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KR-102964138-B1 - Cancer combination therapy

KR102964138B1KR 102964138 B1KR102964138 B1KR 102964138B1KR-102964138-B1

Abstract

The present disclosure provides a method for administering an antibody that specifically binds to human B7-H4 and its antigen-binding fragment in combination with a PD-1/PD-L1 antagonist, such as an anti-PD-1 antibody, to a subject in need of such a combination, e.g., a cancer patient.

Inventors

  • 이남다르 산딥 피
  • 콜린스 헬렌 엘
  • 샹 홍
  • 장 샹
  • 마리나 네이사

Assignees

  • 파이브 프라임 테라퓨틱스, 인크.

Dates

Publication Date
20260512
Application Date
20191015
Priority Date
20181015

Claims (20)

  1. A pharmaceutical composition for treating solid tumors in human subjects, comprising the following (1) composition and (2) composition: (1) A composition for administering to a subject comprising 0.1 to 20 mg/kg of an anti-B7-H4 antibody or an antigen-binding fragment thereof that specifically binds to human B7-H4 and comprises a heavy chain variable region (VH) complementarity determining region (CDR) 1 containing the amino acid sequence of SEQ ID NO: 5, a VH CDR2 containing the amino acid sequence of SEQ ID NO: 6, a VH CDR3 containing the amino acid sequence of SEQ ID NO: 7, a light chain variable region (VL) CDR1 containing the amino acid sequence of SEQ ID NO: 8, a VL CDR2 containing the amino acid sequence of SEQ ID NO: 9, and a VL CDR3 containing the amino acid sequence of SEQ ID NO: 10; and (2) A composition for administering to a subject comprising 200 mg of an anti-PD-1 antibody or an antigen-binding fragment thereof comprising VH CDR1 having the amino acid sequence of SEQ ID NO: 34, VH CDR2 having the amino acid sequence of SEQ ID NO: 35, VH CDR3 having the amino acid sequence of SEQ ID NO: 36, VL CDR1 having the amino acid sequence of SEQ ID NO: 37, VL CDR2 having the amino acid sequence of SEQ ID NO: 38, and VL CDR3 having the amino acid sequence of SEQ ID NO: 39.
  2. A pharmaceutical composition for treating solid tumors in human subjects, comprising the following compositions: (a) and (b): (a) an anti-B7-H4 antibody or an antigen-binding fragment thereof comprising (i) VH CDR 1 having the amino acid sequence of SEQ ID NO: 5, VH CDR2 having the amino acid sequence of SEQ ID NO: 6, VH CDR3 having the amino acid sequence of SEQ ID NO: 7, VL CDR1 having the amino acid sequence of SEQ ID NO: 8, VL CDR2 having the amino acid sequence of SEQ ID NO: 9, and VL CDR3 having the amino acid sequence of SEQ ID NO: 10, which specifically bind to human B7-H4; and (ii) a pharmaceutical composition for administration to a subject, comprising a pharmaceutically acceptable excipient, At least 95% of the anti-B7-H4 antibody or its antigen-binding fragment in the above composition is afucosylated, and A pharmaceutical composition comprising 0.1 to 20 mg/kg of an antibody or an antigen-binding fragment thereof; and (b) A pharmaceutical composition for administration to a subject comprising an anti-PD-1 antibody or an antigen-binding fragment thereof comprising VH CDR1 having the amino acid sequence of SEQ NO: 34, VH CDR2 having the amino acid sequence of SEQ NO: 35, VH CDR3 having the amino acid sequence of SEQ NO: 36, VL CDR1 having the amino acid sequence of SEQ NO: 37, VL CDR2 having the amino acid sequence of SEQ NO: 38, and VL CDR3 having the amino acid sequence of SEQ NO: 39, and a pharmaceutically acceptable excipient, comprising 200 mg of the antibody or antigen-binding fragment.
  3. A pharmaceutical composition according to claim 1 or 2, wherein 20 mg/kg of the anti-B7-H4 antibody or its antigen-binding fragment is included for administration to a subject.
  4. A pharmaceutical composition according to claim 1 or 2, wherein 10 mg/kg of the anti-B7-H4 antibody or its antigen-binding fragment is included for administration to a subject.
  5. A pharmaceutical composition according to claim 1 or 2, wherein 3 mg/kg of the anti-B7-H4 antibody or its antigen-binding fragment is included for administration to a subject.
  6. A pharmaceutical composition according to claim 1 or 2, wherein 1 mg/kg of the anti-B7-H4 antibody or its antigen-binding fragment is included for administration to a subject.
  7. A pharmaceutical composition according to claim 1 or 2, wherein 0.3 mg/kg of the anti-B7-H4 antibody or its antigen-binding fragment is included for administration to a subject.
  8. A pharmaceutical composition according to claim 1 or 2, wherein 0.1 mg/kg of the anti-B7-H4 antibody or its antigen-binding fragment is included for administration to a subject.
  9. A pharmaceutical composition according to claim 1 or 2, wherein the anti-B7-H4 antibody or its antigen-binding fragment and the anti-PD-1 antibody or its antigen-binding fragment are included for simultaneous administration.
  10. A pharmaceutical composition according to claim 9, wherein the anti-B7-H4 antibody or its antigen-binding fragment and the anti-PD-1 antibody or antigen-binding fragment are included for administration as separate formulations on the same day.
  11. A pharmaceutical composition according to claim 1 or 2, wherein the anti-B7-H4 antibody or its antigen-binding fragment and the anti-PD-1 antibody or its antigen-binding fragment are included for sequential administration.
  12. A pharmaceutical composition according to claim 8, wherein the anti-PD-1 antibody or its antigen-binding fragment is included for administration after a composition comprising the anti-B7-H4 antibody or its antigen-binding fragment has been administered.
  13. A pharmaceutical composition according to claim 1 or 2, wherein the anti-B7-H4 antibody or its antigen-binding fragment is included for administration once every 3 weeks.
  14. A pharmaceutical composition according to claim 1 or 2, wherein the anti-PD-1 antibody or its antigen-binding fragment is included for administration once every 3 weeks.
  15. A pharmaceutical composition according to claim 1 or 2, wherein the anti-B7-H4 antibody or its antigen-binding fragment and the anti-PD-1 antibody or its antigen-binding fragment are each included for administration once every 3 weeks.
  16. A pharmaceutical composition according to claim 1 or 2, wherein the anti-B7-H4 antibody or its antigen-binding fragment is included for intravenous administration.
  17. A pharmaceutical composition according to claim 1 or 2, wherein the anti-PD-1 antibody or its antigen-binding fragment is included for intravenous administration.
  18. A pharmaceutical composition according to claim 1 or 2, wherein B7-H4 is detected in solid tumors using immunohistochemistry (IHC) prior to administration.
  19. A pharmaceutical composition according to claim 1 or 2, wherein the anti-B7-H4 antibody or its antigen-binding fragment comprises VH having the amino acid sequence presented in SEQ ID NO: 11 and/or VL having the amino acid sequence presented in SEQ ID NO: 12.
  20. A pharmaceutical composition according to claim 1 or 2, wherein the anti-B7-H4 antibody or antigen-binding fragment comprises a heavy chain constant region and/or a light chain constant region.

Description

Cancer combination therapy The present disclosure relates to a method of co-administering an antibody that specifically binds to human B7-H4 with a PD-1/PD-L1 antagonist, such as pembrolizumab, for the treatment of a disease such as cancer. An advantageous dosage regimen is provided. 1. Background Technology B7-H4 (also known as B7x, B7-S1, and VTCN1) is an immunomodulatory molecule that shares homology with other B7 family members, including PD-L1. It is a type I transmembrane protein composed of IgV and IgC ectododomains. While B7-H4 expression is relatively restricted at the protein level in healthy tissues, B7-H4 is expressed in several solid tumors, such as gynecological carcinomas of the breast, ovary, and endometrium. Expression of B7-H4 in tumors tends to be associated with a poor prognosis. Although receptors for B7-H4 are unknown, they are believed to be expressed on T cells. B7-H4 is believed to directly inhibit T cell activity. Considering the expression and function of B7-H4, antibodies that specifically bind to B7-H4 are being developed for therapies involving the modulation of B7-H4 activity, for example, for cancer treatment. PD-1 is a major immune checkpoint receptor expressed by activated T and B cells and mediates immunosuppression. PD-1 is a member of the CD28 family of receptors, which includes CD28, CTLA-4, ICOS, PD-1, and BTLA. Two cell surface glycoprotein ligands for PD-1, Programmed Death Ligand 1 (PD-L1) and Programmed Death Ligand 2 (PD-L2), have been identified; these are expressed in antigen-presenting cells as well as many human cancers and have been shown to downregulate T cell activation and cytokine secretion upon binding to PD-1. For example, inhibition of the PD-1/PD-L1 interaction by anti-PD-1 or anti-PD-L1 antibodies mediates potent antitumor activity. Therefore, an effective dosage regimen is required to administer antibodies binding to B7-H4 and inhibitors of PD-1/PD-L1 interactions. 2. Overview The present invention provides a method of administering an anti-B7-H4 antibody and its antigen-binding fragment in combination with a PD-1/PD-L1 antagonist using a therapeutically effective dose regimen. The anti-B7-H4 antibody and its antigen-binding fragment may be a 20502 antibody or its antigen-binding fragment; or an antibody or antigen-binding fragment comprising a heavy chain and light chain variable region CDR of a 20502 antibody; or an antibody or antigen-binding fragment comprising a heavy chain and light chain variable region of a 20502 antibody comprising an afucosylated form of any of the above. The PD-1/PD-L1 antagonist may be an anti-PD-1 antibody such as pembrolizumab, or an antibody or antigen-binding fragment comprising a heavy chain and light chain variable region CDR of pembrolizumab; or an antibody or antigen-binding fragment comprising a heavy chain and light chain variable region of pembrolizumab. In a specific aspect, a method for treating a solid tumor in a human subject comprises administering (a) an antibody or its antigen-binding fragment about 0.1 to about 20 mg/kg that specifically binds to human B7-H4 and comprises the sequences of the heavy chain variable region (VH) complementarity determining region (CDR) 1, VH CDR2, VH CDR3 and the light chain variable region (VL) CDR1, VL CDR2, and VL CDR3 of the 20502 antibody; and (b) about 200 mg of pembrolizumab to the subject. In a specific embodiment, (a) and (b) are administered simultaneously or sequentially. In a specific aspect, a method for treating a solid tumor in a human subject comprises administering to the subject (a) (i) an antibody or its antigen-binding fragment that specifically binds to human B7-H4 and comprises the sequences of the heavy chain variable region (VH) complementarity determining region (CDR) 1, VH CDR2, VH CDR3 and the light chain variable region (VL) CDR1, VL CDR2, and VL CDR3 of antibody 20502, and (ii) a pharmaceutical composition comprising a pharmaceutically acceptable excipient, and (b) a pharmaceutical composition comprising pembrolizumab, wherein at least 95% of the antibody or its antigen-binding fragment in the composition is afucosylated, and about 0.1 to about 20 mg/kg of the antibody or its antigen-binding fragment is administered; and about 200 mg of pembrolizumab is administered. In a specific embodiment, (a) and (b) are administered simultaneously or sequentially. In certain aspects, the CDR of the antibody or antigen-binding fragment is a Kabat-defined CDR, a Chothia-defined CDR, or an AbM-defined CDR. In certain aspects, the VH CDR1, VH CDR2, VH CDR3, VL CDR1, VL CDR2, and CDR3 sequences each contain the amino acid sequences presented in Sequence Nos. 5-10. In a specific aspect, about 20 mg/kg or 20 mg/kg of the anti-B7-H4 antibody or its antigen-binding fragment is administered to the subject. In a specific aspect, about 10 mg/kg or 10 mg/kg of the anti-B7-H4 antibody or its antigen-binding fragment is administered to the subject. In a specific aspect,