Antibodies and methods of use thereof

Patent metadata

Field	Value
Publication number	US-11993653-B2
Application number	US-201916435175-A
Country	US
Kind code	B2
Filing date	Jun 7, 2019
Priority date	Dec 7, 2016
Publication date	May 28, 2024
Grant date	May 28, 2024

Abstract

Provided are antibodies that specifically bind to CTLA-4 and/or PD-1 and antagonize CTLA-4 and/or PD-1 function. Also provided are pharmaceutical compositions and kits comprising these antibodies, nucleic acids encoding these antibodies, expression vectors and host cells for making these antibodies, and methods of treating a subject using these antibodies either alone or in combination.

First claim

What is claimed:

1. A method of increasing T cell activation in a subject that has cancer, the method comprising administering to the subject an effective amount of a therapeutic combination comprising a first isolated antibody that specifically binds to human CTLA-4 and a second isolated antibody that specifically binds to human PD-1, wherein:
(a) the first isolated antibody comprises a heavy chain variable region (VH) comprising the complementarity determining regions CDRH1, CDRH2, and CDRH3 of the VH amino acid sequence of SEQ ID NO: 1 and a light chain variable region (VL) comprising the complementarity determining regions CDRL1, CDRL2, and CDRL3 of the VL amino acid sequence of SEQ ID NO: 14, and
(b) the second isolated antibody comprises a heavy chain variable region (VH) comprising the complementarity determining regions CDRH1, CDRH2 and CDRH3 of the VH amino acid sequence of SEQ ID NO: 66 and a light chain variable region (VL) comprising the complementarity determining regions CDRL1, CDRL2 and CDRL3 of the VL amino acid sequence of SEQ ID NO: 74.

2. The method of claim 1 , wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 of the first isolated antibody comprise the amino acid sequences set forth in SEQ ID NOs: 20, 22, 24, 27, 30, and 36, respectively.

3. The method of claim 1 , wherein the first isolated antibody comprises
a heavy chain variable region and a light chain variable region comprising the amino acid sequences set forth in SEQ ID NOs: 1 and 14, respectively.

4. The method of claim 1 , wherein the first isolated antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 51, and a light chain comprising the amino acid sequence of SEQ ID NO: 59.

5. The method of claim 1 , wherein the first isolated antibody comprises:
(a) a heavy chain constant region selected from the group consisting of human IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2;
(b) a heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 60;
(c) an IgG1 heavy chain constant region comprising S239D/I332E mutations, numbered according to the EU numbering system;
(d) a heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 61;
(e) an IgG1 heavy chain constant region comprising S239D/A330L/I332E mutations, numbered according to the EU numbering system;
(f) a heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 62;
(g) an IgG1 heavy chain constant region comprising L235V/F243L/R292P/Y300L/P396L mutations, numbered according to the EU numbering system;
(h) a heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 63;
(i) an IgG1 heavy chain constant region, wherein the IgG1 heavy chain constant region is non-fucosylated;
(j) a light chain constant region selected from the group consisting of human Igκ and Igλ; or
(k) a light chain constant region comprising the amino acid sequence of SEQ ID NO: 64.

6. The method of claim 1 , wherein CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 of the second isolated antibody comprise the amino acid sequences set forth in SEQ ID NOs: 75, 76, 81, 83, 84, and 85, respectively.

7. The method of claim 1 , wherein the second isolated antibody comprises a heavy chain variable region and a light chain variable region comprising the amino acid sequences set forth in SEQ ID NOs: 66 and 74, respectively.

8. The method of claim 1 , wherein the second isolated antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 91 and a light chain comprising the amino acid sequence of SEQ ID NO: 93.

9. The method of claim 1 , wherein:
(a) the first isolated antibody comprises a heavy chain variable region and a light chain variable region comprising the amino acid sequences set forth in SEQ ID NOs: 1 and 14, respectively; and
(b) the second isolated antibody comprises a heavy chain variable region and a light chain variable region comprising the amino acid sequences set forth in SEQ ID NOs: 66 and 74, respectively.

10. The method of claim 1 , wherein:
(a) the first isolated antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 51 and a light chain comprising the amino acid sequence of SEQ ID NO: 59; and
(b) the second isolated antibody comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 91 and a light chain comprising the amino acid sequence of SEQ ID NO: 93.

11. The method of claim 1 , wherein the second isolated antibody comprises:
(a) a heavy chain constant region selected from the group consisting of human IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2;
(b) an IgG1 heavy chain constant region comprising an N297A mutation, numbered according to the EU numbering system;
(c) a heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 94;
(d) an IgG4 heavy chain constant region comprising an S228P mutation, numbered according to the EU numbering system;
(e) a heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 95;
(f) a light chain constant region selected from the group consisting of human Igκ and Igλ; or
(g) a light chain constant region comprising the amino acid sequence of SEQ ID NO: 64.

12. The method of claim 1 , wherein:
(a) the first isolated antibody is administered at 0.3 mg/kg or 1 mg/kg;
(b) the second isolated antibody is administered at 1 mg/kg, 3 mg/kg, or 6 mg/kg;
(c) the second isolated antibody is administered at a dose of 200 mg;
(d) the first isolated antibody is administered at 0.3 mg/kg, and the second isolated antibody is administered at 1 mg/kg;
(e) the first isolated antibody is administered at 1 mg/kg, and the second isolated antibody is administered at 1 mg/kg;
(f) the first isolated antibody is administered at 1 mg/kg, and the second isolated antibody is administered at 3 mg/kg;
(g) the first isolated antibody is administered at 1 mg/kg, and the second isolated antibody is administered at 6 mg/kg;
(h) the first isolated antibody is administered every six weeks;
(i) the second isolated antibody is administered every two weeks or every three weeks;
(j) the first isolated antibody is administered at 0.3 mg/kg every six weeks, and the second isolated antibody is administered at 1 mg/kg every two weeks;
(k) the first isolated antibody is administered at 1 mg/kg every six weeks, and the second isolated antibody is administered at 1 mg/kg every two weeks;
(l) the first isolated antibody is administered at 1 mg/kg every six weeks, and the second isolated antibody is administered at 3 mg/kg every two weeks; or
(m) the first isolated antibody is administered at 1 mg/kg every six weeks, and the second isolated antibody is administered at 6 mg/kg every three weeks.

13. The method of claim 1 , wherein:
(a) the cancer is a metastatic or locally advanced solid tumor;
(b) the cancer is a metastatic or locally advanced, unresectable squamous cell carcinoma, adenosquamous carcinoma, or adenocarcinoma of the cervix,
(c) no standard therapy is available for the cancer;
(d) the cancer is refractory to a standard therapy,
(e) the cancer has relapsed after a standard therapy;
(f) the cancer is HPV positive;
(g) the cancer is a non-small cell lung cancer (NSCLC);
(h) the cancer is a Stage IV, metastatic, or locally advanced NSCLC;
(i) the cancer is a non-small cell lung cancer (NSCLC), and wherein the NSCLC has no EGFR or ALK genomic tumor aberrations;
(j) the cancer is a non-small cell lung cancer (NSCLC), and wherein the subject has received no prior systemic chemotherapy treatment for the NSCLC;
(k) the cancer is a cutaneous squamous-cell carcinoma (cSCC);
(l) the cancer is a cuta

Assignees

• Agenus Inc
• Ludwig Inst For Cancer Res Ltd
• Memorial Sloan Kettering Cancer Center

Inventors

• Van Dijk Marc
• Mundt Cornelia Anne
• Ritter Gerd
• Schaer David
• Wolchok Jedd David
• Merghoub Taha
• Wilson Nicholas Stuart
• Savitsky David Adam
• Findeis Mark Arthur
• Zappasodi Roberta
• Holmgaard Rikke Bæk
• Cuillerot Jean-Marie
• Proscurshim Igor
• Shebanova Olga

Classifications

• A61K2039/507

  Comprising a combination of two or more separate antibodies · CPC title

• C07K2317/34

  Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues · CPC title

• C07K2317/92

  Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value · CPC title

• C07K2317/31

  multispecific · CPC title

• C07K2317/33

  Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity · CPC title