High-efficacy, high-manufacturability human VH domain antibody therapeutics from transgenic sources

Interest in single-domain antibodies (sdAbs) stems from their unique structural/pronounced, hence therapeutically desirable, features. From the outset-as therapeutic modalities-human antibody heavy chain variable domains (V(H)s) attracted a particular attention compared with 'naturally-occurring' camelid and shark heavy-chain-only antibody variable domains (V(H)Hs and V(NAR)s, respectively) due to their perceived lack of immunogenicity. However, they have not quite lived up to their initial promise as the V-H hits, primarily mined from synthetic V-H phage display libraries, have too often been plagued with aggregation tendencies, low solubility and low affinity. Largely unexplored, synthetic camelized human V-H display libraries appeared to have remediated the aggregation problem, but the low affinity of the V-H hits still persisted, requiring undertaking additional, laborious affinity maturation steps to render V(H)s therapeutically feasible. A wholesome resolution has recently emerged with the development of non-canonical transgenic rodent antibody discovery platforms that appear to facilely and profusely generate high affinity, high solubility and aggregation-resistant human V(H)s.

Automated summary

Interest in single-domain antibodies is driven by their unique structural and therapeutic features, but challenges remain in human antibody heavy chain variable domains. Recent development of non-canonical transgenic rodent antibody discovery platforms shows promise in generating high affinity, high solubility, and aggregation-resistant human V(H)s.