Structural basis for continued antibody evasion by the SARS-CoV-2 receptor binding domain.

Many studies have examined the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants on neutralizing antibody activity after they have become dominant strains. Here, we evaluate the consequences of further viral evolution. We demonstrate mechanisms through which the SARS-CoV-2 receptor binding domain (RBD) can tolerate large numbers of simultaneous antibody escape mutations and show that pseudotypes containing up to seven mutations, as opposed to the one to three found in previously studied variants of concern, are more resistant to neutralization by therapeutic antibodies and serum from vaccine recipients. We identify an antibody that binds the RBD core to neutralize pseudotypes for all tested variants but show that the RBD can acquire an N-linked glycan to escape neutralization. Our findings portend continued emergence of escape variants as SARS-CoV-2 adapts to humans.

Stability of IgG isotypes in serum.

Drug development from early discovery to late stage commercialization is a long arduous process where a number of factors are taken into consideration when deciding on a particular immunoglobulin isotype for a therapeutic purpose. There are no general rules for which isotype is selected; however, prior experiences, effector function and the specific therapy targeted, as well as extensive testing early in development help in pairing the number of candidates. Over 20 monoclonal antibodies are FDA-approved, and most are IgG1 isotype, although a number of non-IgG1 molecules have been approved recently and the number in development is on the rise. Analytical techniques that examine the physicochemical properties of a molecule provide vital information on the stability and efficacy of candidate antibody therapeutics, but most of these studies are conducted using standard buffers and under well defined storage conditions. It has recently become apparent that analysis of antibody therapeutics recovered after circulation in blood show altered physicochemical characteristics, and in many instances therapeutic molecules recovered from serum show lower potency. This review examines some of these studies, with a focus on the physicochemical changes observed in the molecules. Technologies that can facilitate rapid screening of candidate antibody therapeutics directly from blood are highlighted. The facts indicate that antibody therapeutic development programs must incorporate understanding of the basic biology of the isotype and its stability in serum, which is the intended environment of the therapeutic.