RT Journal Article
SR Electronic
T1 Designing Feature-Controlled Humanoid Antibody Discovery Libraries Using Generative Adversarial Networks
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.04.12.024844
DO 10.1101/2020.04.12.024844
A1 Tileli Amimeur
A1 Jeremy M. Shaver
A1 Randal R. Ketchem
A1 J. Alex Taylor
A1 Rutilio H. Clark
A1 Josh Smith
A1 Danielle Van Citters
A1 Christine C. Siska
A1 Pauline Smidt
A1 Megan Sprague
A1 Bruce A. Kerwin
A1 Dean Pettit
YR 2020
UL http://biorxiv.org/content/early/2020/04/23/2020.04.12.024844.abstract
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.