Methods for treating muscle-invasive urothelial carcinoma or muscle-invasive bladder cancer with antibody drug conjugates (ADCs) that bind to 191P4D12 protein

ADCs targeting 191P4D12 protein in MIBC and MIUC provide effective neo-adjuvant and perioperative treatment, achieving significant pathological downstaging and improving surgical outcomes for patients ineligible for cisplatin, addressing the lack of standard treatments for these cancers.

JP2025501978APending Publication Date: 2025-01-24AGENSYS INC +1
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Patent Information

Application Number
JP2024539848
Authority / Receiving Office
JP · JP
Patent Type
Applications
Current Assignee / Owner
Priority Date
2022-01-28
Filing Date
2023-01-04
Publication Date
2025-01-24

AI Technical Summary

Technical Problem

Current treatments for muscle-invasive bladder cancer (MIBC) and muscle-invasive urothelial carcinoma (MIUC) are limited, particularly for patients ineligible for cisplatin-based therapies, with no standard neo-adjuvant or perioperative options available, leading to poor prognosis and high recurrence rates.

Method used

Development of antibody-drug conjugates (ADCs) that target the 191P4D12 protein (nectin-4) for administering to patients with MIBC or MIUC, conjugated with monomethyl auristatin E (MMAE), followed by radical cystectomy and pelvic lymph node dissection (RC+PLND), achieving pathological downstaging and improving survival rates.

Benefits of technology

The ADC treatment achieves pathological downstaging rates of at least 50% and demonstrates comparable or superior efficacy to standard of care therapies, maintaining patient health for surgical interventions.

✦ Generated by Eureka AI based on patent content.

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Abstract

Provided herein are methods for treating urothelial or bladder cancer with antibody drug conjugates (ADCs) that bind to the 191P4D12 protein (Nectin-4).
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Claims

1. 1. A method of treating muscle invasive urothelial carcinoma (MIUC) or muscle invasive bladder cancer (MIBC) in a human subject, comprising: (a) administering to the subject an effective amount of an antibody drug conjugate (ADC); the ADC comprises an antibody or antigen-binding fragment thereof that binds to 191P4D12 (Nectin-4) conjugated to one or more units of monomethylauristatin E (MMAE); the subject is ineligible to receive cisplatin therapy (cisplatin-ineligible); The pathological complete response rate (pCRR) is at least 30%. The method.

2. 1. A method of treating muscle invasive urothelial carcinoma (MIUC) or muscle invasive bladder cancer (MIBC) in a human subject, comprising: (a) administering to the subject an effective amount of an antibody drug conjugate (ADC); the ADC comprises an antibody or antigen-binding fragment thereof that binds to 191P4D12 (Nectin-4) conjugated to one or more units of monomethylauristatin E (MMAE); the subject is ineligible to receive cisplatin therapy (cisplatin-ineligible); A pathological downstaging rate (pDSR) of at least 50%; The method.

3. 3. The method of claim 1 or 2, comprising administering 3 cycles of the ADC to the subject.

4. The method of any one of claims 1 to 3, wherein said treatment of said cancer further comprises radical cystectomy and pelvic lymph node dissection (RC+PLND).

5. 5. The method of claim 4, wherein the human subject undergoes the RC+PLND about 4 to about 12 weeks after the ADC is administered to the human subject.

6. 3. The method of claim 1 or 2, further comprising: (b) performing a radical cystectomy and pelvic lymph node dissection (RC+PLND) on the subject.

7. 7. The method of claim 6, wherein (b) is performed about 4 to about 12 weeks after (a).

8. 1. A method of treating muscle invasive urothelial carcinoma (MIUC) or muscle invasive bladder cancer (MIBC) in a human subject, comprising administering to the subject multiple cycles of an effective amount of an antibody drug conjugate (ADC); (a) the ADC comprises an antibody or antigen-binding fragment thereof that binds to 191P4D12 (Nectin-4) conjugated to one or more units of monomethylauristatin E (MMAE); (b) the subject is ineligible to receive cisplatin therapy (cisplatin-ineligible); (c) the number of cycles of ADC therapy administered to said cisplatin-ineligible subject is equal to or less than the number of cycles of standard of care (SOC) therapy used to treat cisplatin-eligible subjects with MIUC or MIBC; The method.

9. The SOC regimen for a cisplatin eligible subject comprises: i. cisplatin, ii. methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC); iii. gemcitabine and cisplatin; iv. administering a programmed cell death 1 (PD-1) inhibitor; or v. Administering a programmed cell death-ligand 1 (PD-L1) inhibitor The method of claim 8 , comprising:

10. 10. The method of claim 8 or 9, wherein the number of cycles of ADC therapy administered to the cisplatin-ineligible subject is 3 or 4.

11. 1. A method of administering neoadjuvant or perioperative therapy for treating muscle invasive urothelial carcinoma (MIUC) or muscle invasive bladder cancer (MIBC) in a human subject, comprising administering to the subject multiple cycles of an effective amount of an antibody drug conjugate (ADC); (a) the ADC comprises an antibody or antigen-binding fragment thereof that binds to 191P4D12 (Nectin-4) conjugated to one or more units of monomethylauristatin E (MMAE); (b) the subject is ineligible to receive cisplatin therapy (cisplatin-ineligible); (c) the subject remains eligible for radical cystectomy and pelvic lymph node dissection (RC+PLND) surgery after said multiple cycles of treatment with the ADC. The method.

12. 12. The method of claim 11, wherein the ADC is administered as a neoadjuvant therapy (i) before the surgery, or (ii) before and after the surgery.

13. 1. A method of treating muscle invasive urothelial carcinoma (MIUC) or muscle invasive bladder cancer (MIBC) in a human subject, comprising administering to the subject multiple cycles of an effective amount of an antibody drug conjugate (ADC); (a) the ADC comprises an antibody or antigen-binding fragment thereof that binds to 191P4D12 (Nectin-4) conjugated to one or more units of monomethylauristatin E (MMAE); (b) the subject is ineligible to receive cisplatin therapy (cisplatin-ineligible); (c) the efficacy of said treatment of said subject with said effective amount of said ADC is similar to the efficacy of treatment observed in cisplatin-eligible patients treated with a standard of care (SOC) regimen used to treat cisplatin-eligible subjects with MIUC or MIBC. The method.

14. 14. The method of claim 13, wherein the efficacy of the treatment is at least as effective as the efficacy of the treatment observed in a SOC for cisplatin-eligible subjects.

15. 15. The method of claim 13 or 14, wherein the measure of efficacy of the treatment is one or more of the following: pathological complete response rate (pCRR), pathological downstaging rate (pDSR), disease-free survival (DFS), recurrence-free survival (EFS), overall survival (OS), progression-free survival (PFS), and duration of response (DoR).

16. 16. The method of claim 15, wherein the pCRR for the cisplatin-ineligible subject is at least 30%.

17. 16. The method of claim 15, wherein the pDSR for the cisplatin-ineligible subjects is at least 50%.

18. The SOC regimen for the cisplatin-eligible subject comprises: (i) cisplatin, (ii) methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC); (iii) gemcitabine and cisplatin; (iv) a programmed cell death 1 (PD-1) inhibitor, or (v) programmed cell death-ligand 1 (PD-L1) inhibitors The method according to any one of claims 14 to 17, comprising:

19. 19. The method of claim 18, wherein (i) the PD-1 inhibitor is nivolumab or pembrolizumab, or (ii) the PD-L1 inhibitor is selected from the group consisting of atezolizumab, avelumab, and durvalumab.

20. The method according to any one of claims 1 to 19, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising a CDR comprising the amino acid sequence of the complementarity determining region (CDR) of the heavy chain variable region set forth in SEQ ID NO: 22, and a light chain variable region comprising a CDR comprising the amino acid sequence of the CDR of the light chain variable region set forth in SEQ ID NO:

23.

21. (i) the antibody or antigen-binding fragment thereof comprises CDR-H1 comprising the amino acid sequence of SEQ ID NO:9, CDR-H2 comprising the amino acid sequence of SEQ ID NO:10, CDR-H3 comprising the amino acid sequence of SEQ ID NO:11, CDR-L1 comprising the amino acid sequence of SEQ ID NO:12, CDR-L2 comprising the amino acid sequence of SEQ ID NO:13, and CDR-L3 comprising the amino acid sequence of SEQ ID NO:14; (ii) the antibody or antigen-binding fragment thereof comprises CDR-H1 comprising the amino acid sequence of SEQ ID NO: 16, CDR-H2 comprising the amino acid sequence of SEQ ID NO: 17, CDR-H3 comprising the amino acid sequence of SEQ ID NO: 18, CDR-L1 comprising the amino acid sequence of SEQ ID NO: 19, CDR-L2 comprising the amino acid sequence of SEQ ID NO: 20, and CDR-L3 comprising the amino acid sequence of SEQ ID NO: 21; (iii) the antibody or antigen-binding fragment thereof comprises a CDR-H1 consisting of the amino acid sequence of SEQ ID NO:9, a CDR-H2 consisting of the amino acid sequence of SEQ ID NO:10, a CDR-H3 consisting of the amino acid sequence of SEQ ID NO:11, a CDR-L1 consisting of the amino acid sequence of SEQ ID NO:12, a CDR-L2 consisting of the amino acid sequence of SEQ ID NO:13, and a CDR-L3 consisting of the amino acid sequence of SEQ ID NO:14; or (iv) the antibody or antigen-binding fragment thereof comprises CDR-H1 consisting of the amino acid sequence of SEQ ID NO: 16, CDR-H2 consisting of the amino acid sequence of SEQ ID NO: 17, CDR-H3 consisting of the amino acid sequence of SEQ ID NO: 18, CDR-L1 consisting of the amino acid sequence of SEQ ID NO: 19, CDR-L2 consisting of the amino acid sequence of SEQ ID NO: 20, and CDR-L3 consisting of the amino acid sequence of SEQ ID NO: 21; The method according to any one of claims 1 to 20.

22. 22. The method of any one of claims 1 to 21, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:22 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:

23.

23. The method of any one of claims 1 to 22, wherein the antibody comprises a heavy chain comprising an amino acid sequence ranging from the 20th amino acid (glutamic acid) to the 466th amino acid (lysine) of SEQ ID NO:7, and a light chain comprising an amino acid sequence ranging from the 23rd amino acid (aspartic acid) to the 236th amino acid (cysteine) of SEQ ID NO:

8.

24. The method of any one of claims 1 to 22, wherein the antigen-binding fragment is a Fab, F(ab')2, Fv, or scFv.

25. The method of any one of claims 1 to 23, wherein the antibody is a fully human antibody.

26. The method of any one of claims 1 to 23 and 25, wherein the antibody is an IgG1 and the light chain is a kappa light chain.

27. The method of any one of claims 1 to 26, wherein the antibody or antigen-binding fragment thereof is recombinantly produced.

28. 28. The method of any one of claims 1 to 27, wherein the antibody or antigen-binding fragment is conjugated to each unit of MMAE via a linker, optionally the linker is an enzyme-cleavable linker, which forms a bond with a sulfur atom of the antibody or antigen-binding fragment thereof, and optionally the linker has the formula -Aa-Ww-Yy-, where -A- is a Stretcher unit, a is 0 or 1, -W- is an Amino Acid unit, w is an integer in the range of 0 to 12, -Y- is a Spacer unit, and y is 0, 1, or 2.

29. The Stretcher unit has the structure of formula (1) below, the Amino Acid unit is valine-citrulline, and the Spacer unit is a PAB group having the structure of formula (2) below: Optionally, the Stretcher unit forms a bond with a sulfur atom of the antibody or antigen-binding fragment thereof, and the Spacer unit is linked to MMAE via a carbamate group.

29. The method of claim 28.

30. The ADC is (i) 1 to 20 units of MMAE per antibody or antigen-binding fragment thereof; (ii) 1 to 10 units of MMAE per antibody or antigen-binding fragment thereof; (iii) 2 to 8 units of MMAE per antibody or antigen-binding fragment thereof; or (iv) 3 to 5 units of MMAE per antibody or antigen-binding fragment thereof The method according to any one of claims 1 to 29, comprising:

31. The ADC has the following structure: having 31. The method of any one of claims 1 to 30, wherein L- represents the antibody or antigen-binding fragment thereof and p is 1 to 10.

32. (i) p is 2 to 8, (ii) p is 3 to 5, (iii) p is 3 to 4, or (iv) p is about 4; 32. The method of claim 31 .

33. 33. The method of claim 31 or 32, wherein the effective amount of the antibody drug conjugate has an average p-value of about 3.

8.

34. 34. The method of any one of claims 1 to 33, wherein the ADC is formulated in a pharmaceutical composition comprising L-histidine, polysorbate-20 (TWEEN®-20), and trehalose dehydrate.

35. The ADC is (i) a pharmaceutical composition comprising about 20 mM L-histidine, about 0.02% (w / v) TWEEN®-20, about 5.5% (w / v) trehalose dihydrate, and hydrochloride, wherein the pH of the pharmaceutical composition is about 6.0 at 25° C.; or (ii) a pharmaceutical composition comprising about 9 mM histidine, about 11 mM histidine hydrochloride monohydrate, about 0.02% (w / v) TWEEN®-20, and about 5.5% (w / v) trehalose dihydrate, wherein the pH of the pharmaceutical composition is about 6.0 at 25° C. The method according to any one of claims 1 to 34, wherein the pharmaceutical composition is formulated in

36. The ADC has the following structure: having 36. The method of any one of claims 1-35, wherein L- represents the antibody or antigen-binding fragment thereof, p is about 3 to about 4, the antibody comprises a heavy chain comprising the amino acid sequence ranging from the 20th amino acid (glutamic acid) to the 466th amino acid (lysine) of SEQ ID NO:7, and a light chain comprising the amino acid sequence ranging from the 23rd amino acid (aspartic acid) to the 236th amino acid (cysteine) of SEQ ID NO:8, the ADC is administered at a dose of about 1.25 mg / kg subject body weight, and the dose is administered by IV infusion on days 1 and 8 of every 3 weeks.

37. The method of any one of claims 1 to 36, wherein the subject has cT2-T4aN0M0 stage MIBC.

38. The subject meets the following criteria: (a) a GFR of less than 60 mL / min but equal to or greater than 30 mL / min, wherein the GFR is measured by the Cockcroft-Gault method, the Modification of Diet in Renal Disease (MDRD), or a 24-hour urine collection; (b) ECOG performance status of 2; (c) hearing loss of grade 2 or greater on the NCI CTCAE version 4.03; and (d) NYHA class III heart failure The method according to any one of claims 1 to 37, wherein the patient is considered cisplatin-ineligible if one or more of the following conditions are met:

39. The method of any one of claims 1 to 38, wherein the subject has not received previous systemic treatment for MIBC, chemoradiotherapy, and / or radiotherapy.

40. 40. The method of any one of claims 1 to 39, wherein the subject is not receiving an immune checkpoint inhibitor (CPI), and optionally, the CPI is a programmed cell death 1 (PD-1) inhibitor or a programmed cell death-ligand 1 (PD-L1) inhibitor.

41. The method of any one of claims 1 to 40, wherein the subject has not received a CD137 agonist, a CTLA-4 inhibitor, or an OX-40 agonist.

42. 42. The method of any one of claims 1-41, wherein the effective amount of the ADC is about 1 to about 10 mg / kg, about 1 to about 5 mg / kg, about 1 to about 2.5 mg / kg, about 1 to about 1.25 mg / kg, about 0.25 mg / kg, about 0.5 mg / kg, about 0.75 mg / kg, about 1.0 mg / kg, about 1.25 mg / kg, about 1.5 mg / kg, about 1.75 mg / kg, about 2.0 mg / kg, about 2.25 mg / kg, or about 2.5 mg / kg of the subject's body weight.

43. 42. The method of any one of claims 1 to 41, wherein the effective amount of the ADC is about 1 mg / kg body weight of the subject.

44. 42. The method of any one of claims 1-41, wherein the effective amount of the ADC is about 1.25 mg / kg of subject body weight.

45. 3. The method of claim 1 or 2, wherein in (a), the effective amount of the ADC is administered to the subject on days 1 and 8 of a cycle every 3 weeks for a total of 3 cycles.

46. 46. ​​The method of claim 45, wherein the effective amount of the ADC is about 1.25 mg / kg of subject body weight.

47. 6. The method of claim 4 or 5, wherein in (a), the effective amount of the ADC is administered to the subject on days 1 and 8 of a cycle every 3 weeks for a total of 3 cycles.

48. 48. The method of any one of claims 4, 5, or 47, further comprising (b) administering to the subject about 8 weeks after the subject receives the RC+PLND, the effective amount of the ADC on days 1 and 8 of a cycle every 3 weeks, for a total of 6 cycles.

49. 49. The method of claim 47 or 48, wherein the effective amount of the ADC is about 1.25 mg / kg of subject body weight.

50. 8. The method of claim 6 or 7, wherein in (a), the effective amount of the ADC is administered to the subject on days 1 and 8 of a cycle every 3 weeks for a total of 3 cycles.

51. 51. The method of any one of claims 6, 7, or 50, further comprising: (c) about 8 weeks after (b), administering to the subject the effective amount of the ADC on days 1 and 8 of a three-week cycle, for a total of three cycles.

52. 52. The method of claim 50 or 51, wherein the effective amount of the ADC is about 1.25 mg / kg of subject body weight.

53. 45. The method of any one of claims 8-44, wherein the effective amount of the ADC is administered to the human subject on days 1 and 8 of a three-week cycle for a total of three cycles.

54. 54. The method of any one of claims 1 to 53, wherein the ADC is administered by intravenous (IV) injection or infusion.

55. 55. The method of any one of claims 1 to 54, wherein the cancer is muscle invasive urothelial carcinoma (MIUC).

56. 55. The method of any one of claims 1 to 54, wherein the cancer is muscle invasive bladder cancer (MIBC).

57. The method of any one of claims 1 to 56, wherein the ADC is enfortumab vedotin (EV).

58. 58. The method of any one of claims 1-57, wherein the overall survival of the subject is extended by at least 2 months, at least 4 months, at least 6 months, at least 8 months, at least 10 months, or at least 12 months.

59. The method of any one of claims 1 to 58, wherein the ADC is administered as a monotherapy.