Biology subjects

Borenstein-Katz, A.

Publications and source records attributed to Borenstein-Katz, A..

2 recordsLinked to original sources

bioRxiv2023

Dissecting the impact of somatic hypermutation on SARS-CoV-2 neutralization and viral escape

Somatic hypermutation (SHM) drives affinity maturation and continues over months in SARS-CoV-2 neutralizing antibodies. Yet, several potent SARS-CoV-2 antibodies carry no or only few mutations, leaving the question of how ongoing SHM affects neutralization. Here, we reverted variable region mutations of 92 antibodies and tested their impact on SARS-CoV-2 binding and neutralization. Reverting higher numbers of mutations correlated with decreasing antibody functionality. However, some antibodies, including the public clonotype VH1-58, remained unaffected for Wu01 activity. Moreover, while mutations were dispensable for Wu01-induced VH1-58 antibodies to neutralize Alpha, Beta, and Delta variants, they were critical to neutralize Omicron BA.1/BA.2. Notably, we exploited this knowledge to convert the clinical antibody tixagevimab into a BA.1/BA.2-neutralizer. These findings substantially broaden our understanding of SHM as a mechanism that not only improves antibody responses during affinity maturation, but also counteracts antigenic imprinting through antibody diversification and thus increases the chances of neutralizing viral escape variants.

immunology↗

bioRxiv2021

Biomolecular recognition of the glycan neoantigen CA19-9 by distinct antibodies

Glycans decorate cell surface, secreted glycoproteins and glycolipids. Altered glycans are often found in cancers. Despite their high diagnostic and therapeutic potentials, glycans are polar and flexible molecules that are quite challenging for the development and design of high-affinity binding antibodies. To understand the mechanisms by which glycan neoantigens are specifically recognized by antibodies, we analyze the biomolecular recognition of a single tumor-associated carbohydrate antigen CA19-9 by two distinct antibodies using X-ray crystallography. Despite the plasticity of glycans and the very different antigen-binding surfaces presented by the antibodies, both structures reveal an essentially identical extended CA19-9 conformer, suggesting that this conformers stability selects the antibodies. Starting from the bound structure of one of the antibodies, we use the AbLIFT computational method to design a variant with seven core mutations that exhibited tenfold improved affinity for CA19-9. The results reveal strategies used by antibodies to specifically recognize glycan antigens and show how automated antibody-optimization methods may be used to enhance the clinical potential of existing antibodies.

molecular biology↗