PT  - JOURNAL ARTICLE
AU  - Tileli Amimeur
AU  - Jeremy M. Shaver
AU  - Randal R. Ketchem
AU  - J. Alex Taylor
AU  - Rutilio H. Clark
AU  - Josh Smith
AU  - Danielle Van Citters
AU  - Christine C. Siska
AU  - Pauline Smidt
AU  - Megan Sprague
AU  - Bruce A. Kerwin
AU  - Dean Pettit
TI  - Designing Feature-Controlled Humanoid Antibody Discovery Libraries Using Generative Adversarial Networks
AID  - 10.1101/2020.04.12.024844
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.04.12.024844
4099  - http://biorxiv.org/content/early/2020/04/23/2020.04.12.024844.short
4100  - http://biorxiv.org/content/early/2020/04/23/2020.04.12.024844.full
AB  - We demonstrate the use of a Generative Adversarial Network (GAN), trained from a set of over 400,000 light and heavy chain human antibody sequences, to learn the rules of human antibody formation. The resulting model surpasses common in silico techniques by capturing residue diversity throughout the variable region, and is capable of generating extremely large, diverse libraries of novel antibodies that mimic somatically hypermutated human repertoire response. This method permits us to rationally design de novo humanoid antibody libraries with explicit control over various properties of our discovery library. Through transfer learning, we are able to bias the GAN to generate molecules with key properties of interest such as improved stability and developability, lower predicted MHC Class II binding, and specific complementarity-determining region (CDR) characteristics. These approaches also provide a mechanism to better study the complex relationships between antibody sequence and molecular behavior, both in vitro and in vivo. We validate our method by successfully expressing a proof-of-concept library of nearly 100,000 GAN-generated antibodies via phage display. We present the sequences and homology-model structures of example generated antibodies expressed in stable CHO pools and evaluated across multiple biophysical properties. The creation of discovery libraries using our in silico approach allows for the control of pharmaceutical properties such that these therapeutic antibodies can provide a more rapid and cost-effective response to biological threats.Competing Interest StatementAll authors are employed by Just - Evotec Biologics, Inc whose business includes biotherapeutic discovery and development.