JPWO2021089794A5

JPWO2021089794A5 -

Info

Publication number: JPWO2021089794A5
Application number: JP2022525992A
Authority: JP
Publication date: 2023-11-14

Claims

A medicament for treating cancer in a subject comprising a platinum- based drug in combination with an antibody-drug conjugate that binds tissue factor (TF), the antibody-drug conjugate comprising auristatin or an anti-TF antibody or antigen-binding fragment thereof conjugated to a functional analog or functional derivative thereof, wherein the medicament comprises an anti-TF antibody or an antigen-binding fragment thereof conjugated to a functional analog or derivative thereof, wherein the medicament comprises an anti-TF antibody or an antigen-binding fragment thereof conjugated to a functional analog or derivative thereof, wherein the antibody-drug conjugate is are administered at a range of doses and are administered about once a week for three consecutive weeks, followed by a washout period of about one week without administration of the antibody-drug conjugate, with each cycle period ending with the washout period. A medicine characterized in that it is used for about 28 days including the period.

A medicament for treating cancer in a subject , comprising a platinum- based drug , characterized in that it is used in combination with an antibody-drug conjugate that binds tissue factor (TF ) , the antibody-drug conjugate comprising: the gate comprises an anti-TF antibody or antigen-binding fragment thereof conjugated to auristatin or a functional analog or derivative thereof , and the medicament comprises an antibody-drug conjugate of about 0.5 mg/kg to administered at doses ranging from about 2.1 mg/kg, and administered about once a week for 3 consecutive weeks, followed by a washout period of about 1 week without administration of the antibody-drug conjugate; A medicament, characterized in that it is used so that the cycle period is about 28 days, including the drug holiday .

A medicament for treating cancer in a subject, comprising an antibody -drug conjugate that binds to tissue factor ( TF ) , the antibody-drug conjugate being used in combination with a platinum-based drug. the gate comprises an anti-TF antibody or antigen-binding fragment thereof conjugated to auristatin or a functional analog or derivative thereof, and the medicament comprises an antibody-drug conjugate of about 0.5 mg/kg to administered at doses ranging from about 2.1 mg/kg, and administered about once a week for 3 consecutive weeks, followed by a washout period of about 1 week without administration of the antibody-drug conjugate; A medicament, characterized in that it is used so that the cycle period is about 28 days, including the drug holiday .

The antibody-drug conjugate may be about 0.65 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, about 1.0 mg/kg, about 1.1 mg/kg, about 1.2 mg/kg, about Medicament according to any one of claims 1 to 3 , characterized in that it is used to be administered at a dose of 1.3 mg/kg, about 1.4 mg/kg or about 1.5 mg/kg .

The antibody-drug conjugate is 0.65mg/kg, 0.7mg/kg, 0.8mg/kg, 0.9mg/kg, 1.0mg/kg, 1.1mg/kg, 1.2mg/kg, 1.3mg/kg, 1.4mg/kg Medicament according to any one of claims 1 to 4 , characterized in that it is used to be administered at a dose of 1.5 mg/kg or 1.5 mg/kg .

said antibody-drug conjugate is administered once per week for three consecutive weeks, followed by a one-week washout period without administration of said antibody-drug conjugate, and each cycle period includes said washout period. The medicament according to any one of claims 1 to 5 , characterized in that it is used for a period of 28 days.

The antibody-drug conjugate is administered on about days 1, 8, and 15 of about a 4-week cycle, or on days 1, 8, and 15 of a 4-week cycle. The medicament according to any one of claims 1 to 5 , characterized in that it is used as follows .

characterized in that the platinum-based agent is administered at a dose of AUC = about 4 to about 6, optionally a dose of AUC = about 5, or a dose of AUC = 5. , the medicament according to any one of claims 1 to 7 .

optionally about once every three weeks or so that said platinum-based agent is administered about once a week, about once every two weeks, about once every three weeks, or about once every four weeks. 9. The medicament according to claim 1, wherein the medicament is administered once every three weeks .

10. According to any one of claims 1 to 9 , the platinum-based drug is used to be administered on about day 1 of about a 21 day cycle , or on day 1 of a 21 day cycle. Medications listed.

The medicament according to any one of claims 1 to 10 , wherein the cancer is bladder cancer.

The medicament according to any one of claims 1 to 10 , wherein the cancer is cervical cancer.

13. The medicament according to claim 12 , wherein the subject is not a candidate for radical therapy, optionally said radical therapy comprising radiotherapy and/or evisceration .

14. A medicament according to claim 12 or 13 , wherein the subject has not received previous systemic therapy for cervical cancer.

15. The medicament according to any one of claims 12 to 14 , wherein the cervical cancer is adenocarcinoma, adenosquamous carcinoma, squamous cell carcinoma, or non-squamous cell carcinoma.

The medicament according to any one of claims 12 to 15 , wherein the cervical cancer is advanced stage cervical cancer.

17. The medicament according to claim 16 , wherein the advanced stage cervical cancer is stage 3 or stage 4 cervical cancer.

18. The medicament according to claim 16 or 17 , wherein the advanced stage cervical cancer is metastatic cervical cancer.

The medicament according to any one of claims 12 to 18 , wherein the cervical cancer is recurrent cervical cancer.

The medicament according to any one of claims 1 to 19 , wherein the auristatin is monomethyl auristatin , preferably monomethyl auristatin E (MMAE).

21. The medicament according to any one of claims 1 to 20 , wherein the anti-TF antibody or antigen-binding fragment thereof of the antibody-drug conjugate is a monoclonal antibody or a monoclonal antigen-binding fragment thereof.

The anti-TF antibody or antigen-binding fragment thereof of the antibody-drug conjugate comprises a heavy chain variable region and a light chain variable region, and the heavy chain variable region
(i) CDR-H1 comprising the amino acid sequence of SEQ ID NO:1;
(ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO:2; and (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO:3;
and the light chain variable region comprises:
(i) CDR-L1 comprising the amino acid sequence of SEQ ID NO:4;
(ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO:5; and (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO:6;
22. The medicament according to any one of claims 1 to 21 , wherein the CDRs of the anti-TF antibody or antigen-binding fragment thereof are defined by the IMGT numbering scheme.

The anti-TF antibody or antigen-binding fragment thereof of the antibody-drug conjugate has a heavy chain variable region comprising an amino acid sequence at least 85% identical to the amino acid sequence of SEQ ID NO:7, and the amino acid sequence of SEQ ID NO:8. 23. A medicament according to any one of claims 1 to 22 , comprising a light chain variable region comprising at least 85% identical amino acid sequence.

the anti-TF antibody or antigen-binding fragment thereof of the antibody-drug conjugate comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:7 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:8; The medicament according to any one of claims 1 to 23 .

25. The medicament according to any one of claims 1 to 24 , wherein the anti-TF antibody of the antibody-drug conjugate is tisotumab or a biosimilar thereof.

Claims 1-1, wherein the antibody-drug conjugate further comprises a linker between the anti-TF antibody or antigen-binding fragment thereof and the monomethyl auristatin, and optionally, the linker is a cleavable peptide linker. 25. The medicament according to any one of item 25 .

The cleavable peptide linker has the formula: -MC-vc-PAB-, where:
a) MC is

and
b) vc is the dipeptide valine-citrulline;
c) PAB is

27. The medicament according to claim 26 .

28. The medicament according to claim 26 or 27 , wherein the linker is bonded to a sulfhydryl residue of an anti-TF antibody obtained by partial reduction or complete reduction of the anti-TF antibody or antigen-binding fragment thereof.

the linker is attached to MMAE, in which case the antibody-drug conjugate has the following structure:

, where p represents a number from 1 to 8, S represents a sulfhydryl residue of said anti-TF antibody, Ab represents said anti-TF antibody or an antigen-binding fragment thereof, and optionally said antibody - Medicament according to claim 28 , wherein the mean value of p in the population of drug conjugates is about 4 .

The medicament according to any one of claims 1 to 29 , wherein the antibody-drug conjugate is tisotumab vedotin or a biosimilar thereof.

The medicament according to any one of claims 1 to 30 , characterized in that the antibody-drug conjugate is used for intravenous administration .

32. A medicament according to any one of claims 1 to 31 , wherein the platinum-based drug is selected from the group consisting of carboplatin, cisplatin, oxaliplatin, and nedaplatin.

32. A medicament according to any one of claims 1 to 31 , wherein the platinum-based drug is carboplatin or the platinum-based drug is cisplatin .

Medicament according to any one of claims 1 to 33 , characterized in that the platinum-based drug is used for intravenous administration .

Medicament according to any one of claims 1 to 34 , characterized in that the platinum-based drug and the antibody-drug conjugate are used to be administered sequentially or simultaneously .

at least about 0.1%, at least about 1%, at least about 2%, at least about 3%, at least about 4%, at least about 5%, at least about 6%, at least about 7%, at least about 8%, of the cervical cancer cells. at least about 9%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, 36. The medicament according to any one of claims 1 to 35 , wherein at least about 60%, at least about 70%, or at least about 80% express TF.

one or more therapeutic effects in said subject are improved following administration of said antibody-drug conjugate and said platinum-based agent as compared to baseline , optionally said one or more therapeutic effects are Any one of claims 1 to 36 selected from the group consisting of tumor size derived from cervical cancer, objective response rate, duration of response, time to response, progression-free survival, and overall survival. Medicines listed in section.

the size of the tumor derived from cervical cancer is at least about 10%, at least about 15% compared to the size of the tumor derived from cervical cancer before administration of the antibody-drug conjugate and the platinum-based agent; , at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70%, or at least about 80 38. The medicament according to any one of claims 1 to 37 , wherein the medicament decreases by %.

Objective response rate is at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 60%, at least about 70% , or at least about 80%, and/or
said subject at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months after administration of said antibody-drug conjugate and said platinum-based agent; at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 18 months, at least about 2 years, at least about 3 years, at least about 4 years, or exhibit a progression-free survival of at least about 5 years, and/or
said subject at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months after administration of said antibody-drug conjugate and said platinum-based agent; at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 18 months, at least about 2 years, at least about 3 years, at least about 4 years, or exhibit an overall survival of at least approximately 5 years;
The medicament according to any one of claims 1 to 38 .

the duration of response of said antibody-drug conjugate is at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, at least about 7 months, at least about 8 months, at least about 9 months, at least about 10 months, at least about 11 months, at least about 12 months, at least about 18 months, at least about 2 years, at least about 40. The medicament according to any one of claims 1 to 39 , for 3 years, at least about 4 years, or at least about 5 years.

the subject has one or more adverse events, and the medicament is used in combination with an additional therapeutic agent to eliminate or reduce the severity of the one or more adverse events; Optionally, the one or more adverse events include bleeding, nausea, alopecia, conjunctivitis, keratitis, conjunctival ulcer, mucositis, constipation, anorexia, diarrhea, vomiting, neutropenia, febrile neutropenia, decreased platelet count, or increased bleeding; optionally, the one or more adverse events are grade 3 or higher adverse events; optionally, the one or more adverse events are grade 3 or higher adverse events; 41. The medicament according to any one of claims 1 to 40 , wherein the adverse event is a serious adverse event .

the subject is at risk of developing one or more adverse events, and the medicament is combined with an additional therapeutic agent to prevent or reduce the severity of the one or more adverse events Optionally, the one or more adverse events include bleeding, nausea, alopecia, conjunctivitis, keratitis, conjunctival ulcer, mucositis, constipation, anorexia, diarrhea, vomiting, cytopenia, febrile neutropenia, decreased platelet count, or increased bleeding; optionally, the one or more adverse events are Grade 3 or higher adverse events; 42. The medicament according to any one of claims 1 to 41 , wherein the one or more adverse events are serious adverse events .

the one or more adverse events are conjunctivitis, conjunctival ulceration, and/or keratitis, and the additional agent is a preservative-free lubricating eye drop, an ophthalmic vasoconstrictor and/or a steroid eye drop; 43. The medicament according to claim 41 or 42 .

44. The medicament according to any one of claims 1 to 43 , wherein the subject is a human.

45. A medicament according to any one of claims 1 to 44 , wherein the antibody-drug conjugate is present as a pharmaceutical composition comprising the antibody-drug conjugate and a pharmaceutically acceptable carrier.

46. A medicament according to any one of claims 1 to 45 , wherein the platinum-based drug is present as a pharmaceutical composition comprising the platinum-based drug and a pharmaceutically acceptable carrier.

(a) a platinum-based drug , optionally carboplatin, at a dose ranging from AUC = about 4 to about 6;
(b) a dose ranging from about 5 mg to about 200 mg of an antibody-drug conjugate that binds tissue factor (TF) , comprising auristatin or a functional analog or functional derivative thereof , optionally monomethyl auristatin; an antibody-drug conjugate comprising an anti-TF antibody or antigen-binding fragment thereof conjugated to a statin , optionally tisotumab vedotin or a biosimilar thereof ; and (c) any one of claims 1-46. A kit comprising instructions for using the platinum-based drug and the antibody-drug conjugate in a medicament according to paragraph 1.

47. Use of an antibody-drug conjugate that binds TF for the manufacture of a medicament according to any one of claims 1 to 46 , wherein said medicament is for use in combination with a platinum-based drug. and the antibody-drug conjugate comprises an anti-TF antibody or antigen-binding fragment thereof conjugated to auristatin, optionally monomethyl auristatin or a functional analog or derivative thereof.

47. Use of a platinum-based medicament for the manufacture of a medicament according to any one of claims 1 to 46 , said medicament for use in combination with an antibody-drug conjugate that binds TF. and the antibody-drug conjugate comprises an anti-TF antibody or antigen-binding fragment thereof conjugated to auristatin, optionally monomethyl auristatin or a functional analog or functional derivative thereof. .