IP Library › Patent Application 17957302

Patent Application

App. No. 17/957,302

AXL-SPECIFIC ANTIBODY-DRUG CONJUGATES FOR CANCER TREATMENT

Loading inventors, assignments & file history…

Monitor This Case

Get email alerts when status or documents change.

Order Certified Copies

Most orders are placed with the USPTO same day — all within 24 business hours.

Order via The Patent Place →

Pre-filled with this patent's details

Quick Facts

Patent No.: US None
App. No.: 17/957,302

External Links

USPTO Patent Center↗ Full Patent PDF↗

Abstract

Antibody-drug conjugates (ADCs) binding to human AXL for therapeutic use, particularly for treatment of melanoma in combination with one or more MAPK pathway inhibitors such as, e.g., a BRAF inhibitor and/or a MEK inhibitor.

Claims (147)

1 . A method of treating melanoma comprising administering to a subject in need thereof a therapeutically effective amount of an antibody-drug conjugate (ADC) comprising an antibody which binds to human AXL in combination with one or more inhibitors of the MAP kinase (MAPK) pathway.

2 . The method of claim 1 , wherein the one or more inhibitors of the MAPK pathway comprises a B-RAF(BRAF) inhibitor, a MEK inhibitor, an ERK inhibitor, or a combination of any two or more thereof.

3 . The method of claim 1 , wherein the one or more inhibitors of the MAPK pathway comprises a serine/threonine kinase inhibitor, a tyrosine kinase inhibitor, or both.

4 - 9 . (canceled)

10 . The method of claim 1 , wherein the melanoma exhibits a mutation in BRAF.

11 . The method of claim 10 , wherein the mutation is in a BRAF residue selected from V600, L597 and K601.

12 . (canceled)

13 . The method of claim 10 , wherein the melanoma does not exhibit a mutation at residue Q61, G12, or G13 in NRAS.

14 . The method of claim 13 , wherein the melanoma does not exhibit an activating mutation in NRAS.

15 . (canceled)

16 . The method of claim 2 , wherein the MEK inhibitor is trametinib, cobimetinib, binimetinib, selumetinib, refametinib, pimasertib, U0126-EtOH, PD184352, BIX 02189, or a therapeutically effective analog or derivative of any thereof.

17 - 20 . (canceled)

21 . The method of claim 16 , wherein the melanoma exhibits a mutation in NRAS at residue Q61, G12, or G13.

22 - 23 . (canceled)

24 . The method of claim 2 , wherein the ERK inhibitor is LTT-462, ulixertinib, SCH772984 and VTX11E, or a therapeutically effective analog or derivative of any thereof.

25 . The method of claim 1 , wherein the ADC is administered in combination with a BRAF-inhibitor and a MEK inhibitor.

26 - 29 . (canceled)

30 . The method of claim 25 , wherein the melanoma has a BRAF mutation at residue V600, L597, or K601.

31 . (canceled)

32 . The method of claim 30 , wherein the melanoma does not exhibit an NRAS mutation at residue Q61, G12, or G13.

33 . The method of claim 32 , wherein the melanoma does not exhibit an activating NRAS mutation.

34 . (canceled)

35 . The method of claim 1 , wherein the melanoma has not earlier been treated with the or more inhibitors.

36 . The method of claim 1 , wherein the melanoma is undergoing treatment with one or more inhibitors of the MAPK pathway.

37 . The method of claim 1 , wherein the melanoma has earlier been treated with one or more inhibitors of the MAPK pathway.

38 . The elaimsmethod of claim 1 , wherein the melanoma is resistant to the one or more inhibitors of the MAPK pathway.

39 - 40 . (canceled)

41 . The method of claim 1 , wherein the melanoma is a relapsed melanoma.

42 - 43 . (canceled)

44 . The method of claim 1 , wherein the melanoma is not resistant to the one or more inhibitors.

45 - 46 . (canceled)

47 . The method of claim 1 , wherein the ADC comprises a cytotoxic agent, a chemotherapeutic drug, or a radioisotope linked to the antibody.

48 . The method of claim 47 , wherein the cytotoxic agent is linked to the ADC with a linker.

49 . The method of claim 48 , wherein the linker is mc-vc-PAB and the cytotoxic agent is MMAE.

50 . The method of claim 1 , wherein the antibody does not compete with Growth Arrest-Specific 6 (Gas6) for binding to human AXL.

51 . (canceled)

52 . The method of claim 1 , wherein the antibody comprises at least one binding region comprising a VH region and a VL region selected from the group consisting of:

(a) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 36, 37, and 38, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 39, the amino acid sequence GAS, and SEQ ID NO: 40, respectively;

(b) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 46, 47, and 48, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 49, the amino acid sequence AAS, and SEQ ID NO: 50, respectively;

(c) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 114, 115, and 116, respectively, and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 117, the amino acid sequence DAS, and SEQ ID NO: 118, respectively;

(d) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 51, 52, and 53, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 55, the amino acid sequence GAS, and SEQ ID NO: 56, respectively;

(e) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 51, 52, and 54, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO: 55, the amino acid sequence GAS, and SEQ ID NO: 56, respectively;

(f) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 57, 58, and 59, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO: 60, the amino acid sequence GAS, and SEQ ID NO: 61, respectively;

(g) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 62, 63, and 64, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO: 65, the amino acid sequence GAS, and SEQ ID NO: 66, respectively;

(h) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 67, 68, and 69, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO: 70, the amino acid sequence GAS, and SEQ ID NO: 71, respectively;

(i) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 72, 73, and 75, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO: 76, the amino acid sequence ATS, and SEQ ID NO: 77, respectively;

(j) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 72, 74, and 75, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO: 76, the amino acid sequence ATS, and SEQ ID NO: 77, respectively;

(k) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 78, 79, and 80, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO: 81, the amino acid sequence AAS, and SEQ ID NO: 82, respectively;

(1) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 83, 84, and 85, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO: 86, the amino acid sequence GAS, and SEQ ID NO: 87, respectively;

(m)a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 88, 89, and 90, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO: 91, the amino acid sequence GAS, and SEQ ID NO: 92, respectively;

(n) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 93, 94, and 95, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO: 96, the amino acid sequence GAS, and SEQ ID NO: 97, respectively;

(o) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 98, 99, and 100, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO: 101, the amino acid sequence DAS, and SEQ ID NO: 102, respectively;

(p) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 103, 104, and 105, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO: 106, the amino acid sequence GAS, and SEQ ID NO: 107, respectively;

(q) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 108, 109, and 110, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO: 112, the amino acid sequence AAS, and SEQ ID NO: 113, respectively;

(r) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 108, 109, and 111, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO: 112, the amino acid sequence AAS, and SEQ ID NO: 113, respectively;

(s) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 41, 42, and 43, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO: 44, the amino acid sequence AAS, and SEQ ID NO: 45, respectively;

(t) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 93, 94, and 95, respectively, and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO: 128, the amino acid sequence XAS, wherein X is D or G, and SEQ ID NO: 129, respectively;

(u) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 46, 119, and 120, respectively; and a VL region comprising CDR1, CDR2, and CDR3 sequences of SEQ ID NO: 49, the amino acid sequence AAS, and SEQ ID NO: 50, respectively;

(v) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 123, 124, and 125, respectively; and a VL region comprising CDR1, CDR2, and CDR3 sequences of SEQ ID NO: 60, the amino acid sequence GAS, and SEQ ID NO: 61, respectively;

(w) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 121, 109, and 122, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO: 112, the amino acid sequence AAS, and SEQ ID NO: 113, respectively; and

(x) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NOs:93, 126, and 127, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO: 96, the amino acid sequence GAS, and SEQ ID NO: 97, respectively.

53 . (canceled)

54 . The method of claim 1 , wherein the antibody comprises at least one binding region comprising a VH region and a VL region selected from the group consisting of:

(a) a VH region which is at least 95% identical to SEQ ID NO: 1 and a VL region which is at least 95% identical to SEQ ID NO: 2;

(b) a VH region which is at least 95% identical to SEQ ID NO: 5 and a VL region which is at least 95% identical to SEQ ID NO: 6;

(c) a VH region which is least 95% identical to SEQ ID NO: 34 and a VL region which is at least 95% identical to SEQ ID NO: 35;

(d) a VH region which is least 95% identical to SEQ ID NO: 7 and a VL region which is, at least 95% identical to SEQ ID NO: 9;

(e) a VH region which is at least 95% identical to SEQ ID NO: 10 and a VL region which is at least 95% identical to SEQ ID NO: 11;

(f) a VH region which is at least 95% identical to SEQ ID NO: 16 and a VL region which is at least 95% identical to SEQ ID NO: 18;

(g) a VH region which is at least 95% identical to SEQ ID NO: 25 and a VL region which is at least 95% identical to SEQ ID NO: 26;

(h) a VH region which is at least 95% identical to SEQ ID NO: 31 and a VL region which is at least 95% identical to SEQ ID NO: 33;

(i) a VH region which is at least 95% identical to SEQ ID NO: 3 and a VL region which is at least 95% identical to SEQ ID NO: 4;

(j) a VH region which is at least 95% identical to SEQ ID NO: 8 and a VL region which is at least 95% identical to SEQ ID NO: 9;

(k) a VH region which is at least 95% identical to SEQ ID NO: 12 and a VL region which is at least 95% identical to SEQ ID NO: 13;

(1) a VH region which is at least 95% identical to SEQ ID NO: 14 and a VL region which is at least 95% identical to SEQ ID NO: 15;

(m)a VH region which is at least 95% identical to SEQ ID NO: 17 and a VL region which is at least 95% identical to SEQ ID NO: 18;

(n) a VH region which is at least 95% identical to SEQ ID NO: 19 and a VL region which is at least 95% identical to SEQ ID NO: 20;

(o) a VH region which is at least 95% identical to SEQ ID NO: 21 and a VL region which is at least 95% identical to SEQ ID NO: 22;

(p) a VH region which is at least 95% identical to SEQ ID NO: 23 and a VL region which is at least 95% identical to SEQ ID NO: 24;

(q) a VH region which is at least 95% identical to SEQ ID NO: 27 and a VL region which is at least 95% identical to SEQ ID NO: 28;

(r) a VH region which is at least 95% identical to SEQ ID NO: 29 and a VL region which is at least 95% identical to SEQ ID NO: 30; and

(s) a VH region which is at least 95% identical to SEQ ID NO: 32 and a VL region which is at least 95% identical to SEQ ID NO: 33.

55 - 56 . (canceled)

57 . The method of claim 1 , wherein the antibody comprises at least one binding region comprising a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 36, 37, and 38, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO: 39, the amino acid sequence GAS, and SEQ ID NO: 40, respectively, the linker is mc-vc-PAB, and the cytotoxic agent is MMAE.

58 . The method of claim 1 , wherein the antibody comprises at least one binding region comprising a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 36, 37, and 38, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO: 39, the amino acid sequence GAS, and SEQ ID NO: 40, respectively, the linker is SSP, and the cytotoxic agent is DM1.

59 . The method of claim 1 , wherein the antibody binds to an epitope on AXL recognized by an antibody comprising:

(a) a VH region comprising SEQ ID NO: 1 and a VL region comprising SEQ ID NO: 2;

(b) a VH region comprising SEQ ID NO: 5 and a VL region comprising SEQ ID NO: 6;

(d) a VH region comprising SEQ ID NO: 7 and a VL region comprising SEQ ID NO: 9;

(e) a VH region comprising SEQ ID NO: 10 and a VL region comprising SEQ ID NO: 11;

(f) a VH region comprising SEQ ID NO: 16 and a VL region comprising SEQ ID NO: 18;

(g) a VH region comprising SEQ ID NO: 25 and a VL region comprising SEQ ID NO: 26;

(h) a VH region comprising SEQ ID NO: 31 and a VL region comprising SEQ ID NO: 33;

(i) a VH region comprising SEQ ID NO: 3 and a VL region comprising SEQ ID NO: 4;

(j) a VH region comprising SEQ ID NO: 8 and a VL region comprising SEQ ID NO: 9;

(k) a VH region comprising SEQ ID NO: 12 and a VL region comprising SEQ ID NO: 13;

(1) a VH region comprising SEQ ID NO: 14 and a VL region comprising SEQ ID NO: 15;

(m) a VH region comprising SEQ ID NO: 17 and a VL region comprising SEQ ID NO: 18;

(n) a VH region comprising SEQ ID NO: 19 and a VL region comprising SEQ ID NO: 20;

(o) a VH region comprising SEQ ID NO: 21 and a VL region comprising SEQ ID NO: 22;

(p) a VH region comprising SEQ ID NO: 23 and a VL region comprising SEQ ID NO: 24;

(q) a VH region comprising SEQ ID NO: 27 and a VL region comprising SEQ ID NO: 28;

(r) a VH region comprising SEQ ID NO: 29 and a VL region comprising SEQ ID NO: 30; or

(s) a VH region comprising SEQ ID NO: 32 and a VL region comprising SEQ ID : 33.

60 . The method of claim 1 , wherein the antibody binds to:

(a) an epitope within the Ig1 domain of AXL, the epitope comprising or requiring one or more amino acids corresponding to positions L121 to Q129 or T112 to Q124 of human AXL;

(b) an epitope within the Ig2 domain of AXL, the epitope comprising or requiring the amino acids corresponding to position D170 or the combination of D179 and one or more amino acids corresponding to positions T182 to R190 of human AXL;

(c) an epitope within the FN1 domain of human AXL, the epitope comprising or requiring one or more amino acids corresponding to positions Q272 to A287 and G297 to P301 of human AXL; or

(d) an epitope within the FN2 domain of human AXL, the epitope comprising or requiring the amino acids corresponding to positions A359, R386, and one or more amino acids corresponding to positions Q436 to K439 of human AXL.

61 - 63 . (canceled)

64 . The method of claim 1 , wherein the antibody comprises a heavy chain of an isotype selected from the group consisting of IgG1, IgG2, IgG3, and IgG4.

65 . (canceled)

66 . The method of claim 1 , wherein the antibody is a full-length monoclonal antibody.

67 . The method of claim 1 , wherein the ADC is formulated in a pharmaceutical composition comprising a pharmaceutical acceptable carrier.

68 . A method of treating melanoma in a subject in need thereof comprising administering a therapeutically effective amount of an ADC comprising an antibody which binds to human AXL in combination with a BRAF inhibitor and/or a MEK-inhibitor,

wherein the ADC comprises an antibody comprising at least one binding region comprising a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 36, 37, and 38, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO: 39, the amino acid sequence GAS, and SEQ ID NO: 40, respectively, linked to MMAE via an mc-vc-PAB linker, and

wherein the AXL-ADC and the inhibitor are administered simultaneously, separately or sequentially.

69 - 77 . (canceled)

78 . A kit comprising (i) an ADC comprising an antibody which binds to human AXL and comprises

(a) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 36, 37, and 38, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO: 39, the amino acid sequence GAS, and SEQ ID NO: 40, respectively;

(b) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 46, 47, and 48, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO: 49, the amino acid sequence AAS, and SEQ ID NO: 50, respectively;

(c) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 114, 115, and 116, respectively, and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO: 117, the amino acid sequence DAS, and SEQ ID NO: 118, respectively;

(d) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 51, 52, and 53, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO: 55, the amino acid sequence GAS, and SEQ ID NO: 56, respectively;

(m) a VH region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NOs: 88, 89, and 90, respectively; and a VL region comprising the CDR1, CDR2, and CDR3 sequences of SEQ ID NO: 91, the amino acid sequence GAS, and SEQ ID NO: 92, respectively;

(ii) one or more inhibitors of the MAPK pathway,

wherein the ADC and the one or more inhibitors are for simultaneous, separate or sequential administration.

79 - 88 . (canceled)

Assignments (6)

SECURITY INTEREST Recorded Dec 15, 2025

From: GENMAB A/S; GENMAB B.V.; GENMAB HOLDING B.V.

To: MORGAN STANLEY SENIOR FUNDING, INC.

Reel/Frame 073933/0597 →

NOTICE OF GRANT OF SECURITY INTEREST IN PATENTS Recorded Dec 15, 2025

From: GENMAB A/S; GENMAB B.V.; GENMAB HOLDING B.V.

To: WILMINGTON TRUST, NATIONAL ASSOCIATION

Reel/Frame 073949/0722 →

CORRECTIVE ASSIGNMENT TO CORRECT THE SPELLING OF INVENTOR DAVID SATIJN'S LAST NAME FROM "SATIJIN" TO SATIJN ON THE NOTICE OF RECORATION PREVIOUSLY RECORDED AT REEL: 062552 FRAME: 0390. ASSIGNOR(S) HEREBY CONFIRMS THE ASSIGNMENT. Recorded Feb 10, 2023

From: BREIJ, ESTHER; KOOPMAN, LOUISE; SATIJN, DAVID; VAN DEN BRINK, EDWARD; VERZIJL, DENNIS; DE JONG, ROB N.; VAN DIJKHUIZEN-RADERSMA, RIEMKE; PARREN, PAUL

To: GENMAB A/S

Reel/Frame 062746/0595 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 31, 2023

From: BOSHUIZEN, JULIA; PEEPER, DANIEL

To: STICHTING HET NEDERLANDS KANKER INSTITUUT-ANTONI VAN LEEUWENHOEK ZIEKENHUIS

Reel/Frame 062551/0959 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 31, 2023

From: STICHTING HET NEDERLANDS KANKER INSTITUUT-ANTONI VAN LEEUWENHOEK ZIEKENHUIS

To: GENMAB A/S

Reel/Frame 062551/0974 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 31, 2023

From: BREIJ, ESTHER; KOOPMAN, LOUISE; SATIJIN, DAVID; VAN DEN BRINK, EDWARD; VERZIJL, DENNIS; DE JONG, ROB N.; VAN DIJKHUIZEN-RADERSMA, RIEMKE; PARREN, PAUL

To: GENMAB A/S

Reel/Frame 062552/0390 →