WO2019075378A1 - B-MATURATION ANTIGEN BINDING PROTEINS - Google Patents

B-MATURATION ANTIGEN BINDING PROTEINS Download PDF

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Publication number
WO2019075378A1
WO2019075378A1 PCT/US2018/055682 US2018055682W WO2019075378A1 WO 2019075378 A1 WO2019075378 A1 WO 2019075378A1 US 2018055682 W US2018055682 W US 2018055682W WO 2019075378 A1 WO2019075378 A1 WO 2019075378A1
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Prior art keywords
seq
amino acid
bcma
acid sequence
set forth
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English (en)
French (fr)
Inventor
Holger Wesche
Bryan D. LEMON
Richard J. Austin
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Harpoon Therapeutics Inc
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Harpoon Therapeutics Inc
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Priority to IL315737A priority Critical patent/IL315737A/en
Priority to NZ763714A priority patent/NZ763714B2/en
Priority to AU2018346955A priority patent/AU2018346955B2/en
Priority to KR1020227026663A priority patent/KR102923236B1/ko
Priority to IL287045A priority patent/IL287045B2/en
Priority to JP2020520033A priority patent/JP7066837B2/ja
Priority to CN201880080944.0A priority patent/CN111465612B/zh
Priority to MX2020003856A priority patent/MX2020003856A/es
Priority to EP18866074.0A priority patent/EP3694871A4/en
Priority to CR20200195A priority patent/CR20200195A/es
Priority to BR112020007249-4A priority patent/BR112020007249B1/pt
Priority to MYPI2020001856A priority patent/MY205058A/en
Priority to CN202410763158.8A priority patent/CN118667018A/zh
Priority to EA202090739A priority patent/EA202090739A1/ru
Application filed by Harpoon Therapeutics Inc filed Critical Harpoon Therapeutics Inc
Priority to CA3078799A priority patent/CA3078799A1/en
Priority to PE2020000393A priority patent/PE20200781A1/es
Priority to SG11202003341UA priority patent/SG11202003341UA/en
Priority to KR1020207013756A priority patent/KR102429747B1/ko
Publication of WO2019075378A1 publication Critical patent/WO2019075378A1/en
Priority to IL273886A priority patent/IL273886B/en
Priority to PH12020550247A priority patent/PH12020550247A1/en
Anticipated expiration legal-status Critical
Priority to ZA2020/02089A priority patent/ZA202002089B/en
Priority to CONC2020/0005651A priority patent/CO2020005651A2/es
Priority to DO2020000075A priority patent/DOP2020000075A/es
Priority to MX2024014843A priority patent/MX2024014843A/es
Priority to JP2022071736A priority patent/JP7348349B2/ja
Priority to JP2023144740A priority patent/JP7780481B2/ja
Priority to AU2024266817A priority patent/AU2024266817A1/en
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
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    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6849—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • 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
    • 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
    • C07K16/2809—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 the T-cell receptor (TcR)-CD3 complex
    • 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
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/22—Immunoglobulins specific features characterized by taxonomic origin from camelids, e.g. camel, llama or dromedary
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/33—Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/52—Constant or Fc region; Isotype
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—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
    • C07K2317/50—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
    • C07K2317/569—Single domain, e.g. dAb, sdAb, VHH, VNAR or nanobody®
    • 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
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
    • C07K2317/732—Antibody-dependent cellular cytotoxicity [ADCC]
    • 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
    • C07K2317/734—Complement-dependent cytotoxicity [CDC]
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    • C07—ORGANIC CHEMISTRY
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    • 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
    • C—CHEMISTRY; METALLURGY
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    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/94—Stability, e.g. half-life, pH, temperature or enzyme-resistance

Definitions

  • Cancer is the second leading cause of human death next to coronary disease. Worldwide, millions of people die from cancer every year. In the United States alone, cancer causes the death of well over a half-million people each year, with some 1.4 million new cases diagnosed per year. While deaths from heart disease have been declining significantly, those resulting from cancer generally are on the rise. In the early part of the next century, cancer is predicted to become the leading cause of death.
  • Cancer is a complex disease characterized by genetic mutations that lead to uncontrolled cell growth. Cancerous cells are present in all organisms and, under normal circumstances, their excessive growth is tightly regulated by various physiological factors.
  • the present disclosure provides single domain B cell maturation antigen (BCMA) binding proteins which can be used for diagnosing and treating indications correlated to the expression of BCMA.
  • BCMA single domain B cell maturation antigen
  • a single domain B cell maturation agent (BCMA) binding protein comprising complementarity determining regions CDR1, CDR2, and CDR3, wherein (a) the amino acid sequence of CDR1 is as set forth in X 1 X 2 X 3 X 4 X 5 X 6 X 7 PX 8 G (SEQ ID NO: 1), wherein Xi is T or S; X 2 is N, D, or S; X 3 is I, D, Q, H, V, or E; X 4 is F, S, E, A, T, M, V, I, D, Q, P, R, or G; X 5 is S, M, R, or N; X 6 is I, K, S, T, R, E, D, N, V, H, L, A, Q, or G; X 7 is S, T, Y, R, or N; and X 8 is M, G, or Y; (b) the amino acid sequence of CDR2 is as set forth in X 1 X 2 X 3
  • AIX 9 GX 10 X 11 TX 12 YADSVK (SEQ ID NO: 2), wherein X 9 is H, N, or S; X 10 is F, G, K, R, P, D, Q, H, E, N, T, S, A, I, L, or V; 3 ⁇ 4i is S, Q, E, T, K, or D; and X i2 is L, V, I, F, Y, or W; and (c) the amino acid sequence of CDR3 is as set forth in VPWGXi 3 YHPXi 4 Xi 5 VXi 6 (SEQ ID NO: 3), wherein X 13 is D, I, T, K, R, A, E, S, or Y; X 14 is R, G, L, K, T, Q, S, or N; X i5 is N, K, E, V, R, M, or D; and X i6 is Y, A, V, K, H, L, M, T, R, Q
  • the CDR1 does not comprise an amino acid sequence of SEQ ID NO: 473.
  • the CDR2 does not comprise an amino acid sequence of SEQ ID NO: 474.
  • the CDR3 does not comprise an amino acid sequence of SEQ ID NO: 475.
  • the CDR1 and CDR2 do not comprise amino acid sequences of SEQ ID NO: 473 and 474, respectively.
  • the CDR1 and CDR3 do not comprise amino acid sequences of SEQ ID NO: 473 and 475, respectively.
  • the CDR2 and CDR3 do not comprise amino acid sequences of SEQ ID NO: 474 and 475, respectively.
  • the CDR1, CDR2 and CDR3 do not comprise amino acid sequences of SEQ ID NO: 473, 474 and 475, respectively.
  • a single domain BCMA binding protein wherein said protein comprises the following formula: fl-rl-f2-r2-f3-r3-f4, wherein, rl is SEQ ID NO: 1; r2 is SEQ ID NO: 2; and r3 is SEQ ID NO: 3; and wherein fl, f2, f3 and f4 are framework residues selected so that said protein is from about eighty percent (80%) to about 99% identical to the amino acid sequence set forth in SEQ ID NO: 346 or 472.
  • a single domain BCMA binding protein wherein said protein comprises the following formula: fl-rl-f2-r2-f3-r3- f4, wherein, rl is SEQ ID NO: 1; r2 is SEQ ID NO: 2; and r3 is SEQ ID NO: 3; and wherein fl, f2, f3 and f4 are framework residues selected so that said protein is from about 80% to about 90% identical to the amino acid sequence set forth in SEQ ID NO: 346 or 472.
  • the amino acid sequence of the single domain BCMA binding protein does not comprise SEQ ID NO: 472.
  • rl comprises an amino acid sequence set forth as any one of SEQ ID NOS: 4-117.
  • r2 comprises an amino acid sequence set forth as any one of SEQ ID NOS: 118-231.
  • r3 comprises an amino acid sequence set forth as any one of SEQ ID NOS: 232-345.
  • the protein comprises an amino sequence set forth as any one of SEQ ID NOS: 346-460.
  • fl in a single domain BCMA binding protein, can comprise SEQ ID NO: 461 or 462.
  • f2 in a single domain BCMA binding protein, can comprise SEQ ID NO: 463.
  • f3 in a single domain BCMA binding protein, can comprise SEQ ID NO: 464 or 465.
  • f4 can comprise SEQ ID NO: 466 or 467.
  • rl comprises SEQ ID NO: 76, 114, 115, 116 or 117. In one non-limiting example, rl comprises SEQ ID NO: 76.
  • rl comprises SEQ ID NO: 76
  • r2 is SEQ ID NO: 190
  • r3 is SEQ ID NO: 304.
  • rl comprises SEQ ID NO: 114
  • r2 comprises SEQ ID NO:
  • 228 and r3 comprises SEQ ID NO: 342.
  • rl comprises SEQ ID NO: 115
  • r2 comprises SEQ ID NO:
  • 229 and r3 comprises SEQ ID NO: 343.
  • rl comprises SEQ ID NO: 117
  • r2 comprises SEQ ID NO: 231
  • r3 comprises SEQ ID NO: 345.
  • rl comprises SEQ ID NO: 116
  • r2 comprises SEQ ID NO:
  • 230 and r3 comprises SEQ ID NO: 344.
  • a domain BCMA binding protein can have an elimination half-time of at least 12 hours, at least 20 hours, at least 25 hours, at least 30 hours, at least 35 hours, at least 40 hours, at least 45 hours, at least 50 hours, at least 100 hours or more.
  • the single domain BCMA binding protein further comprises a Fc domain.
  • the single domain BCMA binding protein further comprises an anti-cancer agent.
  • Such a single domain BCMA binding protein can be human, humanized, affinity matured, or a combination thereof.
  • a method for the treatment or amelioration of a B cell lineage cancer in a subject in need thereof comprising administering to the subject a single domain BCMA binding protein described herein.
  • a multispecific binding protein comprising the single domain BCMA binding protein described herein.
  • a method for the treatment or amelioration of a B cell lineage cancer in a subject in need thereof comprising administering to the subject a multispecific binding protein described herein.
  • the B cell lineage cancer can be a primary cancer or a metastatic cancer.
  • a B cell lineage cancer to be treated with the methods described herein can be a multiple myeloma, a leukemia, a lymphoma.
  • Fig. 1 illustrates the effect of exemplary BCMA targeting molecules (01H08, 01F07, 02F02, and BH253), containing an anti-BCMA binding protein according to the present disclosure in killing of EJM cells that express BCMA compared to a negative control.
  • Fig. 2 is an image of an SDS-PAGE of representative purified BCMA trispecific molecules.
  • Lane 1 01F07-M34Y TriTAC non-reduced; Lane 2:01F07-M34G-TriTAC non- reduced; Lane 3 : 02B05 TriTAC non-reduced; Lane 4: 02G02-M34Y TriTAC non-reduced; Lane 5: 02G02 M34G TriTAC non-reduced; Lane 6: Broad Range SDS-PAGE Standard (Bio- Rad #1610317); Lane 7: 01F07-M34Y TriTAC non-reduced; Lane 8:01F07-M34G-TriTAC non-reduced; Lane 9: 02B05 TriTAC non-reduced; Lane 10: 02G02-M34Y TriTAC non- reduced; Lane 11 : 02G02 M34G TriTAC non-reduced; and Lane 12: Broad Range SDS-PAGE Standard (Bio-Rad #1610317).
  • Figs. 3A-3I illustrate the effect of exemplary BCMA trispecific targeting molecules containing an anti-BCMA binding protein according to the present disclosure in killing of Jekol (Figs. 3A-3C), MOLP-8 (Figs. 3D-3F) or OPM-2 (Figs. 3G-3I) cells that express BCMA compared to a negative control.
  • Figs. 4A-4D illustrate binding of an exemplary BCMA trispecific targeting protein containing a BCMA binding protein of this disclosure (02B05) to purified T Cells from four different human donors, donor 02 (Fig. 4A), donor 35 (Fig. 4B), donor 81 (Fig. 4C), donor 86 (Fig. 4D)
  • Figs. 5A-5F illustrate binding of an exemplary BCMA trispecific targeting protein (02B05) to cells expressing BCMA, NCI-H929 (Fig. 5A), EJM (Fig. 5B), OPM2 (Fig. 5D), RPMI8226 (Fig. 5E); or cell lines lacking expression of BCMA, NCI-H510A (Fig. 5C), and DMS-153 (Fig. 5F).
  • Fig. 6 illustrates the results of a TDCC assay using an exemplary BCMA trispecific targeting protein (02B05) and BCMA expressing EJM cells, in presence or absence of human serum albumin (HSA).
  • HSA human serum albumin
  • Fig. 7 illustrates the results of a TDCC assay using an exemplary BCMA trispecific targeting protein (02B05) and BCMA expressing EJM cells, using varying effector cells to target cells ratio.
  • Fig. 8 illustrates the results of a TDCC assay using an exemplary BCMA trispecific targeting protein (02B05) and BCMA expressing OPM2 cells, using varying effector cells to target cells ratio.
  • Fig. 9 illustrates the results of a TDCC assay using an exemplary BCMA trispecific targeting protein (02B05) and BCMA expressing NCI-H929 cells, using varying time-points and a 1 : 1 effector cells to target cells ratio.
  • Fig. 10 illustrates the results of a TDCC assay using an exemplary BCMA trispecific targeting protein (02B05), BCMA expressing EJM cells, and T cells from four different donors, in presence of human serum albumin (HSA).
  • HSA human serum albumin
  • Fig. 11 illustrates the results of a TDCC assay using an exemplary BCMA trispecific targeting protein (02B05), BCMA expressing NCI-H929 cells, and T cells from four different donors, in presence of human serum albumin (HSA).
  • HSA human serum albumin
  • Fig. 12 illustrates the results of a TDCC assay using an exemplary BCMA trispecific targeting protein (02B05), BCMA expressing OPM2 cells, and T cells from four different donors, in presence of human serum albumin (HSA).
  • HSA human serum albumin
  • Fig. 13 illustrates the results of a TDCC assay using an exemplary BCMA trispecific targeting protein (02B05), BCMA expressing RPMI8226 cells, and T cells from four different donors, in presence of human serum albumin (HSA).
  • HSA human serum albumin
  • Fig. 14 illustrates the results of a TDCC assay using an exemplary BCMA trispecific targeting protein (02B05), BCMA non-expressing OVCAR8 cells, and T cells from four different donors, in presence of human serum albumin (HSA).
  • HSA human serum albumin
  • Fig. 15 illustrates the results of a TDCC assay using an exemplary BCMA trispecific targeting protein (02B05), BCMA non-expressing NCI-H510A cells, and T cells from four different donors, in presence of human serum albumin (HSA).
  • HSA human serum albumin
  • Fig. 16 illustrates the results of a TDCC assay using an exemplary BCMA trispecific targeting protein (02B05), BCMA expressing NCI-H929 cells, and peripheral blood
  • PBMC mononuclear cells from two different cynomolgus, in presence of human serum albumin (HSA).
  • HSA human serum albumin
  • FIG. 17 illustrates the results of a TDCC assay using an exemplary BCMA trispecific targeting protein containing a BCMA binding protein of this disclosure (02B05), BCMA expressing RPMI8226 cells, and peripheral blood mononuclear cells (PBMC) from two different cynomolgus donors, in presence of human serum albumin (HSA).
  • PBMC peripheral blood mononuclear cells
  • Fig. 18 illustrates the expression level of T cell activation biomarker CD69, following a TDCC assay using an exemplary BCMA targeting trispecific protein containing a BCMA binding protein of this disclosure (02B05) and BCMA expressing cells EJM.
  • Fig. 19 illustrates the expression level of T cell activation biomarker CD25, following TDCC assay using an exemplary BCMA targeting trispecific protein containing a BCMA binding protein of this disclosure (02B05) and BCMA expressing cells EJM.
  • Fig. 20 illustrates the expression level of T cell activation biomarker CD69, following TDCC assay using an exemplary BCMA targeting trispecific protein containing a BCMA binding protein of this disclosure (02B05) and BCMA expressing cells OPM2.
  • Fig. 21 illustrates the expression level of T cell activation biomarker CD25, following TDCC assay using an exemplary BCMA targeting trispecific protein containing a BCMA binding protein of this disclosure (02B05) and BCMA expressing cells OPM2.
  • Fig. 22 illustrates the expression level of T cell activation biomarker CD69, following TDCC assay using an exemplary BCMA targeting trispecific protein containing a BCMA binding protein of this disclosure (02B05) and BCMA expressing cells RPMI8226.
  • Fig. 23 illustrates the expression level of T cell activation biomarker CD25, following TDCC assay using an exemplary BCMA targeting trispecific protein containing a BCMA binding protein of this disclosure (02B05) and BCMA expressing cells RPMI8226.
  • Fig. 24 illustrates the expression level of T cell activation biomarker CD69, following TDCC assay using an exemplary BCMA targeting trispecific protein containing a BCMA binding protein of this disclosure (02B05) and BCMA non-expressing cells OVCAR8.
  • Fig. 25 illustrates the expression level of T cell activation biomarker CD25, following TDCC assay using an exemplary BCMA targeting trispecific protein containing a BCMA binding protein of this disclosure (02B05) and BCMA non-expressing cells OVCAR8.
  • Fig. 26 illustrates the expression level of T cell activation biomarker CD69, following TDCC assay using an exemplary BCMA targeting trispecific protein containing a BCMA binding protein of this disclosure (02B05) and BCMA non-expressing cells NCI-H510A.
  • Fig. 27 illustrates the expression level of T cell activation biomarker CD25, following TDCC assay using an exemplary BCMA targeting trispecific protein containing a BCMA binding protein of this disclosure (02B05) and BCMA non-expressing cells NCI-H510A.
  • Fig. 28 illustrates the expression level a cytokine, TNF-a, in co-cultures of T cells and BCMA expressing target cells (EJM cells) treated with increasing concentrations of an exemplary BCMA targeting trispecific protein containing a BCMA binding protein of this disclosure (02B05) or with a negative control GFP trispecific protein.
  • Fig. 29 illustrates tumor growth reduction in RPMI8226 xenograft model, treated with exemplary BCMA targeting trispecific protein containing a BCMA binding protein of this disclosure (02B05), at varying concentrations, or with a control vehicle.
  • Fig. 30 illustrates tumor growth reduction in Jekol xenograft model, treated with an exemplary BCMA targeting trispecific protein containing a BCMA binding protein of this disclosure (02B05), at varying concentrations, or with a control vehicle.
  • FIG. 31 illustrates concentration of BCMA targeting trispecific protein in serum samples from cynomolgus monkeys dosed with varying concentrations of an exemplary BCMA targeting trispecific protein containing a BCMA binding protein of this disclosure (02B05).
  • Fig. 32 the results of a TDCC assay using BCMA trispecific targeting protein obtained from serum samples of cynomolgus monkeys dosed with varying concentrations of an exemplary BCMA targeting trispecific protein containing a BCMA binding protein of this disclosure (02B05), BCMA expressing EJM cells, and purified human T cells, in presence of serum from cynomolgus monkeys that were not exposed to a BCMA targeting trispecific protein.
  • the term “about” or “approximately” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, e.g., the limitations of the measurement system. For example, “about” can mean within 1 or more than 1 standard deviation, per the practice in the given value. Where particular values are described in the application and claims, unless otherwise stated the term “about” should be assumed to mean an acceptable error range for the particular value.
  • the terms “individual,” “patient,” or “subject” are used interchangeably. None of the terms require or are limited to situation characterized by the supervision (e.g. constant or intermittent) of a health care worker (e.g. a doctor, a registered nurse, a nurse practitioner, a physician's assistant, an orderly, or a hospice worker).
  • an "antibody” typically refers to a Y-shaped tetrameric protein comprising two heavy (H) and two light (L) polypeptide chains held together by covalent disulfide bonds and non- covalent interactions.
  • Human light chains comprise a variable domain (VL) and a constant domain (CL) wherein the constant domain may be readily classified as kappa or lambda based on amino acid sequence and gene loci.
  • Each heavy chain comprises one variable domain (VH) and a constant region, which in the case of IgG, IgA, and IgD, comprises three domains termed CHI, CH2, and CH3 (IgM and IgE have a fourth domain, CH4).
  • IgG, IgA, and IgD classes the CHI and CH2 domains are separated by a flexible hinge region, which is a proline and cysteine rich segment of variable length (generally from about 10 to about 60 amino acids in IgG).
  • the variable domains in both the light and heavy chains are joined to the constant domains by a "J" region of about 12 or more amino acids and the heavy chain also has a "D" region of about 10 additional amino acids.
  • Each class of antibody further comprises inter-chain and intra- chain disulfide bonds formed by paired cysteine residues.
  • Inter-chain disulfide bonds are located on the surface of the immunoglobulin, are accessible to solvent and are usually relatively easily reduced. In the human IgGl isotype there are four inter-chain disulfide bonds, one from each heavy chain to the light chain and two between the heavy chains. The inter-chain disulfide bonds are not required for chain association.
  • cysteine rich IgGl hinge region of the heavy chain has generally been held to consist of three parts: an upper hinge, a core hinge, and a lower hinge.
  • the IgGl hinge region contain the cysteines in the heavy chain that comprise the inter-chain disulfide bonds (two heavy/heavy, two heavy/light), which provide structural flexibility that facilitates Fab movements.
  • the inter-chain disulfide bond between the light and heavy chain of IgGl are formed between C214 of the kappa or lambda light chain and C220 in the upper hinge region of the heavy chain.
  • the inter-chain disulfide bonds between the heavy chains are at positions C226 and C229 (all numbered per the EU index according to Kabat, et al., infra.)
  • antibody includes polyclonal antibodies, multiclonal antibodies, monoclonal antibodies, chimeric antibodies, humanized and primatized antibodies, CDR grafted antibodies, human antibodies, recombinantly produced antibodies, intrabodies, multispecific antibodies, bispecific antibodies, monovalent antibodies, multivalent antibodies, anti -idiotypic antibodies, synthetic antibodies, including muteins and variants thereof,
  • immunospecific antibody fragments such as Fd, Fab, F(ab')2, F(ab') fragments, single-chain
  • fragments e.g., ScFv and ScFvFc
  • disulfide-linked Fvs sdFv
  • a Fd fragment consisting of the VH and CHI domains linear antibodies, single domain antibodies such as sdAb (VH, VL, or
  • VHH domains such as a heavy chain only antibody devoid of a light chain
  • the term further comprises all classes of antibodies (i.e. IgA, IgD, IgE, IgG, and IgM) and all subclasses (i.e.,
  • Heavy-chain constant domains that correspond to the different classes of antibodies are typically denoted by the corresponding lower case Greek letter alpha, delta, epsilon, gamma, and mu, respectively.
  • vertebrate species can be assigned to one of two clearly distinct types, called kappa (kappa) and lambda (lambda ), based on the amino acid sequences of their constant domains.
  • Framework residues refer to variable domain residues other than the CDR or hypervariable region residues as herein defined.
  • a "human consensus framework” is a framework which represents the most commonly occurring amino acid residue in a selection of human immunoglobulin VL or VH framework sequences.
  • variable region refers to the fact that certain portions of the variable domains differ extensively in sequence among antibodies and are used in the binding and specificity of each particular antibody for its particular antigen. However, the variability is not evenly distributed throughout the variable domains of antibodies. It is concentrated in three segments called complementarity-determining regions (CDRs) or hypervariable regions both in the light-chain and the heavy-chain variable domains. The more highly conserved portions of variable domains are called the framework (FR).
  • CDRs complementarity-determining regions
  • FR framework
  • the variable domains of native heavy and light chains each comprise four FR regions, largely adopting a ⁇ -sheet configuration, connected by three CDRs, which form loops connecting, and in some cases forming part of, the Psheet structure.
  • the CDRs in each chain are held together in close proximity by the FR regions and, with the CDRs from the other chain, contribute to the formation of the antigen-binding site of antibodies (see, Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, National Institute of Health, Bethesda, Md. (1991)).
  • the constant domains are not involved directly in binding an antibody to an antigen, but exhibit various effector functions, such as participation of the antibody in antibody-dependent cellular toxicity.
  • “Variable domain residue numbering as in Kabat” or “amino acid position numbering as in Kabat,” and variations thereof, refers to the numbering system used for heavy chain variable domains or light chain variable domains of the compilation of antibodies in Kabat et al., Sequences of Proteins of
  • a heavy chain variable domain may include a single amino acid insert (residue 52a according to Kabat) after residue 52 of H2 and inserted residues ⁇ e.g., residues 82a, 82b, and 82c, etc according to Kabat) after heavy chain FR residue 82.
  • the Kabat numbering of residues may be determined for a given antibody by alignment at regions of homology of the sequence of the antibody with a "standard” Kabat numbered sequence. It is not intended that CDRs of the present disclosure necessarily correspond to the Kabat numbering convention.
  • the BCMA binding proteins comprise a heavy chain only antibody, such as a VH or a VHH domain.
  • the BCMA binding proteins comprise a heavy chain only antibody that is an engineered human VH domain.
  • the engineered human VH domain is produced by panning of phage display libraries.
  • the BCMA binding proteins comprise a VHH.
  • VHH refers to single chain antibody binding domain devoid of light chain.
  • a VHH is derived from an antibody of the type that can be found in Camelidae or cartilaginous fish which are naturally devoid of light chains or to a synthetic and non-immunized VHH which can be constructed accordingly.
  • Each heavy chain comprises a variable region encoded by V-, D- and J exons.
  • a VHH in some cases, is a natural VHH, such as a Camelid- derived VHH, or a recombinant protein comprising a heavy chain variable domain.
  • the VHH is derived from a species selected from the group consisting of camels, llamas, vicugnas, guanacos, and cartilaginous fish (such as, but not limited to, sharks).
  • the VHH is derived from an alpaca (such as, but not limited to, a Huacaya Alpaca or a Suri alpaca).
  • Percent (%) amino acid sequence identity with respect to a sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical with the amino acid residues in the specific sequence, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in various ways that are within the skill in the art, for instance, using publicly available computer software programs such as EMBOSS MATCHER, EMBOSS WATER, EMBOSS STRETCHER, EMBOSS NEEDLE, EMBOSS LALIGN, BLAST, BLAST-2, ALIGN or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared.
  • binding affinity refers to the affinity of the proteins described in the disclosure to their binding targets, and is expressed numerically using "Kd" values. If two or more proteins are indicated to have comparable binding affinities towards their binding targets, then the Kd values for binding of the respective proteins towards their binding targets, are within ⁇ 2-fold of each other. If two or more proteins are indicated to have comparable binding affinities towards single binding target, then the Kd values for binding of the respective proteins towards said single binding target, are within ⁇ 2-fold of each other. If a protein is indicated to bind two or more targets with comparable binding affinities, then the Kd values for binding of said protein to the two or more targets are within ⁇ 2-fold of each other.
  • a higher Kd value corresponds to a weaker binding.
  • the "Kd” is measured by a radiolabeled antigen binding assay (RIA) or surface plasmon resonance assays using a BIACORE®-2000 or a BIACORE®-3000 (BIAcore, Inc.,
  • an "on-rate” or “rate of association” or “association rate” or “kon” and an “off-rate” or “rate of dissociation” or “dissociation rate” or “koff” are also determined with the surface plasmon resonance technique using a BIACORE®-2000 or a BIACORE®-3000 (BIAcore, Inc., Piscataway, N.J.).
  • the "Kd”, "kon", and “koff are measured using the OCTET® Systems (Pall Life Sciences).
  • the ligand e.g., biotinylated human BCMA
  • the OCTET® streptavidin capillary sensor tip surface which streptavidin tips are then activated according to manufacturer's instructions using about 20-50 ⁇ g/ml human BCMA protein.
  • a solution of PBS/Casein is also introduced as a blocking agent.
  • BCMA binding protein variants are introduced at a concentration ranging from about 10 ng/mL to about 100 ⁇ g/mL, about 50 ng/mL to about 5 ⁇ g/mL, or about 2 ng/mL to about 20 ⁇ g/mL.
  • the BCMA binding single domain proteins are used at a concentration ranging from about 2 ng/mL to about 20 ⁇ g/mL. Complete dissociation is observed in case of the negative control, assay buffer without the binding proteins. The kinetic parameters of the binding reactions are then determined using an appropriate tool, e.g., ForteBio software.
  • BCMA binding proteins Described herein are BCMA binding proteins, pharmaceutical compositions as well as nucleic acids, recombinant expression vectors, and host cells for making such BCMA binding proteins. Also provided are methods of using the disclosed BCMA binding proteins in the prevention, and/or treatment of diseases, conditions and disorders.
  • the BCMA binding proteins are capable of specifically binding to BCMA.
  • the BCMA binding proteins are capable of specifically binding to BCMA.
  • proteins include additional domains, such as a CD3 binding domain and an albumin binding domain.
  • BCMA B cell maturation antigen
  • B cell maturation antigen (BCMA, T FRSF17, CD269) is a transmembrane protein belonging to the tumor necrosis family receptor (TNFR) super family that is primarily expressed on terminally differentiated B cells.
  • BCMA expression is restricted to the B cell lineage and mainly present on plasma cells and plasmablasts and to some extent on memory B cells, but virtually absent on peripheral and naive B cells.
  • BCMA is also expressed on multiple myeloma (MM) cells, on leukemia cells and lymphoma cells.
  • BCMA was identified through molecular analysis of a t(4; 16)(q26;pl3) translocation found in a human intestinal T cell lymphoma and an in-frame sequence was mapped to the
  • Human BCMA cDNA has an open reading frame of 552 bp that encodes a 184 amino acid polypeptide.
  • the BCMA gene is organized into three exons that are separated by two introns, each flanked by GT donor and AG acceptor consensus splicing sites, and codes for a transcript of 1.2 kb.
  • the structure of BCMA protein includes an integral transmembrane protein based on a central 24 amino acid hydrophobic region in an alpha-helix structure.
  • the murine BCMA gene is located on chromosome 16 syntenic to the human 16pl3 region, and also includes three exons that are separated by two introns. The gene encodes a 185 amino acid protein.
  • Murine BCMA mRNA is expressed as a 404 bp transcript at the highest levels in plasmacytoma cells (J558) and at modest levels in the A20 B cell lymphoma line.
  • Murine BCMA mRNA transcripts have also been detected at low levels in T cell lymphoma (EL4, BW5147) and dendritic cell (CB1D6, D2SC1) lines in contrast to human cell lines of T cell and dendritic cell origin.
  • the murine BCMA cDNA sequence has 69.3% nucleotide identity with the human BCMA cDNA sequence and slightly higher identity (73.7%) when comparing the coding regions between these two cDNA sequences.
  • Mouse BCMA protein is 62% identical to human BCMA protein and, like human BCMA, contains a single hydrophobic region, which may be an internal transmembrane segment.
  • BCMA protein contains six conserved cysteine residues, consistent with the formation of a cysteine repeat motif found in the extracellular domain of T FRs. Similar to members of the T FR superfamily, BCMA protein contains a conserved aromatic residue four to six residues C-terminal from the first cysteine.
  • BCMA is not expressed at the cell surface, but rather, is located on the Golgi apparatus.
  • the amount of BCMA expression is proportional to the stage of cellular differentiation (highest in plasma cells).
  • BCMA is involved in B cell development and homeostasis due to its interaction with its ligands BAFF (B cell activating factor, also designated as TALL-1 or TNFSF13B) and APRIL (A proliferation inducing ligand).
  • BAFF B cell activating factor, also designated as TALL-1 or TNFSF13B
  • APRIL A proliferation inducing ligand
  • BCMA regulates different aspects of humoral immunity, B cell development and homeostasis along with its family members TACI (transmembrane activator and cyclophylin ligand interactor) and BAFF-R (B cell activation factor receptor, also known as tumor necrosis factor receptor superfamily member 13C).
  • TACI transmembrane activator and cyclophylin ligand interactor
  • BAFF-R B cell activation factor receptor, also known as tumor necrosis factor receptor superfamily member 13C.
  • Expression of BCMA appears rather late in B cell differentiation and contributes to the long term survival of plasmablasts and plasma cells in the bone marrow. BCMA also supports growth and survival of multiple myeloma (MM) cells.
  • MM myeloma
  • BCMA is mostly known for its functional activity in mediating the survival of plasma cells that maintain long-term humoral immunity.
  • BCMA solid tumor diseases related to the overexpression of BCMA, such as cancer multiple myeloma, leukemias and lymphomas.
  • present disclosure provides, in certain embodiments, single domain proteins which specifically bind to BCMA on the surface of tumor target cells.
  • BCMA binding proteins are provided herein in certain embodiments.
  • binding proteins such as anti-BCMA single domain antibodies or antibody variants, which bind to an epitope in the BCMA protein.
  • the BCMA binding protein binds to a human BCMA protein comprising the sequence of SEQ ID NO: 468.
  • the BCMA binding protein binds to a human BCMA protein comprising a truncated sequence compared to SEQ ID NO: 468.
  • the BCMA binding protein binds to a human BCMA protein comprising amino acid residues 5-51 of SEQ ID NO: 468.
  • the BCMA binding proteins of the present disclosure can be expressed within a multidomain protein that includes additional immunoglobulin domains. Such multidomain proteins can act via immunotoxin-based inhibition of tumor growth and induction of antibody-dependent cellular cytotoxicity (ADCC). In some embodiments, the multidomain proteins containing the BCMA binding proteins of the present disclosure exhibit complement- dependent cytotoxicity (CDC) activity. In some embodiments, the multidomain proteins containing the BCMA binding proteins of the present disclosure exhibit both ADCC and CDC activity, against cancer cells expressing BCMA.
  • An amino acid sequence of a Fc domain can be added on to the BCMA binding proteins described herein to induce ACDD or CDC. Amino acid sequences of Fc domains are known in the art and are contemplated herein.
  • a BCMA binding protein described herein binds to the extracellular domain of BCMA.
  • a BCMA binding protein described herein binds to amino acid residues 5-51 of human BCMA.
  • the BCMA binding protein is an anti-BCMA antibody or an antibody variant.
  • antibody variant refers to variants and derivatives of an antibody described herein.
  • amino acid sequence variants of the anti- BCMA antibodies described herein are contemplated.
  • amino acid sequence variants of anti-BCMA antibodies described herein are contemplated to improve the binding affinity and/or other biological properties of the antibodies. Exemplary methods for preparing amino acid variants include, but are not limited to, introducing
  • modifications include, for example, deletions from, and/or insertions into and/or substitutions of residues within the amino acid sequences of the antibody.
  • any combination of deletion, insertion, and substitution can be made to arrive at the final construct, provided that the final construct possesses the desired characteristics, e.g., antigen- binding.
  • antibody variants having one or more amino acid substitutions are provided. Sites of interest for substitution mutagenesis include the CDRs and framework regions. Examples of such substitutions are described below. Amino acid substitutions may be introduced into an antibody of interest and the products screened for a desired activity, e.g., retained/improved antigen binding, decreased immunogenicity, or improved antibody-dependent cell mediated cytotoxicity (ADCC) or complement dependent cytotoxicity (CDC). Both conservative and non-conservative amino acid substitutions are contemplated for preparing the antibody variants.
  • ADCC antibody-dependent cell mediated cytotoxicity
  • CDC complement dependent cytotoxicity
  • variant anti-BCMA antibody In another example of a substitution to create a variant anti-BCMA antibody, one or more hypervariable region residues of a parent antibody are substituted. In general, variants are then selected based on improvements in desired properties compared to a parent antibody, for example, increased affinity, reduced affinity, reduced immunogenicity, increased pH
  • an affinity matured variant antibody can be generated, e.g., using phage display -based affinity maturation techniques such as those described herein and known in the field.
  • the BCMA binding protein described herein is a single domain antibody such as a heavy chain variable domain (VH), a variable domain (VHH) of llama derived sdAb, peptide, ligand or a small molecule entity specific for BCMA.
  • VH heavy chain variable domain
  • VHH variable domain of llama derived sdAb
  • peptide peptide
  • ligand or a small molecule entity specific for BCMA.
  • the BCMA binding domain of the BCMA binding protein described herein is any domain that binds to BCMA including, but not limited to, domains from a monoclonal antibody, a polyclonal antibody, a recombinant antibody, a human antibody, a humanized antibody.
  • the BCMA binding protein is a single-domain antibody.
  • the BCMA binding protein is a peptide.
  • the BCMA binding protein is a small molecule.
  • single domain antibody as used herein in its broadest sense is not limited to a specific biological source or to a specific method of
  • Single domain antibodies are antibodies whose complementary determining regions are part of a single domain polypeptide. Examples include, but are not limited to, heavy chain antibodies, antibodies naturally devoid of light chains, single domain antibodies derived from conventional 4-chain antibodies, engineered antibodies and single domain scaffolds other than those derived from antibodies. Single domain antibodies may be any of the art, or any future single domain antibodies. Single domain antibodies may be derived from any species including, but not limited to mouse, human, camel, llama, goat, rabbit, and bovine.
  • the single domain antibodies of the disclosure are obtained: (1) by isolating the VHH domain of a naturally occurring heavy chain antibody; (2) by expression of a nucleotide sequence encoding a naturally occurring VHH domain; (3) by "humanization” of a naturally occurring VHH domain or by expression of a nucleic acid encoding a such humanized VHH domain; (4) by "camelization” of a naturally occurring VH domain from any animal species, and in particular from a species of mammal, such as from a human being, or by expression of a nucleic acid encoding such a camelized VH domain; (5) by "camelisation” of a "domain antibody” or “Dab", or by expression of a nucleic acid encoding such a camelized VH domain; (6) by using synthetic or semi-synthetic techniques for preparing proteins, polypeptides or other amino acid sequences; (7) by preparing a nucleic acid encoding a single domain antibody using techniques for
  • a single domain antibody corresponds to the VHH domains of naturally occurring heavy chain antibodies directed against BCMA.
  • VHH sequences can generally be generated or obtained by suitably immunizing a species of Llama with BCMA, (i.e., so as to raise an immune response and/or heavy chain antibodies directed against BCMA), by obtaining a suitable biological sample from said Llama (such as a blood sample, serum sample or sample of B-cells), and by generating VHH sequences directed against BCMA, starting from said sample, using any suitable technique known in the field.
  • VHH domains against BCMA are obtained from naive libraries of Camelid VHH sequences, for example by screening such a library using BCMA, or at least one part, fragment, antigenic determinant or epitope thereof using one or more screening techniques known in the field.
  • libraries and techniques are, for example, described in WO 99/37681, WO 01/90190, WO 03/025020 and WO 03/035694.
  • improved synthetic or semi-synthetic libraries derived from naive VHH libraries are used, such as VHH libraries obtained from naive VHH libraries by techniques such as random mutagenesis and/or CDR shuffling, as for example, described in WO 00/43507.
  • yet another technique for obtaining VHH sequences directed against BCMA involves suitably immunizing a transgenic mammal that is capable of expressing heavy chain antibodies (i.e., so as to raise an immune response and/or heavy chain antibodies directed against BCMA), obtaining a suitable biological sample from said transgenic mammal (such as a blood sample, serum sample or sample of B-cells), and then generating VHH sequences directed against BCMA, starting from said sample, using any suitable technique known in the field.
  • a suitable biological sample such as a blood sample, serum sample or sample of B-cells
  • VHH sequences directed against BCMA starting from said sample, using any suitable technique known in the field.
  • the heavy chain antibody-expressing rats or mice and the further methods and techniques described in WO 02/085945 and in WO 04/049794 can be used.
  • an anti-BCMA antibody as described herein comprises single domain antibody with an amino acid sequence that corresponds to the amino acid sequence of a naturally occurring VHH domain, but that has been "humanized", i.e., by replacing one or more amino acid residues in the amino acid sequence of said naturally occurring VHH sequence (and in particular in the framework sequences) by one or more of the amino acid residues that occur at the corresponding position(s) in a VH domain from a conventional 4-chain antibody from a human being (e.g., as indicated above).
  • This can be performed in a manner known in the field, which will be clear to the skilled person, for example on the basis of the further description herein.
  • humanized anti-BCMA single domain antibodies of the disclosure are obtained in any suitable manner known per se (i.e., as indicated under points (l)-(8) above) and thus are not strictly limited to polypeptides that have been obtained using a polypeptide that comprises a naturally occurring VHH domain as a starting material.
  • a single domain BCMA antibody as described herein, comprises a single domain antibody with an amino acid sequence that corresponds to the amino acid sequence of a naturally occurring VH domain, but that has been "camelized", i.e., by replacing one or more amino acid residues in the amino acid sequence of a naturally occurring VH domain from a conventional 4-chain antibody by one or more of the amino acid residues that occur at the corresponding position(s) in a VHH domain of a heavy chain antibody.
  • the VH sequence that is used as a starting material or starting point for generating or designing the camelized single domain is preferably a VH sequence from a mammal, more preferably the VH sequence of a human being, such as a VH3 sequence.
  • camelized anti- BCMA single domain antibodies of the disclosure are obtained in any suitable manner known in the field (i.e., as indicated under points (l)-(8) above) and thus are not strictly limited to polypeptides that have been obtained using a polypeptide that comprises a naturally occurring VH domain as a starting material.
  • both "humanization” and “camelization” are performed by providing a nucleotide sequence that encodes a naturally occurring VHH domain or VH domain, respectively, and then changing, one or more codons in said nucleotide sequence in such a way that the new nucleotide sequence encodes a "humanized” or “camelized” single domain antibody, respectively.
  • This nucleic acid can then be expressed, so as to provide the desired anti-BCMA single domain antibody of the disclosure.
  • the amino acid sequence of the desired humanized or camelized anti-BCMA single domain antibody of the disclosure are designed and then synthesized de novo using known techniques for peptide synthesis.
  • a nucleotide sequence encoding the desired humanized or camelized anti-BCMA single domain antibody of the disclosure, respectively is designed and then synthesized de novo using known techniques for nucleic acid synthesis, after which the nucleic acid thus obtained is expressed in using known expression techniques, so as to provide the desired anti-BCMA single domain antibody of the disclosure.
  • VHH sequences for example comprises combining one or more parts of one or more naturally occurring VH sequences (such as one or more framework (FR) sequences and/or complementarity determining region (CDR) sequences), one or more parts of one or more naturally occurring VHH sequences (such as one or more FR sequences or CDR sequences), and/or one or more synthetic or semi-synthetic sequences, in a suitable manner, so as to provide an anti-BCMA single domain antibody of the disclosure or a nucleotide sequence or nucleic acid encoding the same.
  • VH sequences such as one or more framework (FR) sequences and/or complementarity determining region (CDR) sequences
  • CDR complementarity determining region
  • the BCMA binding protein is fairly small and no more than 25 kD, no more than 20 kD, no more than 15 kD, or no more than 10 kD in some embodiments. In certain instances, the BCMA binding protein is 5 kD or less if it is a peptide or small molecule entity.
  • the BCMA binding protein is an anti-BCMA specific antibody comprising a heavy chain variable complementarity determining region CDR1, a heavy chain variable CDR2, a heavy chain variable CDR3, a light chain variable CDR1, a light chain variable CDR2, and a light chain variable CDR3.
  • the BCMA binding protein comprises any domain that binds to BCMA including but not limited to domains from a monoclonal antibody, a polyclonal antibody, a recombinant antibody, a human antibody, a humanized antibody, or antigen binding fragments such as single domain antibodies (sdAb), Fab, Fab', F(ab)2, and Fv fragments, fragments comprised of one or more CDRs, single-chain antibodies (e.g., single chain Fv fragments (scFv)), disulfide stabilized (dsFv) Fv fragments, heteroconjugate antibodies (e.g., bispecific antibodies), pFv fragments, heavy chain monomers or dimers, light chain monomers or dimers, and dimers consisting of one heavy chain and one light chain.
  • the BCMA binding protein is a single domain antibody.
  • the anti-BCMA single domain antibody comprises heavy chain variable complementarity determining regions (CDR), CDR1, CDR2, and C
  • the BCMA binding protein of the present disclosure is a polypeptide comprising an amino acid sequence that is comprised of four framework
  • regions/sequences (fl -f4) interrupted by three complementarity determining regions/sequences, as represented by the formula: fl-rl-f2-r2-f3-r3-f4, wherein rl, r2, and r3 are complementarity determining regions CDRl, CDR2, and CDR3, respectively, and fl, f2, f3, and f4 are framework residues.
  • the rl residues of the BCMA binding protein of the present disclosure comprise, for example, amino acid residues 26, 27, 28, 29, 30, 31, 32, 33 and 34;
  • the r2 residues of the BCMA binding protein of the present disclosure comprise, for example, amino acid residues, for example, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59,60, 61, 62 and 63;
  • the r3 residues of the BCMA binding protein of the present disclosure comprise, for example, amino acid residues, for example, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107 and 108.
  • the BCMA binding protein comprises an amino acid sequence selected from SEQ ID NOs: 346-460.
  • the CDRl does not comprise an amino acid sequence of
  • the CDR2 does not comprise an amino acid sequence of SEQ ID NO: 474.
  • the CDR3 does not comprise an amino acid sequence of SEQ ID NO: 475.
  • the CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 1 or a variant thereof having one, two, three, four, five, six, seven, eight, nine, or ten amino acid substitutions.
  • An exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 4.
  • Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 5.
  • Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 6.
  • Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 7.
  • Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 8.
  • Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 9.
  • Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 10 Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 11 Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 12 Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 13 Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 14 Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 15 Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 16 Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 17 Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 18 Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 19 Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 20 Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 21 Another
  • Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 23.
  • Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 24.
  • Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 25.
  • Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 26.
  • Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 27.
  • Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 28.
  • Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 29.
  • Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 30.
  • Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 31.
  • Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 32.
  • Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 33.
  • Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 34.
  • Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 35.
  • Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 36.
  • Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 37.
  • Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 38.
  • Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 39.
  • Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 40.
  • Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 41.
  • Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 42.
  • Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 43.
  • Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 44.
  • Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 45.
  • Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 46.
  • Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 47.
  • Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 48.
  • Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 49.
  • Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 50.
  • Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 51.
  • Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 52.
  • Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 53.
  • Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 54.
  • Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 55.
  • Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 56.
  • Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 57.
  • Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 58.
  • Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 59.
  • Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 60.
  • Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 61.
  • Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 62.
  • Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 63. Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 64. Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 65. Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 66. Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 67. Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 68. Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 69. Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 70.
  • Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 71.
  • Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 72.
  • Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 73.
  • Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 74.
  • Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 75.
  • Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 76.
  • Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 77.
  • Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 78.
  • Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 79. Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 80. Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 81. Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 82. Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 83. Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 84. Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 85. Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 86.
  • Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 87.
  • Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 88.
  • Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 89.
  • Another exemplary CDRl comprises the amino acid sequence as set forth in SEQ ID NO: 90.
  • Another exemplary CDR1 comprises the amino acid sequence as set forth in SEQ ID NO: 91.
  • Another exemplary CDR1 comprises the amino acid sequence as set forth in SEQ ID NO: 92.
  • Another exemplary CDR1 comprises the amino acid sequence as set forth in SEQ ID NO: 93.
  • Another exemplary CDR1 comprises the amino acid sequence as set forth in SEQ ID NO: 94.
  • Another exemplary CDR1 comprises the amino acid sequence as set forth in SEQ ID NO: 95.
  • Another exemplary CDR1 comprises the amino acid sequence as set forth in SEQ ID NO: 96.
  • Another exemplary CDR1 comprises the amino acid sequence as set forth in SEQ ID NO: 97.
  • Another exemplary CDR1 comprises the amino acid sequence as set forth in SEQ ID NO: 98.
  • Another exemplary CDR1 comprises the amino acid sequence as set forth in SEQ ID NO: 99.
  • Another exemplary CDR1 comprises the amino acid sequence as set forth in SEQ ID NO: 100 Another exemplary CDR1 comprises the amino acid sequence as set forth in SEQ ID NO: 101 Another exemplary CDR1 comprises the amino acid sequence as set forth in SEQ ID NO: 102 Another exemplary CDR1 comprises the amino acid sequence as set forth in SEQ ID NO: 103 Another exemplary CDR1 comprises the amino acid sequence as set forth in SEQ ID NO: 104 Another exemplary CDR1 comprises the amino acid sequence as set forth in SEQ ID NO: 105 Another exemplary CDR1 comprises the amino acid sequence as set forth in SEQ ID NO: 106 Another exemplary CDR1 comprises the amino acid sequence as set forth in SEQ ID NO: 107 Another exemplary CDR1 comprises the amino acid sequence as set forth in SEQ ID NO: 108 Another exemplary CDR1 comprises the amino acid sequence as set forth in SEQ ID NO: 109 Another exemplary CDR1 comprises the amino acid sequence as set forth in SEQ ID NO: 110 Another exemplary CDR1 comprises the amino acid sequence as set forth in
  • the CDR2 comprises a sequence as set forth in SEQ ID NO: 1
  • Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 118.
  • Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 119.
  • Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 120.
  • Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 121.
  • Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 122.
  • Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 123.
  • Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 124. Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 125. Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 126. Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 127. Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 128. Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 129. Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 130. Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 131.
  • Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 132. Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 133. Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 134. Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 135. Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 136. Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 137. Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 138. Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 139.
  • Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 140.
  • Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 141.
  • Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 142.
  • Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 143.
  • Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 144.
  • Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 145.
  • Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 146.
  • Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 147.
  • Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 148. Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 149. Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 150. Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 151. Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 152. Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 153. Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 154. Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 155.
  • Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 156. Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 157. Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 158. Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 159. Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 160. Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 161. Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 162. Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 163.
  • Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 164. Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 165. Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 166. Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 167. Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 168. Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 169. Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 170. Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 171.
  • Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 172.
  • Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 173.
  • Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 174.
  • Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 175.
  • Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 176.
  • Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 177.
  • Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 178.
  • Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 179.
  • Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 180. Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 181. Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 182. Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 183. Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 184. Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 185. Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 186. Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 187.
  • Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 188.
  • Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 189.
  • Another exemp] ary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 190.
  • Another exemp] ary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 191.
  • Another exemp] ary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 192.
  • Another exemp] ary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 193.
  • Another exemp] ary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 194.
  • ary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 195.
  • Another exemp] ary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 196.
  • Another exemp] ary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 197.
  • Another exemp] ary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 198.
  • Another exemp] ary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 199.
  • Another exemp] ary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 200.
  • Another exemp] ary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 201.
  • ary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 202. Another exemp] ary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 203. Another exemp] ary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 204. Another exemp] ary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 205. Another exemp] ary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 206. Another exemp] ary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 207. Another exemp] ary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 208.
  • ary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 209. Another exemp] ary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 210. Another exemp] ary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 211. Another exemp] ary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 212. Another exemp] ary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 213. Another exemp] ary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 214. Another exemp] ary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 215.
  • ary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 216.
  • Another exemp] ary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 217.
  • Another exemp] ary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 218.
  • Another exemp] ary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 219.
  • Another exemp] ary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 220.
  • Another exemp] ary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 221.
  • Another exemp] ary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 222.
  • Another exemp] ary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 223.
  • Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 224.
  • Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 225.
  • Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 226.
  • Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 227.
  • Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 228.
  • Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 229.
  • Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 230.
  • Another exemplary CDR2 comprises the amino acid sequence as set forth in SEQ ID NO: 231.
  • the CDR3 comprises a sequence as set forth in SEQ ID NO: 1
  • Another exemplary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 232.
  • Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 233.
  • Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 234.
  • Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 235.
  • Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 236.
  • Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 237.
  • Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 238. Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 239. Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 240. Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 241. Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 242. Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 243. Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 244.
  • Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 245.
  • Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 246.
  • Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 247.
  • Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 248.
  • Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 249.
  • Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 250.
  • Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 251.
  • Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 252. Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 253. Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 254. Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 255. Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 256. Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 257. Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 258.
  • Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 259. Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 260. Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 261. Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 262. Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 263. Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 264. Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 265.
  • Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 266. Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 267. Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 268. Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 269. Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 270. Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 271. Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 272.
  • Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 273.
  • Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 274.
  • Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 275.
  • Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 276.
  • Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 277.
  • Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 278.
  • Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 279.
  • Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 280. Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 281. Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 282. Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 283. Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 284. Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 285. Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 286.
  • Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 287. Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 288. Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 289. Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 290. Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 291. Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 292. Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 293.
  • Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 294.
  • Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 295.
  • Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 296.
  • Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 297.
  • Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 298.
  • Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 299.
  • Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 300.
  • Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 301. Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 302. Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 303. Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 304. Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 305. Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 306. Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 307.
  • Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 308. Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 309. Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 310. Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 311. Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 312. Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 313. Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 314.
  • Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 315. Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 316. Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 317. Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 318. Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 319. Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 320. Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 321.
  • Another exemp ary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 322.
  • Another exemplary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 323.
  • Another exemplary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 324.
  • Another exemplary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 325.
  • Another exemplary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 326.
  • Another exemplary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 327.
  • Another exemplary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 328.
  • Another exemplary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 329.
  • Another exemplary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 330.
  • Another exemplary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 331.
  • Another exemplary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 332.
  • Another exemplary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 333.
  • Another exemplary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 334.
  • Another exemplary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 335.
  • Another exemplary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 336.
  • Another exemplary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 337.
  • Another exemplary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 338. Another exemplary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 339. Another exemplary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 340. Another exemplary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 341. Another exemplary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 342. Another exemplary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 343. Another exemplary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 344. Another exemplary CDR3 comprises the amino acid sequence as set forth in SEQ ID NO: 345.
  • the BCMA binding protein of the present disclosure has a CDR1 that has an amino acid sequence that is at least about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% identical to an amino acid sequence selected from SEQ ID NOs: 4-117.
  • the BCMA binding protein of the present disclosure has a CDR2 that has an amino acid sequence that is at least about 75%, about 76%, about 77%, about 78%, about 79%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% identical to an amino acid sequence selected from SEQ ID NOs: 1 18-231.
  • a complementarity determining region of the BCMA binding protein of the present disclosure has a CDR3 that has an amino acid sequence that is at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%), about 98%, about 99%, or about 100% identical to an amino acid sequence selected from SEQ ID NOs: 232-345.
  • a BCMA binding protein of the present disclosure has an amino acid sequence that is at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% identical to an amino acid sequence selected from SEQ ID NOs: 346-460.
  • a BCMA binding protein of the present disclosure has a framework 1 (fl) that has an amino acid sequence that is at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% identical to the amino acid sequence set forth in SEQ ID NO: 461 or SEQ ID NO: 462.
  • a BCMA binding protein of the present disclosure has a framework 2 (f2) that has an amino acid sequence that is at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% identical to the amino acid sequence set forth in SEQ ID NO: 463.
  • a BCMA binding protein of the present disclosure has a framework 3 (f3) that has an amino acid sequence that is at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or about 100% identical to the amino acid sequence set forth in SEQ ID NO: 464 or SEQ ID NO: 465.
  • a BCMA binding protein of the present disclosure has a framework 4 (f4) that has an amino acid sequence that is at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 81%, about 82%, about 83%, about 84%, about 85%, about 86%, about 87%, about 88%, about 89%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%), or about 100% identical to the amino acid sequence set forth in SEQ ID NO: 466 or SEQ ID NO: 467.
  • the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 346. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 347. In some
  • the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 348. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 349. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 350. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 351. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 352. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 353.
  • the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 354. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 355. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 356. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 357. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 358. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 359.
  • the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 360. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 361. In some embodiments,
  • the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 362. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 363. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 364. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 365. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 366. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 367. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 368. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 369.
  • the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 370. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 371. In some embodiments,
  • the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 372. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 373. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 374. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 375. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 376. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 377. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 378. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 379.
  • the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 380. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 381. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 382. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 383. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 384. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 385.
  • the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 386. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 387. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 388. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 389.
  • the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 390. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 391. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 392. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 393. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 394. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 395.
  • the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 396. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 397. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 398. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 399.
  • the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 400. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 401. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 402. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 403. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 404. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 405.
  • the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 406. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 407. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 408. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 409.
  • the BCMA binding protein is a humanized single domain antibody comprising the sequence of SEQ ID NO: 410. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 411. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 412. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 413. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 414. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 415.
  • the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 416. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 417. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 418. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 419.
  • the BCMA binding protein is a humanized single domain antibody comprising the sequence of SEQ ID NO: 420. In some embodiments, the BCMA binding protein is a humanized single domain antibody comprising the sequence of SEQ ID NO: 421. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 422. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 423. In some
  • the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 424. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 425. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 426. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 427. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 428. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 429.
  • the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 430. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 431. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 432. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 433. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 434. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 435.
  • the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 436. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 437. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 438. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 439.
  • the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 440. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 441. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 442. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 443. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 444. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 445.
  • the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 446. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 447. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 448. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 449. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 450.
  • the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 451. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 452. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 453. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 454. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 455. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 456.
  • the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 457. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 458. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 459. In some embodiments, the BCMA binding protein is a single domain antibody comprising the sequence of SEQ ID NO: 460.
  • a BCMA binding protein described herein can bind to human BCMA with a
  • Kd ranges from about 0.1 nM to about 500 nM. In some embodiments, the hKd ranges from about 0.1 nM to about 450 nM. In some embodiments, the hKd ranges from about 0.1 nM to about 400 nM. In some embodiments, the hKd ranges from about 0.1 nM to about 350 nM. In some embodiments, the hKd and ranges from about 0.1 nM to about 300 nM. In some embodiments, the hKd ranges from about 0.1 nM to about 250 nM. In some embodiments, the hKd ranges from about 0.1 nM to about 200 nM.
  • the hKd ranges from about 0.1 nM to about 150 nM. In some embodiments, the hKd ranges from about 0.1 nM to about 100 nM. In some embodiments, the hKd ranges from about 0.1 nM to about 90 nM. In some embodiments, the hKd range from about 0.2 nM to about 80 nM. In some embodiments, the hKd ranges from about 0.3 nM to about 70 nM. In some embodiments, the hKd ranges from about 0.4 nM to about 50 nM. In some embodiments, the hKd ranges from about 0.5 nM to about 30 nM.
  • the hKd ranges from about 0.6 nM to about 10 nM. In some embodiments, the hKd ranges from about 0.7 nM to about 8 nM. In some embodiments, the hKd ranges from about 0.8 nM to about 6 nM. In some embodiments, the hKd ranges from about 0.9 nM to about 4 nM. In some embodiments, the hKd ranges from about 1 nM to about 2 nM.
  • any of the foregoing BCMA binding proteins are affinity peptide tagged for ease of purification.
  • the affinity peptide tag is six consecutive histidine residues, also referred to as a His tag or a 6X-His tag (e.g., SEQ ID NO: 471).
  • the BCMA binding proteins according to the present disclosure may be incorporated into BCMA targeting trispecific proteins.
  • the trispecific binding protein comprises a CD3 binding domain, a human serum albumin (HSA) binding domain and an anti-BCMA binding domain according to the present disclosure.
  • the trispecific binding protein comprises the domains described above in the following orientation: BCMA-HS A-CD3.
  • the BCMA binding proteins of the present disclosure preferentially bind membrane bound BCMA over soluble BCMA.
  • Membrane bound BCMA refers to the presence of BCMA in or on the cell membrane surface of a cell that expresses BCMA.
  • Soluble BCMA refers to BCMA that is no longer on in or on the cell membrane surface of a cell that expresses or expressed BCMA.
  • the soluble BCMA is present in the blood and/or lymphatic circulation in a subject.
  • the BCMA binding proteins bind membrane-bound BCMA at least 5 fold, 10 fold, 15 fold, 20 fold, 25 fold, 30 fold, 40 fold, 50 fold, 100 fold, 500 fold, or 1000 fold greater than soluble BCMA. In one
  • the antigen binding proteins of the present disclosure preferentially bind membrane-bound BCMA 30 fold greater than soluble BCMA. Determining the preferential binding of an antigen binding protein to membrane bound BCMA over soluble BCMA can be readily determined using assays well known in the art.
  • the BCMA binding proteins of the present disclosure can, in certain examples, be incorporated into a chimeric antigen receptor (CAR).
  • An engineered immune effector cell e.g., a T cell or NK cell, can be used to express a CAR that includes an anti-BCMA single domain antibody as described herein.
  • the CAR including an anti-BCMA single domain antibody as described herein is connected to a transmembrane domain via a hinge region, and further a costimulatory domain, e.g., a functional signaling domain obtained from OX40, CD27, CD28, CD5, ICAM-1, LFA-1 (CD1 la/CD18), ICOS (CD278), or 4-1BB.
  • the CAR further comprises a sequence encoding an intracellular signaling domain, such as 4- IBB and/or CD3 zeta.
  • One embodiment provides a multispecific protein comprising a BCMA binding domain, wherein the BCMA binding domain is according to any one of above embodiments.
  • the multispecific protein comprises the BCMA binding domain according to any one of above embodiments (anti-BCMA domain), a CD3 binding domain (anti-CD3 domain), and an albumin binding domain (anti-ALB domain).
  • the BCMA targeting multispecific protein is a trispecific protein, wherein the trispecific protein has a domain order of H 2 N-(C)-(A)-(B)-COOH.
  • the anti-BCMA domain (the anti-target domain, T), the anti-CD3 domain (C), and the anti-ALB domain (A) are in an anti- CD3 : anti-ALB: anti-BCMA (CAT) orientation. In some embodiments, the anti-BCMA domain (the anti-target domain, T) the anti-CD3 domain (C), and the anti-ALB domain (A) are in an anti-BCMA: anti-ALB: anti-CD3 (TAC) orientation.
  • the BCMA binding proteins of the disclosure reduces the growth of tumor cells in vivo when administered to a subject who has tumor cells that express BCMA.
  • Measurement of the reduction of the growth of tumor cells can be determined by multiple different methodologies well known in the art. Non-limiting examples include direct measurement of tumor dimension, measurement of excised tumor mass and comparison to control subjects, measurement via imaging techniques (e.g., CT or MRI) that may or may not use isotopes or luminescent molecules (e.g., luciferase) for enhanced analysis, and the like.
  • administration of the antigen binding agents of the disclosure results in a reduction of in vivo growth of tumor cells as compared to a control antigen binding agent by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%, with an about 100% reduction in tumor growth indicating a complete response and disappearance of the tumor.
  • administration of the antigen binding agents of the disclosure results in a reduction of in vivo growth of tumor cells as compared to a control antigen binding agent by about 50-100%), about 75-100%) or about 90-100%).
  • administration of the antigen binding agents of the disclosure results in a reduction of in vivo growth of tumor cells as compared to a control antigen binding agent by about 50-60%>, about 60-70%, about 70- 80%, about 80-90%, or about 90-100%.
  • BCMA binding proteins described herein encompass derivatives or analogs in which (i) an amino acid is substituted with an amino acid residue that is not one encoded by the genetic code, (ii) the mature polypeptide is fused with another compound such as
  • polyethylene glycol or (iii) additional amino acids are fused to the protein, such as a leader or secretory sequence or a sequence to block an immunogenic domain and/or for purification of the protein.
  • Typical modifications include, but are not limited to, acetylation, acylation,
  • Modifications are made anywhere in the BCMA binding proteins described herein, including the peptide backbone, the amino acid side-chains, and the amino or carboxyl termini.
  • Certain common peptide modifications that are useful for modification of BCMA binding proteins include glycosylation, lipid attachment, sulfation, gamma-carboxylation of glutamic acid residues, hydroxylation, blockage of the amino or carboxyl group in a
  • polypeptide or both, by a covalent modification, and ADP-ribosylation.
  • the polynucleotide molecules are provided as DNA constructs. In other embodiments, the polynucleotide molecules are provided as messenger RNA transcripts.
  • the polynucleotide molecules are constructed by known methods such as by combining the genes encoding the anti-BCMA binding protein, operably linked to a suitable promoter, and optionally a suitable transcription terminator, and expressing it in bacteria or other appropriate expression system such as, for example CHO cells.
  • the polynucleotide is inserted into a vector, preferably an expression vector, which represents a further embodiment.
  • This recombinant vector can be constructed according to known methods.
  • Vectors of particular interest include plasmids, phagemids, phage derivatives, virii (e.g., retroviruses, adenoviruses, adeno-associated viruses, herpes viruses, lentiviruses, and the like), and cosmids.
  • a variety of expression vector/host systems may be utilized to contain and express the polynucleotide encoding the polypeptide of the described BCMA binding protein.
  • Examples of expression vectors for expression in E.coli are pSKK (Le Gall et al, J Immunol Methods. (2004) 285(1): 111-27), pcDNA5 (Invitrogen) for expression in mammalian cells, PICHIAPINKTM Yeast Expression Systems (Invitrogen), BACUVANCETM Baculovirus Expression System (GenScript).
  • the BCMA binding proteins as described herein are produced by introducing a vector encoding the protein as described above into a host cell and culturing said host cell under conditions whereby the protein domains are expressed, may be isolated and, optionally, further purified.
  • compositions comprising a BCMA binding protein described herein, a vector comprising the polynucleotide encoding the polypeptide of the BCMA binding proteins or a host cell transformed by this vector and at least one pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier includes, but is not limited to, any carrier that does not interfere with the effectiveness of the biological activity of the ingredients and that is not toxic to the patient to whom it is administered. Examples of suitable pharmaceutical carriers are well known in the art and include phosphate buffered saline solutions, water, emulsions, such as oil/water emulsions, various types of wetting agents, sterile solutions etc.
  • compositions are sterile. These compositions may also contain adjuvants such as preservative, emulsifying agents and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents.
  • a further embodiment provides one or more of the above described binding proteins, such as anti-BCMA single domain antibodies or antigen-binding fragments thereof packaged in lyophilized form, or packaged in an aqueous medium.
  • the BCMA binding protein described herein is encapsulated in nanoparticles.
  • the nanoparticles are fullerenes, liquid crystals, liposome, quantum dots, superparamagnetic nanoparticles, dendrimers, or nanorods.
  • the BCMA binding protein is attached to liposomes.
  • the BCMA binding protein is conjugated to the surface of liposomes.
  • the BCMA binding protein is encapsulated within the shell of a liposome.
  • the liposome is a cationic liposome.
  • the BCMA binding proteins described herein are contemplated for use as a medicament.
  • Administration is effected by different ways, e.g., by intravenous, intraperitoneal, subcutaneous, intramuscular, topical or intradermal administration.
  • the route of administration depends on the kind of therapy and the kind of compound contained in the pharmaceutical composition.
  • the dosage regimen will be determined by the attending physician and other clinical factors. Dosages for any one patient depends on many factors, including the patient ' s size, body surface area, age, sex, the particular compound to be administered, time and route of administration, the kind of therapy, general health and other drugs being administered concurrently.
  • An "effective dose” refers to amounts of the active ingredient that are sufficient to affect the course and the severity of the disease, leading to the reduction or remission of such pathology and may be determined using known methods.
  • the BCMA binding proteins of this disclosure are administered at a dosage of up to 10 mg/kg at a frequency of once a week. In some cases, the dosage ranges from about 1 ng/kg to about 10 mg/kg. In some embodiments, the dose is from about 1 ng/kg to about 10 ng/kg, about 5 ng/kg to about 15 ng/kg, about 12 ng/kg to about 20 ng/kg, about 18 ng/kg to about 30 ng/kg, about 25 ng/kg to about 50 ng/kg, about 35 ng/kg to about 60 ng/kg, about 45 ng/kg to about 70 ng/kg, about 65 ng/kg to about 85 ng/kg, about 80 ng/kg to about 1 ⁇ g/kg, about 0.5 ⁇ g/kg to about 5 ⁇ g/kg, about 2 ⁇ g/kg to about 10 ⁇ g/kg, about 7 ⁇ g/kg to about 15 ⁇ g/kg, about 12 ⁇ g/kg to
  • the dosage is about 0.1 mg/kg to about 0.2 mg/kg; about 0.25 mg/kg to about 0.5 mg/kg, about 0.45 mg/kg to about 1 mg/kg, about 0.75 mg/kg to about 3 mg/kg, about 2.5 mg/kg to about 4 mg/kg, about 3.5 mg/kg to about 5 mg/kg, about 4.5 mg/kg to about 6 mg/kg, about 5.5 mg/kg to about 7 mg/kg, about 6.5 mg/kg to about 8 mg/kg, about 7.5 mg/kg to about 9 mg/kg, or about 8.5 mg/kg to about 10 mg/kg.
  • the frequency of administration in some embodiments, is about less than daily, every other day, less than once a day, twice a week, weekly, once in 7 days, once in two weeks, once in two weeks, once in three weeks, once in four weeks, or once a month. In some cases, the frequency of administration is weekly. In some cases, the frequency of administration is weekly and the dosage is up to 10 mg/kg. In some cases, duration of administration is from about 1 day to about 4 weeks or longer.
  • kits and uses for stimulating the immune system of an individual in need thereof comprising administration of a BCMA binding protein as described herein.
  • the administration of a BCMA binding protein described herein induces and/or sustains cytotoxicity towards a cell expressing a target antigen.
  • the cell expressing a target antigen is a terminally
  • differentiated B cell that is a cancer or tumor cell, or a metastatic cancer or tumor cell.
  • Also provided herein are methods and uses for a treatment of a disease, disorder or condition associated with BCMA comprising administering to an individual in need thereof a BCMA binding protein or a multispecific binding protein comprising the BCMA binding protein described herein.
  • BCMA Diseases, disorders or conditions associated with BCMA include, but are not limited to, a cancer or a metastasis that is of a B cell lineage.
  • leukemias include, but are not limited to,: acute
  • ALL lymphoblastic leukemia
  • AML acute myeloid leukemia
  • CLL chronic lymphocytic leukemia
  • CML chronic myeloid leukemia
  • HCL Hairy cell leukemia
  • T-PLL T-cell prolymphocytic leukemia
  • Acute lymphoblastic leukemia (ALL) subtypes to be treated include, but are not limited to, precursor B acute lymphoblastic leukemia, precursor T acute lymphoblastic leukemia, Burkitt's leukemia, and acute biphenotypic leukemia.
  • Chronic lymphocytic leukemia (CLL) subtypes to be treated include, but are not limited to, B-cell prolymphocytic leukemia.
  • Acute myelogenous leukemia (AML) subtypes to be treated include, but are not limited to, acute promyelocytic leukemia, acute myeloblastic leukemia, and acute megakaryoblastic leukemia.
  • Chronic myelogenous leukemia (CML) subtypes to be treated include, but are not limited to, chronic myelomonocytic leukemia.
  • lymphoma to be treated with the subject methods include, but not limited to Hodgkin's disease, non-Hodgkin's disease, or any subtype of lymphoma.
  • multiple myelomas include, but are not limited to, a multiple myeloma of the bone or other tissues including, for example, a smoldering multiple myeloma, a non-secretory myeloma, a osteosclerotic myeloma, etc.
  • treatment or “treating” or “treated” refers to therapeutic treatment wherein the object is to slow (lessen) an undesired physiological condition, disorder or disease, or to obtain beneficial or desired clinical results.
  • beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent of the condition, disorder or disease; stabilization ⁇ i.e., not worsening) of the state of the condition, disorder or disease; delay in onset or slowing of the progression of the condition, disorder or disease; amelioration of the condition, disorder or disease state; and remission (whether partial or total), whether detectable or undetectable, or enhancement or improvement of the condition, disorder or disease.
  • Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment.
  • treatment or “treating” or “treated” refers to prophylactic measures, wherein the object is to delay onset of or reduce severity of an undesired physiological condition, disorder or disease, such as, for example is a person who is predisposed to a disease ⁇ e.g., an individual who carries a genetic marker for a disease such as breast cancer).
  • the BCMA binding proteins as described herein are administered in combination with an agent for treatment of the particular disease, disorder or condition.
  • Agents include, but are not limited to, therapies involving antibodies, small molecules (e.g., chemotherapeutics), hormones (steroidal, peptide, and the like), radiotherapies ( ⁇ -rays, X-rays, and/or the directed delivery of radioisotopes, microwaves, UV radiation and the like), gene therapies (e.g., antisense, retroviral therapy and the like) and other immunotherapies.
  • a BCMA binding protein as described herein is administered in combination with anti-diarrheal agents, anti-emetic agents, analgesics, opioids and/or non-steroidal anti-inflammatory agents.
  • a BCMA binding protein as described herein is administered in combination with anti-cancer agents.
  • anti-cancer agents Non-limiting examples of anti-cancer agents that can be used in the various anti-cancer agents that can be used in the various anti-cancer agents that can be used in the various
  • compositions and dosage forms and kits of the disclosure include: acivicin; aclarubicin; acodazole hydrochloride; acronine;
  • adozelesin aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin; calusterone;
  • caracemide caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin;
  • cedefingol chlorambucil; cirolemycin; cisplatin; cladribine; crisnatol mesylate;
  • cyclophosphamide cytarabine; dacarbazine; dactinomycin; daunorubicin hydrochloride;
  • decitabine dexormaplatin; dezaguanine; dezaguanine mesylate; diaziquone; docetaxel;
  • doxorubicin doxorubicin hydrochloride
  • droloxifene droloxifene citrate
  • dromostanolone propionate duazomycin
  • edatrexate eflornithine hydrochloride
  • elsamitrucin enloplatin
  • estramustine estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; cambine; fenretinide; floxuridine; fludarabine phosphate; fluorouracil; flurocitabine; fosquidone; fostriecin sodium; gemcitabine; gemcitabine
  • hydrochloride hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine; interleukin II (including recombinant interleukin II, or rIL2), interferon alpha-2a; interferon alpha-2b;
  • melphalan menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine;
  • meturedepa mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin;
  • mitosper mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxisuran; paclitaxel; pegaspargase; peliomycin; pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine; procarbazine hydrochloride; puromycin;
  • puromycin hydrochloride pyrazofurin; riboprine; rogletimide; safingol; safingol hydrochloride; semustine; pumprazene; sparfosate sodium; sparsomycin; spirogermanium hydrochloride;
  • spiromustine spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium; tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone; testolactone;
  • thiamiprine thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinzolidine sulfate; vinzolidine sulfate; vorozole; zeniplatin;
  • anti-cancer drugs include, but are not limited to: 20-epi-l,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin;
  • acylfulvene adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine;
  • ambamustine amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide;
  • anastrozole andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti-dorsalizing morphogenetic protein- 1; antiandrogen, prostatic carcinoma; antiestrogen;
  • antineoplaston antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine;
  • azatyrosine baccatin III derivatives; balanol; batimastat; BCR/ABL antagonists; benzochlorins; benzoylstaurosporine; beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A;
  • bizelesin breflate; bropirimine; budotitane; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2; capecitabine; carboxamide-amino-triazole;
  • carboxyamidotriazole CaRest M3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomifene analogues; clotrimazole;
  • collismycin A collismycin B; combretastatin A4; combretastatin analogue; conagenin;
  • crambescidin 816 crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A;
  • cyclopentanthraquinones cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor;
  • cytostatin cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone;
  • dexifosfamide dexifosfamide
  • dexrazoxane dexverapamil
  • diaziquone didemnin B
  • didox diethylnorspermine
  • dihydro-5-azacytidine dihydrotaxol, 9-; dioxamycin; diphenyl spiromustine; docetaxel;
  • docosanol dolasetron; doxifluridine; droloxifene; dronabinol; duocarmycin SA; ebselen;
  • ecomustine ecomustine; edelfosine; edrecolomab; eflornithine; elemene; emitefur; epirubicin; epristeride; estramustine analogue; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate; exemestane; fadrozole; trasrabine; fenretinide; filgrastim; finasteride; flavopiridol; flezelastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex;
  • ganirelix gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin;
  • hexamethylene bisacetamide hypericin; ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imidazoacridones; imiquimod; immunostimulant peptides; insulin-like growth factor-I receptor inhibitor; interferon agonists; interferons; interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin;
  • lenograstim lentinan sulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocyte alpha interferon; leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogue; lipophilic disaccharide peptide; lipophilic platinum compounds;
  • HMG-CoA reductase inhibitor such as but not limited to, Lovastatin, Pravastatin, Fluvastatin, Statin, Simvastatin, and Atorvastatin); loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides; maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone; meterelin; methioninase;
  • HMG-CoA reductase inhibitor such as but not limited to, Lovastatin, Pravastatin, Fluvastatin, Statin, Simvastatin, and Atorvastatin
  • loxoribine such as but not limited to, Lovastatin, Pravastatin, Fluvastatin, Statin, Simvastatin, and Atorvastatin
  • loxoribine such as
  • metoclopramide MIF inhibitor; mifepristone; miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone; mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonal antibody, human chorionic gonadotrophin; monophosphoryl lipid A+myobacterium cell wall sk; mopidamol; multiple drug resistance gene inhibitor; multiple tumor suppressor 1 -based therapy; mustard anticancer agent; mycaperoxide B; mycobacterial cell wall extract; myriaporone; N- acetyldinaline; N-substituted benzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin
  • piritrexim placetin A; placetin B; plasminogen activator inhibitor; platinum complex; platinum compounds; platinum-triamine complex; porfimer sodium; porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2; proteasome inhibitors; protein A-based immune modulator;
  • protein kinase C inhibitor protein kinase C inhibitor
  • protein kinase C inhibitors microalgal
  • protein tyrosine phosphatase inhibitors purine nucleoside phosphorylase inhibitors
  • purpurins pyrazoloacridine
  • pyridoxylated hemoglobin polyoxyethylene conjugate raf antagonists; raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors; ras inhibitors; ras-GAP inhibitor; retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide; rohitukine; romurtide; roquinimex; rubiginone Bl ; ruboxyl; safingol; saintopin; SarCNU;
  • sarcophytol A sargramostim; Sdi 1 mimetics; semustine; senescence derived inhibitor 1; sense oligonucleotides; signal transduction inhibitors; signal transduction modulators; single chain antigen binding protein; sizofiran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; sparfosic acid; spicamycin D; spiromustine; splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-cell division inhibitors;
  • stipiamide stromelysin inhibitors
  • sulfinosine superactive vasoactive intestinal peptide antagonist
  • suradista suramin
  • suramin suramin
  • swainsonine synthetic glycosaminoglycans
  • tamoxifen methiodide tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; temoporfin; temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin; toremifene; totipotent stem cell factor; translation inhibitors; tretinoin; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turoster
  • Additional anti-cancer drugs are 5-fluorouracil and leucovorin. These two agents are particularly useful when used in methods employing thalidomide and a topoisomerase inhibitor.
  • the anti-BCMA single domain binding protein of the present disclosure is used in combination with gemcitabine.
  • a BCMA binding proteins as described herein is administered before, during, or after surgery.
  • the anti-cancer agent is conjugated via any suitable means to the trispecific protein.
  • kits for detecting expression of BCMA in vitro or in vivo include the foregoing BCMA binding proteins ⁇ e.g., a labeled anti-BCMA single domain antibody or antigen binding fragments thereof), and one or more compounds for detecting the label.
  • the label is selected from the group consisting of a fluorescent label, an enzyme label, a radioactive label, a nuclear magnetic resonance active label, a luminescent label, and a chromophore label.
  • BCMA expression is detected in a biological sample.
  • the sample can be any sample, including, but not limited to, tissue from biopsies, autopsies and pathology specimens.
  • Biological samples also include sections of tissues, for example, frozen sections taken for histological purposes.
  • Biological samples further include body fluids, such as blood, serum, plasma, sputum, spinal fluid or urine.
  • a biological sample is typically obtained from a mammal, such as a human or non-human primate.
  • a method of determining if a subject has cancer by contacting a sample from the subject with an anti-BCMA single domain antibody as disclosed herein; and detecting binding of the single domain antibody to the sample.
  • An increase in binding of the antibody to the sample as compared to binding of the antibody to a control sample identifies the subject as having cancer.
  • a method of confirming a diagnosis of cancer in a subject by contacting a sample from a subject diagnosed with cancer with an anti- BCMA single domain antibody as disclosed herein; and detecting binding of the antibody to the sample.
  • An increase in binding of the antibody to the sample as compared to binding of the antibody to a control sample confirms the diagnosis of cancer in the subject.
  • the single domain antibody is directly labeled.
  • the methods further include contacting a second antibody that specifically binds the single domain antibody with the sample; and detecting the binding of the second antibody.
  • An increase in binding of the second antibody to the sample as compared to binding of the second antibody to a control sample detects cancer in the subject or confirms the diagnosis of cancer in the subject.
  • the cancer is a lymphoma, a leukemia or a multiple myeloma.
  • the control sample is a sample from a subject without cancer.
  • the sample is a blood or tissue sample.
  • the antibody that binds (for example specifically binds) BCMA is directly labeled with a detectable label.
  • the antibody that binds (for example, specifically binds) BCMA (the first antibody) is unlabeled and a second antibody or other molecule that can bind the antibody that specifically binds BCMA is labeled.
  • a second antibody is chosen such that it is able to specifically bind the specific species and class of the first antibody.
  • the first antibody is a llama IgG
  • the secondary antibody may be an anti-llama-IgG.
  • Other molecules that can bind to antibodies include, without limitation, Protein A and Protein G, both of which are available commercially.
  • Suitable labels for the antibody or secondary antibody are described above, and include various enzymes, prosthetic groups, fluorescent materials, luminescent materials, magnetic agents and radioactive materials. Non-limiting examples of suitable enzymes include horseradish peroxidase, alkaline
  • Non-limiting examples of suitable prosthetic group complexes include streptavidin/biotin and avidin/biotin.
  • suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin.
  • a non-limiting exemplary luminescent material is luminol; a non-limiting exemplary a magnetic agent is gadolinium, and non-limiting exemplary radioactive labels include 1251, 1311, 35S or 3H.
  • BCMA can be assayed in a biological sample by a competition immunoassay utilizing BCMA standards labeled with a detectable substance and an unlabeled antibody that specifically binds BCMA.
  • a competition immunoassay utilizing BCMA standards labeled with a detectable substance and an unlabeled antibody that specifically binds BCMA.
  • the biological sample, the labeled BCMA standards and the antibody that specifically bind BCMA are combined and the amount of labeled BCMA standard bound to the unlabeled antibody is determined.
  • the amount of BCMA in the biological sample is inversely proportional to the amount of labeled BCMA standard bound to the antibody that specifically binds BCMA.
  • the antibody that specifically binds BCMA may be used to detect the production of BCMA in cells in cell culture.
  • the antibody can be used to detect the amount of BCMA in a biological sample, such as a tissue sample, or a blood or serum sample.
  • the BCMA is cell-surface BCMA.
  • the BCMA is soluble BCMA (e.g., BCMA in a cell culture supernatant or soluble BCMA in a body fluid sample, such as a blood or serum sample).
  • a kit is provided for detecting BCMA in a biological sample, such as a blood sample or tissue sample. For example, to confirm a cancer diagnosis in a subject, a biopsy can be performed to obtain a tissue sample for histological examination.
  • kits for detecting a polypeptide will typically comprise a single domain antibody, according to the present disclosure, that specifically binds BCMA.
  • an antibody fragment such as a scFv fragment, a VH domain, or a Fab is included in the kit.
  • the antibody is labeled (for example, with a fluorescent, radioactive, or an enzymatic label).
  • kits includes instructional materials disclosing means of use of an antibody that binds BCMA.
  • the instructional materials may be written, in an electronic form (such as a computer diskette or compact disk) or may be visual (such as video files), or provided through an electronic network, for example, over the internet, World Wide Web, an intranet, or other network.
  • the kits may also include additional components to facilitate the particular application for which the kit is designed.
  • the kit may additionally contain means of detecting a label (such as enzyme substrates for enzymatic labels, filter sets to detect fluorescent labels, appropriate secondary labels such as a secondary antibody, or the like).
  • the kits may additionally include buffers and other reagents routinely used for the practice of a particular method. Such kits and appropriate contents are well known to those of skill in the art.
  • the diagnostic kit comprises an immunoassay.
  • the method of detecting BCMA in a biological sample generally includes the steps of contacting the biological sample with an antibody which specifically reacts, under immunologically reactive conditions, to a BCMA polypeptide.
  • the antibody is allowed to specifically bind under immunologically reactive conditions to form an immune complex, and the presence of the immune complex (bound antibody) is detected directly or indirectly.
  • the antibodies can be conjugated to other compounds including, but not limited to, enzymes, magnetic beads, colloidal magnetic beads, haptens, fluorochromes, metal compounds, radioactive compounds or drugs.
  • the antibodies can also be utilized in immunoassays such as but not limited to radioimmunoassays (RIAs), ELISA, or immunohistochemical assays.
  • the antibodies can also be used for fluorescence activated cell sorting (FACS).
  • FACS employs a plurality of color channels, low angle and obtuse light- scattering detection channels, and impedance channels, among other more sophisticated levels of detection, to separate or sort cells (see U.S.
  • Patent No. 5, 061,620 Any of the single domain antibodies that bind BCMA, as disclosed herein, can be used in these assays.
  • the antibodies can be used in a conventional immunoassay, including, without limitation, an ELISA, an RIA, FACS, tissue immunohistochemistry, Western blot or immunoprecipitation.
  • T cells and target cancer cell line cells were mixed together at a 10: 1 ratio in a 384-well plate, and varying amounts of the trispecific proteins being tested were added.
  • the tumor cell lines were engineered to express luciferase protein. After 48 hours, to quantitate the remaining viable tumor cells, STEAD Y-GLO® Luminescent Assay (Promega) was used.
  • STEAD Y-GLO® Luminescent Assay Promega
  • EJM cells were used, which is a cell line that serves as an in vitro model for multiple myeloma and plasma cell leukemia. Viability of the EJM cells is measured after 48 hours. It was seen that the trispecific proteins mediated T cell killing.
  • Fig. 1 shows an example cell viability assay with test proteins 01H08, 01F07, 02F02 and BH253 compared to a negative control.
  • the EC 50 for the TDCC activity of several other test trispecific proteins are listed below in Table 1.
  • Table 1 Binding affinity and TDCC Activity of several BCMA targeting trispecific proteins.
  • 01E08, 02C01, 02E06, 02B06, 02F04, 01G08, 02C06, 01H09, 01F04, 01D02, 02D11, 01A07, 02C03, 02F07, 01E04, 02H09, 01E03, 02F05, 01B05, 01C05, 02F12, 01H11, 02G06, 01E06, 01G11, 02A05, 01 A08, 02G05, 01B09 have at least ten-fold increase TDCC potency and also show increase affinity compared to a molecule with the parental CDRs, 253BH10.
  • T-cell dependent cellular cytotoxicity (TDCC) assay was used to measure the ability of T cell engagers, including trispecific molecules, to direct T cells to kill tumor cells (Nazarian et al., 2015. J. Biomol. Screen., 20:519-27).
  • T cells and target cancer cell line cells are mixed together at a 10: 1 ratio in a 384-well plate, and varying amounts of the trispecific proteins being tested are added.
  • the tumor cell lines are engineered to express luciferase protein. After 48 hours, to quantitate the remaining viable tumor cells, STEAD Y-GLO® Luminescent Assay (Promega) was used.
  • TDCC assays T cell Dependent Cell Cytotoxicity assays
  • Fig. 3 shows an example cell viability assay with test proteins compared to a negative control.
  • the EC 50 for the TDCC activity of several other test trispecific proteins are listed below in Table 2.
  • Table 2 TDCC EC 50 Values for 3 Cell Lines for Select Binder Sequences in
  • BCMA binding protein according to the present disclosure.
  • This study is directed to determining the ability of an exemplary anti-BCMA multidomain antibody of the present disclosure to mediate ADCC as compared to a parental llama anti-BCMA antibody which does not have sequence modifications or substitutions as the exemplary antibody of the disclosure. Both antibodies are expressed as multidomain proteins which include an additional immunoglobulin Fc domain.
  • Donors are leukophoresed, and NK cells are isolated from the leukopack by the
  • NK cells are held overnight at 4° C on a rocker, then washed, counted and resuspended at 4 ⁇ 10 6 cells/mL in complete RPMI for use in the ADCC assay.
  • Targets Tumor cell targets are selected based on BCMA expression. Targets are washed and counted. 6 ⁇ 10 6 targets are resuspended in complete RPMI and labeled in a final concentration of 10 ⁇ calcein (Sigma #C 1359-00UL calcein am 4 mm in anhydrous DMSO) for 40 minutes at 37 °C, 5% C0 2 . Cells are washed twice in PBS, resuspended in complete RPMI and incubated at 37 °C, 5% C0 2 for 2 hrs. After labeling, target cells are washed, recounted and resuspended at 0.2 ⁇ 10 6 cells/mL in complete RPMI for use in the ADCC assay.
  • 10 ⁇ calcein Sigma #C 1359-00UL calcein am 4 mm in anhydrous DMSO
  • the ADCC assay is performed in a 96-well round bottom tissue culture plate
  • test proteins are titrated from 20 ⁇ g/mL to 0.0002 ⁇ g/mL by carrying 10 iL in 1000 ⁇ _, of complete RPMI containing 10% FCS (a 1 : 10 dilution).
  • Calcein labeled targets are added, 50 iL to contain 10,000 cells.
  • Target cells and various concentrations of the multidomain proteins containing either the exemplar anti-BCMA single domain antibody or the comparator antibody are incubated for 40 minutes at 4 °C, then K cell effectors added, 50 iL to contain 100,000 cells (10: 1 E:T ratio).
  • Percent (%) specific lysis is defined as (sample fluorescence) - (spontaneous lysis fluorescence) / (100% lysis-spontaneous lysis fluorescence).
  • Spontaneous lysis is determined by wells containing only targets and 100%) lysis is determined by wells where targets are lysed with IGEPAL CA 630 detergent.
  • Raw data is entered in an Excel spreadsheet with embedded formulae to calculate %> specific lysis and resultant values transferred to graphic program (GraphPad Prism) where the data is transformed in a curve fit graph. Subsequent analyses (linear regression calculations) are done in GraphPad to generate EC 50 values.
  • exemplar anti-BCMA single domain antibody To evaluate the anti-tumor activity of exemplar anti-BCMA single domain antibody, according to the present disclosure, against cancer cells, the cytotoxic activity in A431/H9 and NCI-H226 cell models in the presence of human serum as a source of complement is tested.
  • the exemplar anti-BCMA single domain antibody is expressed as a multidomain protein containing a Fc domain.
  • a multidomain protein containing the exemplar anti-BCMA single domain antibody of the present disclosure exerts potent CDC activity by killing cancer cell lines, and shows no activity on a BCMA-negative cell line.
  • BCMA binding protein of this disclosure 02B05 (SEQ ID NO: 383) was evaluated in a xenograft model.
  • NCG mice were subcutaneously inoculated with RPMI-8226 cells, and also intraperitoneally implanted with normal human peripheral blood mononuclear cells (PBMCs). Treatment with the exemplary BCMA targeting trispecific protein was also started on day 0 (qdxlO) (once daily for 10 days). The dosage of administration was 5 ⁇ g/kg, 50 ⁇ g/kg, or 500 ⁇ g/kg of the BCMA targeting trispecific protein 02B05, or a vehicle as control. Tumor volumes were determined for 25 days. As shown in Fig.
  • the mean tumor volumes were significantly lower in mice treated with the exemplary BCMA targeting trispecific protein (02B05) (at 50 ⁇ g/kg, or 500 ⁇ g/kg), as compared to the mice treated with the vehicle or the lower dose of BCMA targeting trispecific protein (02B05) (at 5 ⁇ g/kg).
  • NCG mice were subcutaneously inoculated with Jeko 1 cells, and also intraperitoneally implanted with normal human peripheral blood mononuclear cells (PBMCs).
  • Treatment with the exemplary BCMA targeting trispecific protein was started on day 3 (qdxlO) (once daily for 10 days).
  • the dosage of administration was 5 ⁇ g/kg, 50 ⁇ g/kg, or 500 ⁇ g/kg of the BCMA targeting trispecific protein 02B05, or a vehicle as control.
  • Tumor volumes were determined for 25 days. As shown in Fig.
  • the mean tumor volumes were significantly lower in mice treated with the exemplary BCMA targeting trispecific protein (02B05) (at 500 ⁇ g/kg), as compared to the mice treated with the vehicle or the lower doses of BCMA targeting trispecific protein (02B05) (at 5 ⁇ g/kg or 50 ⁇ g/kg).
  • Affinity Measurements for human and cynomolgus BCMA, CD3e, and albumin, using an exemplary BCMA targeting trispecific containing a BCMA binding protein of this disclosure protein of this disclosure [00208] The aim of this study was to assess the affinity of an exemplary BCMA targeting trispecific protein containing a BCMA binding protein of this disclosure (02B05) (SEQ ID NO: 383), toward human BCMA, cynomolgus BCMA, human CD3s, cynomolgus CD3s, human albumin, cynomolgus albumin, and mouse albumin. The affinities were measured using an Octet instrument. For these measurements, streptavidin tips were first loaded with 2.5 nM human BCMA-Fc, 2.5 nM cynomologus BCMA-Fc, 2.5 nM human CD3s-Fc, 2.5 nM
  • cynomolgus CD3s-Fc 50 nM human serum albumin (HSA), 50 nM cynomolgus serum albumin, or 50 nM mouse serum albumin.
  • HSA human serum albumin
  • the exemplary BCMA targeting trispecific protein containing a BCMA binding protein of this disclosure 02B05 was incubated with the tips, and following an association period, the tips were moved to a buffer solution to allow the exemplary BCMA targeting trispecific protein containing a BCMA binding protein of this disclosure (02B05) to disassociate.
  • the affinities for binding to human and cynomolgus BCMA and CD3s were measured in the presence of 15 mg/ml human serum albumin. Average calculated K D values from these studies are provided in Table 4 (n indicates the number of independent measurements, n/d indicates no binding detected under the conditions tested).
  • Binding was detected to human BCMA, human CD3s, cynomolgus CD3s, human serum albumin, cynomolgus serum albumin, and mouse serum albumin. Under the conditions tested, no binding was detected to cynomolgus BCMA.
  • Table 4 Measured K D values for exemplary BCMA targeting trispecific protein containing a BCMA binding protein of this disclosure, 02B05, to protein ligands.
  • Exemplary BCMA targeting trispecific protein containing a BCMA binding protein of this disclosure 02B05 (SEQ ID NO: 383) was tested for its ability to bind to purified T cells. Briefly, the BCMA trispecific protein or phosphate buffered saline (PBS) were incubated with purified T cells from 4 different anonymous human donors. After washing unbound protein, the T cells were then incubated with an Alexa Fluor 647 conjugated antibody that recognizes the anti-albumin domain in the 02B05 BCMA trispecific antigen-binding protein. The T cells were then analyzed by flow cytometry.
  • PBS phosphate buffered saline
  • Exemplary BCMA targeting trispecific protein containing a BCMA binding protein of this disclosure 02B05 was tested for its ability to bind to BCMA expressing cells. Briefly, the 02B05 BCMA trispecific antigen-binding protein was incubated with cell lines expressing BCMA (NCI-H929; EJM; RPMI-8226; OPM2) or lacking BCMA (NCI-H510A; DMS-153). Expression of BCMA RNA in these cells is indicated by the FPKM (fragments per kilobase million) values listed in Figs. 5A-F: the RNA FPKM values are from the Cancer Cell Line Encyclopedia (Broad Institute, Cambridge, MA USA).
  • the cells were then incubated with an Alexa Fluor 647 conjugated antibody that recognizes the anti-albumin domain in the 02B05 BCMA trispecific antigen-binding protein.
  • the cells were then analyzed by flow cytometry.
  • As a negative control cells were incubated with a trispecific protein targeting GFP.
  • Cells expressing BCMA RNA and incubated with the BCMA trispecific protein had notable shifts associated with Alexa Fluor 647 staining compared to cells that were incubated with GFP trispecific protein (as in Figs. 5A, 5B, 5D, and 5E).
  • Exemplary BCMA trispecific protein containing a BCMA binding protein of this disclosure 02B05 was tested for its ability to direct T cells to kill BCMA expressing cells in the presence and absence of human serum albumin (HSA) using a standard TDCC assay as described in Example 1. Because the exemplary BCMA trispecific protein contains an anti -albumin domain, this experiment was performed to confirm that binding to albumin would not prevent the BCMA trispecific antigen-binding protein from directing T cells to kill BCMA expressing cells.
  • Five BCMA expressing cell lines were tested: EJM, Jeko, OPM2, MOLP8, and NCI-H929. Representative data for an experiment with the EJM cells are shown in Fig. 6.
  • EJM cells or OPM2 cells per 10 effector cells (T cells) is used in a 48 hour assay.
  • the ability of exemplary BCMA targeting trispecific protein containing an exemplary BCMA binding protein of this disclosure 02B05 (SEQ ID NO: 383) to direct T cells to kill target cells with smaller target cell to effector ratios was tested. The expectation was that less killing would be observed when fewer effector cells were used.
  • Two BCMA expressing cell lines were tested, EJM and OPM2, using target to effector cell ratios of 1 : 1, 1 :3, and 1 : 10, and the experiment was performed in the presence of 15 mg/ml HSA.
  • a GFP targeting trispecific protein was used as a negative control. Data from this experiment is shown in Fig.
  • TDCC assay with EJM cells and Fig. 8 (TDCC assay with OPM2 cells).
  • near complete killing of the target cells was observed with a 1 : 10 target to effector cell ratio.
  • the amount of killing was reduced with decreasing effector cells.
  • the EC 50 values for cell killing with each ratio are listed in Table 6 (n/d indicates insufficient killing was observed to calculate an EC 50 value).
  • the EC 50 values increased when fewer effector cells were present.
  • reducing the number of effector cells to target cells reduced TDCC activity of the BCMA trispecific protein.
  • Table 6 TDCC EC 50 values for an exemplary BCMA targeting trispecific protein containing a BCMA binding protein of this disclosure (02B05) with varied target cell (EJM cells) to effector cell (T cells) ratios (tested in presence of 15 mg/ml HSA)
  • the TDCC assay was performed using EJM and a 1 : 1 target to effector cell ratio, and the experiment was performed in the presence of 15 mg/ml HSA.
  • a GFP targeting trispecific protein was used as a negative control.
  • Target cell viability was measured on days 1, 2, 3, and 4 following incubation of the target cells and effector cells, at a 1 : 1 ratio, in presence of the exemplary 02B05 BCMA trispecific antigen- binding protein and 15 mg/ml HSA, or the GFP targeting trispecific protein and 15 mg/ml HSA. While no target cell killing was observed on day 1, killing was observed at all other time points with the 02B05 BCMA trispecific-antigen-binding protein, with the amount of killing increasing with time (Fig. 9).
  • Table 7 TDCC EC 50 values for an exemplary BCMA targeting trispecific protein containing a BCMA binding protein of this disclosure (02B05) with a 1 to 1 target cell (EJM cells) to effector cell (T cells) ratios (tested in presence of 15 mg/ml HSA), at varied time points
  • Exemplary BCMA trispecific protein containing a BCMA binding protein of this disclosure 02B05 was tested for its ability to direct T cells from four different anonymous human donors to kill four different BCMA expressing cells in the presence of 15 mg/ml human serum albumin (HSA) using a standard TDCC assay as described in
  • Example 1 The BCMA expressing cell lines were EJM, NCI-H929, OPM2, and RPMI8226. As negative controls, two cell lines that lack BCMA expression, OVCAR8 and NCI-H510A, were also tested in the TDCC assays. A control GFP targeting trispecific protein was also used as a negative control. With the four BCMA expressing cell lines and all four T cell donors, cell viability decreased with increasing amounts of the BCMA trispecific protein but not with the GFP trispecific protein (Figs. 10, 11, 12, and 13). The EC 50 values for cell killing are provided in Table 8. The exemplary 02B05 BCMA trispecific antigen-binding protein did not direct killing of the cell lines lacking BCMA expression (Figs. 14 and 15). Thus, it was inferred that the exemplary 02B05 BCMA trispecific antigen-binding protein was able to direct T cells from multiple donors to kill a spectrum of BCMA expressing cell lines.
  • Table 8 Exemplary BCMA trispecific protein EC 50 values from TDCC assays with four BCMA expressing cell lines and four T cell donors in presence of 15 mg/ml HSA
  • Exemplary BCMA targeting trispecific protein containing a BCMA binding protein of this disclosure 02B05 was tested for its ability to direct T cells from cynomolgus monkeys to kill BCMA expressing cells in the presence of 15 mg/ml human serum albumin (HSA).
  • HSA human serum albumin
  • the experimental conditions were the same as described in Example 1 except peripheral blood mononuclear cells (PBMC) from cynomolgus monkeys were used as a source of T cells.
  • PBMC peripheral blood mononuclear cells
  • Two BCMA expressing cell lines were tested, RPMI8226 and NCI-H929. As shown in Figs.
  • the BCMA trispecific protein was able to direct T cells present in the cynomolgus PBMCs to kill the two BCMA expressing cell lines.
  • the EC 50 values for the cell killing are listed in Table 9.
  • a GFP trispecific protein did not affect viability of the BCMA expressing cells.
  • the BCMA expressing trispecific protein which can bind cynomolgus CD3s (as shown in Example 6), can direct cynomolgus T cells to kill cells expressing human BCMA.
  • Exemplary BCMA targeting trispecific protein containing a BCMA binding protein of this disclosure 02B05 was tested for its ability to activate T cells in the presence of BCMA expressing cells.
  • the BCMA expressing cell lines were EJM, OPM2, and RPMI8226. As negative controls, two cells lines that lack BCMA expression were also included, OVCAR8 and NCI-H510A. T cells were obtained from four different anonymous human donors.
  • the assays were set up using the conditions of a standard TDCC assay as described in Example 1 except the assay was adapted to 96-well format and the assay was carried out in the presence of 15 mg/ml HSA.
  • T cell activation was assessed by using flow cytometry to measure expression of T cell activation biomarkers CD25 and CD69 on the surface of the T cells.
  • T cell activation biomarkers CD25 and CD69 were assessed by using flow cytometry to measure expression of T cell activation biomarkers CD25 and CD69 on the surface of the T cells.
  • the exemplary 02B05 BCMA trispecific antigen-binding protein increased expression of CD69 and CD25 was observed on T cells when co-cultured with the BCMA expressing cells (as shown in Figs. 18- 23).
  • the observed interaction was dependent on interaction of the BCMA binding sequence within the exemplary BCMA targeting trispecific protein, as little to no activation was observed with a control GFP trispecific protein (as shown in Figs. 18-23) or with target cells with no BCMA expression (as shown in Figs. 24-27).
  • the exemplary BCMA targeting trispecific protein activated T cells in co-cultures containing BCMA expressing cells.
  • expression of a cytokine, TNFa was measured in the medium collected from a co-culture of T cells and BCMA expressing target cells treated with increasing concentrations of the exemplary BCMA targeting trispecific protein or with the negative control GFP trispecific protein.
  • the co-cultures were set up using the conditions of a standard TDCC assay (as described in Example 1) supplemented with 15 mg/ml HSA. TNFa was measured using an electrochemiluminescent assay (Meso Scale Discovery).
  • Cynomolgus monkeys were administered single intravenous doses of an exemplary BCMA targeting trispecific protein containing a BCMA binding protein of this disclosure (02B05) (SEQ ID NO: 383), at 0.01 mg/kg, 0.1 mg/kg, or 1 mg/kg. Two animals were included per dose group. Following the administration, serum samples were collected and analyzed by two different electrochemiluminescent assays. One assay used biotinylated CD3s as a capture reagent and detected with sulfo tagged BCMA (termed the functional assay).
  • Another assay used as a capture reagent a biotinylated antibody recognizing the anti-albumin domain in the exemplary BCMA targeting trispecific protein containing a BCMA binding protein of this disclosure 02B05 (SEQ ID NO: 383) and used as a detection reagent a sulfo tagged antibody recognizing the anti-CD3 binding domain in the exemplary BCMA targeting trispecific protein containing a BCMA binding protein of this disclosure (i.e., an anti-idiotype antibody).
  • the results from the electrochemiluminescent assays are plotted in Fig. 31. As seen in Fig. 31, the exemplary BCMA targeting trispecific protein was detected in the cynomolgus serum samples, even after 504 hours after the administration.
  • the exemplary BCMA targeting trispecific protein was identified using both the sulfo-tagged BCMA (lines labeled using the term “functional” in Fig. 31) and by the anti-idiotype antibody (lines labeled using the term "anti-idiotype” in Fig. 31).
  • Fresh diluted exemplary BCMA targeting trispecific protein containing a BCMA binding protein of this disclosure 02B05 was compared to the BCMA trispecific protein collected from the test cynomolgus monkeys at 168 h.
  • a GFP trispecific protein was included as a negative control. This study demonstrated that the exemplary BCMA targeting trispecific protein collected from the test cynomolgus monkeys' serum had identical activity as freshly diluted protein, and that the protein in the serum samples retained the ability to direct T cells to kill BCMA expressing EJM cells.

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10543271B2 (en) 2017-05-12 2020-01-28 Harpoon Therapeutics, Inc. Mesothelin binding proteins
US10544221B2 (en) 2016-05-20 2020-01-28 Harpoon Therapeutics, Inc. Single chain variable fragment CD3 binding proteins
US10730954B2 (en) 2017-05-12 2020-08-04 Harpoon Therapeutics, Inc. MSLN targeting trispecific proteins and methods of use
US10815311B2 (en) 2018-09-25 2020-10-27 Harpoon Therapeutics, Inc. DLL3 binding proteins and methods of use
US10844134B2 (en) 2016-11-23 2020-11-24 Harpoon Therapeutics, Inc. PSMA targeting trispecific proteins and methods of use
US10849973B2 (en) 2016-11-23 2020-12-01 Harpoon Therapeutics, Inc. Prostate specific membrane antigen binding protein
US10927180B2 (en) 2017-10-13 2021-02-23 Harpoon Therapeutics, Inc. B cell maturation antigen binding proteins
US10954311B2 (en) 2015-05-21 2021-03-23 Harpoon Therapeutics, Inc. Trispecific binding proteins and methods of use
US11136403B2 (en) 2017-10-13 2021-10-05 Harpoon Therapeutics, Inc. Trispecific proteins and methods of use
US11180563B2 (en) 2020-02-21 2021-11-23 Harpoon Therapeutics, Inc. FLT3 binding proteins and methods of use
WO2022060901A1 (en) 2020-09-16 2022-03-24 Amgen Inc. Methods for administering therapeutic doses of bispecific t-cell engaging molecules for the treatment of cancer
US11453716B2 (en) 2016-05-20 2022-09-27 Harpoon Therapeutics, Inc. Single domain serum albumin binding protein
US11492409B2 (en) 2018-06-01 2022-11-08 Novartis Ag Binding molecules against BCMA and uses thereof
WO2022263507A1 (en) 2021-06-17 2022-12-22 Boehringer Ingelheim International Gmbh Novel tri-specific binding molecules
US11535668B2 (en) 2017-02-28 2022-12-27 Harpoon Therapeutics, Inc. Inducible monovalent antigen binding protein
US11623958B2 (en) 2016-05-20 2023-04-11 Harpoon Therapeutics, Inc. Single chain variable fragment CD3 binding proteins
JP2023525049A (ja) * 2020-05-08 2023-06-14 シアトル・チルドレンズ・ホスピタル・ドゥーイング／ビジネス／アズ・シアトル・チルドレンズ・リサーチ・インスティテュート ナチュラルキラー細胞を標的とするキメラ抗原受容体（ｃａｒ）
US12195544B2 (en) 2018-09-21 2025-01-14 Harpoon Therapeutics, Inc. EGFR binding proteins and methods of use
US12221481B2 (en) 2019-05-21 2025-02-11 Novartis Ag CD19 binding molecules and uses thereof
US12415860B2 (en) 2018-05-14 2025-09-16 Harpoon Therapeutics, Inc. Binding moiety for conditional activation of immunoglobulin molecules
US12516128B2 (en) 2019-05-14 2026-01-06 Harpoon Therapeutics, Inc. EpCAM binding proteins and methods of use
WO2026072671A1 (en) 2024-09-24 2026-04-02 City Of Hope Methods comprising oncolytic viruses expressing bcmat and bcma-targeted therapies

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CN111909271B (zh) * 2020-08-12 2021-03-23 深圳市茵冠生物科技有限公司 一种基于单域抗体的bcma嵌合抗原受体及其应用
CN112028996B (zh) * 2020-10-30 2021-01-22 南京北恒生物科技有限公司 靶向bcma的单域抗体及其用途
AU2022286960A1 (en) * 2021-06-03 2024-01-18 Harpoon Therapeutics, Inc. Bcma targeting trispecific proteins and methods of use

Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5061620A (en) 1990-03-30 1991-10-29 Systemix, Inc. Human hematopoietic stem cell
WO1994004678A1 (en) 1992-08-21 1994-03-03 Casterman Cecile Immunoglobulins devoid of light chains
WO1999037681A2 (en) 1998-01-26 1999-07-29 Unilever Plc Method for producing antibody fragments
WO2000043507A1 (en) 1999-01-19 2000-07-27 Unilever Plc Method for producing antibody fragments
WO2001090190A2 (en) 2000-05-26 2001-11-29 National Research Council Of Canada Single-domain antigen-binding antibody fragments derived from llama antibodies
WO2002085945A2 (en) 2001-04-24 2002-10-31 Erasmus Universiteit Rotterdam Vhh single heavy chain antibody and a method for its preparation in a mammal
WO2003025020A1 (en) 2001-09-13 2003-03-27 Institute For Antibodies Co., Ltd. Method of constructing camel antibody library
WO2003035694A2 (en) 2001-10-24 2003-05-01 Vlaams Interuniversitair Instituut Voor Biotechnologie Vzw Functional heavy chain antibodies, fragments thereof, library thereof and methods of production thereof
WO2004049794A2 (en) 2002-12-03 2004-06-17 The Babraham Institute Single chain antibodies produced in a transgenic mouse
WO2013110531A1 (en) * 2012-01-23 2013-08-01 Ablynx Nv Sequences directed against hepatocyte growth factor (hgf) and polypeptides comprising the same for the treatment of cancers and/or tumors
US20130273055A1 (en) * 2010-11-16 2013-10-17 Eric Borges Agents and methods for treating diseases that correlate with bcma expression
WO2017025038A1 (en) 2015-08-11 2017-02-16 Nanjing Legend Biotech Co., Ltd. Chimeric antigen receptors based on single-domain antibodies and methods of use thereof

Family Cites Families (408)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR901228A (fr) 1943-01-16 1945-07-20 Deutsche Edelstahlwerke Ag Système d'aimant à entrefer annulaire
US4816567A (en) 1983-04-08 1989-03-28 Genentech, Inc. Recombinant immunoglobin preparations
US4943533A (en) 1984-03-01 1990-07-24 The Regents Of The University Of California Hybrid cell lines that produce monoclonal antibodies to epidermal growth factor receptor
US5225539A (en) 1986-03-27 1993-07-06 Medical Research Council Recombinant altered antibodies and methods of making altered antibodies
US6548640B1 (en) 1986-03-27 2003-04-15 Btg International Limited Altered antibodies
GB8607679D0 (en) 1986-03-27 1986-04-30 Winter G P Recombinant dna product
US6362325B1 (en) 1988-11-07 2002-03-26 Advanced Research And Technology Institute, Inc. Murine 4-1BB gene
US6303121B1 (en) 1992-07-30 2001-10-16 Advanced Research And Technology Method of using human receptor protein 4-1BB
US6355476B1 (en) 1988-11-07 2002-03-12 Advanced Research And Technologyinc Nucleic acid encoding MIP-1α Lymphokine
US6534055B1 (en) 1988-11-23 2003-03-18 Genetics Institute, Inc. Methods for selectively stimulating proliferation of T cells
US5858358A (en) 1992-04-07 1999-01-12 The United States Of America As Represented By The Secretary Of The Navy Methods for selectively stimulating proliferation of T cells
US6905680B2 (en) 1988-11-23 2005-06-14 Genetics Institute, Inc. Methods of treating HIV infected subjects
US6352694B1 (en) 1994-06-03 2002-03-05 Genetics Institute, Inc. Methods for inducing a population of T cells to proliferate using agents which recognize TCR/CD3 and ligands which stimulate an accessory molecule on the surface of the T cells
US5530101A (en) 1988-12-28 1996-06-25 Protein Design Labs, Inc. Humanized immunoglobulins
US5703055A (en) 1989-03-21 1997-12-30 Wisconsin Alumni Research Foundation Generation of antibodies through lipid mediated DNA delivery
US5399346A (en) 1989-06-14 1995-03-21 The United States Of America As Represented By The Department Of Health And Human Services Gene therapy
US5585362A (en) 1989-08-22 1996-12-17 The Regents Of The University Of Michigan Adenovirus vectors for gene therapy
GB8928874D0 (en) 1989-12-21 1990-02-28 Celltech Ltd Humanised antibodies
US5859205A (en) 1989-12-21 1999-01-12 Celltech Limited Humanised antibodies
EP0519596B1 (en) 1991-05-17 2005-02-23 Merck & Co. Inc. A method for reducing the immunogenicity of antibody variable domains
US5199942A (en) 1991-06-07 1993-04-06 Immunex Corporation Method for improving autologous transplantation
EP1400536A1 (en) 1991-06-14 2004-03-24 Genentech Inc. Method for making humanized antibodies
US5851795A (en) 1991-06-27 1998-12-22 Bristol-Myers Squibb Company Soluble CTLA4 molecules and uses thereof
US5565332A (en) 1991-09-23 1996-10-15 Medical Research Council Production of chimeric antibodies - a combinatorial approach
AU2764792A (en) 1991-10-04 1993-05-03 Iit Research Institute Conversion of plastic waste to useful oils
GB9125768D0 (en) 1991-12-04 1992-02-05 Hale Geoffrey Therapeutic method
EP0571613B1 (en) 1991-12-13 2003-09-17 Xoma Corporation Methods and materials for preparation of modified antibody variable domains and therapeutic uses thereof
US6005079A (en) 1992-08-21 1999-12-21 Vrije Universiteit Brussels Immunoglobulins devoid of light chains
US5350674A (en) 1992-09-04 1994-09-27 Becton, Dickinson And Company Intrinsic factor - horse peroxidase conjugates and a method for increasing the stability thereof
US5639641A (en) 1992-09-09 1997-06-17 Immunogen Inc. Resurfacing of rodent antibodies
DK0752248T3 (da) 1992-11-13 2000-11-13 Idec Pharma Corp Terapeutisk anvendelse af kimæriske og radioaktivt mærkede antistoffer mod humant B-lymfocytbegrænset differentieringsantig
PT699237E (pt) 1994-03-17 2003-07-31 Merck Patent Gmbh Fvs de cadeia anti-egfr e anticorpos anti-egfr
US7175843B2 (en) 1994-06-03 2007-02-13 Genetics Institute, Llc Methods for selectively stimulating proliferation of T cells
US5731168A (en) 1995-03-01 1998-03-24 Genentech, Inc. Method for making heteromultimeric polypeptides
US6692964B1 (en) 1995-05-04 2004-02-17 The United States Of America As Represented By The Secretary Of The Navy Methods for transfecting T cells
US7067318B2 (en) 1995-06-07 2006-06-27 The Regents Of The University Of Michigan Methods for transfecting T cells
US5773292A (en) 1995-06-05 1998-06-30 Cornell University Antibodies binding portions, and probes recognizing an antigen of prostate epithelial cells but not antigens circulating in the blood
US7060808B1 (en) 1995-06-07 2006-06-13 Imclone Systems Incorporated Humanized anti-EGF receptor monoclonal antibody
US6051227A (en) 1995-07-25 2000-04-18 The Regents Of The University Of California, Office Of Technology Transfer Blockade of T lymphocyte down-regulation associated with CTLA-4 signaling
US5811097A (en) 1995-07-25 1998-09-22 The Regents Of The University Of California Blockade of T lymphocyte down-regulation associated with CTLA-4 signaling
US6136311A (en) 1996-05-06 2000-10-24 Cornell Research Foundation, Inc. Treatment and diagnosis of cancer
US6107090A (en) 1996-05-06 2000-08-22 Cornell Research Foundation, Inc. Treatment and diagnosis of prostate cancer with antibodies to extracellur PSMA domains
EP0826696B1 (de) 1996-09-03 2002-05-29 GSF-Forschungszentrum für Umwelt und Gesundheit GmbH Verwendung bi-und trispezifischer Antikörper zur Induktion einer Tumorimmunität
RU2192281C2 (ru) 1996-10-11 2002-11-10 Бристол-Маерс Сквибб Компани Способы и композиции для иммуномодуляции
DK1027439T3 (da) 1997-10-27 2010-05-10 Bac Ip Bv Multivalente antigenbindende proteiner
CZ121599A3 (cs) 1998-04-09 1999-10-13 Aventis Pharma Deutschland Gmbh Jednořetězcová molekula vázající několik antigenů, způsob její přípravy a léčivo obsahující tuto molekulu
US6682736B1 (en) 1998-12-23 2004-01-27 Abgenix, Inc. Human monoclonal antibodies to CTLA-4
PL354286A1 (en) 1999-08-23 2003-12-29 Dana-Farber Cancer Institutedana-Farber Cancer Institute Pd-1, a receptor for b7-4, and uses therefor
EP1212422B1 (en) 1999-08-24 2007-02-21 Medarex, Inc. Human ctla-4 antibodies and their uses
US7605238B2 (en) 1999-08-24 2009-10-20 Medarex, Inc. Human CTLA-4 antibodies and their uses
WO2001030381A2 (de) 1999-10-28 2001-05-03 Hofbauer, Reinhold Verwendung von csf-1-inhibitoren
US6326193B1 (en) 1999-11-05 2001-12-04 Cambria Biosciences, Llc Insect control agent
US20060228364A1 (en) 1999-12-24 2006-10-12 Genentech, Inc. Serum albumin binding peptides for tumor targeting
JP2003520828A (ja) 2000-01-27 2003-07-08 ジェネティクス インスティテュート，エルエルシー Ｃｔｌａ４（ｃｄ１５２）に対する抗体、これを含む結合体、およびその使用
KR20030032922A (ko) 2000-02-24 2003-04-26 싸이트 테라피스 인코포레이티드 세포의 동시 자극 및 농축
US7572631B2 (en) 2000-02-24 2009-08-11 Invitrogen Corporation Activation and expansion of T cells
US6797514B2 (en) 2000-02-24 2004-09-28 Xcyte Therapies, Inc. Simultaneous stimulation and concentration of cells
US6867041B2 (en) 2000-02-24 2005-03-15 Xcyte Therapies, Inc. Simultaneous stimulation and concentration of cells
WO2001087977A2 (en) 2000-05-12 2001-11-22 Amgen Inc. Methods and compositions of matter concerning april/g70, bcma, blys/agp-3, and taci
AU2001275474A1 (en) 2000-06-12 2001-12-24 Akkadix Corporation Materials and methods for the control of nematodes
JP5165175B2 (ja) 2000-09-11 2013-03-21 デイナ ファーバー キャンサー インスティチュート，インコーポレイテッド Ｍｕｃ１細胞外ドメインおよびそれから得られた癌治療組成物
GB0100621D0 (en) 2001-01-10 2001-02-21 Vernalis Res Ltd Chemical compounds VI
CN1294148C (zh) 2001-04-11 2007-01-10 中国科学院遗传与发育生物学研究所 环状单链三特异抗体
CN1195779C (zh) 2001-05-24 2005-04-06 中国科学院遗传与发育生物学研究所 抗人卵巢癌抗人cd3双特异性抗体
US7666414B2 (en) 2001-06-01 2010-02-23 Cornell Research Foundation, Inc. Methods for treating prostate cancer using modified antibodies to prostate-specific membrane antigen
US7595378B2 (en) 2001-06-13 2009-09-29 Genmab A/S Human monoclonal antibodies to epidermal growth factor receptor (EGFR)
CA2450285C (en) 2001-06-13 2016-08-02 Genmab A/S Human monoclonal antibodies to epidermal growth factor receptor (egfr)
US20050215472A1 (en) 2001-10-23 2005-09-29 Psma Development Company, Llc PSMA formulations and uses thereof
JP5355839B2 (ja) 2001-10-23 2013-11-27 ピーエスエムエー デベロプメント カンパニー， エル．エル．シー． Ｐｓｍａ抗体およびタンパク質マルチマー
US7745140B2 (en) 2002-01-03 2010-06-29 The Trustees Of The University Of Pennsylvania Activation and expansion of T-cells using an engineered multivalent signaling platform as a research tool
CA2474616A1 (en) 2002-01-28 2003-08-07 Medarex, Inc. Human monoclonal antibodies to prostate specific membrane antigen (psma)
US20040132101A1 (en) 2002-09-27 2004-07-08 Xencor Optimized Fc variants and methods for their generation
SG187991A1 (en) 2002-05-02 2013-03-28 Wyeth Corp Calicheamicin derivative-carrier conjugates
AU2003244817B2 (en) 2002-06-28 2010-08-26 Domantis Limited Antigen-binding immunoglobulin single variable domains and dual-specific constructs
US9321832B2 (en) 2002-06-28 2016-04-26 Domantis Limited Ligand
JP2006500921A (ja) 2002-07-30 2006-01-12 ブリストル−マイヤーズ　スクイブ　カンパニー ヒト４−１ｂｂに対するヒト化抗体
BRPI0315295C1 (pt) 2002-10-17 2021-05-25 Genmab As anticorpo monoclonal humano isolado, célula hospedeira procariótica, composição farmacêutica, molécula biespecífica, usos de um anticorpo, métodos in vitro de detectar a presença de antígeno de cd20 ou uma célula que expressa cd20 em uma amostra, kit, e, vetor de expressão
CA2505515C (en) 2002-11-07 2013-08-27 Erasmus Universiteit Rotterdam Fret probes and methods for detecting interacting molecules
ZA200503075B (en) 2002-11-07 2006-09-27 Immunogen Inc Anti-CD33 antibodies and method for treatment of acute myeloid leukemia using the same
EP1900753B1 (en) 2002-11-08 2017-08-09 Ablynx N.V. Method of administering therapeutic polypeptides, and polypeptides therefor
EP1558645B1 (en) 2002-11-08 2011-07-27 Ablynx N.V. Stabilized single domain antibodies in pharmaceutical composition adapted for inhalation
US9320792B2 (en) 2002-11-08 2016-04-26 Ablynx N.V. Pulmonary administration of immunoglobulin single variable domains and constructs thereof
TWI335821B (en) 2002-12-16 2011-01-11 Genentech Inc Immunoglobulin variants and uses thereof
CN101899114A (zh) 2002-12-23 2010-12-01 惠氏公司 抗pd-1抗体及其用途
DK1629011T3 (da) 2003-05-31 2010-05-03 Micromet Ag Humane anti-humane-DC3-bindingsmolekyler
KR20060041205A (ko) 2003-07-01 2006-05-11 이뮤노메딕스, 인코오포레이티드 양특이성 항체들의 다가 담체들
HRP20120845T1 (hr) 2003-07-02 2012-11-30 Innate Pharma Protutijela za pan-kir2dl nk-receptor i njihova uporaba u dijagnostici i lijeäśenju
HRP20170342T1 (hr) 2003-07-24 2017-05-19 Innate Pharma S.A. Metode i sastavi za povećanje učinkovitosti terapijskih protutijela koristeći tvari koje potenciraju nk stanice
EP2272566A3 (en) 2003-08-18 2013-01-02 MedImmune, LLC Humanisation of antibodies
WO2005035575A2 (en) 2003-08-22 2005-04-21 Medimmune, Inc. Humanization of antibodies
US7288638B2 (en) 2003-10-10 2007-10-30 Bristol-Myers Squibb Company Fully human antibodies against human 4-1BB
MXPA06004035A (es) 2003-10-16 2006-08-31 Micromet Ag Aglutinantes cd3 de-inmunizados multi-especificos.
CN100376599C (zh) 2004-04-01 2008-03-26 北京安波特基因工程技术有限公司 基因工程重组抗cea抗cd3抗cd28线性单链三特异抗体
WO2005118788A2 (en) 2004-05-27 2005-12-15 The Trustees Of The University Of Pennsylvania Novel artificial antigen presenting cells and uses therefor
TW200607523A (en) 2004-06-01 2006-03-01 Domantis Ltd Drug compositions, fusions and conjugates
EP1786918A4 (en) 2004-07-17 2009-02-11 Imclone Systems Inc NEW BISPECIFIC ANTIBODY TETRAVALENT
US20080069772A1 (en) 2004-08-26 2008-03-20 Eberhard-Karls-Universitaet Tuebingen Universitaetsklinikum Treatment of transformed or infected biological cells
EP1634603A1 (de) 2004-08-26 2006-03-15 Eberhard-Karls-Universität Tübingen Universitätsklinikum Behandlung von transformierten oder infizierten biologischen Zellen
FR2879605B1 (fr) 2004-12-16 2008-10-17 Centre Nat Rech Scient Cnrse Production de formats d'anticorps et applications immunologiques de ces formats
EP1699826B1 (en) 2005-01-05 2009-03-11 f-star Biotechnologische Forschungs- und Entwicklungsges.m.b.H. Synthetic immunoglobulin domains with binding properties engineered in regions of the molecule different from the complementarity determining regions
US20090196850A1 (en) 2005-01-06 2009-08-06 Novo Nordisk A/S Anti-Kir Combination Treatments and Methods
CN101103043A (zh) 2005-01-06 2008-01-09 诺和诺德公司 Kir结合剂和使用其的方法
PT2343320T (pt) 2005-03-25 2018-01-23 Gitr Inc Anticorpos anti-gitr e as suas utilizações
US7833979B2 (en) 2005-04-22 2010-11-16 Amgen Inc. Toxin peptide therapeutic agents
US20060252096A1 (en) 2005-04-26 2006-11-09 Glycofi, Inc. Single chain antibody with cleavable linker
DK2439273T3 (da) 2005-05-09 2019-06-03 Ono Pharmaceutical Co Humane monoklonale antistoffer til programmeret død-1(pd-1) og fremgangsmåder til behandling af cancer ved anvendelse af anti-pd-1- antistoffer alene eller i kombination med andre immunterapeutika
US8188223B2 (en) 2005-05-18 2012-05-29 Ablynx N.V. Serum albumin binding proteins
ES2694247T3 (es) 2005-05-20 2018-12-19 Ablynx N.V. NanobodiesTM mejorados para el tratamiento de trastornos mediados por agregación
EP1726650A1 (en) 2005-05-27 2006-11-29 Universitätsklinikum Freiburg Monoclonal antibodies and single chain antibody fragments against cell-surface prostate specific membrane antigen
PT1907424E (pt) 2005-07-01 2015-10-09 Squibb & Sons Llc Anticorpos monoclonais humanos para o ligando 1 de morte programada (pd-l1)
NZ612578A (en) 2005-08-19 2014-11-28 Abbvie Inc Dual variable domain immunoglobin and uses thereof
EP1940881B1 (en) 2005-10-11 2016-11-30 Amgen Research (Munich) GmbH Compositions comprising cross-species-specific antibodies and uses thereof
CN101300272B (zh) 2005-10-14 2013-09-18 依奈特制药公司 用于治疗增生性病症的组合物和方法
GB0521991D0 (en) 2005-10-28 2005-12-07 Univ Dundee Siglec-9 binding agents
DK1951759T3 (da) 2005-11-12 2010-05-10 Lilly Co Eli Anti-EGFR-antistoffer
EP1962961B1 (en) 2005-11-29 2013-01-09 The University Of Sydney Demibodies: dimerisation-activated therapeutic agents
US7498142B2 (en) 2006-01-31 2009-03-03 Yeda Research And Development Co., Ltd. Methods of identifying combinations of antibodies with an improved anti-tumor activity and compositions and methods using the antibodies
WO2007115230A2 (en) 2006-03-30 2007-10-11 University Of Medicine And Dentistry Of New Jersey A strategy for homo- or hetero-dimerization of various proteins in solutions and in cells
WO2007113648A2 (en) 2006-04-05 2007-10-11 Pfizer Products Inc. Ctla4 antibody combination therapy
US20070269422A1 (en) 2006-05-17 2007-11-22 Ablynx N.V. Serum albumin binding proteins with long half-lives
WO2008020079A1 (en) 2006-08-18 2008-02-21 Ablynx N.V. Amino acid sequences directed against il-6r and polypeptides comprising the same for the treatment of deseases and disorders associated with il-6-mediated signalling
AU2007293614A1 (en) 2006-09-08 2008-03-13 Ablynx N.V. Serum albumin binding proteins with long half-lives
US20100166734A1 (en) 2006-12-20 2010-07-01 Edward Dolk Oral delivery of polypeptides
CN105037549B (zh) 2007-01-11 2018-09-28 诺和诺德公司 抗-kir抗体、制剂及其应用
RU2769948C2 (ru) 2007-04-03 2022-04-11 Эмджен Рисерч (Мьюник) Гмбх CD3-Эпсилон-связывающий домен с межвидовой специфичностью
JP2008278814A (ja) 2007-05-11 2008-11-20 Igaku Seibutsugaku Kenkyusho:Kk アゴニスティック抗ヒトｇｉｔｒ抗体による免疫制御の解除とその応用
CA2687903C (en) 2007-05-24 2016-09-13 Ablynx N.V. Amino acid sequences directed against rank-l and polypeptides comprising the same for the treatment of bone diseases and disorders
BR122017025062B8 (pt) 2007-06-18 2021-07-27 Merck Sharp & Dohme anticorpo monoclonal ou fragmento de anticorpo para o receptor de morte programada humano pd-1, polinucleotídeo e composição compreendendo o referido anticorpo ou fragmento
EP2014680A1 (en) 2007-07-10 2009-01-14 Friedrich-Alexander-Universität Erlangen-Nürnberg Recombinant, single-chain, trivalent tri-specific or bi-specific antibody derivatives
US8591886B2 (en) 2007-07-12 2013-11-26 Gitr, Inc. Combination therapies employing GITR binding molecules
WO2009011572A1 (en) 2007-07-13 2009-01-22 Bac Ip B.V. Single-domain antigen-binding proteins that bind mammalian igg
US20090304719A1 (en) 2007-08-22 2009-12-10 Patrick Daugherty Activatable binding polypeptides and methods of identification and use thereof
EP2195342A1 (en) 2007-09-07 2010-06-16 Ablynx N.V. Binding molecules with multiple binding sites, compositions comprising the same and uses thereof
US7982016B2 (en) 2007-09-10 2011-07-19 Amgen Inc. Antigen binding proteins capable of binding thymic stromal lymphopoietin
EP2535349A1 (en) 2007-09-26 2012-12-19 UCB Pharma S.A. Dual specificity antibody fusions
KR20100110864A (ko) 2008-01-24 2010-10-13 노보 노르디스크 에이/에스 인간화된 항-인간 ｎｋｇ2ａ 모노클로날 항체
CN101970499B (zh) 2008-02-11 2014-12-31 治疗科技公司 用于肿瘤治疗的单克隆抗体
EP2262837A4 (en) 2008-03-12 2011-04-06 Merck Sharp & Dohme PD-1 BINDING PROTEINS
LT2285408T (lt) 2008-06-05 2019-01-25 Ablynx N.V. Aminorūgščių sekos, nukreiptos prieš viruso apvalkalo baltymus, ir tokias sekas turintys polipeptidai, skirti virusinių ligų gydymui
US20100122358A1 (en) 2008-06-06 2010-05-13 Crescendo Biologics Limited H-Chain-only antibodies
NZ590667A (en) 2008-07-02 2013-01-25 Emergent Product Dev Seattle Tgf-b antagonist multi-target binding proteins
US8444976B2 (en) 2008-07-02 2013-05-21 Argen-X B.V. Antigen binding polypeptides
DE102008036127A1 (de) 2008-08-01 2010-02-04 Emitec Gesellschaft Für Emissionstechnologie Mbh Verfahren zum Betrieb einer Abgasanlage mit Lambda-Regelung
AR072999A1 (es) 2008-08-11 2010-10-06 Medarex Inc Anticuerpos humanos que se unen al gen 3 de activacion linfocitaria (lag-3) y los usos de estos
AU2009288730B2 (en) 2008-08-25 2013-06-20 Amplimmune, Inc. Compositions of PD-1 antagonists and methods of use
JP2012500855A (ja) 2008-08-25 2012-01-12 アンプリミューン、インコーポレーテッド Ｐｄ−１アンタゴニストおよび感染性疾患を処置するための方法
EP2352765B1 (en) 2008-10-01 2018-01-03 Amgen Research (Munich) GmbH Cross-species-specific single domain bispecific single chain antibody
DK2352763T4 (da) 2008-10-01 2022-10-17 Amgen Res Munich Gmbh Bispecifikke enkeltkædede antistoffer med specificitet for højmolekylære målantigener
US20110293619A1 (en) 2008-10-01 2011-12-01 Micromet Ag CROSS-SPECIES-SPECIFIC PSMAxCD3 BISPECIFIC SINGLE CHAIN ANTIBODY
EP2692736B1 (en) 2008-10-14 2018-04-18 National Research Council Of Canada Bsa-specific antibodies
EP2367553B1 (en) 2008-12-05 2017-05-03 Novo Nordisk A/S Combination therapy to enhance nk cell mediated cytotoxicity
WO2010077643A1 (en) 2008-12-08 2010-07-08 Tegopharm Corporation Masking ligands for reversible inhibition of multivalent compounds
EP3255060A1 (en) 2008-12-09 2017-12-13 F. Hoffmann-La Roche AG Anti-pd-l1 antibodies and their use to enhance t-cell function
US9345787B2 (en) 2008-12-22 2016-05-24 Targovax Oy Adenoviral vectors and methods and uses related thereto
RU2636046C2 (ru) 2009-01-12 2017-11-17 Сайтомкс Терапьютикс, Инк Композиции модифицированных антител, способы их получения и применения
EP2210902A1 (en) 2009-01-14 2010-07-28 TcL Pharma Recombinant monovalent antibodies
JP5844159B2 (ja) 2009-02-09 2016-01-13 ユニヴェルシテ デクス−マルセイユＵｎｉｖｅｒｓｉｔｅ Ｄ’Ａｉｘ−Ｍａｒｓｅｉｌｌｅ Ｐｄ−１抗体およびｐｄ−ｌ１抗体ならびにその使用
TWI541021B (zh) 2009-03-05 2016-07-11 艾伯維有限公司 Ｉｌ－１７結合蛋白
KR101790802B1 (ko) 2009-09-03 2017-10-27 머크 샤프 앤드 돔 코포레이션 항-ｇｉｔｒ 항체
UY32917A (es) 2009-10-02 2011-04-29 Boehringer Ingelheim Int Moléculas de unión a dll-4
WO2011051327A2 (en) 2009-10-30 2011-05-05 Novartis Ag Small antibody-like single chain proteins
WO2011066342A2 (en) 2009-11-24 2011-06-03 Amplimmune, Inc. Simultaneous inhibition of pd-l1/pd-l2
CN102770456B (zh) 2009-12-04 2018-04-06 弗·哈夫曼-拉罗切有限公司 多特异性抗体、抗体类似物、组合物和方法
EP2332994A1 (en) 2009-12-09 2011-06-15 Friedrich-Alexander-Universität Erlangen-Nürnberg Trispecific therapeutics against acute myeloid leukaemia
ES2722300T3 (es) 2009-12-10 2019-08-09 Hoffmann La Roche Anticuerpos que se unen preferentemente al dominio extracelular 4 de CSF1R y su uso
CA2785907A1 (en) 2009-12-29 2011-07-28 Emergent Product Development Seattle, Llc Ron binding constructs and methods of use thereof
GB2476681B (en) 2010-01-04 2012-04-04 Argen X Bv Humanized camelid VH, VK and VL immunoglobulin domains
DK2530091T3 (en) 2010-01-29 2018-05-28 Chugai Pharmaceutical Co Ltd ANTI-DLL3 ANTIBODY
JP5989547B2 (ja) 2010-03-05 2016-09-07 エフ・ホフマン−ラ・ロシュ・アクチェンゲゼルシャフト ヒトｃｓｆ−１ｒに対する抗体及びその使用
US9169323B2 (en) 2010-03-05 2015-10-27 Hoffmann-La Roche Inc. Antibodies against human CSF-1R
EP4012714A1 (en) 2010-03-23 2022-06-15 Iogenetics, LLC. Bioinformatic processes for determination of peptide binding
WO2011117423A1 (en) 2010-03-26 2011-09-29 Ablynx N.V. Immunoglobulin single variable domains directed against cxcr7
US9556273B2 (en) 2010-03-29 2017-01-31 Vib Vzw Anti-macrophage mannose receptor single variable domains for targeting and in vivo imaging of tumor-associated macrophages
HRP20190047T1 (hr) 2010-05-04 2019-02-22 Five Prime Therapeutics, Inc. Protutijela koja se vežu na csf1r
AU2011262758B8 (en) 2010-06-11 2014-09-04 Kyowa Kirin Co., Ltd. Anti-tim-3 antibody
KR102318383B1 (ko) 2010-07-16 2021-10-27 아디맵 엘엘씨 항체 라이브러리
CA2807664A1 (en) 2010-08-12 2012-02-16 Theraclone Sciences, Inc. Anti-hemagglutinin antibody compositions and methods of use thereof
CN103068847B (zh) 2010-08-24 2019-05-07 罗切格利卡特公司 可活化的双特异性抗体
CN103068846B9 (zh) 2010-08-24 2016-09-28 弗·哈夫曼-拉罗切有限公司 包含二硫键稳定性Fv片段的双特异性抗体
EP2621953B1 (en) 2010-09-30 2017-04-05 Ablynx N.V. Biological materials related to c-met
EP2643350A4 (en) 2010-11-22 2015-01-07 Innate Pharma Sa TREATMENTS WITH NK CELL MODULATION AND METHOD FOR THE TREATMENT OF HEMATOLOGICAL MALIGNOMES
CA2828940C (en) 2011-03-10 2024-04-16 Provectus Pharmaceuticals, Inc. Combination of local and systemic immunomodulative therapies for enhanced treatment of cancer
US9029113B2 (en) 2011-03-11 2015-05-12 Kaneka Corporation Modified aminotransferase, gene thereof, and method for producing optically active amino compound using same
MX361242B (es) 2011-03-30 2018-11-30 Ablynx Nv Anticuerpos de dominio sencillo contra tnf-alfa y usos de los mismos.
CA2832540C (en) 2011-04-08 2020-09-15 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Anti-epidermal growth factor receptor variant iii chimeric antigen receptors and use of same for the treatment of cancer
JP6072771B2 (ja) 2011-04-20 2017-02-01 メディミューン，エルエルシー Ｂ７−ｈ１およびｐｄ−１に結合する抗体およびその他の分子
WO2012158818A2 (en) 2011-05-16 2012-11-22 Fabion Pharmaceuticals, Inc. Multi-specific fab fusion proteins and methods of use
ES2765874T3 (es) 2011-05-25 2020-06-11 Innate Pharma Sa Anticuerpos anti-KIR para el tratamiento de trastornos inflamatorios
KR101972446B1 (ko) 2011-05-27 2019-04-25 글락소 그룹 리미티드 Ｂｃｍａ（ｃｄ２６９／ｔｎｆｒｓｆ１７）­결합 단백질
EP2723771B1 (en) 2011-06-23 2019-09-11 Ablynx NV Serum albumin binding proteins
WO2013006490A2 (en) 2011-07-01 2013-01-10 Cellerant Therapeutics, Inc. Antibodies that specifically bind to tim3
UA117901C2 (uk) 2011-07-06 2018-10-25 Ґенмаб Б.В. Спосіб посилення ефекторної функції вихідного поліпептиду, його варіанти та їх застосування
WO2013036130A1 (en) 2011-09-09 2013-03-14 Universiteit Utrecht Holding B.V. Broadly neutralizing vhh against hiv-1
WO2013039954A1 (en) 2011-09-14 2013-03-21 Sanofi Anti-gitr antibodies
EP2758436B1 (en) 2011-09-23 2019-06-12 Universität Stuttgart Serum half-life extension using immunoglobulin binding domains
JP6219287B2 (ja) 2011-09-30 2017-10-25 アブリンクス エン．ヴェー． ｃ−Ｍｅｔに関連する生物学的物質
TWI679212B (zh) 2011-11-15 2019-12-11 美商安進股份有限公司 針對ｂｃｍａ之e3以及ｃｄ３的結合分子
KR101764096B1 (ko) 2011-11-28 2017-08-02 메르크 파텐트 게엠베하 항-ｐｄ-ｌ1 항체 및 그의 용도
RU2658603C2 (ru) 2011-12-15 2018-06-21 Ф.Хоффманн-Ля Рош Аг Антитела против человеческого csf-1r и их применения
AU2012351728A1 (en) 2011-12-16 2014-06-19 Oncology Institute Of Southern Switzerland Combination of inotuzumab ozogamicin and torisel for the treatment of cancer
EP2793918B1 (en) 2011-12-19 2019-09-11 The Rockefeller University Hdc-sign binding peptides
CA2861003C (en) 2012-01-13 2023-03-28 Julius-Maximilians-Universitat Wurzburg Dual antigen-induced bipartite functional complementation
KR20140127855A (ko) 2012-02-06 2014-11-04 제넨테크, 인크. Csf1r 억제제를 사용하는 조성물 및 방법
CA3285826A1 (en) 2012-02-22 2026-03-02 The Trustees Of The University Of Pennsylvania Compositions and methods for generating a persisting population of t cells useful for the treatment of cancer
BR112014020826A8 (pt) 2012-02-24 2017-09-19 Stem Centrx Inc Anticorpo que se liga especificamente a um epítopo, ácido nucleico, vetor ou célula hospedeira, conjugado de fármaco – anticorpo, composição farmacêutica compreendendo o referido anticorpo, uso do mesmo, kit e método de preparação do conjugado
GB201203442D0 (en) 2012-02-28 2012-04-11 Univ Birmingham Immunotherapeutic molecules and uses
MX353382B (es) 2012-03-01 2018-01-10 Amgen Res Munich Gmbh Moleculas de union polipeptido de larga duracion.
AR090263A1 (es) 2012-03-08 2014-10-29 Hoffmann La Roche Terapia combinada de anticuerpos contra el csf-1r humano y las utilizaciones de la misma
US9975962B2 (en) 2012-03-30 2018-05-22 Bayer Healthcare Llc Thrombin/plasmin-regulated antibodies that bind TFPI
JP6509724B2 (ja) 2012-04-20 2019-05-08 アプティーボ リサーチ アンド デベロップメント エルエルシー Ｃｄ３結合ポリペプチド
RU2670743C9 (ru) 2012-05-11 2018-12-19 Файв Прайм Терапьютикс, Инк. Способы лечения состояний антителами, которые связывают рецептор колониестимулирующего фактора 1 (csf1r)
HK1203971A1 (en) 2012-05-15 2015-11-06 Bristol-Myers Squibb Company Cancer immunotherapy by disrupting pd-1/pd-l1 signaling
KR101566539B1 (ko) 2012-06-08 2015-11-05 국립암센터 신규한 Ｔｈ2 세포 전환용 에피토프 및 이의 용도
US9856314B2 (en) 2012-06-22 2018-01-02 Cytomx Therapeutics, Inc. Activatable antibodies having non-binding steric moieties and methods of using the same
WO2014004549A2 (en) 2012-06-27 2014-01-03 Amgen Inc. Anti-mesothelin binding proteins
UY34887A (es) 2012-07-02 2013-12-31 Bristol Myers Squibb Company Una Corporacion Del Estado De Delaware Optimización de anticuerpos que se fijan al gen de activación de linfocitos 3 (lag-3) y sus usos
AU2013289883B2 (en) 2012-07-13 2018-11-01 Zymeworks Bc Inc. Bispecific asymmetric heterodimers comprising anti-CD3 constructs
CN112587671A (zh) 2012-07-18 2021-04-02 博笛生物科技有限公司 癌症的靶向免疫治疗
US10040870B2 (en) 2012-08-31 2018-08-07 Argenx Bvba Highly diverse combinatorial antibody libraries
CN107759690A (zh) 2012-08-31 2018-03-06 戊瑞治疗有限公司 用结合群落刺激因子1受体(csf1r)的抗体治疗病状的方法
KR101963231B1 (ko) 2012-09-11 2019-03-28 삼성전자주식회사 이중특이 항체의 제작을 위한 단백질 복합체 및 이를 이용한 이중특이 항체 제조 방법
JOP20200236A1 (ar) 2012-09-21 2017-06-16 Regeneron Pharma الأجسام المضادة لمضاد cd3 وجزيئات ربط الأنتيجين ثنائية التحديد التي تربط cd3 وcd20 واستخداماتها
CN104955845B (zh) 2012-09-27 2018-11-16 美国政府(由卫生和人类服务部的部长所代表) 间皮素抗体和引起有效的抗肿瘤活性的方法
PL2904011T3 (pl) 2012-10-02 2018-01-31 Bristol Myers Squibb Co Połączenie przeciwciał anty-kir i przeciwciał anty-pd-1 w leczeniu raka
US9243058B2 (en) * 2012-12-07 2016-01-26 Amgen, Inc. BCMA antigen binding proteins
PL3575326T3 (pl) 2012-12-17 2022-07-11 Pf Argentum Ip Holdings Llc Leczenie komórek chorobowych cd47+ z użyciem fuzji sirp alfa-fc
JO3519B1 (ar) 2013-01-25 2020-07-05 Amgen Inc تركيبات أجسام مضادة لأجل cdh19 و cd3
GB201302447D0 (en) 2013-02-12 2013-03-27 Oxford Biotherapeutics Ltd Therapeutic and diagnostic target
ES2731681T3 (es) 2013-02-22 2019-11-18 Abbvie Stemcentrx Llc Conjugados de anticuerpo anti-DLL3 y PBD y usos de los mismos
BR112015020235A2 (pt) 2013-02-28 2017-10-10 Univ Edinburgh fragmento biologicamente ativo de proteína csf-1 ou um seu homólogo, ácido nucléico, proteína de fusão, ácido nucléico isolado, vetor, célula hospedeira, método de realização da proteína de fusão do primeiro aspeto da invenção, composição, utilização de uma proteína de fusão, método de tratamento para um indivíduo sofrendo de cancro do fígado e que irá ser submetido a cirurgia, método de tratamento para um indivíduo que irá ser submetido a cirurgia de transplante de fígado, e, kit
WO2014138306A1 (en) 2013-03-05 2014-09-12 Baylor College Of Medicine Engager cells for immunotherapy
EP3404111A1 (en) 2013-03-13 2018-11-21 Health Research, Inc. Compositions and methods for use of recombinant t cell receptors for direct recognition of tumor antigen
US9725520B2 (en) 2013-03-14 2017-08-08 The Board Of Regents Of The University Of Texas System HER3 specific monoclonal antibodies for diagnostic and therapeutic use
CN105283201B (zh) 2013-03-14 2019-08-02 斯克利普斯研究所 靶向剂抗体偶联物及其用途
US11634502B2 (en) 2013-03-15 2023-04-25 Amgen Inc. Heterodimeric bispecific antibodies
PL2970449T3 (pl) 2013-03-15 2020-04-30 Amgen Research (Munich) Gmbh Jednołańcuchowe cząsteczki wiążące zawierające N-końcowy ABP
US20140302037A1 (en) 2013-03-15 2014-10-09 Amgen Inc. BISPECIFIC-Fc MOLECULES
US20160009817A1 (en) 2013-03-15 2016-01-14 Bayer Healthcare Llc Pro-drug antibodies against tissue factor pathway inhibitor
UY35468A (es) 2013-03-16 2014-10-31 Novartis Ag Tratamiento de cáncer utilizando un receptor quimérico de antígeno anti-cd19
WO2014193973A2 (en) 2013-05-28 2014-12-04 Dcb-Usa Llc Antibody locker for the inactivation of protein drug
CN105722859B (zh) 2013-07-25 2021-05-07 西托姆克斯治疗公司 多特异性抗体、多特异性可活化抗体及其使用方法
ES2860952T3 (es) 2013-08-01 2021-10-05 Univ Catholique Louvain Proteína anti-garp y usos de la misma
AR097306A1 (es) 2013-08-20 2016-03-02 Merck Sharp & Dohme Modulación de la inmunidad tumoral
KR20160047567A (ko) 2013-08-28 2016-05-02 스템센트알엑스 인코포레이티드 조작된 항-dll3 접합체 및 사용 방법
TW201605896A (zh) 2013-08-30 2016-02-16 安美基股份有限公司 Gitr抗原結合蛋白
CN112552401B (zh) 2013-09-13 2023-08-25 广州百济神州生物制药有限公司 抗pd1抗体及其作为治疗剂与诊断剂的用途
JP6595458B2 (ja) 2013-09-20 2019-10-23 ブリストル−マイヤーズ スクイブ カンパニー 腫瘍を処置するための抗ｌａｇ−３抗体と抗ｐｄ−１抗体との組合せ
KR20210129274A (ko) 2013-09-24 2021-10-27 유니버시티 오브 워싱턴 데스모글레인 2 (dsg2) 결합 단백질 및 그의 용도
CN115160441A (zh) 2013-09-26 2022-10-11 埃博灵克斯股份有限公司 双特异性纳米抗体
US20160263087A1 (en) 2013-11-08 2016-09-15 Iteos Therapeutics Novel 4-(indol-3-yl)-pyrazole derivatives, pharmaceutical compositions and methods for use
US9126984B2 (en) 2013-11-08 2015-09-08 Iteos Therapeutics 4-(indol-3-yl)-pyrazole derivatives, pharmaceutical compositions and methods for use
US9931347B2 (en) 2013-12-03 2018-04-03 Iomet Pharma Ltd. Pharmaceutical compound
US10519251B2 (en) 2013-12-30 2019-12-31 Epimab Biotherapeutics, Inc. Fabs-in-tandem immunoglobulin and uses thereof
US9758505B2 (en) 2014-02-12 2017-09-12 Iteos Therapeutics 3-(indol-3-yl)-pyridine derivatives, pharmaceutical compositions and methods for use
CA2939941A1 (en) 2014-02-21 2015-08-27 Abbvie Stemcentrx Llc Anti-dll3 antibodies and drug conjugates for use in melanoma
JP2017510255A (ja) * 2014-03-04 2017-04-13 メディミューン，エルエルシー Ｂ細胞枯渇療法に反応性があるｂ細胞悪性腫瘍を同定するための組成物および方法
US20170335281A1 (en) 2014-03-15 2017-11-23 Novartis Ag Treatment of cancer using chimeric antigen receptor
EP3119763A1 (en) 2014-03-18 2017-01-25 Iteos Therapeutics Novel 3-indol substituted derivatives, pharmaceutical compositions and methods for use
AU2015237864B2 (en) 2014-03-24 2020-12-03 Cancer Research Technology Limited Modified antibodies containing modified IgG2 domains which elicit agonist or antagonistic properties and use thereof
JPWO2015146437A1 (ja) 2014-03-25 2017-04-13 国立大学法人東北大学 高機能性ＩｇＧ２型二重特異性抗体
UA117289C2 (uk) 2014-04-02 2018-07-10 Ф. Хоффманн-Ля Рош Аг Мультиспецифічне антитіло
US10167257B2 (en) 2014-04-04 2019-01-01 Iomet Pharma Ltd. Indole derivatives for use in medicine
EP4299595A3 (en) 2014-05-02 2024-03-13 Momenta Pharmaceuticals, Inc. Compositions and methods related to engineered fc constructs
EA201650031A1 (ru) 2014-05-15 2017-06-30 Итеос Терапьютик Производные пирролидин-2,5-диона, фармацевтические композиции и способы применения в качестве ингибиторов ido1
SI3148579T1 (sl) 2014-05-28 2021-07-30 Agenus Inc. Proti GITR antitelesa in postopki z njihovo uporabo
EA035419B9 (ru) 2014-05-29 2020-08-07 Мэкроудженикс, Инк. Триспецифичные связывающие молекулы и способы их применения
PE20170441A1 (es) 2014-06-06 2017-04-26 Bristol Myers Squibb Co Anticuerpos contra el receptor del factor de necrosis tumoral inducido por glucocorticoides (gitr) y sus usos
GB201412659D0 (en) 2014-07-16 2014-08-27 Ucb Biopharma Sprl Molecules
BR112017001183A2 (pt) 2014-07-21 2017-11-28 Novartis Ag tratamento de câncer usando receptor de antígeno quimérico anti-bcma humanizado
CA2955947A1 (en) 2014-07-25 2016-01-28 Cytomx Therapeutics, Inc. Anti-cd3 antibodies, activatable anti-cd3 antibodies, multispecific anti-cd3 antibodies, multispecific activatable anti-cd3 antibodies, and methods of using the same
MX384418B (es) 2014-07-31 2025-03-14 Amgen Res Munich Gmbh Constructo de anticuerpo de cadena individual biespecífico con distribución mejorada de tejido.
UY36245A (es) 2014-07-31 2016-01-29 Amgen Res Munich Gmbh Constructos de anticuerpos para cdh19 y cd3
GB201414730D0 (en) 2014-08-19 2014-10-01 Tpp Global Dev Ltd Pharmaceutical compound
RU2017105425A (ru) 2014-08-28 2018-09-28 Академиш Зикенхёйс Лейден Х.О.Д.Н. Люмк Комбинации антитела против cd94/nkg2a и/или cd94/nkg2b и вакцины
MA40609B1 (fr) 2014-09-05 2020-05-29 Janssen Pharmaceutica Nv Agents de liaison cd123 et leurs utilisations
CN109842529B (zh) 2014-09-05 2021-10-26 华为技术有限公司 用于配置业务的方法、装置和网络系统
WO2016038064A1 (en) 2014-09-10 2016-03-17 Innate Pharma Cross reactive siglec antibodies
SG10202007781TA (en) 2014-09-16 2020-09-29 Innate Pharma Treatment Regimens Using Anti-NKG2A Antibodies
MX2017003847A (es) 2014-09-25 2017-12-15 Amgen Inc Proteinas biespecificas activables por proteasas.
BR112017007003A2 (pt) 2014-10-07 2017-12-19 Cellectis método para modulação de atividade de células imunes induzidas por car
WO2016071293A2 (en) 2014-11-03 2016-05-12 Iomet Pharma Ltd Pharmaceutical compound
GB201419579D0 (en) 2014-11-03 2014-12-17 Iomet Pharma Ltd Pharmaceutical compound
GB2537445A (en) 2014-11-10 2016-10-19 Medimmune Ltd Binding molecules specific for CD73 and uses thereof
EP3223907A2 (en) 2014-11-26 2017-10-04 Xencor, Inc. Heterodimeric antibodies that bind cd3 and cd38
EP3029068A1 (en) 2014-12-03 2016-06-08 EngMab AG Bispecific antibodies against CD3epsilon and BCMA for use in the treatment of diseases
US11001625B2 (en) 2014-12-10 2021-05-11 Tufts University VHH based binding antibodies for anthrax and botulinum toxins and methods of making and using therefor
WO2016105450A2 (en) 2014-12-22 2016-06-30 Xencor, Inc. Trispecific antibodies
WO2016125017A1 (en) 2015-02-03 2016-08-11 Universite Catholique De Louvain Anti-garp protein and uses thereof
MY186585A (en) 2015-02-05 2021-07-28 Janssen Vaccines & Prevention Bv Binding molecules directed against influenza hemagglutinin and uses thereof
US20180022819A1 (en) 2015-02-11 2018-01-25 Aptevo Research And Development Llc Compositions and methods for combination therapy with prostate-specific membrane antigen binding proteins
DK3653221T5 (da) 2015-02-19 2024-08-26 Compugen Ltd Anti-pvrig-antistoffer og anvendelsesfremgangsmåder
US10550173B2 (en) 2015-02-19 2020-02-04 Compugen, Ltd. PVRIG polypeptides and methods of treatment
MA41613A (fr) 2015-02-23 2018-01-02 Abbvie Stemcentrx Llc Récepteurs antigéniques chimériques anti-dll3 et procédés d'utilisation desdits récepteurs
MX2017011951A (es) 2015-03-17 2018-06-15 Pfizer Derivados sustituidos de indol 3 novedosos, composiciones farmaceuticas y metodos para uso.
CN114644689A (zh) 2015-04-22 2022-06-21 农业生物群落股份有限公司 杀虫基因和使用方法
EP3288981A1 (en) 2015-05-01 2018-03-07 Genentech, Inc. Masked anti-cd3 antibodies and methods of use
EP3291836A4 (en) 2015-05-06 2018-11-14 Janssen Biotech, Inc. Prostate specific membrane antigen (psma) bispecific binding agents and uses thereof
CN114920848B (zh) 2015-05-13 2024-10-11 埃博灵克斯股份有限公司 基于cd3反应性的t细胞募集多肽
EP3296395B2 (en) 2015-05-13 2024-06-19 Chugai Seiyaku Kabushiki Kaisha Multiple antigen binding molecular fusion, pharmaceutical composition, method for identifying linear epitope, and method for preparing multiple antigen binding molecular fusion
US10945994B2 (en) 2015-05-14 2021-03-16 Pfizer Inc. Combinations comprising a pyrrolidine-2,5-dione IDO1 inhibitor and an anti-body
ES2881683T3 (es) 2015-05-21 2021-11-30 Full Spectrum Genetics Inc Procedimiento para mejorar las características de las proteínas
US9708412B2 (en) 2015-05-21 2017-07-18 Harpoon Therapeutics, Inc. Trispecific binding proteins and methods of use
US10364439B2 (en) 2015-06-03 2019-07-30 AgBiome, Inc. Pesticidal genes and methods of use
CN107709356A (zh) 2015-06-26 2018-02-16 南加利福尼亚大学 用于肿瘤特异性活化的掩蔽嵌合抗原受体t细胞
GB201511790D0 (en) 2015-07-06 2015-08-19 Iomet Pharma Ltd Pharmaceutical compound
US9914777B2 (en) 2015-07-10 2018-03-13 Merus N.V. Human CD3 binding antibody
TWI796283B (zh) 2015-07-31 2023-03-21 德商安美基研究（慕尼黑）公司 Ｍｓｌｎ及ｃｄ３抗體構築體
TWI793062B (zh) 2015-07-31 2023-02-21 德商安美基研究（慕尼黑）公司 Ｄｌｌ３及ｃｄ３抗體構築體
TWI829617B (zh) 2015-07-31 2024-01-21 德商安美基研究（慕尼黑）公司 Ｆｌｔ３及ｃｄ３抗體構築體
SI3331910T1 (sl) * 2015-08-03 2020-07-31 Engmab Sarl Monoklonska protitelesa proti humani antigen dozorevanja limfocitov B (BCMA)
US11667691B2 (en) 2015-08-07 2023-06-06 Novartis Ag Treatment of cancer using chimeric CD3 receptor proteins
EP3334733A1 (en) 2015-08-10 2018-06-20 Pfizer Inc 3-indol substituted derivatives, pharmaceutical compositions and methods for use
WO2017025698A1 (en) 2015-08-11 2017-02-16 Queen Mary University Of London Bispecific, cleavable antibodies
MX2018002043A (es) 2015-08-17 2018-07-06 Janssen Pharmaceutica Nv ANTICUERPOS ANTI-BCMA, MOLí‰CULAS DE UNIí“N A ANTíGENOS BIESPECíFICAS QUE SE UNEN A BCMA Y CD3, Y USOS DE ESTOS.
MX2018002166A (es) 2015-08-20 2018-09-12 Abbvie Stemcentrx Llc Conjugados anticuerpo anti-dll3-farmaco y metodos de uso.
CN106519037B (zh) 2015-09-11 2019-07-23 科济生物医药（上海）有限公司 可活化的嵌合受体
DK3354729T5 (da) 2015-09-24 2024-09-30 Daiichi Sankyo Co Ltd Anti-garp-antistof
CA3003458A1 (en) 2015-10-29 2017-05-04 Alector Llc Anti-siglec-9 antibodies and methods of use thereof
CA3004299A1 (en) 2015-11-05 2017-05-11 City Of Hope Methods for preparing cells for adoptive t cell therapy
WO2017087851A1 (en) 2015-11-19 2017-05-26 Genentech, Inc. Methods of treating cancer using b-raf inhibitors and immune checkpoint inhibitors
FI3377103T4 (fi) 2015-11-19 2025-04-16 Revitope Limited Funktionaalinen vasta-ainefragmenttikomplementointi kaksikomponenttiselle järjestelmälle epätoivottujen solujen uudelleenohjattua tappamista varten
WO2017093969A1 (en) 2015-12-04 2017-06-08 Novartis Ag Compositions and methods for immunooncology
AU2017207807A1 (en) 2016-01-12 2018-07-12 Palleon Pharmaceuticals Inc. Use of Siglec-7 or Siglec-9 antibodies for the treatment of cancer
US9624185B1 (en) 2016-01-20 2017-04-18 Yong Xu Method for preparing IDO inhibitor epacadostat
CN105968204B (zh) 2016-02-03 2020-01-21 中国人民解放军第三军医大学第一附属医院 一种抗前列腺特异性膜抗原的单域重链抗体
IL313507A (en) 2016-02-03 2024-08-01 Amgen Res Munich Gmbh Constructs of bispecific antibodies to BCMA and CD3 that bind to T cells, preparations containing the same and uses thereof
CN105968201A (zh) 2016-02-03 2016-09-28 南昌大学 针对前列腺特异性膜抗原的单域重链抗体
WO2017136549A1 (en) 2016-02-03 2017-08-10 Youhealth Biotech, Limited Compounds for treating eye disorders or diseases
CN109071667A (zh) 2016-03-08 2018-12-21 马弗里克治疗公司 可诱导性结合蛋白和使用方法
EP3430058A4 (en) 2016-03-15 2019-10-23 Generon (Shanghai) Corporation Ltd. MULTISPECIFIC FAB FUSION PROTEINS AND USES THEREOF
WO2017161206A1 (en) 2016-03-16 2017-09-21 Halozyme, Inc. Conjugates containing conditionally active antibodies or antigen-binding fragments thereof, and methods of use
WO2017162587A1 (en) 2016-03-22 2017-09-28 F. Hoffmann-La Roche Ag Protease-activated t cell bispecific molecules
EP3436480A4 (en) 2016-03-30 2019-11-27 Musc Foundation for Research Development METHOD FOR THE TREATMENT AND DIAGNOSIS OF CANCER BY TARGETING GLYCOPROTEIN A REPETITION PREDOMINANT (GARP) AND FOR EFFECTIVE IMMUNOTHERAPY ALONE OR IN COMBINATION
WO2017201493A1 (en) 2016-05-20 2017-11-23 Harpoon Therapeutics, Inc. Single chain variable fragment cd3 binding proteins
MA45054A (fr) 2016-05-20 2019-03-27 Abbvie Stemcentrx Llc Conjugués médicament-anticorps dll3 pour le traitement de tumeurs à risque de transition neuroendocrinienne
EP3493844A4 (en) 2016-05-20 2021-03-24 Harpoon Therapeutics Inc. SINGLE DOMAIN SERUM ALBUMIN BINDING PROTEIN
US11623958B2 (en) 2016-05-20 2023-04-11 Harpoon Therapeutics, Inc. Single chain variable fragment CD3 binding proteins
WO2017210443A1 (en) 2016-06-01 2017-12-07 Xencor, Inc. Bispecific antibodies that bind cd123 and cd3
RU2769282C2 (ru) 2016-06-20 2022-03-30 Кимаб Лимитед Анти-PD-L1 и IL-2 цитокины
WO2018017864A2 (en) 2016-07-20 2018-01-25 Oncomed Pharmaceuticals, Inc. Pvrig-binding agents and uses thereof
TW201815825A (zh) 2016-07-21 2018-05-01 財團法人生物技術開發中心 經修飾之抗原結合fab片段及包含其之抗原結合分子
CA3032498A1 (en) 2016-08-02 2018-02-08 TCR2 Therapeutics Inc. Compositions and methods for tcr reprogramming using fusion proteins
BR112019002331A2 (pt) 2016-08-05 2019-06-18 Allakos Inc anticorpos anti-siglec-7 para o tratamento do câncer e métodos para obtenção dos mesmos
ES2929032T3 (es) 2016-08-08 2022-11-24 Acetylon Pharmaceuticals Inc Combinaciones farmacéuticas de inhibidores de histona desacetilasa 6 y anticuerpos inhibidores de CD20 y usos de los mismos
IL317989A (en) 2016-08-17 2025-02-01 Compugen Ltd Anti-TIGIT antibodies, anti-PVRIG antibodies and combinations thereof
US20190218294A1 (en) 2016-09-09 2019-07-18 Bristol-Myers Squibb Company Use of an anti-pd-1 antibody in combination with an anti-mesothelin antibody in cancer treatment
WO2018067993A1 (en) 2016-10-07 2018-04-12 TCR2 Therapeutics Inc. Compositions and methods for t-cell receptors reprogramming using fusion proteins
US20190225702A1 (en) 2016-10-14 2019-07-25 Harpoon Therapeutics, Inc. Innate immune cell trispecific binding proteins and methods of use
WO2018075359A1 (en) 2016-10-18 2018-04-26 Boger Henry William Wireless power transfer for process control
MX2019005116A (es) 2016-11-01 2019-11-12 Anaptysbio Inc Anticuerpos dirigidos contra la proteina de inmunoglobulina de linfocitos t y de mucina 3 (tim-3).
JP7267914B2 (ja) 2016-11-02 2023-05-02 エンクマフ エスアーエールエル Ｂｃｍａ及びｃｄ３に対する二重特異性抗体、及び多発性骨髄腫を治療するために併用して使用される免疫療法薬
AU2017363300A1 (en) 2016-11-23 2019-06-20 Harpoon Therapeutics, Inc. Prostate specific membrane antigen binding protein
WO2018098356A1 (en) 2016-11-23 2018-05-31 Harpoon Therapeutics, Inc. Psma targeting trispecific proteins and methods of use
EP3551659A1 (en) 2016-12-08 2019-10-16 Eli Lilly and Company Anti-tim-3 antibodies for combination with anti-pd-l1 antibodies
JOP20190133A1 (ar) 2016-12-08 2019-06-02 Innovent Biologics Suzhou Co Ltd أجسام مضادة لـ Tim-3 لمزجها بأجسام مضادة لـ PD-1
RU2754058C2 (ru) 2016-12-13 2021-08-26 Астеллас Фарма Инк. Антитело к cd73 человека
WO2018115859A1 (en) 2016-12-20 2018-06-28 Kymab Limited Multispecific antibody with combination therapy for immuno-oncology
WO2018136725A1 (en) 2017-01-19 2018-07-26 Harpoon Therapeutics, Inc. Innate immune cell inducible binding proteins and methods of use
WO2018133877A1 (zh) 2017-01-23 2018-07-26 科济生物医药（上海）有限公司 靶向bcma的抗体及其应用
US11535668B2 (en) 2017-02-28 2022-12-27 Harpoon Therapeutics, Inc. Inducible monovalent antigen binding protein
WO2018160671A1 (en) 2017-02-28 2018-09-07 Harpoon Therapeutics, Inc. Targeted checkpoint inhibitors and methods of use
WO2018165619A1 (en) 2017-03-09 2018-09-13 Cytomx Therapeutics, Inc. Cd147 antibodies, activatable cd147 antibodies, and methods of making and use thereof
WO2018183366A1 (en) 2017-03-28 2018-10-04 Syndax Pharmaceuticals, Inc. Combination therapies of csf-1r or csf-1 antibodies and a t-cell engaging therapy
WO2018204717A1 (en) 2017-05-03 2018-11-08 Harpoon Therapeutics, Inc. Compositions and methods for adoptive cell therapies
US20200270362A1 (en) 2017-05-12 2020-08-27 Harpoon Therapeutics, Inc. Msln targeting trispecific proteins and methods of use
WO2018209304A1 (en) 2017-05-12 2018-11-15 Harpoon Therapeutics, Inc. Msln targeting trispecific proteins and methods of use
EP3621994A4 (en) 2017-05-12 2020-12-30 Harpoon Therapeutics, Inc. MESOTHELIN BINDING PROTEINS
MY201312A (en) 2017-06-02 2024-02-16 Pfizer Antibodies specific for flt3 and their uses
WO2018232020A1 (en) 2017-06-13 2018-12-20 TCR2 Therapeutics Inc. Compositions and methods for tcr reprogramming using fusion proteins
AU2018298676A1 (en) 2017-07-10 2019-12-19 Innate Pharma Siglec-9-neutralizing antibodies
US11447545B2 (en) 2017-07-10 2022-09-20 Innate Pharma Combination therapy using antibody to human Siglec-9 and antibody to human NKG2A for treating cancer
MA51447A (fr) 2017-08-01 2020-06-10 Medimmune Llc Conjugué anticorps monoclonal-médicament dirigé contre bcma
JP7147270B2 (ja) 2017-09-15 2022-10-05 日本電産株式会社 変速機及びアクチュエータ
MX2020003915A (es) 2017-10-13 2020-10-08 Harpoon Therapeutics Inc Proteinas trispecificas y metodos de uso.
IL315737A (en) 2017-10-13 2024-11-01 Harpoon Therapeutics Inc B-cell maturation antigen-binding proteins
US11564946B2 (en) 2017-11-01 2023-01-31 Juno Therapeutics, Inc. Methods associated with tumor burden for assessing response to a cell therapy
WO2019136305A1 (en) 2018-01-04 2019-07-11 Neumedicines Inc. Cell-based and immune checkpoint inhibitor therapies combined with il-12 for treating cancer
CA3089230A1 (en) 2018-03-02 2019-09-06 Cdr-Life Ag Trispecific antigen binding proteins
WO2019222278A1 (en) * 2018-05-14 2019-11-21 Harpoon Therapeutics, Inc. Dual binding moiety
WO2019222282A1 (en) 2018-05-14 2019-11-21 Harpoon Therapeutics, Inc. Conditionally activated binding protein comprising a sterically occluded target binding domain
BR112020023330A2 (pt) 2018-05-14 2021-04-20 Harpoon Therapeutics, Inc. porção de ligação para ativação condicional de moléculas de imunoglobulina
KR102870868B1 (ko) 2018-06-01 2025-10-15 노파르티스 아게 Bcma에 대한 결합 분자 및 이의 용도
EP3806889A4 (en) 2018-06-18 2022-07-13 Anwita Biosciences, Inc. CYTOKI FUSION PROTEINS AND USES THEREOF
AU2019337974A1 (en) 2018-09-11 2021-04-08 iTeos Belgium SA Thiocarbamate derivatives as A2A inhibitors, pharmaceutical composition thereof and combinations with anticancer agents
US12195544B2 (en) 2018-09-21 2025-01-14 Harpoon Therapeutics, Inc. EGFR binding proteins and methods of use
US20210355219A1 (en) 2018-09-21 2021-11-18 Harpoon Therapeutics, Inc. Conditionally activated target-binding molecules
US20220054544A1 (en) 2018-09-21 2022-02-24 Harpoon Therapeutics, Inc. Conditionally active receptors
US10815311B2 (en) 2018-09-25 2020-10-27 Harpoon Therapeutics, Inc. DLL3 binding proteins and methods of use
US20220000872A1 (en) 2018-10-31 2022-01-06 Oncotracker, Inc. Method of enhancing immune-based therapy
CA3117978A1 (en) 2018-11-08 2020-05-14 Juno Therapeutics, Inc. Methods and combinations for treatment and t cell modulation
CN109593786A (zh) 2019-01-09 2019-04-09 上海怡豪生物科技有限公司 联合EpCAM和MSLN单链抗体的双靶点CAR载体及其构建方法和在乳腺癌应用
JP2022524337A (ja) 2019-03-05 2022-05-02 武田薬品工業株式会社 腫瘍抗原を標的とするｆｃ領域及び部分を含有する条件的に活性化された結合タンパク質
AU2020275002A1 (en) 2019-05-14 2021-12-23 Harpoon Therapeutics, Inc. EpCAM binding proteins and methods of use
WO2020252349A1 (en) 2019-06-13 2020-12-17 Cytomx Therapeutics, Inc. Use of an activatable anti-pdl1 antibody and an anti-ctla-4 antibody in a combination therapy for the treatment of cancer
CN119679936A (zh) 2019-06-24 2025-03-25 诺华股份有限公司 针对靶向b细胞成熟抗原的多特异性抗体的给药方案和组合疗法
WO2020263830A1 (en) 2019-06-25 2020-12-30 Gilead Sciences, Inc. Flt3l-fc fusion proteins and methods of use
WO2021097060A1 (en) 2019-11-13 2021-05-20 Harpoon Therapeutics, Inc. Pro immune modulating molecule comprising a clustering moiety
CN115768463A (zh) 2020-02-21 2023-03-07 哈普恩治疗公司 Flt3结合蛋白及使用方法
WO2021231434A1 (en) 2020-05-12 2021-11-18 Harpoon Therapeutics, Inc. Psma targeting tritacs and methods of use
WO2022031884A2 (en) 2020-08-05 2022-02-10 Synthekine, Inc. Il2rg binding molecules and methods of use
EP4192489A4 (en) 2020-08-05 2024-12-11 Synthekine, Inc. IL2RB-BINDING MOLECULES AND METHODS OF USE
WO2022098909A1 (en) 2020-11-06 2022-05-12 Harpoon Therapeutics, Inc. Epcam targeting trispecific protein for treatment of cancer
WO2022212732A1 (en) 2021-04-01 2022-10-06 Harpoon Therapeutics, Inc. Psma targeting tritacs and methods of use
AU2022286960A1 (en) 2021-06-03 2024-01-18 Harpoon Therapeutics, Inc. Bcma targeting trispecific proteins and methods of use
EP4347637A4 (en) 2021-06-03 2025-04-16 Harpoon Therapeutics, Inc. DLL3 as a target for trispecific proteins and methods of use
WO2022256498A1 (en) 2021-06-03 2022-12-08 Harpoon Therapeutics, Inc. Msln targeting trispecific proteins and methods of use
EP4359443A4 (en) 2021-06-25 2026-02-25 Harpoon Therapeutics Inc Sustained-release immune cell contact proteins and processing methods
EP4416185A4 (en) 2021-10-15 2025-09-03 Harpoon Therapeutics Inc CONDITIONAL ACTIVATION OF IMMUNOGLOBULIN MOLECULES

Patent Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5061620A (en) 1990-03-30 1991-10-29 Systemix, Inc. Human hematopoietic stem cell
WO1994004678A1 (en) 1992-08-21 1994-03-03 Casterman Cecile Immunoglobulins devoid of light chains
WO1999037681A2 (en) 1998-01-26 1999-07-29 Unilever Plc Method for producing antibody fragments
WO2000043507A1 (en) 1999-01-19 2000-07-27 Unilever Plc Method for producing antibody fragments
WO2001090190A2 (en) 2000-05-26 2001-11-29 National Research Council Of Canada Single-domain antigen-binding antibody fragments derived from llama antibodies
WO2002085945A2 (en) 2001-04-24 2002-10-31 Erasmus Universiteit Rotterdam Vhh single heavy chain antibody and a method for its preparation in a mammal
WO2003025020A1 (en) 2001-09-13 2003-03-27 Institute For Antibodies Co., Ltd. Method of constructing camel antibody library
WO2003035694A2 (en) 2001-10-24 2003-05-01 Vlaams Interuniversitair Instituut Voor Biotechnologie Vzw Functional heavy chain antibodies, fragments thereof, library thereof and methods of production thereof
WO2004049794A2 (en) 2002-12-03 2004-06-17 The Babraham Institute Single chain antibodies produced in a transgenic mouse
US20130273055A1 (en) * 2010-11-16 2013-10-17 Eric Borges Agents and methods for treating diseases that correlate with bcma expression
WO2013110531A1 (en) * 2012-01-23 2013-08-01 Ablynx Nv Sequences directed against hepatocyte growth factor (hgf) and polypeptides comprising the same for the treatment of cancers and/or tumors
WO2017025038A1 (en) 2015-08-11 2017-02-16 Nanjing Legend Biotech Co., Ltd. Chimeric antigen receptors based on single-domain antibodies and methods of use thereof

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
FISHMAN ET AL.: "Medicine", 1985, J.B. LIPPINCOTT CO.
GOODMANGILLMAN'S: "The Pharmaceutical Basis of Therapeutics", 1980, pages: 21 - 25
KABAT ET AL.: ", Sequences of Proteins of Immunological Interest", 1991, NATIONAL INSTITUTE OF HEALTH
LE GALL ET AL., J IMMUNOL METHODS., vol. 285, no. 1, 2004, pages 111 - 27
NAZARIAN ET AL., J. BIOMOL. SCREEN., vol. 20, 2015, pages 519 - 27
PHILADELPHIAMURPHY ET AL.: "Informed Decisions: The Complete Book of Cancer Diagnosis, Treatment, and Recovery, Viking Penguin", 1997, PENGUIN BOOKS U.S.A., INC.
RUNNING DEERALLISON, BIOTECHNOL PROG., vol. 20, 2004, pages 880 - 9

Cited By (31)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12084518B2 (en) 2015-05-21 2024-09-10 Harpoon Therapeutics, Inc. Trispecific binding proteins and methods of use
US10954311B2 (en) 2015-05-21 2021-03-23 Harpoon Therapeutics, Inc. Trispecific binding proteins and methods of use
US10544221B2 (en) 2016-05-20 2020-01-28 Harpoon Therapeutics, Inc. Single chain variable fragment CD3 binding proteins
US12528859B2 (en) 2016-05-20 2026-01-20 Harpoon Therapeutics, Inc. Single domain serum albumin binding protein
US11623958B2 (en) 2016-05-20 2023-04-11 Harpoon Therapeutics, Inc. Single chain variable fragment CD3 binding proteins
US11453716B2 (en) 2016-05-20 2022-09-27 Harpoon Therapeutics, Inc. Single domain serum albumin binding protein
US10844134B2 (en) 2016-11-23 2020-11-24 Harpoon Therapeutics, Inc. PSMA targeting trispecific proteins and methods of use
US10849973B2 (en) 2016-11-23 2020-12-01 Harpoon Therapeutics, Inc. Prostate specific membrane antigen binding protein
US11535668B2 (en) 2017-02-28 2022-12-27 Harpoon Therapeutics, Inc. Inducible monovalent antigen binding protein
US10730954B2 (en) 2017-05-12 2020-08-04 Harpoon Therapeutics, Inc. MSLN targeting trispecific proteins and methods of use
US10543271B2 (en) 2017-05-12 2020-01-28 Harpoon Therapeutics, Inc. Mesothelin binding proteins
US11607453B2 (en) 2017-05-12 2023-03-21 Harpoon Therapeutics, Inc. Mesothelin binding proteins
US11136403B2 (en) 2017-10-13 2021-10-05 Harpoon Therapeutics, Inc. Trispecific proteins and methods of use
US11976125B2 (en) 2017-10-13 2024-05-07 Harpoon Therapeutics, Inc. B cell maturation antigen binding proteins
US12371504B2 (en) 2017-10-13 2025-07-29 Harpoon Therapeutics, Inc. Trispecific proteins and methods of use
US10927180B2 (en) 2017-10-13 2021-02-23 Harpoon Therapeutics, Inc. B cell maturation antigen binding proteins
US12415860B2 (en) 2018-05-14 2025-09-16 Harpoon Therapeutics, Inc. Binding moiety for conditional activation of immunoglobulin molecules
US11492409B2 (en) 2018-06-01 2022-11-08 Novartis Ag Binding molecules against BCMA and uses thereof
US12275795B2 (en) 2018-06-01 2025-04-15 Novartis Ag Binding molecules against BCMA and uses thereof
US12195544B2 (en) 2018-09-21 2025-01-14 Harpoon Therapeutics, Inc. EGFR binding proteins and methods of use
US11807692B2 (en) 2018-09-25 2023-11-07 Harpoon Therapeutics, Inc. DLL3 binding proteins and methods of use
US10815311B2 (en) 2018-09-25 2020-10-27 Harpoon Therapeutics, Inc. DLL3 binding proteins and methods of use
US12516128B2 (en) 2019-05-14 2026-01-06 Harpoon Therapeutics, Inc. EpCAM binding proteins and methods of use
US12221481B2 (en) 2019-05-21 2025-02-11 Novartis Ag CD19 binding molecules and uses thereof
EP4106806A4 (en) * 2020-02-21 2024-07-24 Harpoon Therapeutics, Inc. FLT3-BINDING PROTEINS AND METHODS OF USE
US11180563B2 (en) 2020-02-21 2021-11-23 Harpoon Therapeutics, Inc. FLT3 binding proteins and methods of use
JP2023525049A (ja) * 2020-05-08 2023-06-14 シアトル・チルドレンズ・ホスピタル・ドゥーイング／ビジネス／アズ・シアトル・チルドレンズ・リサーチ・インスティテュート ナチュラルキラー細胞を標的とするキメラ抗原受容体（ｃａｒ）
WO2022060901A1 (en) 2020-09-16 2022-03-24 Amgen Inc. Methods for administering therapeutic doses of bispecific t-cell engaging molecules for the treatment of cancer
US12275798B2 (en) 2021-06-17 2025-04-15 Boehringer Ingelheim International Gmbh Tri-specific binding molecules
WO2022263507A1 (en) 2021-06-17 2022-12-22 Boehringer Ingelheim International Gmbh Novel tri-specific binding molecules
WO2026072671A1 (en) 2024-09-24 2026-04-02 City Of Hope Methods comprising oncolytic viruses expressing bcmat and bcma-targeted therapies

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