T cell receptors recognizing MHC class II-restricted MAGE-A3
Inventors
Robbins, Paul F. • Rosenberg, Steven A. • Yao, Xin
Assignees
US Department of Health and Human Services
Publication Number
US-9879065-B2
Publication Date
2018-01-30
Expiration Date
2033-09-13
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Abstract
The invention provides an isolated or purified T-cell receptor (TCR) having antigenic specificity for MHC Class II-restricted MAGE-A3. 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 mammal are further provided by the invention.
Core Innovation
The invention provides isolated or purified T-cell receptors (TCRs) having antigenic specificity for MHC Class II-restricted MAGE-A3, particularly recognizing MAGE-A3 in the context of HLA-DPβ1*04. Related polypeptides, proteins, nucleic acids, recombinant expression vectors, host cells, and populations of cells are also provided, along with antibodies and pharmaceutical compositions related to the TCRs. The invention includes methods for detecting the presence of cancer and methods for treating or preventing cancer in mammals using these TCRs or related compositions.
The problem addressed arises from limitations in adoptive cell therapy (ACT) where T-cells targeting HLA-A*02 restricted epitopes have been successful in some cancers. However, patients lacking HLA-A*02 expression cannot be treated with such T-cells, which restricts the widespread application of adoptive cell therapy. Therefore, there is a need for improved immunological compositions and methods to treat cancer patients who do not express HLA-A*02.
The inventive TCRs recognize MAGE-A3 (especially MAGE-A3243-258) and MAGE-A6, members of the MAGE-A cancer testis antigen family, which are expressed selectively in tumor cells and some germ cells, but not in normal tissues. By targeting MAGE-A3 presented by HLA-DPβ1*04, a prevalent allele expressed in about 70-80% of cancer patients, the invention greatly expands the patient population eligible for treatment. Additionally, these TCRs are capable of targeting multiple cancer types expressing MAGE-A proteins, potentially enabling treatment or prevention of diverse cancers. The specificity for cancer testis antigens also serves to minimize damage to normal non-cancerous cells, reducing toxicity.
Claims Coverage
The patent includes multiple independent claims directed to nucleic acids encoding TCRs with antigenic specificity for MAGE-A3 and MAGE-A6 and related constructs. The inventive features relate to specific amino acid sequences and substitutions that confer antigenic specificity and improved function.
TCR nucleic acids encoding antigen-specific TCRs with defined CDR sequences and variants
Nucleic acids encoding T-cell receptors having antigenic specificity for MAGE-A3243-258 and MAGE-A6, comprising amino acid sequences SEQ ID NOs: 3, 4, 6, 7, or functional variants thereof (notably SEQ ID NOs: 29 and 30 with defined amino acid substitutions). These sequences include variations in complementarity determining regions (CDRs) conferring MAGE-A3 specificity in the context of HLA-DPβ1*04.
TCR nucleic acids encoding TCRs with specified variable and constant regions and functional variants
Nucleic acids encoding TCRs comprising amino acid sequences SEQ ID NOs: 3-8 or 21-22, as well as functional or substituted variants (SEQ ID NOs: 29-34) with antigenic specificity for MAGE-A3 in the context of HLA-DPβ1*04. Variants include those with substitutions in CDR3 regions of alpha or beta chains, potentially enhancing antigen reactivity. Some sequences include murine constant regions (SEQ ID NOs: 25 and 26) to improve TCR pairing.
Nucleic acids encoding polypeptides or proteins comprising functional portions of the specified TCR sequences
Nucleic acids encoding polypeptides that are functional portions of the inventive TCR sequences capable of specifically binding to MAGE-A3 and/or MAGE-A6. These portions include combinations of CDR amino acid sequences (including substitutions as in SEQ ID NOs: 29 and 30), variable regions, full alpha and beta chains, or fusion proteins such as chimeric or recombinant antibodies incorporating the inventive TCR sequences.
Recombinant expression vectors and host cells comprising nucleic acids encoding the inventive TCRs
Recombinant expression vectors containing the nucleic acids encoding the inventive TCRs and host cells, preferably human T cells, transformed with these vectors for expression of the antigen-specific TCRs. Populations of these host cells are also encompassed.
Methods of detecting and treating cancer using cells expressing the inventive TCRs
Methods of detecting cancer by contacting patient samples with cells or molecules comprising the inventive TCRs and detecting complexes indicative of cancer presence, where the cancer expresses MAGE-A3 and/or MAGE-A6. Methods of treating cancer by administering an effective amount of cells expressing the inventive TCRs to mammals with such cancers, including melanoma, breast cancer, lung cancer, prostate cancer, synovial cell sarcoma, head and neck cancer, esophageal cancer, and ovarian cancer.
The claims cover isolated nucleic acids encoding TCRs with specific CDR amino acid sequences and their functional variants that confer antigenic specificity for MAGE-A3 and MAGE-A6 presented by HLA-DPβ1*04, recombinant vectors and host cells expressing these TCRs, and methods of detecting and treating cancers expressing these antigens. Variants include conservative and non-conservative amino acid substitutions improving activity and use of murine constant regions for enhanced function.
Stated Advantages
By targeting MAGE-A3 in the context of HLA-DPβ1*04, the inventive TCRs expand the population of cancer patients eligible for adoptive cell therapy beyond those expressing HLA-A*02.
The TCRs enable targeting of multiple cancer types as MAGE-A3 and MAGE-A6 are expressed in a variety of human cancers including melanoma, breast, lung, ovarian, and others.
Specificity for cancer testis antigens expressed mainly in tumor cells and non-MHC expressing germ cells allows for targeted destruction of cancer cells with minimized toxicity to normal tissues.
Functional variants show increased reactivity and efficacy against cancer cells.
Murine constant region substitution enhances TCR expression and function by promoting better chain pairing.
Documented Applications
Use of TCRs for adoptive cell transfer therapy to treat or prevent cancers expressing MAGE-A3 and/or MAGE-A6, including melanoma, breast cancer, lung cancer, prostate cancer, synovial cell sarcoma, head and neck cancer, esophageal cancer, and ovarian cancer.
Methods of detecting presence of cancer in mammalian hosts by detecting complexes formed between cancer cells and TCRs, polypeptides, proteins, nucleic acids, or antibodies specific for MAGE-A3 and/or MAGE-A6.
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