Directed Evolution of Antibodies with Doug Chapnick

Doug Chapnick is the Co-Founder and CEO of BioLoomics. A platform company using directed evolution to discover antibody therapeutics. Combining cell line engineering, machine learning, and imaging.

At the core of BioLoomics' technology is directed evolution, a process that mimics natural evolution in the lab. The company uses this to create biologics for a given property like target engagement or stability. Traditional directed evolution relies on displaying proteins on the surface of cells or viruses and using binding or activity assays to isolate variants with enhanced characteristics. However, this approach has limitations, especially when evolving complex proteins like antibodies that require proper folding and post-translational modifications found in human cells.

BioLoomics circumvents these issues by using human cell libraries that naturally produce fully human antibodies. Their key innovation is an advanced imaging and computer vision system that can track millions of individual cells in these libraries and quantify cellular phenotypes using fluorescent biosensors. This allows them to precisely identify rare cells producing antibodies with the desired activity.

For example, BioLoomics might engineer biosensor cell lines where a fluorescent protein reports on the degradation of a specific target protein. They can then screen human antibody libraries in these cells, using computer vision to pick out the few cells that show enhanced degradation of the target compared to typical antibodies. By isolating the genetic sequences encoding these rare antibodies, they can rapidly iterate and evolve highly specific protein degraders or other therapeutic antibodies.

This live cell-based directed evolution approach has several key advantages. First, by working in human cells, BioLoomics ensures their engineered antibodies are naturally folded, glycosylated, and trafficked properly for optimal therapeutic activity. Second, the use of biosensors allows them to select for very specific mechanisms of action, rather than just binding - enabling development of precisely targeted degraders or modulators. Finally, the high-throughput nature of their platform facilitates rapid exploration of vast protein sequence landscapes to find optimal solutions.

In our conversation, we also talk about Doug’s work that set up BioLoomics. His PhD work at the University of Colorado Boulder focused on understanding cellular signaling networks and mechanisms through multi-omics approaches like proteomics and metabolomics. After, he was part of the DARPA Rapid Threat Assessment program, where he built out high-throughput microscopy workflows. Where the core idea behind BioLoomics emerged from this DARPA project. Chapnick co-founded BioLoomics in 2019 to bring directed evolution to therapeutic antibody development.

A key focus area for BioLoomics is developing novel antibody degraders that can precisely remove target proteins from cells by marking them for lysosomal degradation. While a few companies have developed degraders based on binding to specific E3 ligase enzymes, BioLoomics' platform allows them to evolve degraders that act through diverse and unexplored mechanisms not limited to any single pathway. For example, they could evolve antibodies that traffick target proteins to lysosomes through interactions with sorting receptors or endocytic adaptor proteins. Or create antibody fusions that oligomerize targets and induce their proteasomal degradation. The diversity of potential mechanisms enabled by their platform could lead to a whole new class of highly specific protein degraders for tackling undruggable targets across multiple disease areas. By combining human cell libraries, advanced imaging, computer vision, and directed evolution, BioLoomics is pioneering a new path for antibody discovery.