JPWO2018213260A5 - - Google Patents

Claims (62)

The heavy chain variable region (VH) complementarity determining regions (CDR) 1 sequence of SEQ ID NO: 20, the VH CDR2 sequence of SEQ ID NO: 21, the VH CDR3 sequence of SEQ ID NO: 22, and the light chain variable region (VL) CDR1 sequence of SEQ ID NO: 23. , An anti-PD-1 antibody or antigen-binding fragment thereof, comprising the VL CDR2 sequence of SEQ ID NO: 24 and the VL CDR3 sequence of SEQ ID NO: 25.
A pharmaceutical composition for the treatment of endometrial cancer in patients;
The pharmaceutical composition comprises an immunoconjugate that binds to folic acid receptor 1 (FOLR1).
The immunoconjugates are the mytansinoid and the VH CDR1 sequence of SEQ ID NO: 9, the VH CDR2 sequence of SEQ ID NO: 10, the VH CDR3 sequence of SEQ ID NO: 12, the VL CDR1 sequence of SEQ ID NO: 6, and the VL CDR2 sequence of SEQ ID NO: 7. And an anti-FOLR1 antibody comprising the VL CDR3 sequence of SEQ ID NO: 8 or an antigen-binding fragment thereof.
Pharmaceutical composition. The pharmaceutical composition according to claim 1, wherein the anti-FOLR1 antibody or an antigen-binding fragment thereof comprises VH containing the sequence of SEQ ID NO: 3 and VL containing the sequence of SEQ ID NO: 5. The pharmaceutical composition of claim 2, wherein the anti-FOLR1 antibody or antigen binding fragment comprises a heavy chain comprising the sequence of SEQ ID NO: 13 and a light chain comprising SEQ ID NO: 15. The pharmaceutical composition according to any one of claims 1 to 3, wherein the maytansinoid is DM4. The pharmaceutical composition according to any one of claims 1 to 4, wherein the maytansinoid is linked to the antibody or an antigen-binding fragment thereof by a sulfo-SPDB linker. Antis comprising VH CDR1 sequence of SEQ ID NO: 20, VH CDR2 sequence of SEQ ID NO: 21 and VH CDR3 sequence of SEQ ID NO: 22 and VL CDR1 sequence of SEQ ID NO: 23, VL CDR2 sequence of SEQ ID NO: 24 and VL CDR3 sequence of SEQ ID NO: 25. For use in combination with a PD-1 antibody or an antigen-binding fragment thereof,
A pharmaceutical composition for the treatment of endometrial cancer in patients;
The pharmaceutical composition comprises an immunoconjugate that binds to FOLR1.
Immunoconjugates contain mytansinoids and (i) heavy chains containing the same amino acid sequence as the heavy chain encoded by the plasmid deposited with the American Culture Cell Conservation Agency (ATCC) as PTA-10772. (Ii) Containing an anti-FOLR1 antibody or antigen-binding fragment thereof, comprising a light chain comprising the same amino acid sequence as the amino acid sequence of the light chain encoded by the plasmid deposited with ATCC as PTA-10774.
Pharmaceutical composition. The pharmaceutical composition according to claim 6, wherein the maytansinoid is DM4, and DM4 is linked to the antibody by sulfo-SPDB. The one according to any one of claims 1 to 7, wherein the immunoconjugate comprises 1 to 10 maytansinoid molecules, 2 to 5 maytansinoid molecules, or 3 to 4 maytansinoid molecules. Pharmaceutical composition. The pharmaceutical composition according to any one of claims 1 to 7, wherein the immunoconjugate has the following chemical structure:

(In the formula, "Ab" represents an anti-FOLR1 antibody or an antigen-binding fragment thereof). The pharmaceutical composition of claim 9, wherein the immunoconjugate comprises 2-5 or 3-4 maytansinoid molecules. The pharmaceutical composition according to any one of claims 1 to 10, wherein the immunoconjugate is administered once every three weeks. The pharmaceutical composition according to any one of claims 1 to 11, wherein the immunoconjugate is administered at a dose of about 6 mg / kg adjusted ideal body weight (AIBW). The pharmaceutical composition according to any one of claims 1 to 12, wherein the anti-PD-1 antibody or an antigen-binding fragment thereof comprises VH containing the sequence of SEQ ID NO: 26 and VL containing the sequence of SEQ ID NO: 27. 13. The pharmaceutical composition of claim 13, wherein the anti-PD-1 antibody or antigen-binding fragment thereof is pembrolizumab. The pharmaceutical composition according to any one of claims 1 to 14, wherein the anti-PD-1 antibody or an antigen-binding fragment thereof is administered once every three weeks. The pharmaceutical composition according to any one of claims 1 to 15, wherein the anti-PD-1 antibody or an antigen-binding fragment thereof is administered at a dose of about 200 mg. The pharmaceutical composition according to any one of claims 1 to 16, wherein the endometrial cancer is serous endometrial cancer. The pharmaceutical composition according to any one of claims 1 to 16, wherein the endometrial cancer is endometrial endometrial cancer. The pharmaceutical composition according to any one of claims 1 to 18, wherein administration of the composition reduces CA125. The pharmaceutical composition according to any one of claims 1 to 18, wherein the endometrial cancer is a primary endometrial cancer. The pharmaceutical composition according to any one of claims 1 to 20, wherein the endometrial cancer expresses the FOLR1 protein. 21. The pharmaceutical composition of claim 21, wherein expression of the FOLR1 protein is measured by immunohistochemistry (IHC) in a tumor sample obtained from a patient. 22. The pharmaceutical composition of claim 22, wherein the staining score of at least 1 hetero, at least 1 homo, at least 2 hetero, at least 2 homo or at least 3 hetero is measured by IHC. 22. The pharmaceutical composition of claim 22, wherein at least 25%, at least 33%, at least 50%, at least 66%, or at least 75% of the cells in a sample obtained from a patient have an IHC score of at least 2. 22. The pharmaceutical composition of claim 22, wherein at least 25%, at least 33%, at least 50%, at least 66%, or at least 75% of the cells in the sample obtained from the patient have an IHC score of at least 3. 22. The pharmaceutical composition of claim 22, wherein the patient is determined to be folate receptor-alpha (FRα) positive. 26. The pharmaceutical composition of claim 26, comprising tumor cells with FOLR1 membrane staining, where FRα positivity is at least 50% visible under a 10 × microscopic objective. 22. The pharmaceutical composition of claim 22, wherein at least 25% of the cells in the sample obtained from the patient have an IHC score of at least 2. 28. The pharmaceutical composition of claim 28, wherein at least 25% to 49% or less of the cells in the sample have an IHC score of at least 2. 28. The pharmaceutical composition of claim 28, wherein at least 50% to 74% or less of the cells in the sample have an IHC score of at least 2. 28. The pharmaceutical composition of claim 28, wherein at least 75% to 100% of the cells in the sample have an IHC score of at least 2. The pharmaceutical composition according to any one of claims 1 to 31, wherein the endometrial cancer expresses PD-L1. The pharmaceutical composition according to any one of claims 1-32, wherein the patient has at least one lesion that meets the definition of a disease measurable according to RECIST 1.1. The pharmaceutical composition according to any one of claims 1 to 33, wherein the immunoconjugate and the anti-PD-1 antibody or an antigen-binding fragment thereof are sequentially administered in separate pharmaceutical compositions. 34. The pharmaceutical composition of claim 34, wherein the immunoconjugate is administered prior to the anti-PD-1 antibody or antigen-binding fragment thereof. The pharmaceutical composition according to any one of claims 1 to 35, wherein the immunoconjugate is administered intravenously or intraperitoneally. The pharmaceutical composition according to any one of claims 1 to 36, wherein the anti-PD-1 antibody or an antigen-binding fragment thereof is administered intravenously. The pharmaceutical composition according to any one of claims 1 to 37, wherein the pharmaceutical composition is used in the first-line therapy. The pharmaceutical composition according to any one of claims 1 to 38, wherein the pharmaceutical composition is used in second-line therapy. The pharmaceutical composition according to any one of claims 1 to 39, wherein the pharmaceutical composition is a third-line therapy or is used after the third-line therapy. The pharmaceutical composition according to any one of claims 1 to 40, wherein the endometrial cancer is recurrent. Claims 1 to claim that the use of an immunoconjugate with an anti-PD-1 antibody or antigen-binding fragment thereof provides greater therapeutic benefit than administration of the immunoconjugate alone or the anti-PD-1 antibody or antigen-binding fragment thereof alone. The pharmaceutical composition according to any one of 41. Any of claims 1-42, wherein the use of an immunoconjugate and an anti-PD-1 antibody or an antigen-binding fragment thereof results in less toxicity than administration of the immunoconjugate alone or the anti-PD-1 antibody or an antigen-binding fragment thereof alone. The pharmaceutical composition according to item 1. The pharmaceutical composition according to any one of claims 1-43, further comprising administering a steroid to the patient. 44. The pharmaceutical composition of claim 44, wherein the steroid is administered prior to administration of the immunoconjugate. The pharmaceutical composition of claim 45, wherein the steroid is administered approximately 30 minutes prior to administration of the immunoconjugate. The pharmaceutical composition according to any one of claims 44 to 46, wherein the steroid is a corticosteroid. The pharmaceutical composition according to any one of claims 44 to 47, wherein the steroid is dexamethasone. The pharmaceutical composition according to any one of claims 44 to 48, wherein the steroid is administered orally, intravenously, or in combination thereof. The pharmaceutical composition according to claim 49, wherein the steroid is administered as an eye drop. The pharmaceutical composition according to claim 50, wherein the eye drop is a lubricating eye drop. The pharmaceutical composition according to any one of claims 1 to 51, further comprising administering acetaminophen, diphenhydramine or a combination thereof to the patient. For use in combination with 200 mg pembrolizumab,
A pharmaceutical composition for the treatment of endometrial cancer,
The pharmaceutical composition comprises an immunoconjugate that binds to FOLR1 at 6 mg / AIBW kg.
Here, the immunoconjugate bound to FOLR1 comprises an antibody linked to the maytansinoid DM4 by a sulfo-SPDB linker, wherein the antibody comprises (i) a heavy chain comprising the sequence of SEQ ID NO: 13 and (i). ii) A light chain comprising the sequence of SEQ ID NO: 15, and
Pharmaceutical composition. For use in combination with 200 mg pembrolizumab,
A pharmaceutical composition for the treatment of endometrial cancer,
The pharmaceutical composition comprises an immunoconjugate that binds to FOLR1 at 6 mg / AIBW kg.
Here, the immunoconjugate that binds to FOLR1 comprises an antibody linked to the mitansinoid DM4 by a sulfo-SPDB linker, wherein the antibody is (i) PTA-10772, an American cultured cell lineage preservation organization (ATCC). ) Containing a heavy chain containing the same amino acid sequence as the heavy chain encoded by the plasmid deposited in), and (ii) the same amino acid sequence as the light chain encoded by the plasmid deposited by ATCC as PTA-10774. Light chain, including sequence, and, including,
Pharmaceutical composition. The pharmaceutical composition according to claim 53 or 54, wherein the immunoconjugate comprises 1 to 10, 2 to 5 or 3 to 4 maytansinoids. The pharmaceutical composition according to claim 53 or 54, wherein the immunoconjugate has the following chemical structure:

(In the formula, "Ab" represents an anti-FOLR1 antibody or an antigen-binding fragment thereof). 56. The pharmaceutical composition of claim 56, wherein the immunoconjugate comprises 2-5 or 3-4 maytansinoids. The pharmaceutical composition according to any one of claims 53 to 57, wherein at least 25% of the cells of the tumor sample obtained from the patient have a FOLR1 IHC score of at least 2. The pharmaceutical composition according to any one of claims 53 to 58, wherein the immunoconjugate and pembrolizumab are administered intravenously, and the immunoconjugate is administered prior to pembrolizumab. The pharmaceutical composition according to any one of claims 53 to 59, wherein the steroid is administered prior to the administration of the immunoconjugate. The pharmaceutical composition according to any one of claims 1-41, wherein the patient has moderate or high FRα expression for endometrial cancer. The pharmaceutical composition according to any one of claims 1 to 61, wherein the patient has a FOLR1 positive state.