T cell receptors recognizing HLA-A1- or HLA-CW7-restricted mage
Inventors
Robbins, Paul F. • Rosenberg, Steven A. • Zhu, Shiqui • Feldman, Steven A. • Morgan, Richard A.
Assignees
US Department of Health and Human Services
Publication Number
US-11306131-B2
Publication Date
2022-04-19
Expiration Date
2032-09-11
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Abstract
The invention provides an isolated or purified T cell receptor (TCR) having antigenic specificity for a) melanoma antigen family A (MAGE A)-3 in the context of HLA-A1 or b) MAGE-A12 in the context of HLA-Cw7. 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 isolated or purified T cell receptors (TCRs) having antigenic specificity for melanoma antigen family A (MAGE A)-3 in the context of HLA-A1 or MAGE-A12 in the context of HLA-Cw7. The invention further encompasses related polypeptides and proteins, nucleic acids, recombinant expression vectors, host cells, and populations of cells. It also provides antibodies or antigen binding portions thereof, as well as pharmaceutical compositions related to these TCRs. Moreover, methods for detecting the presence of cancer in a host and treating or preventing cancer by administering these inventive materials are disclosed.
The problem being addressed arises from limitations in adoptive cell therapy (ACT) which typically uses T-cells targeting HLA-A2 restricted T-cell epitopes. Patients lacking HLA-A2 expression cannot be treated with such T-cells, posing an obstacle to the widespread application of ACT. There is a need for improved immunological compositions and methods that can treat cancer patients with other HLA types, thereby expanding the eligible patient population for adoptive cell therapy.
Claims Coverage
The claims cover nucleic acids encoding T cell receptors with specificity for MAGE-A12 presented by HLA-Cw7, recombinant expression vectors, host cells, populations of cells, pharmaceutical compositions, and methods of detecting and treating cancer.
Nucleic acid encoding TCR with MAGE-A12 specificity restricted by HLA-Cw7
An isolated or purified nucleic acid encoding a T cell receptor having antigenic specificity for MAGE-A12 presented by HLA-Cw7, the TCR comprising the amino acid sequences of SEQ ID NOs: 26-31.
Polypeptide and protein comprising MAGE-A12-specific TCR sequences
Isolated or purified nucleic acids encoding polypeptides or proteins comprising amino acid sequences of SEQ ID NOs: 26-31 and optionally SEQ ID NOs: 32-35. The protein can comprise a first polypeptide chain with SEQ ID NOs: 26-28 and a second polypeptide chain with SEQ ID NOs: 29-31, and can be a fusion protein or a recombinant antibody.
Recombinant expression vector and host cells comprising nucleic acid encoding the TCR
Recombinant expression vectors comprising nucleic acids encoding the TCR, and isolated host cells, including peripheral blood lymphocytes (PBL), T cells, or tumor infiltrating lymphocytes (TIL), comprising the recombinant expression vectors.
Populations of host cells and pharmaceutical compositions
Populations comprising at least one host cell transduced with the recombinant vector, and pharmaceutical compositions comprising such populations with pharmaceutically acceptable carriers.
Methods of detecting and treating cancer with cells expressing the TCR
Methods of detecting presence of cancer by contacting cancer cells with the population of cells expressing the TCR and detecting complexes formed, wherein detection indicates cancer presence. Methods of treating cancer by administering an effective amount of the TCR-expressing cell population to a host with cancer expressing a MAGE-A12 epitope presented by HLA-Cw7.
Cells being autologous to the host
The host cells or cells of the population used in the detection or treatment methods can be autologous to the host.
The claims collectively cover isolated nucleic acids encoding TCRs with specificity to MAGE-A12 presented by HLA-Cw7, recombinant vectors, host cells including T cells, pharmaceutical compositions comprising these cells, and methods of detecting and treating cancers expressing MAGE-A12 in the context of HLA-Cw7, including melanoma and urinary bladder cancer.
Stated Advantages
The TCRs targeting MAGE-A3 presented by HLA-A1 or MAGE-A12 presented by HLA-Cw7 greatly expand the patient population treatable by adoptive cell therapy, including those not expressing HLA-A2.
Because MAGE-A3 and MAGE-A12 are expressed by cells of multiple cancer types, the inventive TCRs provide the ability to treat multiple types of cancer.
The TCRs target cancer testis antigens expressed only in tumor cells and non-MHC expressing germ cells, thereby minimizing or eliminating destruction of normal cells and reducing toxicity.
Documented Applications
Use in adoptive cell therapy for treating cancer patients who express HLA-A1 or HLA-Cw7 by targeting MAGE-A3 or MAGE-A12 antigen, respectively.
Methods for detecting presence of cancer in a host by contacting cancer cells with the TCRs, polypeptides, proteins, nucleic acids, recombinant vectors, host cells, or antibodies and detecting complex formation.
Pharmaceutical compositions comprising TCR-expressing host cells for administration to treat or prevent cancers, including melanoma and urinary bladder cancer.
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