Adimab scientists report a new class of llama-derived heavy chain-only antibodies (HCAbs) that target CD3, designed to simplify and enhance the performance of T cell-engaging therapeutics. Conventional bispecific T cell engagers rely on full IgG architectures, which can pose challenges for expression, assembly, and stability. By contrast, HCAbs lack the light chain, offering a smaller, more stable, and modular format for multispecific antibody engineering.

Key findings and highlights:

• Using llama immunization combined with Adimab’s yeast-based platform, an immune library was built and hundreds of anti-CD3 HCAbs were isolated, humanized, and optimized for affinity, cross-reactivity, and biophysical properties such as thermal stability, hydrophobicity, and polyspecificity.
• A diverse panel of human-specific HCAbs demonstrated favorable developability profiles, including high thermostability (T_m >60 °C) and low non-specific binding.
• Reformatted as bispecific molecules (anti-CD3 × anti-CD20), selected HCAbs mediated potent T cell–dependent cytotoxicity (TDCC) against CD20-positive Raji cells, comparable to benchmark anti-CD3 antibodies.
• Functional assays confirmed that these HCAbs trigger robust T cell activation, inducing CD69 upregulation, IL-2 secretion, and cytolytic activity, while maintaining human-specific CD3 binding.
• Lead candidates achieved efficacies similar to established clinical molecules, such as tebentafusp, demonstrating their utility as modular components in complex bispecific or multispecific antibody formats.

These novel anti-CD3 HCAbs combine the precision of Adimab’s yeast-based platform with the unique simplicity of heavy chain-only scaffolds to offer a versatile foundation for next-generation T cell engagers, supporting more efficient design, improved manufacturability, and potentially safer, more effective immunotherapies.

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