Antibodies recognise their targets through hypervariable complementarity-determining regions (CDRs), which are interleaved with conserved frameworks in sequence space, making de novo CDR design an infilling problem. Autoregressive models generate residues left-to-right, which precludes full framework context during CDR generation and conflates framework and CDR likelihoods, leaving no natural prompt-response interface for feedback to steer generation. We present GenCDR, a family of LLaMa-based autoregressive language models that read all frameworks as a conditioning prompt and generate all CDRs jointly as a variable-length response, making CDR likelihoods a clean, separable target for reward attribution. The family comprises IgGenCDR, p-IgGenCDR, and NanoGenCDR, trained on unpaired, paired, and nanobody chains, respectively. GenCDR achieves the highest CDR recovery among autoregressive models and produces natural, diverse, human-like CDRs whose likelihoods correlate with fitness and developability assays. The prompt-response boundary also enables principled alignment: reward signals for binding affinity, expression, or developability can be composed to steer CDR generation. Over four rounds of alignment against antibody-antigen co-folding and developability objectives, we find that NanoGenCDR, which uses no explicit antigen encoding, can reach in silico structural interface metrics competitive with those of a structure-conditioned diffusion pipeline at roughly half the sampling budget, with more natural, developable designs. The same interface can be extended to integrate experimental feedback, opening a path to closed-loop antibody de novo design.
Gonzalez Hernandez, F., Turnbull, O. M., Sultana, M., Roldan-Martin, L., Kumar, R. J., Diethe, T., Croasdale-Wood, R., Deane, C., Oglic, D.
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