Research ArticleIMMUNOTHERAPY

Bispecific antibodies targeting mutant RAS neoantigens

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Science Immunology  01 Mar 2021:
Vol. 6, Issue 57, eabd5515
DOI: 10.1126/sciimmunol.abd5515

Diabodies see the unseeable

RAS oncogene mutations are common in various cancers, controlling their growth and survival. Targeting mutant RAS proteins with antibodies has been unsuccessful due to low surface expression, even when targeting mutant RAS peptides presented via HLA on the surface of cancer cells. Douglass et al. used phage display to generate single-chain variable fragments (scFvs) specific for mutant RAS peptide-HLA complexes. The authors tested various bispecific, T cell–engaging antibody formulations, finding that single-chain diabodies (scDbs) combining the aforementioned scFv with an anti-CD3 scFv were able to induce T cell activation and subsequent killing of tumor cells expressing mutant RAS peptide-HLA complexes. This scDb approach opens the door for antibody-based therapies against mutant neoantigens expressed at very low levels on the surface of cancer cells.

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