Anti-SSX-2 T cell receptors and related materials and methods of use
Inventors
Morgan, Richard A. • Chinnasamy, Nachimuthu • Rosenberg, Steven A.
Assignees
US Department of Health and Human Services
Publication Number
US-10864252-B2
Publication Date
2020-12-15
Expiration Date
2031-09-14
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Abstract
The invention provides an isolated or purified T cell receptor (TCR) having antigenic specificity for synovial sarcoma X Breakpoint (SSX)-2. The invention further provides related polypeptides and proteins, as well as related nucleic acids, recombinant expression vectors, host cells, and populations of cells. Further provided by the invention are antibodies, or an antigen binding portion thereof, and pharmaceutical compositions relating to the TCRs of the invention. Methods of detecting the presence of cancer in a host and methods of treating or preventing cancer in a host are further provided by the invention.
Core Innovation
The invention provides an isolated or purified T cell receptor (TCR) having antigenic specificity for synovial sarcoma X Breakpoint (SSX)-2. These TCRs can comprise specified amino acid sequences, including those set forth in SEQ ID NOs: 13-18, 19 and 20, 23 and 24, or 25 and 26. The invention further encompasses related polypeptides, proteins, nucleic acids, recombinant expression vectors, host cells, populations of cells, antibodies or antigen binding portions thereof, and pharmaceutical compositions relating to the TCRs.
Methods are provided for detecting the presence of cancer in a host by contacting a sample comprising cancer cells with any of the inventive TCR materials or antibodies, forming a complex, and detecting the complex, wherein detection indicates the presence of cancer. Additionally, methods of treating or preventing cancer in a host involve administering any of the inventive TCRs, polypeptides, proteins, nucleic acids, recombinant expression vectors, or host cells expressing same in an amount effective to treat or prevent cancer.
The problem being solved is the difficulty in generating human T cells with anti-tumor potential for adoptive cell therapy (ACT) and the toxicity to normal tissues caused by transferred T cells. The invention addresses the need for improved immunological compositions and methods for treating cancer by providing TCRs specific for SSX-2, which is expressed in multiple cancer types and limited in normal tissues, thereby offering targeted and potentially less toxic cancer immunotherapy.
Claims Coverage
The claims disclose multiple inventive features related to recombinant expression vectors encoding TCRs specific for SSX-2 and related components, host cells, populations of cells, pharmaceutical compositions, and methods of detecting and treating cancer using these components.
Recombinant expression vector encoding TCR specific for SSX-2
A recombinant expression vector comprising a nucleic acid encoding a T cell receptor having antigenic specificity for SSX-2 (SEQ ID NO: 1), wherein the TCR comprises amino acid sequences of SEQ ID NOs: 19 and 20.
TCR recognizing multiple SSX family proteins
The TCR encoded by the vector also recognizes any one or more of SSX-3, SSX-4, SSX-5, SSX-9, and SSX-10 (SEQ ID NOs: 3, 4, 5, 6, 7).
TCR specific for SSX-2 peptides
The TCR has antigenic specificity for an SSX-2 peptide comprising KASEKIFYV (SEQ ID NO: 2) and recognizes peptides KVSEKIVYV, KSSEKIVYV, KASEKIIYV, KSSEKIIYV, and KASEKILYV (SEQ ID NOs: 8-12).
Inclusion of mouse constant regions in TCR
The TCR further comprises mouse constant regions as set forth in SEQ ID NOs: 21 and 22, or comprises polypeptide pairs SEQ ID NOs: 23 and 24 or SEQ ID NOs: 25 and 26.
Recombinant expression vectors encoding polypeptides and proteins
Vectors encoding polypeptides comprising SEQ ID NOs: 13-18, variable regions SEQ ID NOs: 19 and 20, and proteins comprising chains of SEQ ID NOs: 19 and 20 or chimeric or fusion proteins including recombinant antibodies.
Host cells and populations comprising the recombinant vectors
Isolated host cells, including peripheral blood lymphocytes (PBLs), CD8+ and CD4+ T cells, and populations of cells comprising the recombinant vectors.
Pharmaceutical compositions
Pharmaceutical compositions comprising the recombinant vectors or populations of cells and a pharmaceutically acceptable carrier.
Methods for detecting cancer
Methods of detecting cancer expressing SSX-2 peptide KASEKIFYV presented by HLA-A2 by contacting a sample with the population of engineered cells and detecting complex formation indicative of cancer presence.
Methods for treating cancer
Methods of treating cancers, including ovarian cancer, glioma, melanoma, hepatocellular carcinoma, and others, by administering the population of cells expressing the TCR.
Combination therapy
Methods further comprising administering 5-aza-2′-deoxycytidine (DAC) to enhance recognition of cancer cells by the engineered T cells.
The claims collectively cover recombinant vectors encoding SSX-2-specific TCRs with defined sequences, host cells and cell populations expressing these TCRs, pharmaceutical compositions containing them, and their use in methods for detecting and treating various cancers expressing SSX-2 peptides, including improvements by codon optimization and mouse constant regions, and combination with demethylating agents.
Stated Advantages
The inventive TCRs can destroy multiple types of cancer cells due to expression of SSX family proteins in diverse cancers.
Targeting cancer testis antigens expressed only in tumor cells and non-MHC expressing germ cells reduces toxicity to normal tissues.
Recognition of multiple cancer antigens by a single TCR increases the range of tumor cells targeted and maintains efficacy against mutated antigens.
Documented Applications
Detecting the presence of cancer in a host by forming and detecting complexes with SSX-2 antigen-specific TCRs, polypeptides, proteins, nucleic acids, recombinant vectors, host cells, or antibodies.
Treating or preventing cancers including sarcomas (e.g., synovial sarcoma, osteogenic sarcoma, leiomyosarcoma uteri, alveolar rhabdomyosarcoma), lymphomas, hepatocellular carcinoma, glioma, head-neck cancer, melanoma, ovarian cancer, pancreatic cancer, prostate cancer, and others by administering TCR-engineered cells or related pharmaceutical compositions.
Combination therapy comprising administering demethylating agent 5-aza-2′-deoxycytidine (DAC) to enhance cancer cell recognition by the TCR-engineered cells.
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