Search

US-12616733-B2 - XBP1, CD138, and CS1 peptides, pharmaceutical compositions that include the peptides, and methods of using such peptides and compositions

US12616733B2US 12616733 B2US12616733 B2US 12616733B2US-12616733-B2

Abstract

The disclosure features, inter alia, immunogenic XBP1-, CD138-, and CS1-derived peptides (and pharmaceutical compositions thereof). The peptides can be used in a variety of methods such as methods for inducing an immune response, methods for producing an antibody, and methods for treating a cancer (e.g., breast cancer, colon cancer, pancreatic cancer, a blood cancer, e.g., leukemia or a plasma cell disorder such as multiple myeloma or Waldenstrom's macroglobulinemia). The peptides (and pharmaceutical compositions comprising the peptides) can be used, e.g., in a method of treating a precancerous condition such as smoldering multiple myeloma. The peptides can also be included in MHC molecule multimer compositions and used in, e.g., methods for detecting a T cell in a population of cells.

Inventors

  • Jooeun Bae
  • Nikhil Munshi
  • Kenneth Anderson

Assignees

  • DANA-FARBER CANCER INSTITUTE, INC.

Dates

Publication Date
20260505
Application Date
20210210

Claims (16)

  1. 1 . An immunogenic, HLA-A24-binding pharmaceutical composition comprising: (i) a non-spliced XBP1 peptide consisting of the amino acid sequence of SEQ ID NO: 29, (ii) a spliced XBP1 peptide consisting of the amino acid sequence of SEQ ID NO: 30, (iii) a CD138 peptide consisting of the amino acid sequence of SEQ ID NO: 31, (iv) a CS-1 peptide consisting of the amino acid sequence of SEQ ID NO: 32, one or more immune stimulating agents or immune modulating agents, and a pharmaceutically acceptable carrier.
  2. 2 . The pharmaceutical composition of claim 1 , wherein the immune stimulating agent is selected from an adjuvant comprising carboxymethylcellulose, polyinosinic-polycytidylic acid, and poly-L-lysine double-stranded RNA; an adjuvant comprising a water-and-oil emulsion; and an adjuvant comprising a protein.
  3. 3 . The pharmaceutical composition of claim 1 , wherein the immune modulating agent is selected from an antibody which activates the immune system, anti-PD-1 antibody, anti-PDL-1 antibody, and a small molecule adjuvant.
  4. 4 . A kit comprising the pharmaceutical composition of claim 1 , and instructions for administering the composition to a subject.
  5. 5 . An article of manufacture comprising: a container and the pharmaceutical composition of claim 1 contained within the container.
  6. 6 . A method for inducing an immune response in a subject, the method comprising delivering to a subject the pharmaceutical composition of claim 1 .
  7. 7 . The method of claim 6 , wherein the subject is a human.
  8. 8 . The method of claim 6 , wherein the subject has breast cancer, colon cancer, pancreatic cancer, leukemia, multiple myeloma or Waldenstrom's macroglobulinemia.
  9. 9 . A method for treating breast cancer, colon cancer, pancreatic cancer, leukemia, multiple myeloma or Waldenstrom's macroglobulinemia, the method comprising: administering to a subject the pharmaceutical composition of claim 1 , wherein the subject has breast cancer, colon cancer, pancreatic cancer, leukemia, multiple myeloma or Waldenstrom's macroglobulinemia.
  10. 10 . A method for treating smoldering multiple myeloma, the method comprising: administering to a subject the pharmaceutical composition of claim 1 , wherein the subject has smoldering multiple myeloma.
  11. 11 . A method of treating breast cancer in a subject, the method comprising administering a pharmaceutical composition comprising: (i) a non-spliced XBP1 peptide of 35 amino acids or less in length comprising the amino acid sequence of SEQ ID NO: 29, (ii) a spliced XBP1 peptide of 35 amino acids or less in length and comprising the amino acid sequence of SEQ ID NO: 30 , (iii) a CD138 peptide of 35 amino acids or less in length and comprising the amino acid sequence of SEQ ID NO: 31, (iv) a CS-1 peptide of 35 amino acids or less in length comprising the amino acid (iv) sequence of SEQ ID NO: 32, and a pharmaceutically acceptable carrier, to thereby treat the subject having breast cancer.
  12. 12 . A method of treating colon cancer in a subject, the method comprising administering a pharmaceutical composition comprising: (i) a non-spliced XBP1 peptide of 35 amino acids or less in length comprising the amino acid sequence of SEQ ID NO: 29, (ii) a spliced XBP1 peptide of 35 amino acids or less in length and comprising the amino acid sequence of SEQ ID NO: 30, (iii) a CD138 peptide of 35 amino acids or less in length and comprising the amino acid sequence of SEQ ID NO: 31, (iv) a CS-1 peptide of 35 amino acids or less in length comprising the amino acid sequence of SEQ ID NO: 32, and a pharmaceutically acceptable carrier, to thereby treat the subject having colon cancer.
  13. 13 . A method of treating pancreatic cancer in a subject, the method comprising administering a pharmaceutical composition comprising: (i) a non-spliced XBP1 peptide of 35 amino acids or less in length comprising the amino acid sequence of SEQ ID NO: 29, (ii) a spliced XBP1 peptide of 35 amino acids or less in length and comprising the amino acid sequence of SEQ ID NO: 30, (iii) a CD138 peptide of 35 amino acids or less in length and comprising the amino acid sequence of SEQ ID NO: 31, (iv) a CS-1 peptide of 35 amino acids or less in length comprising the amino acid (iv) sequence of SEQ ID NO: 32, and a pharmaceutically acceptable carrier, to thereby treat the subject having pancreatic cancer.
  14. 14 . A method of treating leukemia in a subject, the method comprising administering the pharmaceutical composition of claim 1 , to thereby treat the subject having leukemia.
  15. 15 . The method of claim 11 , wherein the breast cancer comprises estrogen receptor positive breast cancer, estrogen receptor negative breast cancer, HER-2 positive breast cancer, HER-2 negative breast cancer, triple negative breast cancer, or inflammatory breast cancer.
  16. 16 . The pharmaceutical composition of claim 1 , wherein any of (i)-(iv) have a binding affinity for HLA-A24 that is the same as, or higher than, the binding affinity of HIV envelope protein 583-591 peptide (SEQ ID NO: 537) to HLA-A24.

Description

CROSS REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. application Ser. No. 15/689,159, filed Aug. 29, 2017, which is a continuation of U.S. application Ser. No. 14/440,442, filed Nov. 5, 2013, which is a U.S. National Phase Application under 35 U.S.C. § 371 of International Application No. PCT/US2013/068582, filed Nov. 5, 2013, which claims priority to U.S. Ser. No. 61/722,446 filed Nov. 5, 2012, and U.S. Ser. No. 61/790,780 filed Mar. 15, 2013 the entire contents of which are incorporated herein by reference. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with government support under grant numbers P01CA078378, P01CA155258, and P50CA100707 awarded by The National Institute of Health. The government has certain rights in the invention. SEQUENCE LISTING The instant application contains a Sequence Listing which has been submitted electronically in ASCII format. Said ASCII copy, created on Dec. 9, 2013, is named 02017-7001WO_SL.txt and is 117,979 bytes in size. BACKGROUND Several types of vaccines have been developed for the prevention of infectious diseases including attenuated microorganisms, recombinant proteins and DNA vaccines. Recently, research has been carried out on the development of vaccine immunotherapy to treat cancer patients. SUMMARY The present disclosure relates to immunogenic peptides that bind to MHC class 1 molecules such as HLA-A molecules. It was found that peptides from X-Box Protein 1 (XBP1)-, CD138-, and CD2 Subset 1 (CS1) are immunogenic and are useful, e.g., to induce an immune response against various cancer cells. In some embodiments the peptides possess elevated affinity for HLA-A molecules, elevated stability within the peptide binding cleft of HLA-A, and the ability, when expressed on the surface of cell (e.g., a cancer cell) in the context of an MHC molecule, to induce the activation and proliferation of T cells (e.g., effector memory T cells and/or central memory T cells). In addition, it was found that combinations of these peptides can induce a broad spectrum of immune responses against the target antigens and this broad spectrum response can overcome major therapeutic hurdles including, inter alia, the heterogeneity of tumor associated antigen expression, frequent mutations of specific antigens and the variability of the human T-cell repertoire among individuals. Thus, administration of various combinations of these peptides, e.g., combined in a pharmaceutical composition, may provide an enhanced immune response against various cancers. It will be evident from the following description that the peptides (and pharmaceutical compositions thereof) can be used in a variety of applications such as methods for inducing an immune response, methods for activating a T cell (e.g., including effectory memory T cells and/or central memory T cells), methods for producing an antibody, and methods for treating, e.g., a cancer (e.g., breast cancer, colon cancer, pancreatic cancer, prostate cancer, leukemia, e.g., AML or CML), multiple myeloma, Waldenstrom's Macroglobulinemia and precancerous conditions, e.g., smoldering multiple myeloma. In one aspect, the disclosure features peptides, e.g., XBP1 peptides, CD138 peptides and CS-1 peptides, that have affinity for multiple MHC molecules, e.g., HLA-A molecules such as HLA-A2 and HLA-A24, elevated stability within the peptide binding cleft of multiple MHC molecules, e.g., HLA-A2 and HLA-A24, and the ability, when expressed on the surface of cell (e.g., a cancer cell) in the context of an MHC molecule, e.g., HLA-A2 or HLA-A24, to induce the activation and proliferation of T cells including, e.g., effector memory T cells and/or central memory T cells). It will be evident from the following description that the peptides (and pharmaceutical compositions thereof) can be used in a variety of applications such as methods for inducing an immune response, methods for activating a T cell (e.g., effector memory T cells and/or central memory T cells), methods for producing an antibody, and methods for treating, e.g., a cancer (e.g., lung cancer, liver cancer, bile duct cancer, stomach cancer, cervical cancer, nasopharyngeal cancer, breast cancer, colon cancer, pancreatic cancer, prostate cancer, leukemia, e.g., AML or CML), multiple myeloma and precancerous conditions, e.g., smoldering multiple myeloma. In one aspect, the disclosure features an isolated peptide comprising an amino acid sequence that is at least 66 (e.g., at least 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99) % identical to any one of SEQ ID NOS: 51-536. The peptide can bind to a major histocompatibility complex (MHC) molecule such as an MHC class I or class II molecule. In one embodiment, the peptide is 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, up to 25, 30 or 35 amino acids in length and comprises an amino acid sequence of