Deep learning-based design and experimental validation of a medicine-like human antibody library.

Antibody generation requires the use of one or more time-consuming methods, namely animal immunization, and in vitro display technologies. However, the recent availability of large amounts of antibody sequence and structural data in the public domain along with the advent of generative deep learning algorithms raises the possibility of computationally generating novel antibody sequences with desirable developability attributes. Here, we describe a deep learning model for computationally generating libraries of highly human antibody variable regions whose intrinsic physicochemical properties resemble those of the variable regions of the marketed antibody-based biotherapeutics (medicine-likeness). We generated 100000 variable region sequences of antigen-agnostic human antibodies belonging to the IGHV3-IGKV1 germline pair using a training dataset of 31416 human antibodies that satisfied our computational developability criteria. The in-silico generated antibodies recapitulate intrinsic sequence, structural, and physicochemical properties of the training antibodies, and compare favorably with the experimentally measured biophysical attributes of 100 variable regions of marketed and clinical stage antibody-based biotherapeutics. A sample of 51 highly diverse in-silico generated antibodies with >90th percentile medicine-likeness and > 90% humanness was evaluated by two independent experimental laboratories. Our data show the in-silico generated sequences exhibit high expression, monomer content, and thermal stability along with low hydrophobicity, self-association, and non-specific binding when produced as full-length monoclonal antibodies. The ability to computationally generate developable human antibody libraries is a first step towards enabling in-silico discovery of antibody-based biotherapeutics. These findings are expected to accelerate in-silico discovery of antibody-based biotherapeutics and expand the druggable antigen space to include targets refractory to conventional antibody discovery methods requiring in vitro antigen production.

Pubmed ID: 39851074