Antibodies that target the human leukocyte antigen cathepsin G peptide complex.

Abstract

This disclosure provides antibodies or antigen-binding moieties that specifically bind to antigens related to myelomatous malignancies, various compositions of such antibodies or antigen-binding moieties, and methods for using them. The disclosure provides such antibodies, fragments of such antibodies that retain myelomatous malignancy antigen-binding ability, pharmaceutical compositions comprising such antibodies or antigen-binding fragments, and diagnostic compositions comprising such antibodies or antigen-binding fragments. The disclosure further provides isolated nucleic acids encoding such antibodies, amino acid sequences of such antibodies, and host cells transformed thereby. In addition, the disclosure provides therapeutic and diagnostic methods using the antibodies and nucleic acids of the disclosure. Finally, the disclosure provides recombinant bispecific antibodies capable of specifically binding to CG1 and CD3.

Claims

1. A heavy chain (HC) variable region is an HC variable region sequence containing a CDR1 sequence containing one of sequence numbers 67-78; and The light chain (LC) variable region is an LC variable region sequence containing a CDR1 sequence that includes one of sequence numbers 96-105. An isolated antibody containing or its antigen-binding moiety.

2. The isolated antibody or antibody fragment according to claim 1, wherein the HC variable region further comprises a CDR2 sequence including one of sequence numbers 79-87 or 129-131.

3. The isolated antibody or antibody fragment according to claim 1 or claim 2, wherein the LC variable region further comprises a CDR2 sequence including one of sequence numbers 106 to 117.

4. The isolated antibody or antibody fragment according to any one of claims 1 to 3, wherein the HC variable region further comprises a CDR3 sequence including one of sequence numbers 88 to 95.

5. The isolated antibody or antibody fragment according to any one of claims 1 to 4, wherein the LC variable region further comprises a CDR3 sequence including one of sequence numbers 118 to 123.

6. The isolated antibody or antibody fragment according to any one of claims 1 to 5, wherein the antibody or antibody fragment is a human antibody or a human antibody fragment.

7. (a) a heavy chain variable region (VH) having at least 90% identity with any one of sequence numbers 7, 8, 9, 15, 16, 55, 133, or 134; and (b) A light chain variable region (VL) having at least 90% identity with one of sequence numbers 24, 35, 36, 42, 43, 56, or 132. An isolated antibody containing or its antigen-binding moiety.

8. The isolated antibody or antibody fragment according to any one of claims 1 to 7, wherein the antibody fragment is a monovalent scFv (single-chain fragment variable) antibody, a bivalent scFv, a Fab fragment, an F(ab')2 fragment, an F(ab')3 fragment, an Fv fragment, or a single-chain antibody.

9. The isolated antibody or antibody fragment according to any one of claims 1 to 8, wherein the antibody is a chimeric antibody, a bispecific antibody, a trispecific or other polyspecific antibody, or BiTE.

10. The isolated antibody or antibody fragment according to any one of claims 1 to 9, wherein the antibody is an IgG antibody, a recombinant IgG antibody, or an antibody fragment.

11. The antibody or antibody fragment a) Compared to samples from wild-type subjects or subjects without cancer, HLA-A ＊ Increased binding affinity to CG1 presented by 0201 An isolated antibody or antibody fragment according to any one of claims 1 to 10, having the characteristics of the isolated antibody or antibody fragment according to any one of claims 1 to 10.

12. An isolated antibody or antibody fragment according to any one of claims 1 to 11, wherein the antibody is conjugated or fused with an imaging agent, a cytotoxic agent, a metal, or a radioactive moiety.

13. The isolated antibody or antibody fragment according to claim 12, wherein the imaging agent is a fluorophore.

14. The isolated antibody or antibody fragment according to claim 12, wherein the radioactive portion comprises at least one of Zr-89, Cu-64, F-18, Y-90, Lu-177, At-211, Ac-225, or Pb-212.

15. The isolated antibody or antibody fragment according to any one of claims 1 to 14, wherein the antibody is an immunoconjugate or a radioimmunoconjugate.

16. The isolated antibody or antibody fragment according to any one of claims 1 to 15, wherein the antibody is an antibody-drug conjugate.

17. An isolated antibody or antibody fragment according to any one of claims 1 to 16, further comprising an amino acid having at least 90% identity with SEQ ID NO:

57.

18. An isolated antibody or antibody fragment according to any one of claims 1 to 17, comprising an amino acid sequence having at least 90% similarity to any one of sequence numbers 55, 56, and 57.

19. An isolated antibody or antibody fragment according to any one of claims 1 to 18, comprising any one of sequence numbers 55 to 57.

20. An isolated antibody or antibody fragment according to any one of claims 1 to 19, comprising essentially one of sequence numbers 55 to 57.

21. (a) a heavy chain variable region (VH) having at least 90% identity with any one of sequence numbers 7, 8, 9, 15, 16, 55, 133, or 134; and (b) A light chain variable region (VL) having at least 90% identity with one of sequence numbers 34, 35, 36, 42, 43, 56, or 132. An isolated antibody or antibody fragment according to any one of claims 1 to 20, comprising essentially the above.

22. (a) any one of sequence numbers 7, 8, 9, 15, 16, 55, 133, or 134; and (b) Any one of sequence numbers 34, 35, 36, 42, 43, 56, or 132 An isolated antibody or antibody fragment according to any one of claims 1 to 20, comprising essentially the above.

23. (a) an extracellular target binding domain comprising an antibody or antigen-binding moiety according to any one of claims 1 to 22; (b) transmembrane domain; and (c) Signal transduction domain A chimeric antigen receptor (CAR) that includes this receptor.

24. The CAR according to claim 23, wherein the antibody or its antigen-binding portion is a single-chain antibody fragment, a single-chain Fv (scFv), a single-chain Fab, a single-chain Fab', a single-domain antibody fragment, a single-domain polyspecific antibody, an intrabody, a nanobody, or a single-chain immunokine.

25. The CAR according to claim 23 or 24, wherein the antibody or its antigen-binding portion is an scFv containing an amino acid sequence that is at least 90% identical to SEQ ID NOs: 1-27, 133, or 134.

26. The CAR according to any one of claims 23 to 25, wherein the hinge and transmembrane domains include a CD8α or CD28 hinge and transmembrane domain.

27. A CAR according to any one of claims 23 to 26, wherein the signal transduction domain comprises a 4-1BB signal transduction domain, a CD28 signal transduction domain, an OX-40 signal transduction domain, and / or a CD3ζ signal transduction domain.

28. A CAR according to any one of claims 23 to 27, further comprising a leader array and / or hinge domains.

29. A CAR according to any one of claims 23 to 28, comprising an amino acid sequence that is at least 90% identical to SEQ ID NOs: 1 to 27, 133, or 134.

30. The CAR according to any one of claims 23 to 29, wherein the extracellular target binding domain further comprises one or more additional antigen-binding domains.

31. The CAR according to claim 30, wherein one or more additional antigen-binding domains specifically bind to CD3.

32. An antibody or antigen-binding moiety thereof according to any one of claims 1 to 22, or a recombinant nucleic acid molecule encoding a CAR according to any one of claims 23 to 31.

33. An isolated nucleic acid encoding an antibody heavy chain and / or light chain variable region of an antibody or antibody fragment according to any one of claims 1 to 32, or other amino acids.

34. An expression vector comprising the nucleic acid described in claim 33.

35. A hybridoma or engineered cell comprising an antibody or antibody fragment according to any one of claims 1 to 22, or a nucleic acid encoding a CAR according to any one of claims 1 to 32.

36. A hybridoma or engineered cell comprising the nucleic acid described in claim 35.

37. (a) pharmaceutically acceptable carriers; and (b) A cell comprising an isolated antibody or its antigen-binding moiety according to any one of claims 1 to 22, or a CAR according to any one of claims 23 to 31. Pharmaceutical preparations containing the above.

38. (a) pharmaceutically acceptable carriers; and (b) The isolated antibody or antigen-binding moiety according to any one of claims 1 to 22 Diagnostic preparations containing these ingredients.

39. A method for treating a subject having cancer, comprising administering a therapeutically effective amount of the pharmaceutical preparation described in claim 37 to the subject in need of such treatment.

40. A method for treating a subject having cancer, comprising administering to the subject in need an effective amount of an isolated antibody or antibody fragment according to any one of claims 1 to 22, or cells containing CAR according to any one of claims 23 to 31.

41. A method for diagnosing cancer, (a) administering an effective amount of the diagnostic preparation described in claim 28 to a subject who requires it, and (b) Determining the presence of cancer by detecting the binding of an isolated antibody or its antigen-binding portion. A method that includes this.

42. A method for detecting the presence of cancer or malignant cells in a biological sample, (a) Contacting the sample with the diagnostic preparation described in claim 38, and (b) Determining the presence of cancer or malignant cells by detecting the amount of an isolated antibody or its antigen-binding portion bound to it. A method that includes this.

43. The method according to any one of claims 39 to 42, wherein the cancer is a myeloma malignant disease.

44. The method according to claim 43, wherein the myelogenic disease is acute myeloid leukemia (AML), chronic myeloid leukemia (CML), or myelodysplastic syndrome (MDS).

45. The method according to any one of claims 39 to 42, wherein the cancer is non-myeloid leukemia.

46. The method according to claim 45, wherein the non-myeloid leukemia is acute lymphoblastic leukemia (ALL) or chronic lymphocytic leukemia (CLL).

47. The method according to any one of claims 39 to 42, wherein the cancer is a solid tumor malignancy.

48. The method according to claim 47, wherein the solid tumor malignancy is lung cancer.

49. A method for producing an isolated antibody or antibody fragment according to any one of claims 1 to 22, comprising culturing a hybridoma or engineered cell according to claim 35 or 36 under conditions that enable antibody expression, and optionally isolating the antibody from the culture.

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