Cancer vaccines targeting MUC16 and uses thereof
Inventors
Yan, Jian • SLAGER, Anna • GARMAN, Bradley • COOCH, Neil
Assignees
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Publication Number
US-12285473-B2
Publication Date
2025-04-29
Expiration Date
Abstract
Disclosed herein are nucleic acid molecules comprising one or more nucleic acid sequences that encode a modified consensus MUC16 antigen. Vectors, compositions, and vaccines comprising one or more nucleic acid sequences that encode a modified consensus MUC16 antigen are disclosed. Methods of treating a subject with a MUC16-expressing tumor and methods of preventing a MUC16-expressing tumor are disclosed. Modified consensus MUC16 antigen is disclosed.
Core Innovation
The disclosure relates to cancer vaccines targeting MUC16 using engineered modified/consensus MUC16 antigens. The engineered antigens are defined by nucleic acid sequences encoding specified portions of proteins and by proteins that are at least 95% identical to those portions while comprising at least one repeat micro-consensus (RMC) of RMC1-RMC4.
The invention covers nucleic acids comprising specified SEQ ID NO regions and fragments that are at least 95% identical to those regions, where fragments encode at least one RMC of RMC1-RMC4. For SEQ ID NO: 6, it specifies variant proteins comprising alanine at amino acid position 628, an alanine at amino acid position 651, and an alanine at amino acid position 657 relative to SEQ ID NO: 6.
The disclosure also describes synthetic consensus MUC16 immunogens using repeat micro-consensus elements RMC1-RMC4 and the incorporation of native repeats into a synthetic consensus carboxy terminal domain (CTD). It further describes nucleic acid-based vaccines and vaccine formulations intended to generate immune effects, including T cell responses.
Claims Coverage
The independent claims cover 2 inventive features: nucleic acid molecules encoding specified MUC16 protein portions with RMC1-RMC4 elements and defined protein identity, and nucleic acid molecules defined by specific nucleotide regions and fragments that encode the same RMC-containing or alanine-substituted protein features.
Specified MUC16-portion nucleic acids with RMC micro-consensus elements
A nucleic acid molecule comprising one or more nucleic acid sequences selected from sequences encoding amino acids 19-1490 of SEQ ID NO: 2; or proteins at least 95% identical to amino acids 19-1490 of SEQ ID NO: 2 comprising at least one repeat micro-consensus (RMC) of RMC1-RMC4 of SEQ ID NO: 2; or sequences encoding SEQ ID NO: 2; or proteins at least 95% identical to SEQ ID NO: 2 comprising at least one RMC of RMC1-RMC4 of SEQ ID NO: 2; or sequences encoding amino acids 19-642 of SEQ ID NO: 4; or proteins at least 95% identical to amino acids 19-642 of SEQ ID NO: 4 comprising at least one RMC of RMC1-RMC4 of SEQ ID NO: 4; or sequences encoding SEQ ID NO: 4; or proteins at least 95% identical to SEQ ID NO: 4 comprising at least one RMC of RMC1-RMC4 of SEQ ID NO: 4; or sequences encoding amino acids 19-710 of SEQ ID NO: 6; or proteins at least 95% identical to amino acids 19-710 of SEQ ID NO: 6, wherein the protein comprises an alanine at amino acid position 628, an alanine at amino acid position 651, and an alanine at amino acid position 657 relative to SEQ ID NO: 6; or sequences encoding SEQ ID NO: 6; or proteins at least 95% identical to SEQ ID NO: 6, wherein the protein comprises the alanine substitutions at positions 628, 651, and 657.
Specified nucleic-acid regions and fragments encoding RMCs and defined alanine substitutions
A nucleic acid molecule comprising one or more nucleic acid sequences selected from nucleotides 55-4470 of SEQ ID NO: 1; or fragments at least 95% identical to nucleotides 55-4470 of SEQ ID NO: 1, wherein the fragment encodes at least one RMC of RMC1-RMC4 of SEQ ID NO: 2; or SEQ ID NO: 1; or fragments at least 95% identical to SEQ ID NO: 1 wherein the fragment encodes at least one RMC of RMC1-RMC4 of SEQ ID NO: 2; or nucleotides 55-1926 of SEQ ID NO: 3; or fragments at least 95% identical to nucleotides 55-1926 of SEQ ID NO: 3, wherein the fragment encodes at least one RMC of RMC1-RMC4 of SEQ ID NO: 4; or SEQ ID NO: 3; or fragments at least 95% identical to SEQ ID NO: 3 wherein the fragment encodes at least one RMC of RMC1-RMC4 of SEQ ID NO: 4; or nucleotides 55-2130 of SEQ ID NO: 5; or fragments at least 95% identical to nucleotides 55-2130 of SEQ ID NO: 5, wherein the fragment encodes an alanine at amino acid position 628, an alanine at amino acid position 651, and an alanine at amino acid position 657 relative to SEQ ID NO: 6; or SEQ ID NO: 5; or fragments at least 95% identical to SEQ ID NO: 5, wherein the fragment encodes the alanine substitutions at positions 628, 651, and 657.
Across the independent claims, the core claimed subject matter is nucleic acid molecules encoding modified/consensus MUC16 antigens defined by specified SEQ ID NO regions and fragments, with at least 95% identity variant proteins and explicit repeat micro-consensus (RMC1-RMC4) inclusion, plus defined alanine substitutions for one protein region.
Stated Advantages
Immune responses are generated against MUC16-expressing cancers, including humoral immunity and CD8+ CTL and CD4+ T cells mediated effects with IFN-gamma.
Tumor treatment effects are provided, including tumor-free survival reduction and tumor mass reductions.
Antigen-specific cellular immune responses are reported as increased, including fold increases in cellular immunity and IFN-gamma.
Broad sequence coverage for nucleic acids and encoded proteins, including variants with defined identity ranges and RMC1-RMC4 elements.
Documented Applications
Vaccine formulation and immune response generation targeting MUC16-expressing cancers, including ovarian cancer.
Cancer vaccines targeting MUC16-expressing tumors, including ovarian cancer, using modified/consensus MUC16 antigens.
Therapeutic and prophylactic use against MUC16-expressing tumors.
Combination use with immune checkpoint inhibitors (PD-1/PD-L1).
Vaccine formulations incorporating immune modulator adjuvants including IL-12, IL-15, IL-28, and RANTES.
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