Modified T cell receptors and related materials and methods
Inventors
Robbins, Paul F. • Morgan, Richard A. • Rosenberg, Steven A.
Assignees
Adaptimmune Ltd • US Department of Health and Human Services
Publication Number
US-9128080-B2
Publication Date
2015-09-08
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 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. The invention also encompasses polypeptides, proteins, nucleic acids, recombinant expression vectors, host cells, cell populations, antibodies, and pharmaceutical compositions related to the modified TCRs.
The problem being solved arises from the need to improve adoptive immunotherapy for cancer treatment. While autologous T lymphocytes transduced with anti-cancer antigen TCR genes persist and mediate regression of tumors, current approaches require enhancement of transgene expression and function. The invention addresses the need in the art for modified TCRs that increase efficacy in treating diseases, particularly cancer.
The modified TCRs provide biological improvements wherein the modified TCR has an enhanced ability to recognize antigens presented by target cells when expressed in CD4+ T cells, while maintaining antigen specificity when expressed in CD8+ T cells. Preferably, these substitutions are located within the complementarity determining regions (CDRs) of the β chain, especially CDR2. The invention includes methods of detecting diseased cells using these modified TCRs and methods of treating or preventing diseases by administering pharmaceutical compositions comprising the modified TCRs or related materials.
Claims Coverage
The claims cover fourteen main inventive features focused on nucleic acids encoding modified TCRs with specific substitutions, recombinant vectors, host cells, and cell populations for enhanced antigen recognition and maintained specificity.
Modified TCR encoding nucleic acid with up to three substitutions in CDR2 beta chain
An isolated nucleic acid encoding a modified T cell receptor comprising a wild-type TCR amino acid sequence with no more than three amino acid substitutions located in the complementarity determining region 2 (CDR2) of the β chain. The modified TCR has an enhanced ability to recognize target cells when expressed by CD4+ T cells and does not decrease antigen specificity when expressed by CD8+ T cells. The modified TCR is specific for the cancer antigen MART-1, with the wild-type TCR comprising SEQ ID NOs: 9 and 10 or 11 and 12.
Specific nucleotide sequences encoding the modified TCR
The isolated nucleic acid optionally comprises either (a) nucleotide sequences corresponding to SEQ ID NO: 28 or 29 combined with SEQ ID NO: 26, or (b) nucleotide sequences corresponding to SEQ ID NO: 32 or 33 combined with SEQ ID NO: 30.
Recombinant expression vector comprising modified TCR nucleic acid
Recombinant expression vectors comprising the isolated nucleic acids encoding the modified TCR described above, enabling expression of the modified TCR in host cells.
Host cells comprising recombinant expression vectors
Isolated host cells, including peripheral blood lymphocytes (PBLs), comprising the recombinant expression vectors encoding the modified TCRs. The PBLs may include CD8+ or CD4+ T cells.
Populations of host cells with recombinant vectors
Populations of cells comprising at least one host cell containing a recombinant expression vector encoding the modified TCR, supporting therapeutic or diagnostic uses.
Use of conservative amino acid substitutions in modified TCR
The amino acid substitutions in the modified TCR are preferably conservative substitutions selected from T→A, G→A, A→I, T→V, A→M, T→I, A→V, T→G, and T→S.
Modified TCR comprising specific amino acid sequences
The modified TCR comprises an amino acid sequence selected from SEQ ID NOs: 4 to 6, 13, and 95 to 103, or more specifically from SEQ ID NOs: 17 to 20, 37 to 39, and 104 to 109.
Combinations of modified beta and wild-type alpha chains
The modified TCR comprises a combination of either (i) any of SEQ ID NOs: 17, 20, 37 to 39, and 104 to 109 with SEQ ID NO: 9, or (ii) SEQ ID NO: 18 or 19 with SEQ ID NO: 11.
Overall, the claims encompass isolated nucleic acids encoding specific modified TCRs with limited substitutions in the CDR2 region of the β chain that retain antigen specificity while enhancing recognition by CD4+ T cells, recombinant vectors carrying such nucleic acids, host cells containing these vectors, and populations thereof. They define the types of amino acid substitutions allowed, characterize preferred sequences, and specify the utility in immune cell contexts relevant to cancer antigen MART-1 recognition.
Stated Advantages
The modified TCRs exhibit an enhanced ability to recognize target cells when expressed by CD4+ T cells.
The modified TCRs retain antigen specificity without decrease when expressed by CD8+ T cells.
The invention provides durable regression of large established tumors through adoptive immunotherapy using modified TCR-expressing cells.
The modified TCRs improve the expression and function of transgene TCRs used in adoptive cell transfer therapies.
Documented Applications
Methods of detecting diseased cells in a host by contacting cells with modified TCRs that recognize disease-specific antigens.
Methods of treating or preventing a disease in a host by administering pharmaceutical compositions comprising modified TCRs or cells expressing them.
Identifying candidate adoptive immunotherapy TCRs based on their enhanced ability to recognize target cells via CD4+ T cells while maintaining CD8+ T cell antigen specificity.
Treatment of cancer, including melanoma, by adoptive cell transfer of T cells expressing the modified TCRs.
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