Modified T cell receptors and related materials and methods
Inventors
Robbins, Paul F. • Morgan, Richard A. • Rosenberg, Steven A. • Bennett, Alan David
Assignees
Adaptimmune Ltd • Medigene Ltd • US Department of Health and Human Services
Publication Number
US-8088379-B2
Publication Date
2012-01-03
Expiration Date
2027-09-26
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Abstract
The invention is directed to a modified T cell receptor (TCR) comprising an amino acid sequence of a wild-type (WT) TCR with no more than three amino acid substitutions, wherein the modified TCR, as compared to the WT TCR, (i) has an enhanced ability to recognize target cells when expressed by CD4+ T cells and (ii) does not exhibit a decrease in antigen specificity when expressed by CD8+ T cells. Polypeptides, proteins, nucleic acids, recombinant expression vectors, host cells, populations of cells, antibodies, and pharmaceutical compositions related to the modified TCR also are part of the invention. Further, the invention is directed to methods of detecting a diseased cell in a host, methods of treating or preventing a disease in a host, and methods of identifying a candidate adoptive immunotherapy TCR.
Core Innovation
The invention provides a modified T cell receptor (TCR) comprising an amino acid sequence of a wild-type (WT) TCR with no more than three amino acid substitutions, wherein the modified TCR, as compared to the WT TCR, (i) has an enhanced ability to recognize target cells when expressed by CD4+ T cells and (ii) does not exhibit a decrease in antigen specificity when expressed by CD8+ T cells. This enhancement enables improved recognition of antigens without loss of specificity.
The problem being solved is the need to improve expression and function of TCR transgenes used in adoptive cell transfer therapies for diseases such as cancer. Existing clinical trials demonstrated some success but highlighted insufficient efficacy, thus necessitating modified TCRs with enhanced target recognition and retained antigen specificity to better treat patients with disease.
Claims Coverage
The patent contains one independent claim that covers a modified TCR with specific structural and functional characteristics. The key inventive features focus on the precise nature of amino acid substitutions, antigen specificity, and enhanced recognition capabilities.
Modified TCR with up to three substitutions in CDR2 of beta chain
A T cell receptor comprising a wild-type sequence with no more than three amino acid substitutions located in the complementarity determining region (CDR) 2 of the beta chain, retaining antigen specificity, and having enhanced ability to recognize target cells when expressed by CD4+ T cells without reduced specificity in CD8+ T cells.
Specific cancer antigen specificity
The modified TCR has antigen specificity either for the cancer antigen MART-1, or for the cancer antigen NY-ESO-1 with a sequence based on SEQ ID NO: 8 with up to three substitutions in its CDR2.
Preference for conservative amino acid substitutions
Amino acid substitutions in the modified TCR are preferably conservative, selected from a defined group including T→A, G→A, A→I, T→V, and others.
Specific sequences for beta and alpha chains
The modified TCR may comprise specific listed amino acid sequences identified by SEQ ID numbers representing variable and full-length beta chains, optionally combined with specified wild-type alpha chains.
Inclusion of leader sequences
The modified TCR can comprise leader sequences selected from SEQ ID NOs: 110 to 115.
The claims comprehensively cover modified TCRs with up to three specific amino acid substitutions in the beta chain CDR2 that enhance target cell recognition in CD4+ T cells while maintaining specificity in CD8+ T cells, with requirements on cancer antigen specificity and defined sequence embodiments.
Stated Advantages
The modified TCRs have enhanced ability to recognize target cells when expressed by CD4+ T cells.
The modified TCRs do not exhibit a decrease in antigen specificity when expressed by CD8+ T cells.
Documented Applications
Treating or preventing diseases in a host using pharmaceutical compositions comprising the modified TCRs, specifically for diseases involving antigens such as infectious diseases, autoimmune diseases, and cancers including melanoma.
Detecting diseased cells in a host, such as cancer cells or infected cells, by contacting a sample with the modified TCRs and detecting antigen binding complexes.
Identifying candidate adoptive immunotherapy TCRs by producing nucleic acids encoding modified TCRs, expressing them in CD4+ and CD8+ T cells, and assaying for enhanced target recognition and maintained specificity.
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