vw??ipl?ses a heavy chain comprising
  • SEQ ID NO: 101 can also include the signal peptide of the invention (SEQ ID NO: 36) producing SEQ ID NO: 43 or contain a different signal peptide.
  • the antibody or antigen binding fragment thereof comprises a heavy chain consisting of SEQ ID NO: 101 or 43.
  • the antibody or antigen binding fragment thereof comprises a heavy chain comprising QVQLVQSGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGS
  • SEQ ID NO: 102 can also include the signal peptide of the invention (SEQ ID NO: 36) producing SEQ ID NO: 44 or contain a different signal peptide.
  • the antibody or antigen binding fragment thereof comprises a heavy chain consisting of SEQ ID NO: 102 or 44.
  • the antibody or antigen binding fragment thereof comprises a heavy chain comprising QVQLVQSGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGS
  • SEQ ID NO: 103 can also include the signal peptide of the invention (SEQ ID NO: 36) producing SEQ ID NO: 45 or contain a different signal peptide.
  • the antibody or antigen binding fragment thereof comprises a heavy chain consisting of SEQ ID NO: 103 or 45.
  • the antibody or antigen binding fragment thereof comprises a heavy chain comprising
  • SEQ ID NO: 108 can also include the signal peptide of the invention (SEQ ID NO: 36) producing SEQ ID NO: 109 or contain a different signal peptide.
  • the antibody or antigen binding fragment thereof comprises a heavy chain comprising QVQLVQSGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSNIYSN
  • SEQ ID NO: 110 can also include the signal peptide of the invention (SEQ ID NO: 36) producing SEQ ID NO: 111 or contain a different signal peptide.
  • the antibody or antigen binding fragment thereof comprises a heavy chain comprising QVQLVQSGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSNIYSN ⁇ 9v ⁇ A 2 A°? 5 AbSVEGRFTISRDNSKNTLYLQMNSLRAEDTAVY ⁇ ISl / A ⁇ P ⁇ 5 J 0 ?i?'fF
  • SEQ ID NO: 115 can also include the signal peptide of the invention (SEQ ID NO: 36) producing SEQ ID NO: 116 or contain a different signal peptide.
  • the antibody or antigen binding fragment thereof comprises a heavy chain comprising
  • LSLSLGK (SEQ ID NO: 117), wherein X25 is any amino acid other than N and C.
  • SEQ ID NO: 117 can also include the signal peptide of the invention (SEQ ID NO: 36) producing SEQ ID NO: 118 or contain a different signal peptide.
  • the antibody or antigen binding fragment thereof comprises a heavy chain comprising QVQLVQSGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSNIYSN PX26RTYYADSVEGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKAPGDYTAYF
  • LSLSLGK (SEQ ID NO: 119), wherein X26 is G, D, S, E, Q or N. It will be understood that
  • SEQ ID NO: 119 can also include the signal peptide of the invention (SEQ ID NO: 36) ID NO: 120 or contain a different signal peptide.
  • the antibody or antigen binding fragment thereof comprises a heavy chain consisting of any one of SEQ ID NO: 108 to 111.
  • the antibody or antigen binding fragment thereof comprises a heavy chain consisting of any one of SEQ ID NO: 108 to 111.
  • the antibody or antigen binding fragment thereof comprises a heavy chain consisting of any one of SEQ ID NO: 115-120.
  • the antibody or antigen binding fragment thereof comprises a heavy chain consisting of any one of SEQ ID NO: 108-111 and 115-120.
  • the antibody or antigen binding fragment comprises a heavy chain comprising a sequence selected from SEQ ID NO: 39-45, 52-53 and 75-83. In some embodiments, the antibody or antigen binding fragment comprises a heavy chain comprising a sequence selected from SEQ ID NO: 86-103. In some embodiments, the antibody or antigen binding fragment comprises a heavy chain comprising a sequence selected from SEQ ID NO: 9, 39-45, 52-53 and 75-83. In some embodiments, the antibody or antigen binding fragment comprises a heavy chain comprising a sequence selected from SEQ ID NO: 85- 103.
  • the antibody or antigen binding fragment comprises a heavy chain consisting of a sequence selected from SEQ ID NO: 39-45, 52-53 and 75-83. In some embodiments, the antibody or antigen binding fragment comprises a heavy chain consisting of a sequence selected from SEQ ID NO: 86-103. In some embodiments, the antibody or antigen binding fragment comprises a heavy chain consisting of a sequence selected from SEQ ID NO: 9, 39-45, 52-53 and 75-83. In some embodiments, the antibody or antigen binding fragment comprises a heavy chain consisting of a sequence selected from SEQ ID NO: 85-103.
  • the light chain comprises an N-terminal peptide comprising SEQ ID NO: 36. In some embodiments, the light chain comprises an N-terminal peptide consisting of SEQ ID NO: 36. In some embodiments, the light chain comprises an amino acid sequence of SEQ ID NO: 36. In some embodiments, the light chain comprises an amino acid sequence of SEQ ID NO: 36 N-terminal to any one of SEQ ID NO: 8 and SEQ ID NO: 35. In some embodiments, the N-terminal peptide is a signal peptide. In some embodiments, the light chain comprises a signal peptide. In some embodiments, the light chain is devoid of a signal peptide.
  • the light chain lacks a signal peptide.
  • the light chain comprises a signal peptide when first expressed in a cell and the signal peptide is cleaved and the secreted light chain lacks the signal peptide.
  • the light chain comprises a C-termirEf p3p 2 uv 2 ⁇ ?5Pi?p? ⁇ sing RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQES VTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 38).
  • the light chain comprises a C-terminal peptide consisting of SEQ ID NO: 38. In some embodiments, the C-terminal peptide is a light chain constant region. In some embodiments, the light chain comprises an amino acid sequence of SEQ ID NO: 38. In some embodiments, the light chain comprises an amino acid sequence of SEQ ID NO: 38 C-terminal to any one of SEQ ID NO: 8, and SEQ ID NO: 35. In some embodiments, the C-terminal peptide comprises a CL domain. In some embodiments, the CL is a kappa CL domain. In some embodiments, the CL is a lambda CL domain.
  • the disulfide bridge that forms between the CHI domain of the heavy chain and the CL domain of the light chain are sufficient for heavy chain-light chain dimerization and formation of a function antibody or antigen binding fragment.
  • the C-terminal peptide comprises a dimerization domain.
  • the dimerization domain is sufficient to induce dimerization between the heavy chain and the light chain.
  • the antibody comprises a light chain comprising the sequence ELVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYGASSRAT GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPPYTFGQGTKVEIKRTVAA PSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDS KDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO:
  • SEQ ID NO: 104 can also include the signal peptide of the invention (SEQ ID NO: 36) producing SEQ ID NO: 10 or contain a different signal peptide.
  • the antibody or antigen binding fragment thereof comprises a light chain comprising
  • SEQ ID NO: 105 can also include the signal peptide of the invention (SEQ ID NO: 36) producing SEQ ID NO: 46 or contain a different signal peptide.
  • the antibody or antigen binding fragment thereof comprises a light chain consisting of SEQ ID NO: 104 or 10.
  • the antibody or antigen binding fragment thereof comprises a light chain consisting of SEQ ID NO: 105 or 46.
  • the antibody or antigen binding fragment coE ⁇ I ⁇ a ⁇ fi ⁇ P ⁇ thain comprising a sequence selected from SEQ ID NO: 10 and SEQ ID NO: 46. .
  • the antibody or antigen binding fragment comprises a light chain comprising a sequence selected from SEQ ID NO: 104 and SEQ ID NO: 105. In some embodiments, the antibody or antigen binding fragment comprises a light chain consisting of a sequence selected from SEQ ID NO: 10 and SEQ ID NO: 46. In some embodiments, the antibody or antigen binding fragment comprises a light chain consisting of a sequence selected from
  • the heavy chain and the light chain are joined by a linker.
  • the linker is an amino acid linker.
  • the linker is at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 15, 16, 18, 20, 22, 24 or 25 amino acids long. Each possibility represents a separate embodiment of the invention.
  • the linker is at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 15, 16, 18, 20, 22, 24 or 25 amino acids long. Each possibility represents a separate embodiment of the invention.
  • the linker is between 1-25, 5-25, 10-25, 15-25, 20-25, 1-20, 5-20, 10-20, 15-
  • the antibody or antigen binding fragment thereof is selected from those provided in Table 1.
  • the antibody comprises a heavy chain variable region comprising or consisting of SEQ ID NO: 32 and a light chain variable region comprising or consisting of SEQ ID NO: 8. In some embodiments, the antibody comprises a heavy chain comprising or consisting of SEQ ID NO: 101 and a light chain comprising or consisting of SEQ ID NO: 104. In some embodiments, the antibody comprises a heavy chain comprising or consisting of SEQ ID NO: 43 and a light chain comprising or consisting of SEQ ID NO: 10.
  • the antibody comprises a heavy chain variable region comprising or consisting of SEQ ID NO: 33 and a light chain variable region comprising or consisting of SEQ ID NO: 8. In some embodiments, the antibody comprises a heavy chain comprising or consisting of SEQ ID NO: 102 and a light chain comprising or consisting of SEQ ID NO: 104. In some embodiments, the antibody comprises a heavy chain comprising or consisting of SEQ ID NO: 44 and a light chain comprising or consisting of SEQ ID NO: 10.
  • the antibody comprises a heavy chain variable region comprising or consisting of SEQ ID NO: 34 and a light chain variable region comprising or consisting of SEQ ID NO: 8. In some embodiments, the antibody comprises a heavy chain comprising or consisting of SEQ ID NO: 103 and a light chain comprising or consisting of SEQ ID NO: 104. In some embodiments, the antibody comprises a heavy chain comprising or consisting of SEQ ID NO: 45 and a light chain comprising or consisting of SEQ ID NO: 10.
  • the antibody comprises a heavy chain variable region comprising or consisting of SEQ ID NO: 30 and a light chain variable region comprising or consisting of SEQ ID NO: 8. In some embodiments, the antibody comprises a heavy chain comprising or consisting of SEQ ID NO: 88 and a light chain comprising or consisting of SEQ ID NO: 104. In some embodiments, the antibody comprises a heavy chain comprising or consisting of SEQ ID NO: 41 and a light chain comprising or consisting of SEQ ID NO: 10.
  • the antibody comprises a heavy ?£EiI L ?S??Z2?2 3 1vgion comprising or consisting of SEQ ID NO: 50 and a light chain variable region comprising or consisting of SEQ ID NO: 8.
  • the antibody comprises a heavy chain comprising or consisting of SEQ ID NO: 90 and a light chain comprising or consisting of SEQ ID NO: 104.
  • the antibody comprises a heavy chain comprising or consisting of SEQ ID NO: 52 and a light chain comprising or consisting of SEQ ID NO: 10.
  • the antibody comprises a heavy chain variable region comprising or consisting of SEQ ID NO: 66 and a light chain variable region comprising or consisting of SEQ ID NO: 8. In some embodiments, the antibody comprises a heavy chain comprising or consisting of SEQ ID NO: 92 and a light chain comprising or consisting of SEQ ID NO: 104. In some embodiments, the antibody comprises a heavy chain comprising or consisting of SEQ ID NO: 75 and a light chain comprising or consisting of SEQ ID NO: 10.
  • the antibody comprises a heavy chain variable region comprising or consisting of SEQ ID NO: 67 and a light chain variable region comprising or consisting of SEQ ID NO: 8. In some embodiments, the antibody comprises a heavy chain comprising or consisting of SEQ ID NO: 93 and a light chain comprising or consisting of SEQ ID NO: 104. In some embodiments, the antibody comprises a heavy chain comprising or consisting of SEQ ID NO: 76 and a light chain comprising or consisting of SEQ ID NO: 10.
  • the antibody comprises a heavy chain variable region comprising or consisting of SEQ ID NO: 68 and a light chain variable region comprising or consisting of SEQ ID NO: 8. In some embodiments, the antibody comprises a heavy chain comprising or consisting of SEQ ID NO: 94 and a light chain comprising or consisting of SEQ ID NO: 104. In some embodiments, the antibody comprises a heavy chain comprising or consisting of SEQ ID NO: 77 and a light chain comprising or consisting of SEQ ID NO: 10.
  • the antibody comprises a heavy chain variable region comprising or consisting of SEQ ID NO: 69 and a light chain variable region comprising or consisting of SEQ ID NO: 8. In some embodiments, the antibody comprises a heavy chain comprising or consisting of SEQ ID NO: 95 and a light chain comprising or consisting of SEQ ID NO: 104. In some embodiments, the antibody comprises a heavy chain comprising W? 2022/208 ⁇ 5 ⁇ SEQ ID NO: 78 and a light chain comprising or conliPJ/i ⁇ v ⁇ NO: 10.
  • the antibody comprises a heavy chain variable region comprising or consisting of SEQ ID NO: 70 and a light chain variable region comprising or consisting of SEQ ID NO: 8. In some embodiments, the antibody comprises a heavy chain comprising or consisting of SEQ ID NO: 96 and a light chain comprising or consisting of SEQ ID NO: 104. In some embodiments, the antibody comprises a heavy chain comprising or consisting of SEQ ID NO: 79 and a light chain comprising or consisting of SEQ ID NO: 10.
  • the antibody comprises a heavy chain variable region comprising or consisting of SEQ ID NO: 71 and a light chain variable region comprising or consisting of SEQ ID NO: 8. In some embodiments, the antibody comprises a heavy chain comprising or consisting of SEQ ID NO: 97 and a light chain comprising or consisting of SEQ ID NO: 104. In some embodiments, the antibody comprises a heavy chain comprising or consisting of SEQ ID NO: 80 and a light chain comprising or consisting of SEQ ID NO: 10.
  • the antibody comprises a heavy chain variable region comprising or consisting of SEQ ID NO: 72 and a light chain variable region comprising or consisting of SEQ ID NO: 8. In some embodiments, the antibody comprises a heavy chain comprising or consisting of SEQ ID NO: 98 and a light chain comprising or consisting of SEQ ID NO: 104. In some embodiments, the antibody comprises a heavy chain comprising or consisting of SEQ ID NO: 81 and a light chain comprising or consisting of SEQ ID NO: 10.
  • the antibody comprises a heavy chain variable region comprising or consisting of SEQ ID NO: 73 and a light chain variable region comprising or consisting of SEQ ID NO: 8. In some embodiments, the antibody comprises a heavy chain comprising or consisting of SEQ ID NO: 99 and a light chain comprising or consisting of SEQ ID NO: 104. In some embodiments, the antibody comprises a heavy chain comprising or consisting of SEQ ID NO: 82 and a light chain comprising or consisting of SEQ ID NO: 10.
  • the antibody comprises a heavy chain variable region comprising or consisting of SEQ ID NO: 74 and a light chain variable region comprising or consisting of SEQ ID NO: 8.
  • the antibody comprises a heavy chain consisting of SEQ ID NO: 100 and a light chain com]SS7i ⁇ S? 2 3Z,?Slai?ig of SEQ ID NO: 104.
  • the antibody comprises a heavy chain comprising or consisting of SEQ ID NO: 83 and a light chain comprising or consisting of SEQ ID NO: 10.
  • the antibody comprises a heavy chain variable region comprising or consisting of SEQ ID NO: 31 and a light chain variable region comprising or consisting of SEQ ID NO: 8. In some embodiments, the antibody comprises a heavy chain comprising or consisting of SEQ ID NO: 89 and a light chain comprising or consisting of SEQ ID NO: 104. In some embodiments, the antibody comprises a heavy chain comprising or consisting of SEQ ID NO: 42 and a light chain comprising or consisting of SEQ ID NO: 10.
  • the antibody comprises a heavy chain variable region comprising or consisting of SEQ ID NO: 28 and a light chain variable region comprising or consisting of SEQ ID NO: 8. In some embodiments, the antibody comprises a heavy chain comprising or consisting of SEQ ID NO: 86 and a light chain comprising or consisting of SEQ ID NO: 104. In some embodiments, the antibody comprises a heavy chain comprising or consisting of SEQ ID NO: 39 and a light chain comprising or consisting of SEQ ID NO: 10.
  • the antibody comprises a heavy chain variable region comprising or consisting of SEQ ID NO: 29 and a light chain variable region comprising or consisting of SEQ ID NO: 8. In some embodiments, the antibody comprises a heavy chain comprising or consisting of SEQ ID NO: 87 and a light chain comprising or consisting of SEQ ID NO: 104. In some embodiments, the antibody comprises a heavy chain comprising or consisting of SEQ ID NO: 40 and a light chain comprising or consisting of SEQ ID NO: 10.
  • the antibody comprises a heavy chain variable region comprising or consisting of SEQ ID NO: 51 and a light chain variable region comprising or consisting of SEQ ID NO: 8. In some embodiments, the antibody comprises a heavy chain comprising or consisting of SEQ ID NO: 91 and a light chain comprising or consisting of SEQ ID NO: 104. In some embodiments, the antibody comprises a heavy chain comprising or consisting of SEQ ID NO: 53 and a light chain comprising or consisting of SEQ ID NO: 10. W .
  • the antibody comprises a heavy ?i9ZiI L ?S??Z2?2 3 1vgion comprising or consisting of SEQ ID NO: 7 and a light chain variable region comprising or consisting of SEQ ID NO: 35.
  • the antibody comprises a heavy chain comprising or consisting of SEQ ID NO: 85 and a light chain comprising or consisting of SEQ ID NO: 105.
  • the antibody comprises a heavy chain comprising or consisting of SEQ ID NO: 9 and a light chain comprising or consisting of SEQ ID NO: 46.
  • the antibody comprises a heavy chain variable region comprising or consisting of SEQ ID NO: 30 and a light chain variable region comprising or consisting of SEQ ID NO: 35. In some embodiments, the antibody comprises a heavy chain comprising or consisting of SEQ ID NO: 88 and a light chain comprising or consisting of SEQ ID NO: 105. In some embodiments, the antibody comprises a heavy chain comprising or consisting of SEQ ID NO: 41 and a light chain comprising or consisting of SEQ ID NO: 46.
  • the antibody comprises a heavy chain variable region comprising or consisting of SEQ ID NO: 31 and a light chain variable region comprising or consisting of SEQ ID NO: 35. In some embodiments, the antibody comprises a heavy chain comprising or consisting of SEQ ID NO: 89 and a light chain comprising or consisting of SEQ ID NO: 105. In some embodiments, the antibody comprises a heavy chain comprising or consisting of SEQ ID NO: 42 and a light chain comprising or consisting of SEQ ID NO: 46.
  • an antibody or antigen binding fragment comprising at least 70% amino acid identity to an antibody or antigen binding fragment provided in Table 1 and comprising the same CDRs as that antibody.
  • the CDRs define the binding specificity of the antibody/binding fragment and therefore, so long as the CDRs are retained the sequence around the CDRs can be modified/altered.
  • at least 70% is at least 75%, 80%, 85%, 90%, 92%, 95%, 97%, 99% or 100%. Each possibility represents a separate embodiment of the invention.
  • at least 70% is at least 80%. In some embodiments, at least 70% is at least 90%.
  • Engineered antibodies of the invention include those in which modifications have been made to framework residues within VH and/or VL, e.g., to improve the properties of the antibody. Typically, such framework modifications are made to decrease the W£“ ty of the antibody. For example, one approach is to “baw£Iu ⁇ 2 v 22 v® v 0 viSnore framework residues to the corresponding germline sequence. More specifically, an antibody that has undergone somatic mutation can contain framework residues that differ from the germline sequence from which the antibody is derived. Such residues can be identified by comparing the antibody framework sequences to the germline sequences from which the antibody is derived.
  • a framework amino acid at position 25, 68 and 82a all differ from the germline and can be backmutated to the germline by substitutions H25S, S68T and T82aT respectively.
  • Another type of framework modification involves mutating one or more residues within the framework region, or even within one or more CDR regions, to remove T cell epitopes to thereby reduce the potential immunogenicity of the antibody. This approach is also referred to as “deimmunization” and is described in further detail in U.S. Patent
  • antibodies of the invention can be engineered to include modifications within the Fc region, typically to alter one or more functional properties of the antibody, such as serum half-life, complement fixation, Fc receptor binding, and/or antigen-dependent cellular cytotoxicity.
  • an antibody of the invention can be chemically modified (e.g., one or more chemical moieties can be attached to the antibody) or be modified to alter its glycosylation, again to alter one or more functional properties of the antibody.
  • the antibody is an IgG4 isotype antibody comprising a Serine to Proline mutation at a position corresponding to position 228 (S228P; EU index) in the hinge region of the heavy chain constant region.
  • S228P Serine to Proline mutation at a position corresponding to position 228
  • EU index EU index
  • This mutation has been reported to abolish the heterogeneity of inter-heavy chain disulfide bridges in the hinge region (Angal et al. supra; position 241 is based on the Kabat numbering system).
  • the hinge region of CHI is modified such that the number of cysteine residues in the hinge region is altered, e.g., increased or decreased.
  • the number of cysteine residues in the hinge region of CHI is altered to, for example, facilitate assembly of the light and heavy chains or to increase or decrease the stability of the antibody.
  • the Fc hinge region of an antibody P IdC 1T11/UILLO2.L0V/2Vl2/ I0 kJ50 U3U4L8l Cdd C the biological half-life of the antibody.
  • one or more amino acid mutations are introduced into the CH2-CH3 domain interface region of the Fc-hinge fragment such that the antibody has impaired Staphylococcyl protein A (SpA) binding relative to native Fc- hinge domain SpA binding.
  • SpA Staphylococcyl protein A
  • the antibody is modified to increase its biological half-life.
  • Various approaches are possible. For example, one or more of the following mutations can be introduced: T252L, T254S, T256F, as described in U.S. Pat. No. 6,277,375.
  • the antibody can be altered within the CHI or CL region to contain a salvage receptor binding epitope taken from two loops of a CH2 domain of an Fc region of an IgG, as described in U.S. Pat. Nos. 5,869,046 and 6,121,022.
  • the Fc region is altered by replacing at least one amino acid residue with a different amino acid residue to alter the effector function(s) of the antibody.
  • one or more amino acids selected from amino acid residues 234, 235, 236, 237, 297, 318, 320 and 322 can be replaced with a different amino acid residue such that the antibody has an altered affinity for an effector ligand but retains the antigen-binding ability of the parent antibody.
  • the effector ligand to which affinity is altered can be, for example, an Fc receptor or the Cl component of complement. This approach is described in further detail in U.S. Pat. Nos. 5,624,821 and 5,648,260.
  • one or more amino acids selected from amino acid residues 329, 331 and 322 can be replaced with a different amino acid residue such that the antibody has altered C Iq binding and/or reduced or abolished complement dependent cytotoxicity (CDC).
  • CDC complement dependent cytotoxicity
  • one or more amino acid residues within amino acid positions 231 and 239 are altered to thereby alter the ability of the antibody to fix complement. This approach is described further in PCT Publication WO 94/29351.
  • the Fc region is modified to increase the ability of the antibody to mediate antibody dependent cellular cytotoxicity (ADCC) and/or to increase the affinity of the antibody for an Fey receptor by modifying one or more amino acids at the following positions: 238, 239, 248, 249, 252, 254, 255, 256, 258, 265, 267, 268, 269, 270, 272, 276, 278, 280, 283, 285, 286, 289, 290, 292, 293, 294, 295, 296, 298, 301, 303, 305,
  • ADCC antibody dependent cellular cytotoxicity
  • the glycosylation of an antibody is modified.
  • an aglycosylated antibody can be made (i.e., the antibody lacks glycosylation).
  • Glycosylation can be altered to, for example, increase the affinity of the antibody for antigen.
  • carbohydrate modifications can be accomplished by, for example, altering one or more sites of glycosylation within the antibody sequence.
  • one or more amino acid substitutions can be made that result in elimination of one or more variable region framework glycosylation sites to thereby eliminate glycosylation at that site.
  • Such aglycosylation may increase the affinity of the antibody for antigen. See, e.g., U.S. Pat. Nos. 5,714,350 and 6,350,861.
  • an antibody can be made that has an altered type of glycosylation, such as a hypofucosylated antibody having reduced amounts of fucosyl residues or an antibody having increased bisecting GlcNac structures.
  • altered glycosylation patterns have been demonstrated to increase the ADCC ability of antibodies.
  • carbohydrate modifications can be accomplished by, for example, expressing the antibody in a host cell with altered glycosylation machinery. Cells with altered glycosylation machinery have been described in the art and can be used as host cells in which to express recombinant antibodies of the invention to thereby produce an antibody with altered glycosylation.
  • the cell lines Ms704, Ms705, and Ms709 lack the fucosyltransferase gene, FUT8 (a (l,6)-fucosyltransferase), such that antibodies expressed in the Ms704, Ms705, and Ms709 cell lines lack fucose on their carbohydrates.
  • FUT8 a (l,6)-fucosyltransferase
  • the Ms704, Ms705, and Ms709 FUT8-/- cell lines were created by the targeted disruption of the FUT8 gene in CHO/DG44 cells using two replacement vectors (see U.S. Patent Publication No. 20040110704 and Yamane-Ohnuki et al. (2004) Biotechnol Bioeng 87:614-22).
  • EP 1,176,195 describes a cell line with a functionally disrupted FUT8 gene, which encodes a fucosyl transferase, such that antibodies expressed in such a cell line exhibit hypofucosylation by reducing or eliminating the a.- 1,6 bond-related enzyme.
  • Antibodies with a modified glycosylation profile can also be produced in chicken eggs, as described in PCT Publication WO 06/089231.
  • antibodies with a modified glycosylation profile can be produced in plant cells, such as Lemna (U.S. Pat. No. 7,632,983). Methods for production of antibodies in a plant system are disclosed in the U.S. Pat. Nos. 6,998,267 and 7,388,081.
  • PCT Publication WO 99/54342 describes cell lines engineered to express glycoprotein-modifying glycosyl transferases (e.g., P(l,4)-N- acetylglucosaminyltransferase III (GnTIII)) such that antibodies expressed in the engineered cell lines exhibit increased bisecting GlcNac structures which results in increased ADCC activity of the antibodies (see also Umana et al. (1999) Nat. Biotech. 17:176-180).
  • glycoprotein-modifying glycosyl transferases e.g., P(l,4)-N- acetylglucosaminyltransferase III (GnTIII)
  • the fucose residues of the antibody can be cleaved off using a fucosidase enzyme; e.g., the fucosidase a-L-fucosidase removes fucosyl residues from antibodies (Tarentino et al. (1975) Biochem. 14:5516-23).
  • a fucosidase enzyme e.g., the fucosidase a-L-fucosidase removes fucosyl residues from antibodies (Tarentino et al. (1975) Biochem. 14:5516-23).
  • an antibody can be pegylated to, for example, increase the biological (e.g., serum) half-life of the antibody.
  • the antibody, or fragment thereof typically is reacted with polyethylene glycol (PEG), such as a reactive ester or aldehyde derivative of PEG, under conditions in which one or more PEG groups become attached to the antibody or antibody fragment.
  • PEG polyethylene glycol
  • the pegylation is carried out via an acylation reaction or an alkylation reaction with a reactive PEG molecule (or an analogous reactive water-soluble polymer).
  • polyethylene glycol is intended to encompass any of the forms of PEG that have been used to derivatize other proteins, such as mono (C1-C10) alkoxy- or aryloxy-polyethylene glycol or polyethylene glycol-maleimide.
  • the antibody to be pegylated is an aglycosylated antibody. Methods for pegylating proteins are known in the art and can be applied to the antibodies of the invention. See, e.g., EP 0154316 and EP 0401384.
  • a pharmaceutical composition comprising an antibody or antigen binding fragment thereof of the invention.
  • W [ VO12V0.72J2/ A2ll085 d J0k5Ji ⁇ ll,C-, embodiments, pharmaceutical composition P 11 U LCL1LTL11/VI/L120 >22/050348 a pharmaceutically acceptable carrier, excipient or adjuvant.
  • pharmaceutical composition a therapeutically effective amount of the antibody or antigen binding fragment thereof of the invention.
  • carrier refers to any component of a pharmaceutical composition that is not the active antibody or antigen binding fragment thereof.
  • pharmaceutically acceptable carrier refers to non-toxic, inert solid, semi-solid liquid filler, diluent, encapsulating material, formulation auxiliary of any type, or simply a sterile aqueous medium, such as saline.
  • Some examples of the materials that can serve as pharmaceutically acceptable carriers are sugars, such as lactose, glucose and sucrose, starches such as com starch and potato starch, cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt, gelatin, talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; glycols, such as propylene glycol, polyols such as glycerin, sorbitol, mannitol and polyethylene glycol; esters such as ethyl oleate and ethyl laurate, agar; buffering antibodies or antigen binding fragments thereof such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline, Ring
  • substances which can serve as a carrier herein include sugar, starch, cellulose and its derivatives, powered tragacanth, malt, gelatin, talc, stearic acid, magnesium stearate, calcium sulfate, vegetable oils, polyols, alginic acid, pyrogen-free water, isotonic saline, phosphate buffer solutions, cocoa butter (suppository base), emulsifier as well as other non-toxic pharmaceutically compatible substances used in other pharmaceutical formulations.
  • wetting antibodies or antigen binding fragments thereof and lubricants such as sodium lauryl sulfate, as well as coloring antibodies or antigen binding fragments thereof, flavoring antibodies or antigen binding fragments thereof, excipients, stabilizers, antioxidants, and preservatives may also be present.
  • Any non-toxic, inert, and effective carrier may be used to formulate the compositions contemplated herein.
  • Suitable pharmaceutically acceptable carriers, excipients, and diluents in this regard are well known to those of skill in the art, such as those described in The Merck Index, Thirteenth Edition, Budavari et al., Eds., Merck & Co., Inc.,
  • the presently described composition may also be contained in artificially created structures such as liposomes, ISCOMS, slow- releasing particles, and other vehicles which increase the half-life of the peptides or polypeptides in serum.
  • Liposomes include emulsions, foams, micelles, insoluble monolayers, liquid crystals, phospholipid dispersions, lamellar layers and the like.
  • Liposomes for use with the presently described peptides are formed from standard vesicleforming lipids which generally include neutral and negatively charged phospholipids and a sterol, such as cholesterol. The selection of lipids is generally determined by considerations such as liposome size and stability in the blood.
  • the carrier may comprise, in total, from about 0.1% to about 99.99999% by weight of the pharmaceutical compositions presented herein.
  • a therapeutically effective amount refers to an amount of a drug effective to treat a disease or disorder in a mammal.
  • a therapeutically effective amount is an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic or prophylactic result. The exact dosage form and regimen would be determined by the physician according to the patient's condition.
  • the pharmaceutical composition comprises a therapeutically effective amount of the antibody or antigen binding fragment of the invention. In some embodiments, the pharmaceutical composition is a therapeutic composition.
  • the antibody or antigen binding fragm?i ⁇ Ii?Jl 2 Q? ⁇ 2 i9 5 ⁇ Q ⁇ 4 use in treating a disease or condition.
  • the pharmaceutical composition is for use in treating a disease or condition.
  • the disease or condition is characterized by cells expressing HVEM.
  • the cell are disease cells characterized by expressing HVEM.
  • the cells are characterized by overexpressing HVEM.
  • overexpression is as compared to a healthy cell.
  • a healthy cell is a non-diseased cell.
  • overexpression is an increased expression.
  • the disease or condition is an HVEM positive disease or condition.
  • the disease or condition is a BTLA positive disease or condition.
  • the disease or condition is an HVEM positive cancer.
  • the disease or condition is a cancer comprising BTLA positive resident cells.
  • the disease or condition is an HVEM positive precancerous lesion.
  • the cancer is melanoma.
  • the cancer is renal cell carcinoma.
  • the cancer is selected from melanoma, renal cancer, cervical cancer, prostate cancer, pancreatic cancer, lung cancer, ovarian cancer, colon cancer, breast cancer, hepatocellular cancer, cholangiocarcinoma, thymoma and head and neck cancer.
  • the renal cancer is renal cell carcinoma.
  • the disease is an infectious disease.
  • the cells of the infection comprise HVEM expression.
  • an infected cell comprises HVEM expression.
  • the infectious disease is a bacterium, and a bacterial cell comprises HVEM expression.
  • the infectious disease is a fungal infection, and a fungal cell comprises HVEM expression.
  • the infectious disease is a virus, and a virally infected subject cell comprises HVEM expression.
  • the virus is Herpes virus.
  • HVEM expression is HVEM overexpression. In some embodiments, HVEM expression is increased HVEM expression.
  • a method of treating an HVEM positive disease or condition in a subject in need thereof comprising administering to the subject an antibody or antigen binding fragment thereof of the invention, thereby treating the subject.
  • a method of treating an HVEM positive disease or condition in a subject in need thereof comprising administering to the subject a pharmaceutical composition of the invention, thereby treating the subject.
  • the method further comprises n ⁇ ? ⁇ T/Ati 2 ⁇ l? 2 i® 50 ⁇ 3 ⁇ 4 PEM-
  • the method further comprises not substantially inhibiting HVEM-TNFSF14 interaction. In some embodiments, the method further comprises not fully inhibiting HVEM-TNFSF14 interaction.
  • the method further comprises immune checkpoint inhibition of a non-HVEM checkpoint protein.
  • the non-HVEM checkpoint protein is the PD- 1.
  • the method further comprises immune checkpoint blockade of a non-HVEM checkpoint protein.
  • the method further comprises inhibiting interaction between PD-1 and one of its ligands.
  • a PD-1 ligand is selected from PD-L1 and PD-L2.
  • the method further comprises inhibiting PD-1, PD-L1 or PD-L2.
  • the method further comprises inhibiting PD-1 to PD-L1 interaction.
  • the method further comprises inhibiting PD-1 to PD-L2 interaction. In some embodiments, the method further comprises inhibiting PD-1 to PD-L1 or PD-L2 interaction. In some embodiments, inhibiting interaction comprises administering an antibody or antigen binding fragment thereof that inhibits PD-1 to PD-L1 interaction or PD-1 to PD-L2 interaction. In some embodiments, inhibiting interaction comprises administering an antibody or antigen binding fragment thereof that inhibits interaction between PD-1 and at least one of its ligands. In some embodiments, at least one ligand is two ligands. In some embodiments, inhibiting interaction comprises PD-1/PD-L1 blockade.
  • inhibiting interaction comprises PD-1/PD-L1 or PD-L2 blockade. In some embodiments, inhibiting interaction comprises anti-PD-l/PD-Ll therapy. In some embodiments, inhibiting interaction comprises anti-PD- 1/PD-L1 or PD-L2 therapy. In some embodiments, therapy is immunotherapy. In some embodiments, an antibody or antigen binding fragment thereof that inhibits interaction is an anti-PD-1 or anti-PD-Ll antibody. In some embodiments, an antibody or antigen binding fragment thereof that inhibits interaction is an anti-PD-1, anti-PD-Ll or anti-PD-L2 antibody. In some embodiments, an antibody or antigen binding fragment thereof that inhibits interaction is a PD-1/PD-L1 inhibitor.
  • an antibody or antigen binding fragment thereof that inhibits interaction is a PD-1/PD-L1/PD-L2 inhibitor.
  • the antibody is a blocking antibody.
  • PD-L1/L2 and PD-1 therapies are well known in the art and include but are not limited to nivolumab (Opdivo), pembrolizumab (Keytruda), atezolizumab, avelumab, durvalumab, cemiplimab (Libtayo), pidilizumab, AMP-224, AMP-514 and PDR001.
  • the method of treatment further co .IP ⁇ C5JTi/lItL?2 - 0 02 2 2 2/(0?550Pi3?4a P8o.ri •ng another therapeutic against the HVEM-expressing cell.
  • the other therapeutic is an anti-cancer therapeutic.
  • the therapeutic is a non- autologous immune cell.
  • the other therapeutic is an autologous immune cell.
  • the immune cell is a CAR expression immune cell.
  • the CAR is a CAR-T.
  • the CAR is a CAR-NK.
  • the autologous immune cell is TIL therapy. In some embodiments, the non- autologous immune cell is an adoptive cell therapy. In some embodiments, the autologous immune cell is an adoptive cell therapy. In some embodiments, the adoptive cell is a CAR cell. In some embodiments, the adoptive cell is a TIL.
  • composition of the invention and the another therapeutic are administering concomitantly. In some embodiments, the composition of the invention is administered before, after or at the same time as the another therapeutic.
  • the subject is a human. In some embodiments, the subject is a subject suffering from a HVEM positive disease or condition. In some embodiments, the subject is suffering from a disease characterized by HVEM positive cells. In some embodiments, the subject is suffering from cancer. In some embodiments, the cancer is HVEM positive cancer. In some embodiments, the subject is naive to therapy. In some embodiments, the subject is naive to anti-HVEM therapy. In some embodiments, the subject is naive to immunotherapy.
  • administering refers to any method which, in sound medical practice, delivers a composition containing an active agent to a subject in such a manner as to provide a therapeutic effect.
  • One aspect of the present subject matter provides for intravenous administration of a therapeutically effective amount of a composition of the present subject matter to a patient in need thereof.
  • Other suitable routes of administration can include parenteral, subcutaneous, oral, intramuscular, intrathecal, or intraperitoneal.
  • the dosage administered will be dependent upon the age, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired.
  • a method of determining suitability of a subject to be treated by a method of the invention comprising obtaining a sample from 'YiQ. 2 ?uuj?2? 5 S5d determining HVEM levels in the sample, wherein of
  • HVEM indicates the subject is suitable for a method of treatment of the invention.
  • a method of detecting HVEM in a sample comprising contacting the sample with an antibody or antigen binding fragment thereof of the invention, or an antibody or antigen binding fragment thereof of the invention, thereby detecting HVEM.
  • determining HVEM levels comprises detecting HVEM. In some embodiments, the detecting comprises quantitating the amount of HVEM. In some embodiments, the contacting is under conditions suitable for binding of the antibody or antigen binding fragment thereof or antibody or antigen binding fragment thereof to bind to HVEM. In some embodiments, the conditions are suitable for specific binding to HVEM. In some embodiments, binding is hybridizing. Conditions for antibody/antibody or antigen binding fragment thereof binding will depend on the sample. A skilled artisan will appreciate the conditions needed for binding to a tissue sample (dependent on the method/type of fixation) are different than those of binding in a liquid solution, such as a whole cell lysate. Such binding conditions are well known in the art and a skilled artisan can select the proper conditions for a given sample.
  • the sample is a tissue sample. In some embodiments, the sample is a paraffin embedded sample. In some embodiments, the sample is a perfused sample. In some embodiments, the sample is from a subject. In some embodiments, the sample is a healthy sample. In some embodiments, the sample is a diseased sample. In some embodiments, the sample is a diagnostic sample.
  • the method further comprises detecting the antibody or antigen binding fragment thereof of the invention, or an antibody or antigen binding fragment thereof of the invention.
  • the detection is immunohistochemical detection.
  • the detection is immunofluorescent detection.
  • the detection is FACS detection.
  • the detection further comprises contacting the sample with a secondary antibody that recognized the antibody or antigen binding fragment thereof or antibody of the invention.
  • the detection comprises detecting the secondary antibody.
  • the detection comprises microscopy.
  • the subject suffers from a disease or condition.
  • the subject is suspected to suffer from a disease or condition.
  • the subject is at risk of developing a disease o? ⁇ J ⁇ Jiu?PiuM? 5 ?M 4 ⁇ ome embodiments, the subject suffers from a disease or condition which may comprise increased HVEM expression.
  • the subject suffers from a disease or condition which may be characterized by increased HVEM expression.
  • the subject suffers from cancer.
  • the cancer is a cancer that did not respond to first line therapy.
  • the cancer is a cancer relapse.
  • the cancer is a cancer that did not respond to PD-1/PD-L1 therapy.
  • the sample is a disease sample.
  • the sample is a biological fluid.
  • the biological fluid is selected from blood, serum, plasma, urine, feces, bile, semen, tumor fluid, and cerebral spinal fluid.
  • the sample is a blood sample.
  • the sample is a cell sample.
  • the sample comprises cells.
  • the sample comprises disease cells.
  • the sample is a tumor sample.
  • the sample is a biopsy.
  • positive expression of HVEM comprises HVEM expression. In some embodiments, positive expression of HVEM comprises elevated HVEM levels. In some embodiments, positive expression of HVEM comprises increased HVEM levels. In some embodiments, positive expression of HVEM comprises overexpression of HVEM. In some embodiments, positive expression of HVEM is as compared to healthy sample. In some embodiments, the healthy sample is from healthy tissue and/or cells adjacent to the disease tissue and/or cells. In some embodiments, a healthy sample comprises non-infected cells. In some embodiments, a healthy sample is for a healthy donor. In some embodiments, positive expression of HVEM is as compared to a predetermined threshold.
  • kits comprising a pharmaceutical composition of the invention, or an antibody or antigen binding fragment thereof of the invention.
  • the kit further comprises a PD-1 based therapy. In some embodiments, the kit further comprises a PD-L1 based therapy. In some embodiments, the therapy is an immunotherapy. In some embodiments, the therapy is an anti-PD-1 therapy. In some embodiments, the therapy is an anti-PD-Ll therapy. In some embodiments, therapy is a PD-1/PD-L1 blockade therapy. In some embodiments, the therapy is a blocking antibody. In some embodiments, the therapy is an anti-PD-1 antibody. In some embodiments, the therapy is an anti-PD-Ll antibody. In some embodiments, the antibody is a blocking antibody.
  • the kit further comprises a label slatingTnt p* 2 ⁇ ?5Sviutical composition of the invention is for use with a PD-1 and/or PD-L1 based therapy.
  • the kit further comprises a label stating the antibody or antigen binding fragment thereof of the invention is for use with a PD-1 and/or PD-L1 based therapy.
  • the kit further comprises a secondary detection molecule.
  • the detection molecule is for detection an antibody or antigen binding fragment thereof of the invention.
  • the secondary detection molecule is an antibody that binds to an antibody or antigen binding fragment thereof of the invention.
  • the detection molecule comprises a detectable moiety. Examples of detectable moieties include, but are not limited to a fluorescent moiety, a tag, a radiolabel, a dye and a chemiluminescent moiety.
  • the detectable moiety is a fluorescent moiety. Examples of fluorescent moieties include, but are not limited to GFP, REP, YEP, APC, CY5, CY7, and Pacific Blue. Secondary detection molecules are well known in the art and any such molecule that will detect an antibody or antigen binding fragment thereof of the invention may be used.
  • nucleic acid molecule encoding an antibody or antigen binding fragment of the invention.
  • nucleic acid molecule encoding a heavy chain of an antibody or antigen binding fragment of the invention and a nucleic acid molecule encoding a light chain of an antibody or antigen binding fragment of the invention.
  • the nucleic acid molecule is configured for expression. In some embodiments, expression is expression in a cell. In some embodiments, expression is expression in an in vitro expression system.
  • expression refers to the biosynthesis of a coding region, including the transcription and/or translation of the coding region.
  • expression of a nucleic acid molecule may refer to transcription of the nucleic acid fragment (e.g., transcription resulting in mRNA or other functional RNA) and/or translation of RNA into a precursor or mature protein (polypeptide).
  • the coding region encodes the antibody or antigen binding fragment of the invention.
  • the coding region encodes the heavy chain. In some embodiments, the coding region encodes the light chain.
  • coding region within a cell is well known to one skilled in the art. It can be carried out by, among many methods, transfection, viral infection, or direct alteration of the cell’s genome.
  • the coding region is in an expression vector pSaoiiud or viral vector.
  • the vector is an expression vector.
  • a vector nucleic acid sequence generally contains at least an origin of replication for propagation in a cell and optionally additional elements, such as a heterologous polynucleotide sequence, expression control element (e.g., a promoter, enhancer), selectable marker (e.g., antibiotic resistance), poly-Adenine sequence.
  • additional elements such as a heterologous polynucleotide sequence, expression control element (e.g., a promoter, enhancer), selectable marker (e.g., antibiotic resistance), poly-Adenine sequence.
  • the vector may be a DNA plasmid delivered via non-viral methods or via viral methods.
  • the viral vector may be a retroviral vector, a herpesviral vector, an adenoviral vector, an adeno-associated viral vector or a poxviral vector.
  • the promoters may be active in mammalian cells.
  • the promoters may be a viral promoter.
  • the coding region is operably linked to a regulatory element.
  • the coding region is operably linked to a promoter.
  • the regulatory element is a protein.
  • the regulatory element is an enhancer.
  • operably linked is intended to mean that the nucleotide sequence of interest is linked to the regulatory element or elements in a manner that allows for expression of the nucleotide sequence (e.g., in an in vitro transcription/translation system or in a host cell when the vector is introduced into the host cell).
  • the vector is introduced into the cell by standard methods including electroporation (e.g., as described in From et ah, Proc. Natl. Acad. Sci. USA 82, 5824 (1985)), Heat shock, infection by viral vectors, high velocity ballistic penetration by small particles with the nucleic acid either within the matrix of small beads or particles, or on the surface (Klein et al., Nature 3T1. 70-73 (1987)), and/or the like.
  • promoter refers to a group of transcriptional control modules that are clustered around the initiation site for an RNA polymerase i.e., RNA polymerase II. Promoters are composed of discrete functional modules, each consisting of approximately 7-20 bp of DNA, and containing one or more recognition sites for transcriptional activator or repressor proteins.
  • nucleic acid sequences are transcribed by RNA polymerase II (RNAP II and Pol II).
  • RNAP II is an enzyme found in eukaryotic cells. It catalyzes the transcription of DNA to synthesize precursors of mRNA and most snRNA and microRNA.
  • mammalian expression vectors include, but are not limited to, pcDNA3, pcDNA3.1 ( ⁇ ), pGL3, pZeoSV2( ⁇ ), pSecTag2, pDisplay, pEF/myc/cyto, ⁇ i ⁇ P ⁇ yto, pCR3.1, pSinRepS, DH26S, DHBB, pNMTl, pNAPfJ/ ⁇ 9?
  • v 2 /P ⁇ 4 v 8 vhich are available from Invitrogen, pCI which is available from Promega, pMbac, pPbac, pBK- RSV and pBK-CMV which are available from Strategene, pTRES which is available from Clontech, and their derivatives.
  • expression vectors containing regulatory elements from eukaryotic viruses such as retroviruses are used by the present invention.
  • SV40 vectors include pSVT7 and pMT2.
  • vectors derived from bovine papilloma virus include pBV-lMTHA, and vectors derived from Epstein Bar virus include pHEBO, and p2O5.
  • exemplary vectors include pMSG, pAV009/A+, pMTO10/A+, pMAMneo- 5, baculovirus pDSVE, and any other vector allowing expression of proteins under the direction of the SV-40 early promoter, SV-40 later promoter, metallo thionein promoter, murine mammary tumor virus promoter, Rous sarcoma virus promoter, polyhedrin promoter, or other promoters shown effective for expression in eukaryotic cells.
  • recombinant viral vectors which offer advantages such as lateral infection and targeting specificity, are used for in vivo expression.
  • lateral infection is inherent in the life cycle of, for example, retrovirus and is the process by which a single infected cell produces many progeny virions that bud off and infect neighboring cells.
  • the result is that a large area becomes rapidly infected, most of which was not initially infected by the original viral particles.
  • viral vectors are produced that are unable to spread laterally. In one embodiment, this characteristic can be useful if the desired purpose is to introduce a specified gene into only a localized number of targeted cells.
  • viral promoters such as the 35S RNA and 19S RNA promoters of CaMV [Brisson et al., Nature 310:511-514 (1984)], or the coat protein promoter to TMV [Takamatsu et al., EMBO J. 3:17-311 (1987)] are used.
  • plant promoters are used such as, for example, the small subunit of RUBISCO [Coruzzi et al., EMBO J.
  • constructs are introduced into plant cells using Ti plasmid, Ri plasmid, plant viral vectors, direct DNA transformation, microinjection, electroporation and other techniques well known to the skilled artisan. See, for example, Weissbach & Weissbach [Methods for Plant Molecular Biology, Academic Press, NY, Section VIII, pp 421-463 (1988)].
  • Other expression systems such as insects and mammalian host cell systems, which are well known in the art, can also be used by the present invention.
  • the expression construct of the present invention can also include sequences engineered to optimize stability, production, purification, yield or activity of the expressed polypeptide.
  • a length of about 1000 nanometers (nm) refers to a length of 1000 nm+- 100 nm.
  • Affinity maturation To improve binding affinity, the parental antibody was affinity matured using phage display. Heavy and/or light chain CDRs of variable domain regions were semi-randomized using oligonucleotide mutagenesis. Selections were performed using separate heavy and light chain phage libraries and decreasing concentrations of biotinylated His-tagged HVEM target to select the highest affinity binders from each library. Following four rounds of selections individual clones were screened as scFv supernatants in a binding ELISA to identify lead candidates with signals greater than the parental scFv expressed in the same assay. Identified hits were converted into IgG and cloned into mammalian expression vectors.
  • IgGs were captured at a flow rate of 10 ⁇ 2 an immobilisation level (RL) of -50RU.
  • Single cycle kinetics data was obtained using His-tagged HVEM (Aero Biosystems, Newark, USA) as the analyte at a flow rate of 40 pl/min.
  • His-tagged HVEM Anaero Biosystems, Newark, USA
  • a two-fold dilution range from 6.125 nM to 100 nM His-tagged antigen without regeneration between each concentration was used.
  • Multi-Cycle Kinetics Multicycle kinetic analysis was performed on purified antibodies. Kinetic experiments were performed at 25°C on a Biacore 8K. HBS-P+ 0.1% BSA (Cytiva, Marlborough, USA) was used as running buffer. Purified antibodies were diluted to 1.0 pg/mL in mnning buffer and at the start of each cycle, loaded onto Fc2, Fc3 and Fc4 of a Protein A sensor chip (Cytiva, Marlborough, USA). Antibodies were captured at a flow rate of 10 pl/min to give an immobilisation level (RL) of ⁇ 100 RU. The surface was then allowed to stabilise.
  • RL immobilisation level
  • Multi-cycle kinetic data was obtained using His-tagged human HVEM as the analyte injected at a flow rate of 50 pl/min.
  • a eight point, two-fold dilution range from 0.78 nM to 100 nM of antigen were prepared in running buffer.
  • the association phases were monitored for 180 seconds and the dissociation phase was measured for 300 seconds.
  • Regeneration of the sensor chip surface was conducted between cycles using two injections of 10 mM Glycine-HCl, pH 1.5.
  • Cytotoxic assay Nuclear RFP-stained melanoma cells were seeded for overnight incubation to allow them to attach. Then, melanoma cells were pre-incubated with 20 pg/ml of the parental or affinity matured mAbs of the invention or h!gG4 isotype control antibody (Invivogen, France) and TILs were pre-incubated with or without 20 pg/ml of anti-PDl mAb (Nivolumab, BMS) or hIgG4 isotype control antibody (Invivogen, France).
  • Pre-incubated TILs or medium only with anti-PDl or hIgG4 isotype control mAb were added to the melanoma cells together with CellEvent Caspase-3/7 Green Detection Reagent (Invitrogen, USA). Plates were placed in the Incucyte ZOOM system (ESSEN Bioscience, USA) and scanned every hour. Caspase 3/7 positive events, reflecting specific killing of melanoma, were counted.
  • T cell activation assay by Incucyte ZOOM system Nuclear RFP-stained melanoma cells were seeded for overnight incubation to allow them to attach. After overnight incubation, melanoma cells were incubated for one-hour at 37°C with 20 pg/ml mAh of the invention, parental mAh or h!gG4 isotype control. Then, TILs or medium were added to the melanoma cells together with conjugated CD 107a antibody. Plates were placed in the Incucyte ZOOM system and scanned every hour. maturation of anti-HVEM antibody PCT/IL2022/050348
  • the lead antibody of WO2020222235 consisted of a heavy chain as provided in SEQ ID NO: 9 and a light chain as provided in SEQ ID NO: 10.
  • the CDRs were in a human backbone that included an IgG4 backbone bearing the S228P mutation.
  • This antibody bound human HVEM, as well as mouse and cynomolgus HVEM and could bind the protein in solution and on the cell surface.
  • the antibody inhibited binding of BTLA to HVEM but did not inhibit binding of LIGHT to HVEM. Further, the antibody itself had a low -level activating effect, inducing signaling through HVEM by its binding. Most importantly the antibody augmented immune cell cytotoxicity toward cancer and was able to enhance non- autologous immune cell cytotoxicity thus enhancing standard adoptive immune cell therapy.
  • Affinity maturation was performed in the VH and VL CDR regions.
  • the clones produced were sequenced and assayed for their KD to HVEM extracellular domain peptide.
  • the Fold-improvements over the KD observed with the parental antibody are presented in Table 2.
  • the affinity matured clones showed enhanced binding as compared to the parental antibody, indicated their superiority.
  • the various mutant CDRs are combined to make antibodies with combined improved CDRs. The binding affinity of these combination antibodies are assessed.
  • the H4 antibody was found to have the greatest improvement as compared to the parental antibody (fold increase of 9.57).
  • this CDR2 contains a N-linked glycosylation site (NXS/T glycosylation site) that was found to be glycosylated in the final antibody (Fig. 1).
  • NXS/T glycosylation site N-linked glycosylation site
  • Fig. 1 Glycosylation creates variability in batch production of the antibody and can affect function. Therefore, several variants were generated specifically in which the asparagine at position 55 or threonine at position 57 was mutated to a different amino acid. As expected, these variants of H4 were no longer glycosylated (Fig. 1).
  • two of these antibodies T57A and T57N had even better binding (fold increase of 20.66 and 23.51 as compared to parental) than the unmodified H4.
  • HVEM human recombinant HVEM
  • H4 antibody is indeed superior to the parental antibody, and both the T57A and T57N variants are even better binders than the H4.
  • a single-cycle kinetic Biacore assay was also performed with the
  • H4 N55G, H4 N55S, H4 N55D, H4 N55Q, H4 N55E, and H4 T57E antibodies (Fig. 3B).
  • CHO-K1 cells were made to overexpress human HVEM (hHVEM).
  • the cells were then incubated for an hour on ice with 20 pg/ml of the antibodies and then stained with anti-human IgG Fc biotin and anti-biotin FITC.
  • Expression was analyzed by flow cytometry. All four antibodies were able to bind hHVEM and importantly detected surface expression (Fig. 3C). It was hypothesized that such a high concentration (20 pg/ml) was masking differences in binding between the parental antibody and the affinity matured antibodies and so binding was compared between the parental antibody and the T57A antibody at various antibody concentrations.
  • the T57A antibody was indeed found to bind more strongly and at lower than the parental indicating that it is a superior bind ⁇ Pu ⁇ u ⁇ uZ ⁇ t ⁇ EM
  • HVEM-BTLA T cell inhibiting axis promotes cancer cell killing by T cells.
  • RFP positive melanoma cells HVEM positive
  • TILs autologous tumorinfiltrating lymphocytes
  • the parental antibody After nine hours of coculture the parental antibody had produced a 9% increase in specific killing events in the cancer cells as compared to the isotype control (Fig. 5A). While the H4-T57N variant showed similar killing to the parental (9% increase), the T57A and T57G antibodies both showed a significantly greater number of killing events (19% increase, p ⁇ 0.01) indicating a superior cytotoxic effect (Fig. 5A).
  • T57A variant lacks the glycosylation site, was found to bind hHVEM more than twice as strongly as H4 (also superior binding as compared to T57G) and was found to induce cell killing at an increased rate as compared to parental (also superior killing as compared to T57N) this variant antibody was selected for all further testing.
  • the parental antibody can enhance anti-PD-1 mediated T cell activation and thereby cancer cell killing. Therefore, the above-described killing assay was also performed in the presence of anti-PD-1 antibody.
  • the H4 T57A antibody was found to be superior to the parental antibody, increasing specific cell killing by 64% as compared to isotype control as compared to only a 44% increase for the parental (Fig. 5B). Specific killing in the presence of anti-PD-1 antibody is also measured for the other affinity matured antibodies and similar superiority is observed.
  • the activation marker CD107a was measured in these cells when cocultured with melanoma cells in the presence of isotype control, the parental anti-HVEM antibody or the H4 T57A variant antibody. Both anti-HVEM antibodies produced a greater number of CD107a positive cells as compared to the isotype control, but the affinity matured antibody produced a significantly greater number of activated cells (Fig. 6A). When a second melanoma cell line was tested, the same trend, but with an even greater difference between the variant antibody and the parental, was observed (Fig. 6B). Activation as assessed by CD 107a levels is also measured in the presence of the other affinity matured antibodies and similar superiority is observed.
  • an ex vivo killing assay was also performed with primary cancer cells in a similar manner as was performed on the cell lines.
  • Freshly isolated cells from an ovary cancer were cocultured with autologous PBMCs in the presence of isotype control, anti-PDl antibody, the parental mAb or the H4 T57A variant antibody.
  • Specific cancer cell killing was monitored over 55 hours.
  • Anti-PD-1 antibody produced a very minor improvement as compared to the isotype control (9% improvement at 55 hours), whereas the parental 'Y9i?i93u ⁇ °p?8uuced a 48% improvement and the H4 T57A antibE£Ppl?H?u6Q5P 3 u 8 68% improvement (Fig. 7A).
  • murine cancer cells expressing human HVEM are implanted in a transgenic immune competent mouse expressing human BTLA and allowed to grow to form tumors.
  • An affinity matured antibody, an anti-PD-1 antibody, combinations thereof or an IgG isotype control are administered. Tumor growth inhibition is measured.
  • the new antibodies are found superior to the parental and at least comparable to PD-1 alone at inhibiting cancer growth. Further, the new antibodies produced an enhanced synergistic effect with anti-PD-1.
  • H4 antibody and its derivative were found to be superior binders to recombinant HVEM and bound HVEM on the cell surface it was hypothesized that the affinity matured antibodies could be used for clinical evaluation as well as laboratory staining/detection of HVEM.
  • a formalin fixed paraffin embedded (FFPE) cell block of CHO cells overexpressing hHVEM was sliced and mounted on a slide for immunofluorescent detection.
  • the parental antibody and the H4 T57A antibody were used along with a Cy3 (red signal) secondary antibody.
  • Cy3 red signal

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IL307407A IL307407A (en) 2021-04-01 2022-03-31 Improved anti-HVEM antibodies and their use
CA3213956A CA3213956A1 (en) 2021-04-01 2022-03-31 Enhanced anti-hvem antibodies and use thereof
CN202280039545.6A CN117412990A (zh) 2021-04-01 2022-03-31 增强的抗hvem抗体及其应用
KR1020237037195A KR20240047954A (ko) 2021-04-01 2022-03-31 향상된 항-hvem 항체 및 이의 용도
EP22779311.4A EP4320162A4 (en) 2021-04-01 2022-03-31 IMPROVED ANTI-HVEM ANTIBODIES AND THEIR USE
JP2023561005A JP2024514255A (ja) 2021-04-01 2022-03-31 増強された抗ｈｖｅｍ抗体及びその使用
AU2022251320A AU2022251320A1 (en) 2021-04-01 2022-03-31 Enhanced anti-hvem antibodies and use thereof
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WO2014184360A1 (en) * 2013-05-17 2014-11-20 INSERM (Institut National de la Santé et de la Recherche Médicale) Antagonist of the btla/hvem interaction for use in therapy
WO2018129332A1 (en) * 2017-01-06 2018-07-12 Iovance Biotherapeutics, Inc. Expansion of tumor infiltrating lymphocytes (tils) with tumor necrosis factor receptor superfamily (tnfrsf) agonists and therapeutic combinations of tils and tnfrsf agonists
WO2020222235A1 (en) * 2019-04-29 2020-11-05 4C Biomed Inc. Anti-hvem antibodies and use thereof

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EP3511343A1 (en) * 2012-05-04 2019-07-17 Dana Farber Cancer Institute, Inc. Affinity matured anti-ccr4 humanized monoclonal antibodies and methods of use
CN105061597B (zh) * 2015-06-09 2016-04-27 北京东方百泰生物科技有限公司 一种抗pd-1的单克隆抗体及其获得方法
CN113194966A (zh) * 2018-10-03 2021-07-30 柰裴斯生命科学公司 抗cd79抗体及其应用
WO2022074648A1 (en) * 2020-10-05 2022-04-14 4C Biomed Limited Marker for response to pd-1/pd-l1 immunotherapy

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WO2014184360A1 (en) * 2013-05-17 2014-11-20 INSERM (Institut National de la Santé et de la Recherche Médicale) Antagonist of the btla/hvem interaction for use in therapy
WO2018129332A1 (en) * 2017-01-06 2018-07-12 Iovance Biotherapeutics, Inc. Expansion of tumor infiltrating lymphocytes (tils) with tumor necrosis factor receptor superfamily (tnfrsf) agonists and therapeutic combinations of tils and tnfrsf agonists
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