MANAbodies targeting tumor antigens and methods of using
Inventors
Vogelstein, Bert • Kinzler, Kenneth W. • Hsiue, Emily Han-Chung • Douglass, Jacqueline • Hwang, Michael S. • Pearlman, Alexander H. • Papadopoulos, Nickolas • Zhou, Shibin • Mog, Brian J. • Wright, Katharine M. • Gabelli, Sandra B.
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Assignees
MemberJohns Hopkins UniversityJohns Hopkins UniversityFounded in 1876, Johns Hopkins University is recognized as the first research university in the United States. It advances interdisciplinary education, high-impact research, and global outreach, supporting knowledge translation, technological innovation, and community partnerships. The university fosters academic excellence, innovation incubation, outreach, and inclusion across multiple campuses in Baltimore, integrating into the city's social, economic, and cultural life.
Founded in 1876, Johns Hopkins University is recognized as the first research university in the United States. It advances interdisciplinary education, high-impact research, and global outreach, supporting knowledge translation, technological innovation, and community partnerships. The university fosters academic excellence, innovation incubation, outreach, and inclusion across multiple campuses in Baltimore, integrating into the city's social, economic, and cultural life.
Publication Number
US-12674002-B2
Publication Date
2026-07-07
Expiration Date
Abstract
This document provides methods and materials for assessing a mammal having or suspected of having cancer and/or for treating a mammal having cancer. For example, molecules including one or more antigen-binding domains (e.g., a single-chain variable fragment (scFv)) that can bind to a modified peptide (e.g., a tumor antigen), as well as method for using such molecules, are provided.
Core Innovation
The invention relates to a molecule comprising an antigen-binding domain having a variable heavy chain and a variable light chain that can bind to a peptide-HLA complex. The peptide is a modified p53 peptide comprising the amino acid sequence set forth in SEQ ID NO:1, and the antigen-binding domain includes defined CDR-VL1, CDR-VL2, CDR-VL3, CDR-VH1, CDR-VH2, and CDR-VH3 sequences selected from specified groups of CDR sequence sets.
The disclosed subject matter further describes immunotherapy targeting a TP53 mutation-derived neoantigen, supported by the detection and presentation of the p53 R175H neoantigen peptide on cancer cell surface pHLA complexes. It also describes MANAbody scFvs binding mutant p53 peptide presented with specific HLA alleles, including HLA-A*02:01, and conversion to T-cell-engaging bispecific single-chain diabodies (scDb) by linkage to anti-CD3 (UCHT1).
Functional validation is described using IFNγ ELISA and flow cytometry, together with tumor-cell killing measurements. The disclosed scope also includes determination of peptide-HLA binding and structural characterization, including X-ray crystallography of the p53R175H/HLA-A*02:01 ternary complex and assessment of cross-reactivity via peptide scanning.
Claims Coverage
The claim coverage centers on one independent claim directed to a molecule with an antigen-binding domain that binds a modified p53 peptide-HLA complex using specified CDR sequence sets. Dependent claims further refine the HLA-A*02:01 context, add an amino-acid identity threshold, enumerate alternative binding formats, and include an optional second antigen-binding domain to an effector cell receptor.
Modified p53 peptide-HLA binding with specified CDR sets
A molecule comprising an antigen-binding domain with a variable heavy chain and a variable light chain that can bind to a peptide-HLA complex, wherein the peptide is a modified p53 peptide comprising the amino acid sequence set forth in SEQ ID NO:1, and wherein the antigen-binding domain comprises CDR-VL1, CDR-VL2, CDR-VL3, CDR-VH1, CDR-VH2, and CDR-VH3 as set forth in one of groups (i)-(v).
HLA allele-specific targeting of the peptide-HLA complex
The peptide-HLA complex is characterized by an HLA type of HLA-A*02:01.
Antigen-binding domain sequence identity to listed sequences
The antigen-binding domain includes an amino-acid sequence that has at least 90% identity to one of the sequences in SEQ ID NO:137-141.
Engineered binding architecture selection
The molecule is selected from a listed group of antibody-related binding formats, including antibody, scFv, CAR, tandem scFv, bispecific T cell engager, diabody, scDb, scFv-Fc, bispecific antibody, and dual-affinity re-targeting antibody.
Second antigen-binding domain for effector cell receptor targeting
The molecule further includes a second antigen-binding domain with variable heavy and light chains that bind to an effector cell receptor selected from CD3, CD28, CD4, CD8, CD16a, NKG2D, PD-1, CTLA-4, 4-1BB, OX40, ICOS, and CD27.
Overall, the claims coverage centers on an antigen-binding molecule defined by variable heavy and light chains with enumerated CDR-VL and CDR-VH sequence sets that bind a modified p53 peptide (SEQ ID NO:1) presented as a peptide-HLA complex, with dependent claims further refining HLA context, antibody sequence similarity, permissible binding architectures, and addition of a second effector receptor-binding domain.
Stated Advantages
Binding specificity and affinity are described for H2-scDb and H20-scDb in relation to the p53 R175H/HLA-A*02:01 ternary complex.
T-cell activation specificity and cross-reactivity are assessed.
In vivo antitumor efficacy is described as dependent on TP53 status and human T cells.
Documented Applications
Immunotherapy targeting a TP53 mutation-derived neoantigen.
Cancer cell surface pHLA complex detection and presentation of the p53 R175H neoantigen peptide.
TP53-targeting bispecific molecules, including scDb bispecific formats.
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