WO2021119505A1 - Anti-ly6g6d antibodies and methods of use - Google Patents

Anti-ly6g6d antibodies and methods of use Download PDF

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Publication number
WO2021119505A1
WO2021119505A1 PCT/US2020/064635 US2020064635W WO2021119505A1 WO 2021119505 A1 WO2021119505 A1 WO 2021119505A1 US 2020064635 W US2020064635 W US 2020064635W WO 2021119505 A1 WO2021119505 A1 WO 2021119505A1
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Prior art keywords
amino acid
seq
antibody
acid sequence
cdr
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PCT/US2020/064635
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English (en)
French (fr)
Inventor
Weiyu Lin
Christoph Spiess
Liping Sun
Yan Wu
Cecilia P.C. CHIU
Walter Christian DARBONNE
Michael Andrew DILLON
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Genentech Inc
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Genentech Inc
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Priority to AU2020403145A priority Critical patent/AU2020403145B2/en
Priority to CN202080086360.1A priority patent/CN114867494B9/zh
Priority to CA3163950A priority patent/CA3163950A1/en
Priority to PH1/2022/551419A priority patent/PH12022551419A1/en
Priority to CN202311172932.XA priority patent/CN117417448A/zh
Priority to EP20829495.9A priority patent/EP4072584A1/en
Priority to CR20220330A priority patent/CR20220330A/es
Priority to KR1020227024067A priority patent/KR20220113790A/ko
Priority to PE2022001066A priority patent/PE20221511A1/es
Priority to CR20230209A priority patent/CR20230209A/es
Priority to IL293423A priority patent/IL293423A/en
Priority to MX2022007158A priority patent/MX2022007158A/es
Application filed by Genentech Inc filed Critical Genentech Inc
Priority to BR112022011357A priority patent/BR112022011357A2/pt
Priority to CR20230210A priority patent/CR20230210A/es
Publication of WO2021119505A1 publication Critical patent/WO2021119505A1/en
Anticipated expiration legal-status Critical
Priority to ZA2022/06670A priority patent/ZA202206670B/en
Priority to CONC2022/0009737A priority patent/CO2022009737A2/es
Ceased legal-status Critical Current

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    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
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    • A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
    • C07K16/2809—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against the T-cell receptor (TcR)-CD3 complex
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    • C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
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    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
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    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
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    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57407—Specifically defined cancers
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    • G01N33/57484—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites
    • G01N33/57492—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites involving compounds localized on the membrane of tumor or cancer cells
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    • C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
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    • 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
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    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/40—Immunoglobulins specific features characterized by post-translational modification
    • C07K2317/41—Glycosylation, sialylation, or fucosylation
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    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
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    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
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    • G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants

Definitions

  • the disclosure features a bispecific antibody that binds to LY6G6D and CD3, wherein the bispecific antibody comprises a LY6G6D binding domain comprising a heavy chain polypeptide (H1) and a light chain polypeptide (L1) and a CD3 binding domain comprising a heavy chain polypeptide (H2) and a light chain polypeptide (L2), and wherein: (a) H1 comprises the amino acid sequence of SEQ ID NO: 7; (b) L1 comprises the amino acid sequence of SEQ ID NO: 9; (c) H2 comprises the amino acid sequence of SEQ ID NO: 18; and (d) L2 comprises the amino acid sequence of SEQ ID NO: 57.
  • H1 comprises the amino acid sequence of SEQ ID NO: 7
  • L1 comprises the amino acid sequence of SEQ ID NO: 9
  • H2 comprises the amino acid sequence of SEQ ID NO: 18
  • L2 comprises the amino acid sequence of SEQ ID NO: 57.
  • Fig. 5A is a diagram showing the amino acid sequence of the heavy chain variable region of 20A12.QNTv12 (two-cell) (SEQ ID NO: 22) according to the Kabat numbering system.
  • the complementarity-determining regions (CDRs) CDR H1 , CDR H2, and CDR H3 are indicated.
  • CDR sequences according to the Kabat numbering system are underlined.
  • celecoxib or etoricoxib proteosome inhibitor
  • CCI-779 tipifarnib (R11577); orafenib, ABT510
  • Bcl-2 inhibitor such as oblimersen sodium (GENASENSE®)
  • pixantrone farnesyltransferase inhibitors
  • SCH 6636 farnesyltransferase inhibitors
  • pharmaceutically acceptable salts, acids or derivatives of any of the above as well as combinations of two or more of the above such as CHOP, an abbreviation for a combined therapy of cyclophosphamide, doxorubicin, vincristine, and prednisolone
  • FOLFOX an abbreviation for a treatment regimen with oxaliplatin (ELOXATINTM) combined with 5-FU and leucovorin.
  • “Complement dependent cytotoxicity” or “CDC” refers to the lysis of a target cell in the presence of complement. Activation of the classical complement pathway is initiated by the binding of the first component of the complement system (C1q) to antibodies (of the appropriate subclass) that are bound to their cognate antigen.
  • C1q first component of the complement system
  • a CDC assay e.g., as described in Gazzano- Santoro et al., J. Immunol. Methods 202:163 (1996), can be performed.
  • growth inhibitory agent when used herein refers to a compound or composition which inhibits growth of a cell either in vitro or in vivo.
  • growth inhibitory agent is growth inhibitory antibody that prevents or reduces proliferation of a cell expressing an antigen to which the antibody binds.
  • the growth inhibitory agent may be one which significantly reduces the percentage of cells in S phase.
  • aspects of growth inhibitory agents include agents that block cell cycle progression (at a place other than S phase), such as agents that induce G1 arrest and M-phase arrest.
  • PD-1 axis binding antagonist refers to a molecule that inhibits the interaction of a PD-1 axis binding partner with either one or more of its binding partner, so as to remove T cell dysfunction resulting from signaling on the PD-1 signaling axis - with a result being to restore or enhance T cell function (e.g., proliferation, cytokine production, target cell killing).
  • a PD-1 axis binding antagonist includes a PD-1 binding antagonist, a PD-L1 binding antagonist and a PD-L2 binding antagonist.
  • a LY6G6D epitope may be determined by the LY6G6D binding domain of the anti-LY6G6D antibody binding to peptide fragments of the epitope.
  • a LY6G6D epitope may also be determined by alanine scanning mutagenesis.
  • a reduction in binding of a LY6G6D binding domain to mutated LY6G6D by 20%, 30%, 50%, 80% or more indicates the amino acid residue of LY6G6D mutated in an alanine scanning mutagenesis assay is an epitopic residue for the LY6G6D binding domain.
  • a LY6G6D epitope may be determined by mass spectrometry.
  • the epitope is determined by crystallography (e.g., crystallography methods).
  • the invention provides an anti-LY6G6D antibody having a binding domain comprising all six of (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 4; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 5; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 6; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 1 ; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 2; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 107.
  • the anti-LY6G6D antibody may comprise at least one (e.g., 1 , 2, 3, or 4) of (a) an FR-H1 comprising the amino acid sequence of SEQ ID NO: 34; (b) an FR-H2 comprising the amino acid sequence of SEQ ID NO: 35; (c) an FR-H3 comprising the amino acid sequence of SEQ ID NO: 36; and (d) an FR-H4 comprising the amino acid sequence of SEQ ID NO: 37.
  • FR-H1 comprising the amino acid sequence of SEQ ID NO: 34
  • an FR-H2 comprising the amino acid sequence of SEQ ID NO: 35
  • an FR-H3 comprising the amino acid sequence of SEQ ID NO: 36
  • an FR-H4 comprising the amino acid sequence of SEQ ID NO: 37.
  • the anti- LY6G6D antibody may comprise at least one (e.g., 1 , 2, 3, or 4) of (a) an FR-L1 comprising the amino acid sequence of SEQ ID NO: 38; (b) an FR-L2 comprising the amino acid sequence of SEQ ID NO: 61 ;
  • the anti-LY6G6D antibody may have a VH domain comprising the amino acid sequence of SEQ ID NO: 59 and/or a VL domain comprising the amino acid sequence of SEQ ID NO: 60.
  • an anti-CD3 antibody may be humanized.
  • an anti-CD3 antibody comprises CDRs as in any of the above embodiments, and further comprises an acceptor human framework, e.g., a human immunoglobulin framework or a human consensus framework.
  • Diabodies are antibody fragments with two antigen-binding sites that may be bivalent or bispecific. See, for example, EP 404,097; WO 1993/01161 ; Hudson et al. Nat. Med. 9:129-134 (2003); and Hollinger et al. Proc. Natl. Acad. Sci. USA 90: 6444-6448 (1993). Triabodies and tetrabodies are also described in Hudson et al. Nat. Med. 9:129-134 (2003).
  • Human antibodies may also be generated by isolating Fv clone variable domain sequences selected from human-derived phage display libraries. Such variable domain sequences may then be combined with a desired human constant domain. Techniques for selecting human antibodies from antibody libraries are described below.
  • the second domain binding to CD3 comprises all six of (a) a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 15; (b) a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 16; (c) a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 17; (d) a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 12; (e) a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 13; and (f) a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 14.
  • the second domain binding to CD3 may have a VH2 domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or having the sequence of, SEQ ID NO: 20 and/or a VL2 domain comprising an amino acid sequence having at least 90% sequence identity (e.g., at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity) to, or having the sequence of, SEQ ID NO: 55.
  • the anti-CD3 antibody can be 38E4.v1 MD4 or a derivative or clonal relative thereof.
  • the second domain binding to CD3 may comprise at least one (e.g., 1 , 2, 3, or 4) of (a) an FR-H1 comprising the amino acid sequence of SEQ ID NO: 42; (b) an FR-H2 comprising the amino acid sequence of SEQ ID NO: 43 or SEQ ID NO: 62; (c) an FR-H3 comprising the amino acid sequence of SEQ ID NO: 44; and (d) an FR-H4 comprising the amino acid sequence of SEQ ID NO: 45 and/or at least one (e.g., 1 , 2, 3, or 4) of (a) an FR-L1 comprising the amino acid sequence of SEQ ID NO: 46; (b) an FR-L2 comprising the amino acid sequence of SEQ ID NO: 47 or SEQ ID NO: 63; (c) an FR-L3 comprising the amino acid sequence of SEQ ID NO: 48; and (d) an FR-L4 comprising the amino acid sequence of SEQ ID NO: 49.
  • a an
  • Techniques for making multispecific antibodies include, but are not limited to, recombinant coexpression of two immunoglobulin heavy chain-light chain pairs having different specificities (see Milstein and Cuello, Nature 305: 537 (1983)), WO 93/08829, and Traunecker et al., EMBO J. 10: 3655 (1991)), and “knob-in-hole” engineering (see, e.g., U.S. Patent No. 5,731 ,168). “Knob-in-hole” engineering of multispecific antibodies may be utilized to generate a first arm containing a knob and a second arm containing the hole into which the knob of the first arm may bind.
  • the oligosaccharide may include various carbohydrates, e.g., mannose, N-acetyl glucosamine (GlcNAc), galactose, and sialic acid, as well as a fucose attached to a GlcNAc in the “stem” of the biantennary oligosaccharide structure.
  • modifications of the oligosaccharide in an antibody of the invention may be made in order to create antibody variants with certain improved properties.
  • the invention contemplates an anti-LY6G6D and/or an anti-CD3 antibody variant that possesses some but not all effector functions, which make it a desirable candidate for applications in which the half-life of the antibody in vivo is important, yet certain effector functions (such as complement and ADCC) are unnecessary or deleterious.
  • In vitro and/or in vivo cytotoxicity assays can be conducted to confirm the reduction/depletion of CDC and/or ADCC activities.
  • Fc receptor (FcR) binding assays can be conducted to ensure that the antibody lacks FcyR binding (hence likely lacking ADCC activity), but retains FcRn binding ability.
  • ADCC activity of the molecule of interest may be assessed in vivo, e.g., in an animal model such as that disclosed in Clynes et al. Proc. Natl Acad. Sci. USA 95:652-656 (1998).
  • C1q binding assays may also be carried out to confirm that the antibody is unable to bind C1q and hence lacks CDC activity. See, e.g., C1q and C3c binding ELISA in WO 2006/029879 and WO 2005/100402.
  • a CDC assay may be performed (see, for example, Gazzano-Santoro et al. J. Immunol.
  • the anti-CD3 antibody comprising the N297G mutation comprises an anti- LY6G6D arm comprising a first binding domain comprising (a) a VH domain comprising an amino acid sequence of SEQ ID NO: 10 or SEQ ID NO: 59 and (b) a VL domain comprising an amino acid sequence of SEQ ID NO: 11 or SEQ ID NO; 60, and an anti-CD3 arm, wherein (a) the anti-LY6G6D arm comprises T366W and N297G substitution mutations and (b) the anti-CD3 arm comprises T366S, L368A, Y407V, and N297G mutations.
  • an anti-LY6G6D antibody of the invention e.g., bispecific anti-LY6G6D antibody of the invention that binds to LY6G6D, preferably with high affinity (e.g., 20A12.QNTv12), and a second biological molecule, e.g., CD3) provided herein may be further modified to contain additional nonproteinaceous moieties that are known in the art and readily available.
  • the moieties suitable for derivatization of the antibody include but are not limited to water soluble polymers.
  • Polyethylene glycol propionaldehyde may have advantages in manufacturing due to its stability in water.
  • the polymer may be of any molecular weight, and may be branched or unbranched.
  • the number of polymers attached to the antibody may vary, and if more than one polymer are attached, they can be the same or different molecules. In general, the number and/or type of polymers used for derivatization can be determined based on considerations including, but not limited to, the particular properties or functions of the antibody to be improved, whether the antibody derivative will be used in a therapy under defined conditions, etc.
  • the VL2 domain is linked to a CL domain (CL2) and the VH2 is linked to a CH1 domain (CH1 2 ), wherein (a) the CL2 comprises one or more mutations at amino acid residues F116,
  • the CH1 2 comprises one or more mutations at amino acid residues A141 , F170, S181 , S183, and/or V185 (EU numbering).
  • the CL2 comprises one or more of the following substitution mutations: F116A, L135V, S174A, S176F, and/or T178V.
  • the CL2 comprises the following substitution mutations: F116A, L135V, S174A, S176F, and T178V.
  • the CH1 2 comprises one or more of the following substitution mutations: A141 I, F170S, S181 M, S183A, and/or V185A.
  • the CH1 2 comprises the following substitution mutations: A141 I, F170S, S181 M, S183A, and V185A.
  • the CR ? consists of the Q39E substitution mutation.
  • the second binding domain that binds CD3 comprises a VH domain (VH2) comprising a charged region (CR 3 ) and a VL domain (VL2) comprising a charged region (CR 4 ), wherein the CR 3 in the VH2 forms a charge pair with the CR 4 in the VL2.
  • the CR 3 comprises a basic amino acid residue and the CR 4 comprises an acidic amino acid residue.
  • the CR 3 comprises a Q39K substitution mutation (Kabat numbering).
  • the CR 3 consists of the Q39K substitution mutation.
  • a ricin immunotoxin can be prepared as described in Vitetta et al., Science 238:1098 (1987).
  • Carbon-14-labeled 1-isothiocyanatobenzyl-3-methyldiethylene triaminepentaacetic acid (MX- DTPA) is an exemplary chelating agent for conjugation of radionucleotide to the antibody. See W094/11026.
  • the linker may be a “cleavable linker” facilitating release of a cytotoxic drug in the cell.
  • luciferin 2,3-dihydrophthalazinediones
  • horseradish peroxidase HRP
  • alkaline phosphatase b-galactosidase
  • glucoamylase lysozyme
  • saccharide oxidases e.g., glucose oxidase, galactose oxidase, and glucose-6-phosphate dehydrogenase
  • heterocyclic oxidases such as uricase and xanthine oxidase, coupled with an enzyme that employs hydrogen peroxide to oxidize a dye precursor such as HRP, lactoperoxidase, or microperoxidase, biotin/avidin, spin labels, bacteriophage labels, stable free radicals, and the like.
  • the invention provides a method for enhancing immune function in an individual having a cell proliferative disorder.
  • the method comprises administering to the individual an effective amount of an anti-LY6G6D antibody (e.g., a LY6G6D TDB having an anti-CD3 arm (e.g., 38E4.v1 MD1 or 38E4.v1 MD4) and an anti-Ly6G6D arm (e.g., 20A12.QNTv12)) to activate effector cells (e.g., T cells, e.g., CD8+ and/or CD4+ T cells), expand (increase) an effector cell population, reduce a target cell population (e.g., a population of cells expressing LY6G6D), and/or kill a target cell (e.g., target tumor cell).
  • an “individual” is a human.
  • the additional therapeutic agent is an immunomodulatory agent, e.g., a PD-L1 axis binding antagonist, which may be a PD-1 binding antagonist, a PD-L1 binding antagonist, or a PD-L2 binding antagonist.
  • PD-1 (programmed death 1) is also referred to in the art as “programmed cell death 1 ,” “PDCD1 ,” “CD279,” and “SLEB2.”
  • An exemplary human PD-1 is shown in UniProtKB/Swiss-Prot Accession No. Q15116.
  • Example 2 Manufacturing liabilities in anti-LY6G6D 1G4 arm, anti-LY6G6D clone generation, epitope mapping, and humanization
  • rabbit antibodies contain extra cysteine residues.
  • the rabbit 20A12 clone contains a cysteine pair in CDR-H1 and CDR-H2 (C35 at CDR-H1 and C50 at CDR-H2)
  • TDBs comprising the anti-LY6G6D arm 20A12.QNTv12 and the anti-CD3 38E4.v1 (left panel; produced using a two-cell-manufacturing system), 38E4.v1 MD1 (center panel; produced using a one- cell-manufacturing system), or 38E4.v1 MD4 arm (right panel; produced using a one-cell-manufacturing system) were assayed for affinity for a human Ly6G6D polypeptide (Fig. 25) using a BIAcore assay. Results of these assays are provided in Table 8.
  • the anti-gD administered group had the highest exposure compared to the groups administered anti-CD3 antibody variants.
  • the 40G5c administered group had slightly lower exposure based on its AUCiast value compared to the anti-gD administered group and had the highest exposure compared to the rest of the anti-CD3 antibody variants.
  • 38E4v1 had the lowest exposure based on its AUCiast compared to the rest of the anti-CD3 antibody variants.

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WO2024155807A1 (en) 2023-01-18 2024-07-25 Genentech, Inc. Multispecific antibodies and uses thereof
WO2024220256A1 (en) * 2023-04-18 2024-10-24 Qlsf Biotherapeutics, Inc. Antibodies binding to ly6g6d
WO2025139525A1 (zh) * 2023-12-26 2025-07-03 广东东阳光药业股份有限公司 一种靶向Ly6G6D的纳米抗体及其应用

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