Antibody engineering for increased potency, breadth and half-life

Sievers, Stuart A.; Scharf, Louise; West, Anthony P.; Bjorkman, Pamela J.

Although an effective HIV-1 vaccine remains an elusive goal, newly discovered potent HIV-1 bNAbs and advances in engineering antibodies offer possibilities for improved passive delivery strategies to prevent or treat HIV-1. More potent bNAbs could be used therapeutically at a lower concentration and thus reduce cost and/or production time, increase the number of patients being treated and lower the potential for immunogenicity or other side effects related to bNAb administration. There also remains a need to create reagents to combat viral mutation and the natural sequence diversity of HIV-1, which may be possible by identifying common pathways of viral escape and then using structure-based design to engineer resistance to these pathways. Librarybased strategies designed to enhance affinity can also lead to increased breadth and block escape. Bispecific reagents and chemically conjugated reagents offer other ways to target multiple sites to prevent viral escape strategies and combat HIV-1 diversity. Although increased polyreactivity associated with some improved bNAbs may not necessarily be dangerous, polyreactivity correlates with shortened plasma half-life and represents an indicator that a reagent needs to be optimized to improve its biophysical and pharmacokinetic properties. Recent successes in creating bispecific, conjugate and engineered antibody reagents with minimal polyreactivity may be important therapeutically, particularly if gene therapy strategies, such as vector-mediated gene transfer (see Balasz and Baltimore, this issue) [112] , are used to deliver antibodies and antibody-like reagents. 45.