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-10611815-B2
Publication Date
2020-04-07
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) with antigenic specificity for MHC Class II-restricted MAGE-A3, particularly recognizing MAGE-A3243-258 and MAGE-A6 peptides in the context of HLA-DPβ1*04. It includes related polypeptides, proteins, nucleic acids, recombinant vectors, host cells, antibodies, and pharmaceutical compositions. The invention further encompasses methods for detecting cancer presence and treating or preventing cancer using these TCRs and related compositions.
Adoptive cell therapy (ACT) using T cells targeting HLA-A*02 restricted epitopes has shown tumor regression but is limited to patients expressing HLA-A*02. Patients lacking this allele cannot benefit from such therapy, restricting the broader application of ACT. This invention addresses the need for improved immunological compositions and methods that extend treatment options to a wider patient population by targeting MAGE-A3 presented in the highly prevalent HLA-DPβ1*04 context.
The inventive TCRs specifically recognize MAGE-A3/MAGE-A6 peptides presented by HLA-DPβ1*04, enabling treatment of multiple cancer types expressing these antigens. MAGE-A family proteins are cancer testis antigens expressed predominantly on tumors and non-MHC expressing germ cells, allowing targeted destruction of cancer cells while minimizing normal cell toxicity. Functional variants and portions of these TCRs maintain antigen specificity and improved biological activity, broadening therapeutic utility.
Claims Coverage
The patent claims encompass multiple independent inventive features centered on isolated T-cell receptors specific for MAGE-A3 and MAGE-A6 in the context of HLA-DPβ1*04, including various amino acid sequence compositions and functional variants.
Isolated TCRs with specific amino acid sequences and functional variants
Claims cover isolated or purified TCRs having antigenic specificity for MAGE-A3243-258 and MAGE-A6, comprising the amino acid sequences of specified complementarity determining regions (CDRs) SEQ ID NOs: 3, 4, 6, 7, substituted sequences SEQ ID NOs: 29 and 30 with defined amino acid variability, or SEQ ID NOs: 3-8.
TCRs with antigenic specificity for MAGE-A3 in context of HLA-DPβ1*04
Claims include TCRs comprising combinations of SEQ ID NOs: 3-8, 21-22, and variants SEQ ID NOs: 29 and 30, retaining specificity for MAGE-A3 presented by HLA-DPβ1*04 alleles.
TCRs comprising specific functional variants with defined amino acid substitutions
Claims specify TCRs including variants with amino acid substitutions at defined positions in CDR3 regions, especially SEQ ID NOs: 29 and 30 where variable residues Xaa4-Xaa7 are selected from serine, alanine, leucine, isoleucine, valine, or methionine, conferring maintained or enhanced antigen specificity.
TCRs with murine constant regions
Claims include TCRs comprising murine constant regions, particularly those comprising SEQ ID NO: 25 and/or SEQ ID NO: 26, enabling chimeric human/mouse TCR constructs with improved functionality.
TCRs with combinations of variable region sequences and amino acid substitutions
Claims cover TCRs comprising pairs of amino acid sequences from groups including substituted and wild-type forms of SEQ ID NOs: 31, 32, 9, 10 (variable regions of alpha and beta chains), or SEQ ID NOs: 33, 34, 11, 12, 21, 22, 27, 28 (full alpha and beta chains or chimeric forms), retaining antigen specificity.
Polypeptides and proteins comprising functional portions of the TCRs
Claims encompass isolated polypeptides comprising functional portions of the TCRs with specified CDR sequences or variants thereof, and proteins composed of one or more such polypeptides, including fusion proteins and recombinant antibodies containing these TCR-derived sequences.
Pharmaceutical compositions and methods of cancer detection and treatment
Claims include pharmaceutical compositions comprising the inventive TCRs or their variants with pharmaceutically acceptable carriers, and methods of detecting cancer by contacting samples with these TCRs to form complexes indicative of cancer presence, as well as methods of treating cancer by administering effective amounts of the TCRs to mammals.
The claims cover isolated TCRs and functional variants specific for MAGE-A3 and MAGE-A6 peptides presented by HLA-DPβ1*04, including different compositions of amino acid sequences in CDRs and constant regions, polypeptides, proteins, and pharmaceutical compositions containing these TCRs, alongside methods for cancer detection and treatment using these TCRs.
Stated Advantages
Expands patient eligibility for adoptive cell therapy by targeting MAGE-A3 in the context of the highly prevalent HLA-DPβ1*04 allele, expressed in about 70–80% of cancer patients.
Allows treatment of multiple cancer types expressing MAGE-A3 and MAGE-A6, as these antigens are broadly expressed across various malignancies.
Targets cancer testis antigens expressed predominantly by tumor cells, reducing off-target toxicity and minimizing destruction of normal, non-cancerous cells.
Functional variants of the TCRs can exhibit enhanced reactivity against MAGE-A3 relevant peptides, improving therapeutic efficacy.
Murine constant region chimeric TCRs can increase reactivity and pairing efficiency, leading to enhanced anti-tumor activity of transduced T cells.
Documented Applications
Adoptive cell therapy for treating cancer in mammals, including administering T cells transduced with the inventive TCRs recognizing MAGE-A3 and MAGE-A6 in the context of HLA-DPβ1*04.
Detection of cancer presence in a mammal by contacting cancer cell samples with the inventive TCRs or related proteins forming detectable complexes indicating cancer cells expressing MAGE-A3 or MAGE-A6.
Treatment or prevention of a wide variety of cancers expressing MAGE-A3 and/or MAGE-A6, including but not limited to melanoma, breast cancer, lung cancer, prostate cancer, synovial cell sarcoma, head and neck cancer, esophageal cancer, and ovarian cancer.
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