Computational design and translational development of TCR-mimic scFv antibodies for peptide-HLA neoantigen targeting

Single-chain variable fragments (scFvs) penetrate tissue more effectively than full antibodies and are simpler to produce, but the mutant proteins that define a tumor are predominantly intracellular and therefore inaccessible to conventional antibodies. What is accessible is the mutation-derived peptide displayed on cell-surface HLA. This review concerns TCR-mimic scFvs directed at those peptide-HLA complexes. It separates three questions that are frequently conflated: which mutations are predicted to be presented, which presented complexes are genuinely targetable given surface density and cross-reactivity risk, and how immunogenic the resulting therapeutic molecule will itself be. We review computational strategies spanning target identification, AI-driven structure prediction, de novo design, affinity and specificity engineering, half-life extension and deimmunization, and distinguish throughout between the scFv as a recognition module and the effector architecture, such as a CD3 bispecific, a chimeric antigen receptor binding domain or an Fc-containing format, in which it must ultimately be deployed.