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JP-7854948-B2 - MIC antibodies, binders, and methods of using them

JP7854948B2JP 7854948 B2JP7854948 B2JP 7854948B2JP-7854948-B2

Inventors

  • ウー， ジェニファー トンラン

Assignees

  • キャンキュア， エルエルシー

Dates

Publication Date
20260507
Application Date
20210706
Priority Date
20200707

Claims (20)

  1. An isolated antibody or its antigen-binding moiety that specifically binds to MIC, wherein the antibody or its antigen-binding moiety comprises a heavy-chain variable (VH) region and a light-chain variable (VL) region, wherein the VH region comprises a complementarity-determining region HCDR1 sequence having the amino acid sequence represented by SEQ ID NO: 11, HCDR2 having the amino acid sequence represented by SEQ ID NO: 12, and HCDR3 having the amino acid sequence represented by SEQ ID NO: 13, and the VL region comprises an LCDR1 sequence having the amino acid sequence represented by SEQ ID NO: 14, LCDR2 having the amino acid sequence represented by SEQ ID NO: 15, and LCDR3 having the amino acid sequence represented by SEQ ID NO: 16, wherein the VH region comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 1, and the VL region comprises an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 2.
  2. The isolated antibody or its antigen-binding portion according to claim 1, wherein the VH region comprises an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 1.
  3. The isolated antibody or its antigen-binding portion according to claim 1 or 2, wherein the VH region comprises the amino acid sequence of SEQ ID NO: 1.
  4. The isolated antibody or its antigen-binding portion according to any one of claims 1 to 3, wherein the VL region comprises the amino acid sequence of SEQ ID NO: 2.
  5. An isolated antibody or its antigen-binding moiety according to any one of claims 1 to 4, which is an antibody selected from a monoclonal antibody, a bispecific antibody, and a multispecific antibody.
  6. An isolated antibody or its antigen-binding moiety according to any one of claims 1 to 4, wherein the antigen-binding moiety is selected from Fab, Fab', F(ab') 2 , Fv, disulfide bond Fv, scFv , and diabody.
  7. An isolated antibody or its antigen-binding moiety according to any one of claims 1 to 5, wherein the antibody comprises a heavy chain including the VH region and a heavy chain constant region, and a light chain including the VL region and a light chain constant region.
  8. The isolated antibody or its antigen-binding moiety according to claim 7, wherein the heavy chain constant region is an IgG isotype.
  9. The isolated antibody or its antigen-binding moiety according to claim 7 or 8, wherein the heavy chain constant region is an IgG1 constant region or an IgG4 constant region.
  10. The isolated antibody or its antigen-binding moiety according to any one of claims 7 to 9, wherein the heavy chain constant region is Fc null.
  11. The isolated antibody or its antigen-binding moiety according to any one of claims 7 to 10, wherein the heavy chain constant region is an IgG1 constant region and comprises at least one amino acid modification that reduces binding to one or more Fc gamma receptors.
  12. The isolated antibody or its antigen-binding moiety according to any one of claims 7 to 11, wherein the heavy chain constant region is an IgG1 constant region and comprises (i) one or more substitutions that reduce the binding affinity of the Fc domain to the Fc receptor, at least one of which is selected from E233P, L234V, L234A, L235A, L235E, G236A, G237A, E318A, K320A, K322A, A327G, A330S, and P331S (according to the EU index of Kabat numbering); and/or (ii) GGGS between G237 and G238 (according to the EU index of Kabat numbering).
  13. The heavy chain constant region is an IgG1 constant region, and comprises substitutions of L234A and L235A (according to the EU index of Kabat numbering), as described in any one of claims 7 to 12, wherein the isolated antibody or its antigen-binding moiety.
  14. The isolated antibody or its antigen-binding moiety according to claim 13, wherein the heavy chain constant region includes a substitution of P329 (according to the EU index of Kabat numbering).
  15. The heavy chain comprises the amino acid sequence represented by SEQ ID NO: 3, wherein the isolated antibody or its antigen-binding moiety is as described in any one of claims 7 to 9.
  16. The isolated antibody or its antigen-binding moiety according to any one of claims 7 to 15, wherein the light chain constant region is a kappa isotype.
  17. The light chain comprises the amino acid sequence represented by SEQ ID NO: 4, wherein the isolated antibody or its antigen-binding moiety is as described in any one of claims 7 to 16.
  18. A pharmaceutical composition comprising an isolated antibody or its antigen-binding moiety according to any one of claims 1 to 17, and a pharmaceutically acceptable carrier.
  19. A nucleic acid encoding an isolated antibody or its antigen-binding portion according to any one of claims 1 to 17.
  20. The nucleic acid according to claim 19, comprising the nucleic acid sequence represented by SEQ ID NO: 21 and/or the nucleic acid sequence represented by SEQ ID NO: 22.

Description

Cross-reference of related applications This application claims priority to U.S. Provisional Application No. 63/049,012, filed on 7 July 2020, which is incorporated herein by reference in its entirety for all purposes. Information regarding support funds: This invention was made with government support under Small Business Technology Transfer Grant 1R41CA206688-01A1, granted by the U.S. Small Business Administration. The government has certain rights to this invention. Major histocompatibility complex class I chain-related molecules A and B (MICA and MICB, respectively, commonly referred to as MIC) are a family of proteins that bind to NKG2D. NKG2D is an activated immune receptor expressed by natural killer (NK) cells, NKT cells, a subset of gamma delta T cells, and human CD8 T cells. While MIC binding to NKG2D on NK cells or T cells has other effects, in vitro, it activates NK cells and co-stimulates CD8 T cells and gamma delta T cells. The MIC family of molecules is expressed on tumor cells and is thought to be involved in suppressing the immune response against tumor cells. MICA is expressed more frequently and in larger quantities on the surface of tumor cells than MICB. MIC proteins are found in both membrane-bound and soluble (sMIC) forms, the latter being shed from tumor cells. Elevated serum levels of sMIC are associated with many types of cancer, including solid tumors such as melanoma, prostate cancer, ovarian cancer, cervical cancer, breast cancer, lung cancer, colon cancer, kidney cancer, gastrointestinal (GI) cancer, and head and neck cancer, as well as hematological cancers such as lymphoma and multiple myeloma, and bone and soft tissue cancers such as sarcomas. Membrane-bound MIC(B) has been reported to maintain protective antitumor immunity mediated by NKG2D in mice, while the soluble form correlated with tumor progression resulting from decreased NKG2D expression in NK cells and CD8 T cells and impaired peripheral maintenance of NK cells. Therefore, drugs that bind to sMICs could represent a potential therapeutic approach for patients. However, there is still a need for drugs optimized for the treatment of MICs plus cancer in humans. The inventions disclosed herein are, in part, based on MIC-binding antibodies, their antigen-binding moieties, and associated binders that specifically bind to soluble MICs (sMICs) and/or cell membrane-bound MICs (also known as membrane-bound MICs), exhibiting improved therapeutic properties. MICs, and in particular sMICs, are important and advantageous therapeutic targets for the treatment of certain cancers. These MIC-binding antibodies, their antigen-binding moieties, and binders provide compositions and methods based on the use of such antibodies, antigen-binding moieties, and associated binders in the treatment of MIC+ cancers. Accordingly, the present invention provides methods, compositions, kits, and products related to MIC binders. In some embodiments, a binder is provided comprising (i) a heavy chain variable region having the amino acid sequence represented by SEQ ID NO: 1 and (ii) a light chain variable region having the amino acid sequence represented by SEQ ID NO: 2, wherein the framework regions of the heavy chain and light chain are optionally modified by substitution, deletion, or insertion of 1 to 8 amino acids in the framework region. This binder specifically binds to MIC. In some embodiments, the binder specifically binds to MIC with a higher binding affinity than antibody B10G5. In some embodiments, the binder comprises (i) a heavy chain variable region having the amino acid sequence represented by SEQ ID NO: 1 and (ii) a light chain variable region having the amino acid sequence represented by SEQ ID NO: 2. This binder specifically binds to MIC. In some embodiments, the binder specifically binds to MIC with a higher binding affinity than antibody B10G5. In some embodiments, a binder is provided comprising a heavy chain variable (VH) region and a light chain variable (VL) region, wherein the VH region comprises a complementarity-determining region HCDR1 having the amino acid sequence represented by SEQ ID NO: 11, HCDR2 having the amino acid sequence represented by SEQ ID NO: 12, and HCDR3 having the amino acid sequence represented by SEQ ID NO: 13, and the VL region comprises LCDR1 having the amino acid sequence represented by SEQ ID NO: 14, LCDR2 having the amino acid sequence represented by SEQ ID NO: 15, and LCDR3 having the amino acid sequence represented by SEQ ID NO: 16, and the VH region and VL region each comprise a humanized framework region. In some embodiments, the humanized VH framework region is derived from a human germ cell gene having the amino acid sequence represented by IMGT IGHV4-59*11 (SEQ ID NO: 29) and IGHJ4*01 (SEQ ID NO: 30) or IGHV4-30-4*01 (SEQ ID NO: 31) and IGHJ4*01 (SEQ ID NO: 30). In some embodiments, the humanized VL framework region is derived from a human germ cell gene having an amino acid sequence represe