IP Library › Patent Application 17247767

Patent Application

App. No. 17/247,767

ANTIBODIES AND METHODS OF USE THEREOF

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Patent No.: US None
App. No.: 17/247,767

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Abstract

Disclosed herein are methods and compositions for targeting a complex comprising a neoantigen presenting protein and a neoantigen in cancer. Further disclosed herein are antibodies that selectively bind to a complex comprising a neoantigen presenting protein and a neoantigen, as well as methods of use thereof.

Claims (191)

1 . An antibody that selectively binds to a complex comprising a non-classical HLA-I and a peptide.

2 . The antibody of claim 1 , wherein the antibody does not have a binding affinity to (i) the non-classical HLA-I alone; or (ii) the peptide alone.

3 . The antibody of claim 1 , wherein the peptide is expressed by an antigen processing machinery (APM)-proficient cell.

4 . The antibody of claim 3 , wherein the peptide is expressed by a TAP1/2-proficient cell.

5 . The antibody of claim 1 , wherein the peptide is expressed by an antigen processing machinery (APM)-deficient cell.

6 . The antibody of claim 5 , wherein the peptide is expressed by a TAP1/2-deficient cell.

7 . The antibody of claim 1 , wherein the peptide comprises, consisting essentially of, or consisting of a sequence according to SEQ ID NO: 3 (VMAPRTLFL), SEQ ID NO: 13 (VMAPRTLIL), SEQ ID NO: 14 (VMPPRTLLL), SEQ ID NO: 31 (VMAPRTLVL), SEQ ID NO: 19 (YLLPRRGPRL), SEQ ID NO: 20 (AISPRTLNA), SEQ ID NO: 21 (SQAPLPCVL), SEQ ID NO: 15 (YLLEMLWRL), SEQ ID NO: 16 (YMLDLQPETT), SEQ ID NO: 22 (QMRPVSRVL), SEQ ID NO: 23 (ALALVRMLI), SEQ ID NO: 24 (SQQPYLQLQ), SEQ ID NO: 25 (AMAPIKTHL), SEQ ID NO: 26 (AMAPIKVRL), SEQ ID NO: 17 (YLLPAIVHI), SEQ ID NO: 27 (ILDQKINEV), SEQ ID NO: 28 (GVYDGEEHSV), SEQ ID NO: 29 (KVLEYVIKV), SEQ ID NO: 18 (SLLMWITQV), SEQ ID NO: 30 (YLEPGPVTV), SEQ ID NO: 32 (SLLEKSLGL), SEQ ID NO: 22 (QMRPVSRVL), SEQ ID NO: 33 (WIAAVTIAA), SEQ ID NO: 34 (TSDMPGTTL), SEQ ID NO: 35 (MLALLTQVA), SEQ ID NO: 36 (QMFEGPLAL), SEQ ID NO: 37 (VLWDRTFSL), SEQ ID NO: 38 (TLFFQQNAL), SEQ ID NO: 1 (GLADKVYFL), or SEQ ID NO: 2 (ILSPTVVSI).

8 . The antibody of claim 1 , wherein the peptide comprises, consisting essentially of, or consisting of a sequence according to SEQ ID NO: 3 (VMAPRTLFL), SEQ ID NO: 13 (VMAPRTLIL), SEQ ID NO: 14 (VMPPRTLLL), or SEQ ID NO: 31 (VMAPRTLVL).

9 . The antibody of claim 1 , wherein the peptide comprises, consisting essentially of, or consisting of a sequence according to SEQ ID NO. 3 (VMAPRTLFL).

10 . The antibody of claim 1 , wherein the peptide comprises, consisting essentially of, or consisting of a sequence according to SEQ ID NO: 32 (SLLEKSLGL), SEQ ID NO: 22 (QMRPVSRVL), SEQ ID NO: 33 (WIAAVTIAA), SEQ ID NO: 34 (TSDMPGTTL), SEQ ID NO: 35 (MLALLTQVA), SEQ ID NO: 36 (QMFEGPLAL), SEQ ID NO: 37 (VLWDRTFSL), SEQ ID NO: 38 (TLFFQQNAL), SEQ ID NO: 1 (GLADKVYFL), or SEQ ID NO: 2 (ILSPTVVSI).

11 . The antibody of claim 1 , wherein the peptide comprises, consisting essentially of, or consisting of a sequence according to SEQ ID NO: 35 (MLALLTQVA), SEQ ID NO: 1 (GLADKVYFL), or SEQ ID NO: 2 (ILSPTVVSI).

12 . The antibody of claim 1 , wherein the peptide comprises, consisting essentially of, or consisting of a sequence according to SEQ ID NO. 35 (MLALLTQVA).

13 . The antibody of claim 1 , wherein the peptide comprises, consisting essentially of, or consisting of a sequence according to SEQ ID NO. 1 (GLADKVYFL).

14 . The antibody of claim 1 , wherein the peptide comprises, consisting essentially of, or consisting of a sequence according to SEQ ID NO. 2 (ILSPTVVSI).

15 . The antibody of claim 1 , wherein the non-classical HLA-I is HLA-E, HLA-F, HLA-G, or HLA-H.

16 . The antibody of claim 1 , wherein the non-classical HLA-I is HLA-E.

17 . The antibody of claim 16 , wherein the HLA-E is HLA-E*0101 or HLA-E*0103.

18 . The antibody of claim 16 , wherein the antibody selectively binds to the complex comprising the HLA-E and the peptide.

19 . The antibody of claim 18 , wherein the antibody selectively binds to the complex comprising:

(a) the HLA-E*0101 and the peptide;

(b) the HLA-E*0103 and the peptide; or

20 . The antibody of claim 18 , wherein the complex comprises the HLA-E and VMAPRTLFL (SEQ ID NO: 3), the HLA-E and VMAPRTLIL (SEQ ID NO: 13), the HLA-E and VMPPRTLLL (SEQ ID NO: 14), the HLA-E and YLLPRRGPRL (SEQ ID NO: 19), the HLA-E and AISPRTLNA (SEQ ID NO: 20), the HLA-E and SQAPLPCVL (SEQ ID NO: 21), the HLA-E and YLLEMLWRL (SEQ ID NO: 15), the HLA-E and YMLDLQPETT (SEQ ID NO: 16), the HLA-E and QMRPVSRVL (SEQ ID NO: 22), the HLA-E and ALALVRMLI (SEQ ID NO: 23), the HLA-E and SQQPYLQLQ (SEQ ID NO: 24), the HLA-E and AMAPIKTHL (SEQ ID NO: 25), the HLA-E and AMAPIKVRL (SEQ ID NO: 26), the HLA-E and YLLPAIVHI (SEQ ID NO: 17), the HLA-E and ILDQKINEV (SEQ ID NO: 27), the HLA-E and GVYDGEEHSV (SEQ ID NO: 28), the HLA-E and KVLEYVIKV (SEQ ID NO: 29), the HLA-E and SLLMWITQV (SEQ ID NO: 18), the HLA-E and YLEPGPVTV (SEQ ID NO: 30), the HLA-E and SLLEKSLGL (SEQ ID NO: 32), the HLA-E and QMRPVSRVL (SEQ ID NO: 22), the HLA-E and WIAAVTIAA (SEQ ID NO: 33), the HLA-E and TSDMPGTTL (SEQ ID NO: 34), the HLA-E and MLALLTQVA (SEQ ID NO: 35), the HLA-E and QMFEGPLAL (SEQ ID NO: 36), the HLA-E and VLWDRTFSL (SEQ ID NO: 37), the HLA-E and TLFFQQNAL (SEQ ID NO: 38), the HLA-E and GLADKVYFL (SEQ ID NO: 1), or the HLA-E and ILSPTVVSI (SEQ ID NO: 2).

21 . The antibody of claim 18 , wherein the complex comprises the HLA-E and VMAPRTLFL (SEQ ID NO: 3), the HLA-E and VMAPRTLIL (SEQ ID NO: 13), or the HLA-E and VMPPRTLLL (SEQ ID NO: 14).

22 . The antibody of claim 18 , wherein the complex comprises the HLA-E and VMAPRTLFL (SEQ ID NO. 3).

23 . The antibody of claim 18 , wherein the complex comprises the HLA-E and SLLEKSLGL (SEQ ID NO: 32), the HLA-E and QMRPVSRVL (SEQ ID NO: 22), the HLA-E and WIAAVTIAA (SEQ ID NO: 33), the HLA-E and TSDMPGTTL (SEQ ID NO: 34), the HLA-E and MLALLTQVA (SEQ ID NO: 35), the HLA-E and QMFEGPLAL (SEQ ID NO: 36), the HLA-E and VLWDRTFSL (SEQ ID NO: 37), the HLA-E and TLFFQQNAL (SEQ ID NO: 38), the HLA-E and GLADKVYFL (SEQ ID NO: 1), or the HLA-E and ILSPTVVSI (SEQ ID NO: 2).

24 . The antibody of claim 18 , wherein the complex comprises the HLA-E and MLALLTQVA (SEQ ID NO: 35), the HLA-E and GLADKVYFL (SEQ ID NO: 1), or the HLA-E and ILSPTVVSI (SEQ ID NO: 2).

25 . The antibody of claim 18 , wherein the complex comprises the HLA-E and MLALLTQVA (SEQ ID NO. 35).

26 . The antibody of claim 18 , wherein the complex comprises the HLA-E and GLADKVYFL (SEQ ID NO. 1).

27 . The antibody of claim 18 , wherein the complex comprises the HLA-E and ILSPTVVSI (SEQ ID NO. 2).

28 . The antibody of claim 1 , wherein the antibody is a murine antibody, a chimeric antibody, a camelid antibody, a humanized antibody, or a human antibody.

29 . The antibody of claim 1 , wherein the antibody is a TCR-like antibody.

30 . The antibody of claim 1 , wherein the antibody is a single domain antibody.

31 . The antibody of claim 30 , wherein the single domain antibody is a camelid single domain antibody.

32 . The antibody of claim 1 , wherein the antibody is a multispecific antibody.

33 . The antibody of claim 1 , wherein the antibody is a multifunctional antibody.

34 . The antibody of claim 1 , wherein the antibody further comprises a conjugated therapeutic moiety.

35 . The antibody of claim 1 , wherein the selective binding of the antibody to the complex comprising the non-classical HLA-I and the peptide induces an immune response in a cell.

36 . The antibody of claim 35 , wherein the immune response comprises activation of T cells.

37 . The antibody of claim 36 , wherein the T cell is a CD8+ T cell.

38 . The antibody of claim 35 , wherein the immune response comprises activation of cytotoxic T cells (CTLs).

39 . The antibody of claim 35 , wherein the cell is a cancer cell.

40 . A method of treating cancer in an individual in need thereof, comprising administering to the individual an antibody that selectively binds to a complex comprising a non-classical HLA-I and a neoantigen.

41 . The method of claim 40 , wherein the antibody does not have a binding affinity to (i) the non-classical HLA-I alone; or (ii) the neoantigen alone.

42 . The method of claim 40 , wherein the neoantigen is expressed by an antigen processing machinery (APM)-proficient cell.

43 . The method of claim 42 , wherein the neoantigen is expressed by a TAP1/2-proficient cell.

44 . The method of claim 40 , wherein the neoantigen is expressed by an antigen processing machinery (APM)-deficient cell.

45 . The method of claim 44 , wherein the neoantigen is expressed by a TAP1/2-deficient cell.

46 . The method of claim 40 , wherein the neoantigen comprises, consisting essentially of, or consisting of a sequence according to SEQ ID NO: 3 (VMAPRTLFL), SEQ ID NO: 13 (VMAPRTLIL), SEQ ID NO: 14 (VMPPRTLLL), SEQ ID NO: 31 (VMAPRTLVL), SEQ ID NO: 19 (YLLPRRGPRL), SEQ ID NO: 20 (AISPRTLNA), SEQ ID NO: 21 (SQAPLPCVL), SEQ ID NO: 15 (YLLEMLWRL), SEQ ID NO: 16 (YMLDLQPETT), SEQ ID NO: 22 (QMRPVSRVL), SEQ ID NO: 23 (ALALVRMLI), SEQ ID NO: 24 (SQQPYLQLQ), SEQ ID NO: 25 (AMAPIKTHL), SEQ ID NO: 26 (AMAPIKVRL), SEQ ID NO: 17 (YLLPAIVHI), SEQ ID NO: 27 (ILDQKINEV), SEQ ID NO: 28 (GVYDGEEHSV), SEQ ID NO: 29 (KVLEYVIKV), SEQ ID NO: 18 (SLLMWITQV), SEQ ID NO: 30 (YLEPGPVTV), SEQ ID NO: 32 (SLLEKSLGL), SEQ ID NO: 22 (QMRPVSRVL), SEQ ID NO: 33 (WIAAVTIAA), SEQ ID NO: 34 (TSDMPGTTL), SEQ ID NO: 35 (MLALLTQVA), SEQ ID NO: 36 (QMFEGPLAL), SEQ ID NO: 37 (VLWDRTFSL), SEQ ID NO: 38 (TLFFQQNAL), SEQ ID NO: 1 (GLADKVYFL), or SEQ ID NO: 2 (ILSPTVVSI).

47 . The method of claim 40 , wherein the neoantigen comprises, consisting essentially of, or consisting of a sequence according to SEQ ID NO: 3 (VMAPRTLFL), SEQ ID NO: 13 (VMAPRTLIL), SEQ ID NO: 14 (VMPPRTLLL), or SEQ ID NO: 31 (VMAPRTLVL).

48 . The method of claim 40 , wherein the neoantigen comprises, consisting essential of, or consisting of a sequence according to SEQ ID NO. 3 (VMAPRTLFL).

49 . The method of claim 40 , wherein the neoantigen comprises, consisting essentially of, or consisting of a sequence according to SEQ ID NO: 32 (SLLEKSLGL), SEQ ID NO: 22 (QMRPVSRVL), SEQ ID NO: 33 (WIAAVTIAA), SEQ ID NO: 34 (TSDMPGTTL), SEQ ID NO: 35 (MLALLTQVA), SEQ ID NO: 36 (QMFEGPLAL), SEQ ID NO: 37 (VLWDRTFSL), SEQ ID NO: 38 (TLFFQQNAL), SEQ ID NO: 1 (GLADKVYFL), or SEQ ID NO: 2 (ILSPTVVSI).

50 . The method of claim 40 , wherein the neoantigen comprises, consisting essentially of, or consisting of a sequence according to SEQ ID NO: 35 (MLALLTQVA), SEQ ID NO: 1 (GLADKVYFL), or SEQ ID NO: 2 (ILSPTVVSI).

51 . The method of claim 40 , wherein the neoantigen comprises, consisting essentially of, or consisting of a sequence according to SEQ ID NO. 35 (MLALLTQVA).

52 . The method of claim 40 , wherein the neoantigen comprises, consisting essentially of, or consisting of a sequence according to SEQ ID NO. 1 (GLADKVYFL).

53 . The method of claim 40 , wherein the neoantigen comprises, consisting essentially of, or consisting of a sequence according to SEQ ID NO. 2 (ILSPTVVSI).

54 . The method of claim 40 , wherein the non-classical HLA-I is HLA-E, HLA-F, HLA-G, or HLA-H.

55 . The method of claim 40 , wherein the non-classical HLA-I is HLA-E.

56 . The method of claim 55 , wherein the HLA-E is HLA-E*0101 or HLA-E*0103.

57 . The method of claim 55 , wherein the antibody selectively binds to the complex comprising the HLA-E and the neoantigen.

58 . The method of claim 57 , wherein the antibody selectively binds to the complex comprising:

(a) the HLA-E*0101 and the neoantigen;

(b) the HLA-E*0103 and the neoantigen; or

59 . The method of claim 57 , wherein the complex comprises the HLA-E and VMAPRTLFL (SEQ ID NO: 3), HLA-E and VMAPRTLIL (SEQ ID NO: 13), HLA-E and VMPPRTLLL (SEQ ID NO: 14), HLA-E and VMAPRTLVL (SEQ ID NO: 31), HLA-E and YLLPRRGPRL (SEQ ID NO: 19), the HLA-E and AISPRTLNA (SEQ ID NO: 20), the HLA-E and SQAPLPCVL (SEQ ID NO: 21), the HLA-E and YLLEMLWRL (SEQ ID NO: 15), the HLA-E and YMLDLQPETT (SEQ ID NO: 16), the HLA-E and QMRPVSRVL (SEQ ID NO: 22), the HLA-E and ALALVRMLI (SEQ ID NO: 23), the HLA-E and SQQPYLQLQ (SEQ ID NO: 24), the HLA-E and AMAPIKTHL (SEQ ID NO: 25), the HLA-E and AMAPIKVRL (SEQ ID NO: 26), the HLA-E and YLLPAIVHI (SEQ ID NO: 17), the HLA-E and ILDQKINEV (SEQ ID NO: 27), the HLA-E and GVYDGEEHSV (SEQ ID NO: 28), the HLA-E and KVLEYVIKV (SEQ ID NO: 29), the HLA-E and SLLMWITQV (SEQ ID NO: 18), the HLA-E and YLEPGPVTV (SEQ ID NO: 30), the HLA-E and SLLEKSLGL (SEQ ID NO: 32), the HLA-E and QMRPVSRVL (SEQ ID NO: 22), the HLA-E and WIAAVTIAA (SEQ ID NO: 33), the HLA-E and TSDMPGTTL (SEQ ID NO: 34), the HLA-E and MLALLTQVA (SEQ ID NO: 35), the HLA-E and QMFEGPLAL (SEQ ID NO: 36), the HLA-E and VLWDRTFSL (SEQ ID NO: 37), the HLA-E and TLFFQQNAL (SEQ ID NO: 38), the HLA-E and GLADKVYFL (SEQ ID NO: 1), or the HLA-E and ILSPTVVSI (SEQ ID NO: 2).

60 . The method of claim 57 , wherein the complex comprises the HLA-E and VMAPRTLFL (SEQ ID NO: 3), HLA-E and VMAPRTLIL (SEQ ID NO: 13), HLA-E and VMPPRTLLL (SEQ ID NO: 14), or HLA-E and VMAPRTLVL (SEQ ID NO: 31).

61 . The method of claim 57 , wherein the complex comprises the HLA-E and VMAPRTLFL (SEQ ID NO. 3).

62 . The method of claim 57 , wherein the complex comprises the HLA-E and SLLEKSLGL (SEQ ID NO: 32), the HLA-E and QMRPVSRVL (SEQ ID NO: 22), the HLA-E and WIAAVTIAA (SEQ ID NO: 33), the HLA-E and TSDMPGTTL (SEQ ID NO: 34), the HLA-E and MLALLTQVA (SEQ ID NO: 35), the HLA-E and QMFEGPLAL (SEQ ID NO: 36), the HLA-E and VLWDRTFSL (SEQ ID NO: 37), the HLA-E and TLFFQQNAL (SEQ ID NO: 38), the HLA-E and GLADKVYFL (SEQ ID NO: 1), or the HLA-E and ILSPTVVSI (SEQ ID NO: 2).

63 . The method of claim 57 , wherein the complex comprises the HLA-E and MLALLTQVA (SEQ ID NO: 35), the HLA-E and GLADKVYFL (SEQ ID NO: 1), or the HLA-E and ILSPTVVSI (SEQ ID NO: 2).

64 . The method of claim 57 , wherein the complex comprises the HLA-E and MLALLTQVA (SEQ ID NO. 35).

65 . The method of claim 57 , wherein the complex comprises the HLA-E and GLADKVYFL (SEQ ID NO. 1).

66 . The method of claim 57 , wherein the complex comprises the HLA-E and ILSPTVVSI (SEQ ID NO. 2).

67 . The method of claim 40 , wherein the antibody is a murine antibody, a chimeric antibody, a camelid antibody, a humanized antibody, or a human antibody.

68 . The method of claim 40 , wherein the antibody is a TCR-like antibody.

69 . The method of claim 40 , wherein the antibody is a single domain antibody.

70 . The method of claim 69 , wherein the single domain antibody is a camelid single domain antibody.

71 . The method of claim 40 , wherein the antibody is a multispecific antibody.

72 . The method of claim 40 , wherein the antibody is a multifunctional antibody.

73 . The method of claim 40 , wherein the antibody further comprises a conjugated therapeutic moiety.

74 . The method of claim 40 , wherein the selective binding of the antibody to the complex comprising the non-classical HLA-I and the neoantigen induces an immune response.

75 . The method of claim 74 , wherein the immune response comprises activation of T cells.

76 . The method of claim 75 , wherein the T cell is a CD8+ T cell.

77 . The method of claim 74 , wherein the immune response comprises activation of cytotoxic T cells (CTLs).

78 . The method of claim 40 , wherein the antibody is administered continuously for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, 15, 28, 30 or more days.

79 . The method of claim 40 , wherein the antibody is administered at predetermined time intervals for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, 15, 28, 30 or more days.

80 . The method of claim 40 , wherein the antibody is administered is administered intermittently for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, 15, 28, 30 or more days.

81 . The method of claim 40 , wherein the antibody is administered in 1 dose, 2 doses, 3 doses, 4 doses, 5 doses, 6 doses or more.

82 . The method of claim 40 , wherein the antibody is administered at a therapeutically effective amount.

83 . The method of claim 40 , wherein the cancer is breast cancer, kidney cancer, lung cancer, ovarian cancer, or colorectal cancer.

84 . The method of claim 40 , wherein the cancer is a B-cell malignancy.

85 . A method of treating cancer in an individual in need thereof, comprising administering to the individual an antibody that selectively binds to a complex comprising an HLA-E and a neoantigen.

86 . The method of claim 85 , wherein the antibody does not have a binding affinity to (i) the HLA-E alone; or (ii) the neoantigen alone.

87 . The method of claim 85 , wherein the neoantigen is expressed by an antigen processing machinery (APM)-proficient cell.

88 . The method of claim 87 , wherein the neoantigen is expressed by a TAP1/2-proficient cell.

89 . The method of claim 85 , wherein the neoantigen is expressed by an antigen processing machinery (APM)-deficient cell.

90 . The method of claim 89 , wherein the neoantigen is expressed by a TAP1/2-deficient cell.

91 . The method of claim 85 , wherein the neoantigen comprises, consisting essentially of, or consisting of a sequence according to SEQ ID NO: 3 (VMAPRTLFL), SEQ ID NO: 13 (VMAPRTLIL), SEQ ID NO: 14 (VMPPRTLLL), SEQ ID NO: 31 (VMAPRTLVL), SEQ ID NO: 19 (YLLPRRGPRL), SEQ ID NO: 20 (AISPRTLNA), SEQ ID NO: 21 (SQAPLPCVL), SEQ ID NO: 15 (YLLEMLWRL), SEQ ID NO: 16 (YMLDLQPETT), SEQ ID NO: 22 (QMRPVSRVL), SEQ ID NO: 23 (ALALVRMLI), SEQ ID NO: 24 (SQQPYLQLQ), SEQ ID NO: 25 (AMAPIKTHL), SEQ ID NO: 26 (AMAPIKVRL), SEQ ID NO: 17 (YLLPAIVHI), SEQ ID NO: 27 (ILDQKINEV), SEQ ID NO: 28 (GVYDGEEHSV), SEQ ID NO: 29 (KVLEYVIKV), SEQ ID NO: 18 (SLLMWITQV), SEQ ID NO: 30 (YLEPGPVTV), SEQ ID NO: 32 (SLLEKSLGL), SEQ ID NO: 22 (QMRPVSRVL), SEQ ID NO: 33 (WIAAVTIAA), SEQ ID NO: 34 (TSDMPGTTL), SEQ ID NO: 35 (MLALLTQVA), SEQ ID NO: 36 (QMFEGPLAL), SEQ ID NO: 37 (VLWDRTFSL), SEQ ID NO: 38 (TLFFQQNAL), SEQ ID NO: 1 (GLADKVYFL), or SEQ ID NO: 2 (ILSPTVVSI).

92 . The method of claim 85 , wherein the neoantigen comprises, consisting essentially of, or consisting of a sequence according to SEQ ID NO: 3 (VMAPRTLFL), SEQ ID NO: 13 (VMAPRTLIL), SEQ ID NO: 14 (VMPPRTLLL), or SEQ ID NO: 31 (VMAPRTLVL).

93 . The method of claim 85 , wherein the neoantigen comprises, consisting essentially of, or consisting of a sequence according to SEQ ID NO. 3 (VMAPRTLFL).

94 . The method of claim 85 , wherein the neoantigen comprises, consisting essentially of, or consisting of a sequence according to SEQ ID NO: 32 (SLLEKSLGL), SEQ ID NO: 22 (QMRPVSRVL), SEQ ID NO: 33 (WIAAVTIAA), SEQ ID NO: 34 (TSDMPGTTL), SEQ ID NO: 35 (MLALLTQVA), SEQ ID NO: 36 (QMFEGPLAL), SEQ ID NO: 37 (VLWDRTFSL), SEQ ID NO: 38 (TLFFQQNAL), SEQ ID NO: 1 (GLADKVYFL), or SEQ ID NO: 2 (ILSPTVVSI).

95 . The method of claim 85 , wherein the neoantigen comprises, consisting essentially of, or consisting of a sequence according to SEQ ID NO: 35 (MLALLTQVA), SEQ ID NO: 1 (GLADKVYFL), or SEQ ID NO: 2 (ILSPTVVSI).

96 . The method of claim 85 , wherein the neoantigen comprises, consisting essentially of, or consisting of a sequence according to SEQ ID NO. 35 (MLALLTQVA).

97 . The method of claim 85 , wherein the neoantigen comprises, consisting essentially of, or consisting of a sequence according to SEQ ID NO. 1 (GLADKVYFL).

98 . The method of claim 85 , wherein the neoantigen comprises, consisting essentially of, or consisting of a sequence according to SEQ ID NO. 2 (ILSPTVVSI).

99 . The method of claim 85 , wherein the HLA-E is HLA-E*0101 or HLA-E*0103.

100 . The method of claim 99 , wherein the antibody selectively binds to the complex comprising:

(a) the HLA-E*0101 and the neoantigen;

(b) the HLA-E*0103 and the neoantigen; or

101 . The method of claim 85 , wherein the complex comprises the HLA-E and VMAPRTLFL (SEQ ID NO: 3), HLA-E and VMAPRTLIL (SEQ ID NO: 13), HLA-E and VMPPRTLLL (SEQ ID NO: 14), HLA-E and VMAPRTLVL (SEQ ID NO: 31), HLA-E and YLLPRRGPRL (SEQ ID NO: 19), the HLA-E and AISPRTLNA (SEQ ID NO: 20), the HLA-E and SQAPLPCVL (SEQ ID NO: 21), the HLA-E and YLLEMLWRL (SEQ ID NO: 15), the HLA-E and YMLDLQPETT (SEQ ID NO: 16), the HLA-E and QMRPVSRVL (SEQ ID NO: 22), the HLA-E and ALALVRMLI (SEQ ID NO: 23), the HLA-E and SQQPYLQLQ (SEQ ID NO: 24), the HLA-E and AMAPIKTHL (SEQ ID NO: 25), the HLA-E and AMAPIKVRL (SEQ ID NO: 26), the HLA-E and YLLPAIVHI (SEQ ID NO: 17), the HLA-E and ILDQKINEV (SEQ ID NO: 27), the HLA-E and GVYDGEEHSV (SEQ ID NO: 28), the HLA-E and KVLEYVIKV (SEQ ID NO: 29), the HLA-E and SLLMWITQV (SEQ ID NO: 18), the HLA-E and YLEPGPVTV (SEQ ID NO: 30), the HLA-E and SLLEKSLGL (SEQ ID NO: 32), the HLA-E and QMRPVSRVL (SEQ ID NO: 22), the HLA-E and WIAAVTIAA (SEQ ID NO: 33), the HLA-E and TSDMPGTTL (SEQ ID NO: 34), the HLA-E and MLALLTQVA (SEQ ID NO: 35), the HLA-E and QMFEGPLAL (SEQ ID NO: 36), the HLA-E and VLWDRTFSL (SEQ ID NO: 37), the HLA-E and TLFFQQNAL (SEQ ID NO: 38), the HLA-E and GLADKVYFL (SEQ ID NO: 1), or the HLA-E and ILSPTVVSI (SEQ ID NO: 2).

102 . The method of claim 85 , wherein the complex comprises the HLA-E and VMAPRTLFL (SEQ ID NO: 3), HLA-E and VMAPRTLIL (SEQ ID NO: 13), HLA-E and VMPPRTLLL (SEQ ID NO: 14), or HLA-E and VMAPRTLVL (SEQ ID NO: 31).

103 . The method of claim 85 , wherein the complex comprises the HLA-E and VMAPRTLFL (SEQ ID NO. 3).

104 . The method of claim 85 , wherein the complex comprises the HLA-E and SLLEKSLGL (SEQ ID NO: 32), the HLA-E and QMRPVSRVL (SEQ ID NO: 22), the HLA-E and WIAAVTIAA (SEQ ID NO: 33), the HLA-E and TSDMPGTTL (SEQ ID NO: 34), the HLA-E and MLALLTQVA (SEQ ID NO: 35), the HLA-E and QMFEGPLAL (SEQ ID NO: 36), the HLA-E and VLWDRTFSL (SEQ ID NO: 37), the HLA-E and TLFFQQNAL (SEQ ID NO: 38), the HLA-E and GLADKVYFL (SEQ ID NO: 1), or the HLA-E and ILSPTVVSI (SEQ ID NO: 2).

105 . The method of claim 85 , wherein the complex comprises the HLA-E and MLALLTQVA (SEQ ID NO: 35), the HLA-E and GLADKVYFL (SEQ ID NO: 1), or the HLA-E and ILSPTVVSI (SEQ ID NO: 2).

106 . The method of claim 85 , wherein the complex comprises the HLA-E and MLALLTQVA (SEQ ID NO. 35).

107 . The method of claim 85 , wherein the complex comprises the HLA-E and GLADKVYFL (SEQ ID NO. 1).

108 . The method of claim 85 , wherein the complex comprises the HLA-E and ILSPTVVSI (SEQ ID NO. 2).

109 . The method of claim 85 , wherein the antibody is a murine antibody, a chimeric antibody, a camelid antibody, a humanized antibody, or a human antibody.

110 . The method of claim 85 , wherein the antibody is a TCR-like antibody.

111 . The method of claim 85 , wherein the antibody is a single domain antibody.

112 . The method of claim 111 , wherein the single domain antibody is a camelid single domain antibody.

113 . The method of claim 85 , wherein the antibody is a multispecific antibody.

114 . The method of claim 85 , wherein the antibody is a multifunctional antibody.

115 . The method of claim 85 , wherein the antibody further comprises a conjugated therapeutic moiety.

116 . The method of claim 85 , wherein the selective binding of the antibody to the complex comprising the HLA-E and the neoantigen induces an immune response.

117 . The method of claim 116 , wherein the immune response comprises activation of T cells.

118 . The method of claim 117 , wherein the T cell is a CD8+ T cell.

119 . The method of claim 116 , wherein the immune response comprises activation of cytotoxic T cells (CTLs).

120 . The method of claim 85 , wherein the antibody is administered continuously for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, 15, 28, 30 or more days.

121 . The method of claim 85 , wherein the antibody is administered at predetermined time intervals for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, 15, 28, 30 or more days.

122 . The method of claim 85 , wherein the antibody is administered is administered intermittently for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, 15, 28, 30 or more days.

123 . The method of claim 85 , wherein the antibody is administered in 1 dose, 2 doses, 3 doses, 4 doses, 5 doses, 6 doses or more.

124 . The method of claim 85 , wherein the antibody is administered at a therapeutically effective amount.

125 . The method of claim 85 , wherein the cancer is breast cancer, kidney cancer, lung cancer, ovarian cancer, or colorectal cancer.

126 . The method of claim 85 , wherein the cancer is a B-cell malignancy.

127 . A method of producing a camelid antibody that selectively binds to a complex comprising a non-classical HLA-I and a peptide, the method comprising:

(a) administering an effective amount of an immunogen to a camelid for eliciting an immune response, wherein the immunogen comprises a recombinantly expressed complex of a non-classical HLA-I and a peptide;

(b) constructing an antibody library;

(d) isolating the antibody.

128 . The method of claim 127 , wherein the antibody does not have a binding affinity to (i) the non-classical HLA-I alone; or (ii) the peptide alone.

129 . The method of claim 127 , wherein the peptide is expressed by an antigen processing machinery (APM)-proficient cell.

130 . The method of claim 129 , wherein the peptide is expressed by a TAP1/2-proficient cell.

131 . The method of claim 127 , wherein the peptide is expressed by an antigen processing machinery (APM)-deficient cell.

132 . The method of claim 131 , wherein the peptide is expressed by a TAP1/2-deficient cell.

133 . The method of claim 127 , wherein the peptide comprises, consisting essentially of, or consisting of a sequence according to SEQ ID NO: 3 (VMAPRTLFL), SEQ ID NO: 13 (VMAPRTLIL), SEQ ID NO: 14 (VMPPRTLLL), SEQ ID NO: 31 (VMAPRTLVL), SEQ ID NO: 19 (YLLPRRGPRL), SEQ ID NO: 20 (AISPRTLNA), SEQ ID NO: 21 (SQAPLPCVL), SEQ ID NO: 15 (YLLEMLWRL), SEQ ID NO: 16 (YMLDLQPETT), SEQ ID NO: 22 (QMRPVSRVL), SEQ ID NO: 23 (ALALVRMLI), SEQ ID NO: 24 (SQQPYLQLQ), SEQ ID NO: 25 (AMAPIKTHL), SEQ ID NO: 26 (AMAPIKVRL), SEQ ID NO: 17 (YLLPAIVHI), SEQ ID NO: 27 (ILDQKINEV), SEQ ID NO: 28 (GVYDGEEHSV), SEQ ID NO: 29 (KVLEYVIKV), SEQ ID NO: 18 (SLLMWITQV), SEQ ID NO: 30 (YLEPGPVTV), SEQ ID NO: 32 (SLLEKSLGL), SEQ ID NO: 22 (QMRPVSRVL), SEQ ID NO: 33 (WIAAVTIAA), SEQ ID NO: 34 (TSDMPGTTL), SEQ ID NO: 35 (MLALLTQVA), SEQ ID NO: 36 (QMFEGPLAL), SEQ ID NO: 37 (VLWDRTFSL), SEQ ID NO: 38 (TLFFQQNAL), SEQ ID NO: 1 (GLADKVYFL), or SEQ ID NO: 2 (ILSPTVVSI).

134 . The method of claim 127 , wherein the peptide comprises, consisting essentially of, or consisting of a sequence according to SEQ ID NO: 3 (VMAPRTLFL), SEQ ID NO: 13 (VMAPRTLIL), SEQ ID NO: 14 (VMPPRTLLL), or SEQ ID NO: 31 (VMAPRTLVL).

135 . The method of claim 127 , wherein the peptide comprises, consisting essentially of, or consisting of a sequence according to SEQ ID NO. 3 (VMAPRTLFL).

136 . The method of claim 127 , wherein the peptide comprises, consisting essentially of, or consisting of a sequence according to SEQ ID NO: 32 (SLLEKSLGL), SEQ ID NO: 22 (QMRPVSRVL), SEQ ID NO: 33 (WIAAVTIAA), SEQ ID NO: 34 (TSDMPGTTL), SEQ ID NO: 35 (MLALLTQVA), SEQ ID NO: 36 (QMFEGPLAL), SEQ ID NO: 37 (VLWDRTFSL), SEQ ID NO: 38 (TLFFQQNAL), SEQ ID NO: 1 (GLADKVYFL), or SEQ ID NO: 2 (ILSPTVVSI).

137 . The method of claim 127 , wherein the peptide comprises, consisting essentially of, or consisting of a sequence according to SEQ ID NO: 35 (MLALLTQVA), SEQ ID NO: 1 (GLADKVYFL), or SEQ ID NO: 2 (ILSPTVVSI).

138 . The method of claim 127 , wherein the peptide comprises, consisting essentially of, or consisting of a sequence according to SEQ ID NO. 35 (MLALLTQVA).

139 . The method of claim 127 , wherein the peptide comprises, consisting essentially of, or consisting of a sequence according to SEQ ID NO. 1 (GLADKVYFL).

140 . The method of claim 127 , wherein the peptide comprises, consisting essentially of, or consisting of a sequence according to SEQ ID NO. 2 (ILSPTVVSI).

141 . The method of claim 127 , wherein the non-classical HLA-I is HLA-E, HLA-F, HLA-G, or HLA-H.

142 . The method of claim 127 , wherein the non-classical HLA-I is HLA-E.

143 . The method of claim 142 , wherein the HLA-E is HLA-E*0101 or HLA-E*0103.

144 . The method of claim 142 , wherein the antibody selectively binds to the complex comprising the HLA-E and the peptide.

145 . The method of claim 144 , wherein the antibody selectively binds to the complex comprising:

(a) the HLA-E*0101 and the peptide;

(b) the HLA-E*0103 and the peptide; or

146 . The method of claim 144 , wherein the complex comprises the HLA-E and VMAPRTLFL (SEQ ID NO: 3), the HLA-E and VMAPRTLIL (SEQ ID NO: 13), the HLA-E and VMPPRTLLL (SEQ ID NO: 14), the HLA-E and YLLPRRGPRL (SEQ ID NO: 19), the HLA-E and AISPRTLNA (SEQ ID NO: 20), the HLA-E and SQAPLPCVL (SEQ ID NO: 21), the HLA-E and YLLEMLWRL (SEQ ID NO: 15), the HLA-E and YMLDLQPETT (SEQ ID NO: 16), the HLA-E and QMRPVSRVL (SEQ ID NO: 22), the HLA-E and ALALVRMLI (SEQ ID NO: 23), the HLA-E and SQQPYLQLQ (SEQ ID NO: 24), the HLA-E and AMAPIKTHL (SEQ ID NO: 25), the HLA-E and AMAPIKVRL (SEQ ID NO: 26), the HLA-E and YLLPAIVHI (SEQ ID NO: 17), the HLA-E and ILDQKINEV (SEQ ID NO: 27), the HLA-E and GVYDGEEHSV (SEQ ID NO: 28), the HLA-E and KVLEYVIKV (SEQ ID NO: 29), the HLA-E and SLLMWITQV (SEQ ID NO: 18), the HLA-E and YLEPGPVTV (SEQ ID NO: 30), the HLA-E and SLLEKSLGL (SEQ ID NO: 32), the HLA-E and QMRPVSRVL (SEQ ID NO: 22), the HLA-E and WIAAVTIAA (SEQ ID NO: 33), the HLA-E and TSDMPGTTL (SEQ ID NO: 34), the HLA-E and MLALLTQVA (SEQ ID NO: 35), the HLA-E and QMFEGPLAL (SEQ ID NO: 36), the HLA-E and VLWDRTFSL (SEQ ID NO: 37), the HLA-E and TLFFQQNAL (SEQ ID NO: 38), the HLA-E and GLADKVYFL (SEQ ID NO: 1), or the HLA-E and ILSPTVVSI (SEQ ID NO: 2).

147 . The method of claim 144 , wherein the complex comprises the HLA-E and VMAPRTLFL (SEQ ID NO: 3), the HLA-E and VMAPRTLIL (SEQ ID NO: 13), or the HLA-E and VMPPRTLLL (SEQ ID NO: 14).

148 . The method of claim 144 , wherein the complex comprises the HLA-E and VMAPRTLFL (SEQ ID NO. 3).

149 . The method of claim 144 , wherein the complex comprises the HLA-E and SLLEKSLGL (SEQ ID NO: 32), the HLA-E and QMRPVSRVL (SEQ ID NO: 22), the HLA-E and WIAAVTIAA (SEQ ID NO: 33), the HLA-E and TSDMPGTTL (SEQ ID NO: 34), the HLA-E and MLALLTQVA (SEQ ID NO: 35), the HLA-E and QMFEGPLAL (SEQ ID NO: 36), the HLA-E and VLWDRTFSL (SEQ ID NO: 37), the HLA-E and TLFFQQNAL (SEQ ID NO: 38), the HLA-E and GLADKVYFL (SEQ ID NO: 1), or the HLA-E and ILSPTVVSI (SEQ ID NO: 2).

150 . The method of claim 144 , wherein the complex comprises the HLA-E and MLALLTQVA (SEQ ID NO: 35), the HLA-E and GLADKVYFL (SEQ ID NO: 1), or the HLA-E and ILSPTVVSI (SEQ ID NO: 2).

151 . The method of claim 144 , wherein the complex comprises the HLA-E and MLALLTQVA (SEQ ID NO. 35).

152 . The method of claim 144 , wherein the complex comprises the HLA-E and GLADKVYFL (SEQ ID NO. 1).

153 . The method of claim 144 , wherein the complex comprises the HLA-E and ILSPTVVSI (SEQ ID NO. 2).

154 . The method of claim 127 , wherein the antibody is a TCR-like antibody.

155 . The method of claim 127 , wherein the antibody is a single domain antibody.

156 . The method of claim 127 , wherein the antibody is a multispecific antibody.

157 . The method of claim 127 , wherein the antibody is a multifunctional antibody.

158 . The method of claim 127 , wherein the antibody further comprises a conjugated therapeutic moiety.

159 . The method of claim 127 , wherein the selective binding of the antibody to the complex comprising the non-classical HLA-I and the peptide induces an immune response in a cell.

160 . The method of claim 159 , wherein the immune response comprises activation of T cells.

161 . The method of claim 160 , wherein the T cell is a CD8+ T cell.

162 . The method of claim 159 , wherein the immune response comprises activation of cytotoxic T cells (CTLs).

163 . The method of claim 159 , wherein the cell is a cancer cell.

164 . The method of claim 127 , wherein the immunogen is a monomer.

165 . The method of claim 127 , wherein the immunogen is a tetramer.

166 . The method of claim 165 , wherein the tetramer comprises avidin or derivatives thereof.

167 . The method of claim 127 , wherein the immunogen is produced by recombinantly expressing an HLA-I heavy chain and a HLA-I light chain separately in E. coli , and then refolding the HLA-I heavy and light chains with peptide in vitro.

168 . The method of claim 127 , wherein the camelid is a llama.

169 . The method of claim 127 , wherein the antibody library is a phage display library.

170 . The method of claim 127 , wherein the antibody library is a bacteriophage display library.

171 . The method of claim 127 , wherein the antibody library is a yeast display library.

172 . The method of claim 127 , wherein the antibody library is a single domain antibody library.

173 . A pharmaceutical composition comprising:

an antibody according to any of claims 1 - 39 ; and

a pharmaceutically acceptable carrier or excipient.

Assignments (3)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 1, 2022

From: BOEHRINGER INGELHEIM PHARMACEUTICALS, INC.

To: BOEHRINGER INGELHEIM INTERNATIONAL GMBH

Reel/Frame 061615/0332 →

MERGER Recorded Jan 6, 2022

From: ABEXXA BIOLOGICS, INC.

To: BOEHRINGER INGELHEIM PHARMACEUTICALS, INC.

Reel/Frame 058584/0680 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 5, 2021

From: WEIDANZ, JON

To: ABEXXA BIOLOGICS, INC.

Reel/Frame 055822/0655 →