Using a high-throughput yeast-based platform, Adimab scientists have engineered soluble T cell receptors (TCRs) with dramatically enhanced affinity for peptide–HLA (pHLA) complexes, enabling their use in TCR × CD3 bispecific therapeutics. Native TCRs bind pHLA complexes weakly (1–200 µM), which is inadequate for therapeutic formats. To address this, the Adimab platform can express soluble TCRs on the surface of our engineered yeast and then apply iterative rounds of selection to push affinity into therapeutically relevant ranges.

Key findings and highlights:

• The Adimab yeast-based platform produces soluble TCR-Fc proteins that faithfully mirror published monovalent affinity values.
• Affinity maturation of a benchmark TCR (1G4, which targets HLA-A2/NY-ESO-1) via three cycles of optimization yielded variants with up to 300,000-fold improved affinities versus the parental clone.
• When formatted as CD3 bispecifics, optimized TCR variants induced potent T cell activation, target killing, and cytokine secretion, achieving over 1,000-fold enhancement in potency relative to the starting TCR.
• Adimab’s engineering platform supports parallel screening of many clones for biophysical fitness, expression, antigen binding, and functional activity, accelerating optimization of lead TCR candidates.

Adimab’s yeast-based platform provides a scalable route for converting weak-binding natural TCRs into high-affinity, high-specificity, functional bispecifics. These modalities allow targeting of intracellular antigens via pHLA complex recognition.

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