Ultrapotent and Broad Neutralization of SARS-CoV-2 Variants by Modular, Tetravalent, Bi-paratopic Antibodies
| Autor: | Nitin Sharma, Chao Chen, Alberto Zani, Arnaldo Caruso, Shane Miersch, Gaya K. Amarasinghe, Sachdev S. Sidhu, Francesca Caccuri, Reza Saberianfar, Giuseppe Novelli |
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| Rok vydání: | 2021 |
| Předmět: |
2019-20 coronavirus outbreak
mutational escape Coronavirus disease 2019 (COVID-19) Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) passive immunotherapy Trimer bispecific Antibodies Viral Antibodies CP: virus General Biochemistry Genetics and Molecular Biology Bivalent (genetics) Neutralization RBD S protein virus variant Neutralization Tests antibody Humans Viral Neutralizing CP: Immunology CP: Microbiology SARS-CoV-2 bi-paratopic neutralization Antibodies Neutralizing Spike Glycoprotein Coronavirus COVID-19 biology Chemistry Spike Protein Virology Spike Glycoprotein Coronavirus Settore MED/03 biology.protein Antibody |
| DOI: | 10.1101/2021.11.02.466984 |
| Popis: | Neutralizing antibodies (nAbs) that target the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein (S-protein) are promising therapeutics for COVID-19. However, natural bivalent nAbs suffer from limited potency and are vulnerable to SARS-CoV-2 variants with mutated RBDs. We report a novel format that enables modular assembly of bi-paratopic, tetravalent nAbs with antigen-binding sites from two distinct nAbs. The diabody-Fc-Fab format consists of a central Fc with a bivalent diabody fused to its N-terminus and two Fabs fused to its C-terminus. The diabody and Fab modules do not interfere with each other, and thus, any diabody can be combined with any Fab in a facile manner. We engineered a diabody-Fc-Fab that contained the paratopes of two distinct nAbs derived from a phage-displayed library of synthetic Abs. The tetravalent nAb was purified in high yields with methods used to produce conventional IgGs, and it exhibited favorable biophysical characteristics comparable to those of approved therapeutic antibodies. The tetravalent nAb bound to the S-protein trimer at least 100-fold more tightly than the bivalent IgGs (apparent KD |
| Databáze: | OpenAIRE |
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