Guided Sequence-Structure Generative Modeling for Iterative Antibody Optimization

Aniruddh Raghu, Sebastian W. Ober, Maxwell Kazman, Hunter Elliott

Track: Machine learning: computational method and/or computational results

Nature Biotechnology: Yes

Keywords: generative modeling, diffusion, structure, antibody, iterative design

TL;DR: We outline a method for iterative antibody optimization using joint sequence-structure generative models.

Abstract:

Therapeutic antibody candidates often require extensive engineering to improve key functional and developability properties before clinical development.
This can be achieved through iterative design, where starting molecules are optimized over several rounds of in vitro experiments.
While protein structure can provide a strong inductive bias, it is rarely used in iterative design due to the lack of structural data for continually evolving lead molecules over the course of optimization.
In this work, we propose a strategy for iterative antibody optimization that leverages both sequence and structure as well as accumulating lab measurements of binding and developability.
Building on prior work, we first train a sequence-structure diffusion generative model that operates on antibody-antigen complexes.
We then outline an approach to use this model, together with carefully predicted antibody-antigen complexes, to optimize lead candidates throughout the iterative design process.
Further, we describe a guided sampling approach that biases generation toward desirable properties by integrating models trained on experimental data from iterative design.
We evaluate our approach in multiple in silico and in vitro experiments, demonstrating that it produces high-affinity binders at multiple stages of an active antibody optimization campaign.

Anonymization: This submission has been anonymized for double-blind review via the removal of identifying information such as names, affiliations, and identifying URLs.

Presenter: ~Aniruddh_Raghu1

Format: Yes, the presenting author will attend in person if this work is accepted to the workshop.

Funding: No, the presenting author of this submission does *not* fall under ICLR’s funding aims, or has sufficient alternate funding.

Submission Number: 24