Engineering SARS-CoV-2 specific cocktail antibodies into a bispecific format improves neutralizing potency and breadth.

Autor: Ku Z; Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA.; Center for Infectious Disease Research, Science of Life Sciences, Westlake University, Hangzhou, Zhejiang, China., Xie X; Department of Biochemistry and Molecular Biology, Institute for Human Infection and Immunity, Sealy Institute for Vaccine Sciences, Sealy Center for Structural Biology & Molecular Biophysics, Department of Pharmacology & Toxicology, University of Texas Medical Branch, Galveston, TX, USA., Lin J; NTU Institute of Structural Biology and School of Biological Sciences, Nanyang Technological University, Singapore, Singapore., Gao P; Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA., Wu B; NTU Institute of Structural Biology and School of Biological Sciences, Nanyang Technological University, Singapore, Singapore., El Sahili A; NTU Institute of Structural Biology and School of Biological Sciences, Nanyang Technological University, Singapore, Singapore., Su H; Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA., Liu Y; Department of Biochemistry and Molecular Biology, Institute for Human Infection and Immunity, Sealy Institute for Vaccine Sciences, Sealy Center for Structural Biology & Molecular Biophysics, Department of Pharmacology & Toxicology, University of Texas Medical Branch, Galveston, TX, USA., Ye X; Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA.; Center for Infectious Disease Research, Science of Life Sciences, Westlake University, Hangzhou, Zhejiang, China., Tan EY; NTU Institute of Structural Biology and School of Biological Sciences, Nanyang Technological University, Singapore, Singapore., Li X; Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA., Fan X; Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA., Goh BC; NTU Institute of Structural Biology and School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.; Antimicrobial Resistance Interdisciplinary Research Group, Singapore-MIT Alliance for Research and Technology Centre, Singapore, Singapore., Xiong W; Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA., Boyd H; Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA., Muruato AE; Department of Biochemistry and Molecular Biology, Institute for Human Infection and Immunity, Sealy Institute for Vaccine Sciences, Sealy Center for Structural Biology & Molecular Biophysics, Department of Pharmacology & Toxicology, University of Texas Medical Branch, Galveston, TX, USA., Deng H; Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA., Xia H; Department of Biochemistry and Molecular Biology, Institute for Human Infection and Immunity, Sealy Institute for Vaccine Sciences, Sealy Center for Structural Biology & Molecular Biophysics, Department of Pharmacology & Toxicology, University of Texas Medical Branch, Galveston, TX, USA., Zou J; Department of Biochemistry and Molecular Biology, Institute for Human Infection and Immunity, Sealy Institute for Vaccine Sciences, Sealy Center for Structural Biology & Molecular Biophysics, Department of Pharmacology & Toxicology, University of Texas Medical Branch, Galveston, TX, USA., Kalveram BK; Department of Biochemistry and Molecular Biology, Institute for Human Infection and Immunity, Sealy Institute for Vaccine Sciences, Sealy Center for Structural Biology & Molecular Biophysics, Department of Pharmacology & Toxicology, University of Texas Medical Branch, Galveston, TX, USA., Menachery VD; Department of Microbiology & Immunology, University of Texas Medical Branch, Galveston, TX, USA., Zhang N; Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA., Lescar J; NTU Institute of Structural Biology and School of Biological Sciences, Nanyang Technological University, Singapore, Singapore. Julien@ntu.edu.sg., Shi PY; Department of Biochemistry and Molecular Biology, Institute for Human Infection and Immunity, Sealy Institute for Vaccine Sciences, Sealy Center for Structural Biology & Molecular Biophysics, Department of Pharmacology & Toxicology, University of Texas Medical Branch, Galveston, TX, USA. peshi@UTMB.EDU., An Z; Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX, USA. Zhiqiang.An@uth.tmc.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2022 Sep 22; Vol. 13 (1), pp. 5552. Date of Electronic Publication: 2022 Sep 22.
DOI: 10.1038/s41467-022-33284-y
Abstrakt: One major limitation of neutralizing antibody-based COVID-19 therapy is the requirement of costly cocktails to reduce emergence of antibody resistance. Here we engineer two bispecific antibodies (bsAbs) using distinct designs and compared them with parental antibodies and their cocktail. Single molecules of both bsAbs block the two epitopes targeted by parental antibodies on the receptor-binding domain (RBD). However, bsAb with the IgG-(scFv) 2 design (14-H-06) but not the CrossMAb design (14-crs-06) shows increased antigen-binding and virus-neutralizing activities against multiple SARS-CoV-2 variants as well as increased breadth of neutralizing activity compared to the cocktail. X-ray crystallography and cryo-EM reveal distinct binding models for individual cocktail antibodies, and computational simulations suggest higher inter-spike crosslinking potentials by 14-H-06 than 14-crs-06. In mouse models of infections by SARS-CoV-2 and multiple variants, 14-H-06 exhibits higher or equivalent therapeutic efficacy than the cocktail. Rationally engineered bsAbs represent a cost-effective alternative to antibody cocktails and a promising strategy to improve potency and breadth.
(© 2022. The Author(s).)
Databáze: MEDLINE
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