Beyond sequence similarity: ML-powered identification of pHLA off-targets for TCR-mimic antibodies using high throughput binding kinetics.

ABSTRACT: T-cell receptor mimic (TCRm) antibodies are an emerging class of tumor-targeting agents used in advanced immunotherapies such as bispecific T-cell engagers and CAR-T cells. Unlike conventional antibodies, TCRms are designed to recognize peptide - human leukocyte antigen (pHLA) complexes that present intracellular tumor-derived peptides on the cell surface. Due to the typically low surface abundance and high sequence similarity of pHLAs, TCRms require high affinity and exceptional specificity to avoid off-target toxicity. Conventional methods for off-target identification such as sequence similarity searches, motif-based screening, and structural modeling focus on the peptide and are limited in detecting cross-reactive peptides with little or no sequence homology to the target. To address t

SUBMITTER: Sinclair A 

PROVIDER: S-EPMC12710896 | biostudies-literature | 2026 Dec

REPOSITORIES: biostudies-literature