Approaches to expand the conventional toolbox for discovery and selection of antibodies with drug-like physicochemical properties

Abstract

Antibody drugs should exhibit not only high-binding affinity for their target antigens but also favorable physicochemical drug-like properties. Such drug-like biophysical properties are essential for the successful development of antibody drug products. The traditional approaches used in antibody drug development require significant experimentation to produce, optimize, and characterize many candidates. Therefore, it is attractive to integrate new methods that can optimize the process of selecting antibodies with both desired target-binding and drug-like biophysical properties. Here, we summarize a selection of techniques that can complement the conventional toolbox used to de-risk antibody drug development. These techniques can be integrated at different stages of the antibody development process to reduce the frequency of physicochemical liabilities in antibody libraries during initial discovery and to co-optimize multiple antibody features during early-stage antibody engineering and affinity maturation. Moreover, we highlight biophysical and computational approaches that can be used to predict physical degradation pathways relevant for long-term storage and in-use stability to reduce the need for extensive experimentation.

Design and engineering of bispecific antibodies: insights and practical considerations

“…These traits are commonly known as the developability profile and screening for developability is typically done early in the drug development process to avoid investing in antibodies that are unlikely to succeed as clinical candidates ( Jain et al, 2017 ; Raybould et al, 2019 ). Extensive work has been aimed at developing in silico predictive tools and high-throughput assays for early screening of candidate developability liabilities ( Bailly et al, 2020 ; Mieczkowski et al, 2023 ; Svilenov et al, 2023 ). The methods were, however, primarily developed for conventional monoclonal antibodies and extra attention might therefore be required for bsAbs because the engineering strategies used for constructing the bsAb also risk introducing unexpected liabilities.…”

How can we discover developable antibody-based biotherapeutics?

“…Incorporation of additional considerations along with the binding affinity can help narrow down the mutations for experimental testing and therefore the size of the display libraries. At this stage, the mutations that enhance specificity, humanness, and CDR germlining along with developability can be considered by incorporating relevant physicochemical properties and stability criteria ( Khan et al, 2023 ; Svilenov et al, 2023 ). Consequently, the selection of lead antibody candidates with high binding affinity and favorable biophysical properties can be achieved simultaneously.…”

AbNatiV: VQ-VAE-based assessment of antibody and nanobody nativeness for hit selection, humanisation, and engineering

“…These properties, which include long half-life, low immunogenicity, and no toxicity, are difficult to measure accurately and in good throughput, and their molecular determinants remain poorly understood. This hurdle broadly affects therapeutic antibody development also beyond computational design, and a multitude of in vitro assays, referred to as developability screening assays, have been proposed as proxies for binding specificity or in vivo half-life to de-risk antibody development programmes [24][25][26] . However, these assays typically correlate poorly with each other, and have only been shown to somewhat correlate with selected in vivo properties in limited specific examples 17,24,27 .…”