Protein tyrosine kinase 7 antibody and antibody-drug conjugate
Patent Information
- Authority / Receiving Office
- JP · JP
- Patent Type
- Applications
- Current Assignee / Owner
- ELI LILLY & CO
- Filing Date
- 2026-02-18
- Publication Date
- 2026-06-23
Smart Images
Figure 2026102587000001 
Figure 2026102587000002 
Figure 2026102587000003
Abstract
Claims
1. Antibody-drug conjugates (ADCs) containing antibodies conjugated to cytotoxic agents. The antibody binds to human PTK-7, and the heavy chain variable region (VH) and light chain variable region The region (VL) includes the heavy chain complementarity determination region (HCDR) HCDR1, HCDR The VL includes 2 and HCDR3, and the VL is the light chain complementarity determining region (LCDR) LCDR1, L Including CDR2 and LCDR3, a) The HCDR1 includes sequence number 4, and the HCDR2 includes sequence number 5, HCDR3 includes sequence number 6, LCDR1 includes sequence number 7, and LCD R2 includes sequence number 8, and LCDR3 includes sequence number 9. b) HCDR1 includes sequence number 14, and HCDR2 includes sequence number 15. The HCDR3 includes sequence number 16, and the LCDR1 includes sequence number 17. LCDR2 includes sequence number 18, and LCDR3 includes sequence number 19. c) The HCDR1 includes sequence number 24, and the HCDR2 includes sequence number 25. The HCDR3 includes sequence number 26, and the LCDR1 includes sequence number 27. LCDR2 includes sequence number 28, and LCDR3 includes sequence number 29, or d) The HCDR1 includes sequence number 34, and the HCDR2 includes sequence number 35. The HCDR3 includes sequence number 36, and the LCDR1 includes sequence number 37. LCDR2 includes sequence number 18, and LCDR3 includes sequence number 38, ADC 。
2. a) The VH includes sequence number 10, and the VL includes sequence number 11, b) The VH includes sequence number 20, and the VL includes sequence number 21, c) The VH includes sequence number 30, and the VL includes sequence number 31, or d) The claim according to claim 1, wherein VH includes sequence number 39 and VL includes sequence number 40. ADC.
3. The antibody comprises a heavy chain (HC) and a light chain (LC), a) The HC contains amino acids 2 to 441 of SEQ ID NO: 2, and the LC contains amino acids 2 to 441 of SEQ ID NO: 3 include, b) The HC contains amino acids 2 to 448 of SEQ ID NO: 12, and the LC contains amino acids 1 Contains amino acids 2-215 of group 3, c) The HC contains amino acids 2 to 447 of SEQ ID NO: 22, and the LC contains amino acids 2 of SEQ ID NO: 2 Contains amino acids 2 to 215 of group 3, or d) The HC contains amino acids 2 to 444 of SEQ ID NO: 32, and the LC contains amino acids 3 The ADC according to claim 1, comprising 3 amino acids 2 to 215.
4. a) The HC consists of sequence number 2, and the LC consists of sequence number 3. b) The HC is sequence number 12, and the LC is sequence number 13. c) The HC consists of sequence number 22, and the LC consists of sequence number 23, or d) The HC is sequence number 32 and the LC is sequence number 33, according to claim 3. The ADC described.
5. The cytotoxic agent is a microtubule inhibitor, a topoisomerase I inhibitor, a DNA damaging agent, DNA A selected agent from the group consisting of alkylating agents and DNA subgroove binders, according to claims 1 to 4. ADC.
6. The ADC according to claim 5, wherein the cytotoxic agent is a topoisomerase I inhibitor.
7. The AD according to claim 6, wherein the topoisomerase I inhibitor is a camptothecin analog. C.
8. The aforementioned camptothecin analog is given by formula: 【Chemistry 1】 The ADC according to claim 7, comprising the compound.
9. The aforementioned ADC is given by: 【Chemistry 2】 The ADC according to claim 8, comprising the compound.
10. Claims 1 to 1 further include a linker that connects the antibody to the cytotoxic agent. The ADC described in any one of item 9.
11. The ADC according to claim 10, wherein the linker includes a peptide unit or a sugar-cleaving unit.
12. The peptide unit is Val-Ala, Val-Cit, Phe-Lys, or Ala The ADC according to claim 11, comprising -Ala-Asn.
13. The aforementioned ADC is given by: 【Transformation 3】 ADC according to any one of claims 1 to 12, comprising the compound.
14. The aforementioned sugar-cleaving unit is given by the formula: 【Chemistry 4】 The ADC according to claim 11, comprising the compound.
15. The aforementioned ADC is given by: 【Transformation 5】 The ADC according to claim 14, comprising the compound.
16. The linker further comprises a hydrophobic masking group, according to any one of claims 10 to 15. The ADC described.
17. The hydrophobic masking group is selected from polysarcosine or polyethylene glycol. The ADC according to claim 16.
18. The hydrophobic masking group is in a branched arrangement on the linker, according to claim 16 or 17. The ADC described.
19. The aforementioned hydrophobic masking group is, formula: 【Transformation 6】 It is a polysarcosine, In the formula, k is an integer from 6 to 12, and X １ is H, OH, or NH ２ Claim 17 or ADC as described in 18.
20. The linker further comprises a connecting unit, according to any one of claims 10 to 19. C.
21. The aforementioned connection unit is given by: 【Transformation 7】 It is one of the compounds, The ADC according to claim 20, wherein z is 1 to 5 in the formula.
22. The aforementioned ADC is given by: 【Transformation 8】 It is one of the compounds, During the ceremony, Ab is the antibody, a) The HC contains amino acids 2 to 441 of SEQ ID NO: 2, and the LC contains amino acids 2 to 441 of SEQ ID NO: 3 include, b) The HC comprises amino acids 2 to 448 of SEQ ID NO: 12, and the LC comprises amino acids 1 Contains amino acids 2-215 of group 3, c) The HC comprises amino acids 2 to 447 of SEQ ID NO: 22, and the LC comprises amino acids 2 to 447 of SEQ ID NO: 22 Contains amino acids 2 to 215 of group 3, or d) The HC comprises amino acids 2 to 444 of SEQ ID NO: 32, and the LC comprises amino acids 3 It contains amino acids 2 to 215 of group 3, and The ADC according to any one of claims 1 to 21, wherein n is approximately 1 to 16.
23. The aforementioned ADC is given by: 【Chemistry 9】 The ADC according to claim 22, which is a compound of the above.
24. The aforementioned ADC is given by: 【Chemistry 10】 The ADC according to claim 22, which is a compound of the above.
25. The connection to the antibody occurs via one or more cysteine thiol groups of the antibody. The ADC according to any one of claims 22 to 24.
26. Each of the one or more cysteines is a native cysteine in the hinge region of the antibody. The ADC according to claim 25.
27. The aforementioned Ab is an HC containing amino acids 2 to 441 of SEQ ID NO: 2 and an LC containing SEQ ID NO: 3 The ADC according to any one of claims 22 to 26, comprising, wherein n is about 8.
28. The aforementioned Ab is an HC containing amino acids 2-448 of SEQ ID NO: 12 and an amino acid of SEQ ID NO: 13 Any one of claims 22 to 26, comprising LC containing acid 2 to 215, wherein n is about 8. ADC as described above.
29. The aforementioned Ab is an HC containing amino acids 2-447 of SEQ ID NO: 22 and amino acids of SEQ ID NO: 23 Any one of claims 22 to 26, comprising LC containing acid 2 to 215, wherein n is about 8. ADC as described above.
30. The aforementioned Ab consists of amino acids 2-444 of SEQ ID NO: 32 and amino acids 2-21 of SEQ ID NO:
33. A according to any one of claims 22 to 26, comprising LC including 5, wherein n is about 8. DC.
31. An antibody that binds to human PTK-7, wherein the antibody comprises a heavy chain variable region (VH) and a light chain The variable region (VL) is included, and the VH is the heavy chain complementarity determination region (HCDR) HCDR1, H The VL includes CDR2 and HCDR3, and the VL is the Light Chain Complementarity Determination Region (LCDR).
1. Including LCDR2 and LCDR3, a) The HCDR1 includes sequence number 4, and the HCDR2 includes sequence number 5, HCDR3 includes sequence number 6, LCDR1 includes sequence number 7, and LCD R2 includes sequence number 8, and LCDR3 includes sequence number 9. b) HCDR1 includes sequence number 14, and HCDR2 includes sequence number 15. The HCDR3 includes sequence number 16, and the LCDR1 includes sequence number 17. LCDR2 includes sequence number 18, and LCDR3 includes sequence number 19. c) The HCDR1 includes sequence number 24, and the HCDR2 includes sequence number 25. The HCDR3 includes sequence number 26, and the LCDR1 includes sequence number 27. LCDR2 includes sequence number 28, and LCDR3 includes sequence number 29, or d) The HCDR1 includes sequence number 34, and the HCDR2 includes sequence number 35. The HCDR3 includes sequence number 36, and the LCDR1 includes sequence number 37. The antibody wherein LCDR2 contains SEQ ID NO: 18, and LCDR3 contains SEQ ID NO:
38.
32. a) The VH includes sequence number 10, and the VL includes sequence number 11, b) The VH includes sequence number 20, and the VL includes sequence number 21, c) The VH includes sequence number 30, and the VL includes sequence number 31, or d) The representation of claim 31, wherein VH includes sequence number 39 and VL includes sequence number 40. The antibody listed.
33. The antibody comprises a heavy chain (HC) and a light chain (LC), a) The HC contains amino acids 2 to 441 of SEQ ID NO: 2, and the LC contains amino acids 2 to 441 of SEQ ID NO: 3 include, b) The HC comprises amino acids 2 to 448 of SEQ ID NO: 12, and the LC comprises amino acids 1 Contains amino acids 2-215 of group 3, c) The HC comprises amino acids 2 to 447 of SEQ ID NO: 22, and the LC comprises amino acids 2 to 447 of SEQ ID NO: 22 Contains amino acids 2 to 215 of group 3, or d) The HC comprises amino acids 2 to 444 of SEQ ID NO: 32, and the LC comprises amino acids 3 The antibody according to claim 31, comprising amino acids 2 to 215 of 3.
34. a) The HC consists of sequence number 2, and the LC consists of sequence number 3. b) The HC is sequence number 12, and the LC is sequence number 13. c) The HC consists of sequence number 22, and the LC consists of sequence number 23, or d) The HC is sequence number 32, and the LC is sequence number 33, claim 33 The antibody described above.
35. An ADC according to any one of claims 1 to 30, and one or more pharmaceutically acceptable carriers A pharmaceutical composition comprising a diluent or excipient.
36. For patients who require treatment for cancer, an effective amount as described in any one of claims 1 to 30. A method of treating cancer, including administering the listed ADC.
37. The aforementioned cancers include ovarian cancer, lung cancer, breast cancer, stomach cancer, kidney cancer, prostate cancer, liver cancer, The method according to claim 36, wherein the cancer is colorectal cancer.
38. Administering PD-1 inhibitors or PD-L1 inhibitors simultaneously, separately, or sequentially. The method according to claim 36 or 37, further comprising:
39. ADC according to any one of claims 1 to 30 for use in therapy.
40. An ADC according to any one of claims 1 to 30, for use in the treatment of cancer.
41. The aforementioned cancers include ovarian cancer, lung cancer, breast cancer, stomach cancer, kidney cancer, prostate cancer, liver cancer, or colorectal cancer, ADC for use according to claim 40.
42. The ADC is administered simultaneously, separately, or sequentially with a PD-1 inhibitor or a PD-L1 inhibitor. ADC for use according to any one of claims 1 to 30, administered in combination.
43. A drug containing an effective amount of the ADC described in any one of claims 1 to 30, used in the treatment of cancer. A pharmaceutical composition for use.
44. The aforementioned cancers include ovarian cancer, lung cancer, breast cancer, stomach cancer, kidney cancer, prostate cancer, liver cancer, The composition for use according to claim 43, which is for colorectal cancer.
45. AD according to any one of claims 1 to 30 for the manufacture of a drug for the treatment of cancer Use C.
46. The aforementioned cancers include ovarian cancer, lung cancer, breast cancer, stomach cancer, kidney cancer, prostate cancer, liver cancer, The use according to claim 45, or colorectal cancer.
47. Conjugate the antibody according to any one of claims 31 to 34 into the linker payload. A method for preparing an ADC, comprising the action of linking the linker-payload, wherein the linker-payload is of the formula: 【Chemistry 11】 A method comprising one of the compounds.
48. A method for producing an ADC, wherein the antibody according to any one of claims 31 to 34 is used in formula ： 【Chemistry 12】 A method comprising contacting a compound with the compound.