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-10143724-B2
Publication Date
2018-12-04
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. The TCR can comprise specific amino acid sequences such as those set forth in SEQ ID NOs: 13-18, 19 and 20, 23 and 24, or 25 and 26. The invention also provides related polypeptides, proteins, nucleic acids, recombinant expression vectors, host cells, populations of cells, antibodies or antigen binding portions thereof, and pharmaceutical compositions related to these TCRs.
The invention further provides methods for detecting the presence of cancer in a host by contacting a sample comprising cancer cells with the inventive TCRs or related materials and detecting a complex indicative of cancer presence. The invention also discloses methods of treating or preventing cancer in a host by administering these TCRs, polypeptides, proteins, nucleic acids, recombinant vectors, host cells, or populations of host cells in an amount effective to treat or prevent cancer.
The problem solved by the invention arises from limitations in adoptive cell therapy (ACT) for cancer. ACT's success is hindered by difficulty in generating human T cells with anti-tumor potential and by the toxicity of transferred T cells toward normal, non-cancerous tissues. Therefore, there is an unmet need for improved immunological compositions and methods that specifically target cancer cells while minimizing toxicity to normal tissues.
Claims Coverage
The claims cover multiple inventive features related to isolated nucleic acids encoding TCRs specific for SSX-2, recombinant expression vectors, host cells, and pharmaceutical compositions incorporating these elements.
TCR nucleic acid encoding antigenic specificity for SSX-2
An isolated or purified nucleic acid encoding a TCR having antigenic specificity for SSX-2 and comprising the amino acid sequences of SEQ ID NOs: 13-18.
TCR nucleic acid recognizing multiple SSX family members
The TCR also recognizes one or more of SSX-3, SSX-4, SSX-5, SSX-9, and SSX-10 as specified by their SEQ ID NOs.
TCR nucleic acid encoding specificity for SSX-2 peptide KASEKIFYV
The TCR has antigenic specificity for an SSX-2 peptide comprising SEQ ID NO: 2, KASEKIFYV.
TCR nucleic acid encoding recognition of specific SSX peptides
The TCR recognizes peptides KVSEKIVYV, KSSEKIVYV, KASEKIIYV, KSSEKIIYV, and KASEKILYV (SEQ ID NOs: 8-12).
TCR comprising specific CDR or variable regions
The claimed TCR comprises amino acid sequences SEQ ID NOs: 19 and 20, with or without mouse constant regions SEQ ID NOs: 21 and 22.
TCR comprising full α and β chains
The TCR comprises either (a) SEQ ID NOs: 23 and 24 or (b) SEQ ID NOs: 25 and 26 as α and β chains.
Isolated nucleic acid encoding functional TCR portions
Isolated nucleic acids encoding functional portions of the TCR comprising SEQ ID NOs: 13-18, or variable regions SEQ ID NOs: 19 and 20, or full chains SEQ ID NOs: 23-26.
Isolated nucleic acid encoding a protein with two polypeptide chains
Nucleic acid encoding a protein with a first polypeptide chain comprising SEQ ID NOs: 13-15 and a second polypeptide chain comprising SEQ ID NOs: 16-18, or extended sequences 19 and 20, or full chains 23-26.
Protein as a fusion protein or recombinant antibody
The protein encoded may be a fusion protein or recombinant antibody comprising at least one of the inventive polypeptides.
Recombinant expression vectors and host cells
Recombinant expression vectors comprising the nucleic acid encoding the TCR, preferably retroviral vectors, and isolated host cells, including peripheral blood lymphocytes such as CD8+ or CD4+ T cells, containing these vectors.
Pharmaceutical compositions comprising host cells
Pharmaceutical compositions comprising host cells transduced with the recombinant expression vectors and a pharmaceutically acceptable carrier.
The claims comprehensively cover the isolated nucleic acids encoding TCRs specific for SSX-2 and related SSX antigens, including functional portions, proteins, recombinant expression vectors, host cells, and pharmaceutical compositions useful for cancer detection and treatment.
Stated Advantages
The TCRs target multiple cancer types expressing SSX antigens, enabling broad cancer cell destruction.
The TCRs target cancer testis antigens expressed only in tumor cells and non-MHC expressing germ cells of the testis, minimizing toxicity to normal tissues.
The ability to recognize multiple SSX family members increases the likelihood of effective tumor targeting despite antigen mutations.
Codon optimization and introduction of a mouse constant region improve TCR expression and function in human T cells.
The inventive TCRs function in a CD8- and/or CD4-independent manner, broadening their applicability in immune responses.
Documented Applications
Detection of cancer by contacting samples containing cancer cells with TCRs, polypeptides, proteins, nucleic acids, recombinant vectors, host cells, or antibodies and detecting complex formation indicating cancer presence.
Treatment or prevention of various cancers in a host by administering TCRs, polypeptides, proteins, nucleic acids, recombinant expression vectors, host cells, populations of cells, or antibodies in an effective amount.
Enhanced cancer recognition by combining SSX-2 TCR therapy with the demethylating agent 5-aza-2′-deoxycytidine (DAC) to upregulate SSX-2 expression in cancer cells.
Generation of engineered T cells (e.g., peripheral blood lymphocytes) expressing SSX-2 specific TCRs for adoptive cell therapy targeting SSX-expressing cancers.
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