Wei, R. R. | Search bioRxiv

bioRxiv2022

A multispecific antibody confers pan-reactive SARS-CoV-2 neutralization and prevents immune escape

Summary ParagraphDespite effective countermeasures, SARS-CoV-2 persists worldwide due to its ability to diversify and evade human immunity1. This evasion stems from amino-acid substitutions, particularly in the receptor-binding domain of the spike, that confer resistance to vaccines and antibodies 2-16. To constrain viral escape through resistance mutations, we combined antibody variable regions that recognize different receptor binding domain (RBD) sites17,18 into multispecific antibodies. Here, we describe multispecific antibodies, including a trispecific that prevented virus escape >3000-fold more potently than the most effective clinical antibody or mixtures of the parental antibodies. Despite being generated before the evolution of Omicron, this trispecific antibody potently neutralized all previous variants of concern and major Omicron variants, including the most recent BA.4/BA.5 strains at nanomolar concentrations. Negative stain electron microscopy revealed that synergistic neutralization was achieved by engaging different epitopes in specific orientations that facilitated inter-spike binding. An optimized trispecific antibody also protected Syrian hamsters against Omicron variants BA.1, BA.2 and BA.5, each of which uses different amino acid substitutions to mediate escape from therapeutic antibodies. Such multispecific antibodies decrease the likelihood of SARS-CoV-2 escape, simplify treatment, and maximize coverage, providing a strategy for universal antibody therapies that could help eliminate pandemic spread for this and other pathogens.

immunology↗

bioRxiv2017

The molecular basis for Pompe disease revealed by the structure of human acid α-glucosidase

Pompe disease results from a defect in human acid -glucosidase (GAA), a lysosomal enzyme that cleaves terminal 1-4 and 1-6 glucose from glycogen. In Pompe disease (also known as Glycogen Storage Disorder type II), the accumulation of undegraded glycogen in lysosomes leads to cellular dysfunction, primarily in muscle and heart tissues. Pompe disease is an active candidate of clinical research, with pharmacological chaperone therapy tested and enzyme replacement therapy approved. Despite production of large amounts of recombinant GAA annually, the structure of GAA has not been reported until now. Here, we describe the first structure of GAA, at 1.7[A] resolution. Three structures of GAA complexes reveal the molecular basis for the hundreds of mutations that lead to Pompe disease and for pharmacological chaperoning in the protein. The GAA structure reveals a surprising second sugar-binding site 34[A] from the active site, suggesting a possible mechanism for processing of large glycogen substrates. Overall, the structure will assist in the design of next-generation treatments for Pompe disease.

biochemistry↗