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-9345748-B2
Publication Date
2016-05-24
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. It further encompasses related polypeptides, proteins, nucleic acids, recombinant expression vectors, host cells, and cell populations, as well as antibodies and pharmaceutical compositions associated with these TCRs. The invention includes methods for detecting cancer presence by forming and detecting complexes with these materials and methods for treating or preventing cancer by administering these materials in effective amounts to a host.
The background identifies obstacles in adoptive cell therapy (ACT) for cancer, including difficulty generating human T cells with anti-tumor potential and the risk of transferred T cells causing toxicity to normal tissues. There is a need for improved immunological compositions and methods for treating cancer that address these challenges.
The inventive TCRs specifically recognize SSX-2 and can also recognize related SSX family proteins (e.g., SSX-3, SSX-4, SSX-5, SSX-9, and SSX-10) with varying avidities, in an HLA-A2-dependent manner, and in a CD8- and/or CD4-independent manner. These TCRs comprise defined complementarity determining regions (CDRs) and variable regions as set forth in specific SEQ ID NOs. The invention further includes human/mouse chimeric TCRs and functional variants thereof.
Claims Coverage
The claims encompass several inventive features related to isolated or purified TCRs, polypeptides, proteins, and compositions, focusing on specificity for SSX-2 and related SSX proteins, chimeric TCR forms, and pharmaceutical compositions.
TCR with antigenic specificity for SSX-2 and human/mouse chimeric structure
An isolated or purified TCR comprising amino acid sequences SEQ ID NOs: 13-18, 21, and 22, having antigenic specificity for SSX-2 (SEQ ID NO: 1) presented by HLA-A2, also recognizing SSX-4 (SEQ ID NO: 4), and characterized as a human/mouse chimeric TCR.
Recognition of additional SSX family members
The TCR also recognizes one or more of SSX-3 (SEQ ID NO: 3), SSX-5 (SEQ ID NO: 5), SSX-9 (SEQ ID NO: 6), and SSX-10 (SEQ ID NO: 7).
Peptide specificity including SSX-2 peptide
The TCR has antigenic specificity for the SSX-2 peptide KASEKIFYV (SEQ ID NO: 2).
Recognition of specific SSX peptide variants
The TCR recognizes peptides KVSEKIVYV, KSSEKIVYV, KASEKHYV, KSSEKIIYV, and KASEKILYV corresponding to SSX-3, SSX-4, SSX-5, SSX-9, and SSX-10, respectively.
Inclusion of variable region sequences in the TCR
The TCR comprises the amino acid sequences of SEQ ID NOs: 19 and 20.
Inclusion of human/mouse chimeric variable region sequences
The TCR comprises the amino acid sequences of SEQ ID NOs: 25 and 26, representing a chimeric structure.
Isolated polypeptides containing functional portions of TCR CDRs
Isolated or purified polypeptides comprising functional portions of the TCR, particularly amino acid sequences SEQ ID NOs: 13-18, optionally including SEQ ID NOs: 19 and 20, or pairs SEQ ID NOs: 23 and 24 or 25 and 26.
Isolated proteins comprising polypeptide chains with chimeric TCR sequences
Isolated or purified proteins with two polypeptide chains comprising SEQ ID NOs: 13-15 and 21 for the first chain, and SEQ ID NOs: 16-18 and 22 for the second chain, forming a human/mouse chimeric protein; optionally including variable regions SEQ ID NOs: 19 and 20 or 25 and 26.
Fusion proteins and recombinant antibodies
The protein can be a fusion protein or a recombinant antibody comprising at least one of the inventive polypeptides.
Pharmaceutical compositions with inventive TCRs, polypeptides, or proteins
Compositions comprising any of the claimed TCRs, polypeptides, or proteins together with pharmaceutically acceptable carriers.
The claims collectively define isolated TCRs and related polypeptides and proteins with specificity for SSX-2 and related peptides, including human/mouse chimeric variants, and their use in pharmaceutical compositions for cancer therapy.
Stated Advantages
The inventive TCRs enable destruction of cells from multiple cancer types by recognizing multiple SSX antigens.
Targeting cancer testis antigens expressed only in tumors and testes minimizes destruction of normal, non-cancerous cells, thereby reducing toxicity.
Recognition of multiple SSX cancer antigens may increase the range of cancer cells targeted and maintain efficacy despite antigen mutation.
Documented Applications
Detection of cancer in a host by contacting cancerous cells with the inventive TCR materials or antibodies to form detectable complexes.
Treatment or prevention of cancer in a host by administering any of the inventive TCRs, polypeptides, proteins, nucleic acids, recombinant vectors, host cells, or antibodies in effective amounts.
Use of the demethylating agent 5-aza-2'-deoxycytidine (DAC) to enhance recognition of cancer cells by upregulating SSX-2 expression.
The invention is applicable to treating or detecting various cancers including sarcomas, lymphomas, hepatocellular carcinoma, glioma, melanoma, ovarian cancer, pancreatic cancer, prostate cancer, among others.
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