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Engineering SARS-CoV-2 cocktail antibodies into a bispecific format improves neutralizing potency and breadth
Zhiqiang Ku; Xuping Xie; Jianqing Lin; Peng Gao; Abbas El Sahili; Hang Su; Yang Liu; Xiaohua Ye; Xin Li; Xuejun Fan; Boon Chong Goh; Wei Xiong; Hannah Boyd; Antonio E. Muruato; Hui Deng; Hongjie Xia; Zou Jing; Birte K. Kalveram; Vineet D. Menachery; Ningyan Zhang; Julien Lescar; Pei-Yong Shi; Zhiqiang An.
Afiliación
  • Zhiqiang Ku; Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
  • Xuping Xie; Department of Biochemistry and Molecular Biology, Institute for Human Infection and Immunity, Sealy Institute for Vaccine Sciences, Sealy Center for Structural
  • Jianqing Lin; NTU Institute of Structural Biology and School of Biological Sciences, Nanyang Technological University, 636921, Singapore
  • Peng Gao; Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
  • Abbas El Sahili; NTU Institute of Structural Biology and School of Biological Sciences, Nanyang Technological University, 636921, Singapore
  • Hang Su; Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
  • Yang Liu; Department of Biochemistry and Molecular Biology, Institute for Human Infection and Immunity, Sealy Institute for Vaccine Sciences, Sealy Center for Structural
  • Xiaohua Ye; Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
  • Xin Li; Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
  • Xuejun Fan; Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
  • Boon Chong Goh; NTU Institute of Structural Biology and School of Biological Sciences, Nanyang Technological University, 636921, Singapore
  • Wei Xiong; Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
  • Hannah Boyd; Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
  • Antonio E. Muruato; Department of Biochemistry and Molecular Biology, Institute for Human Infection and Immunity, Sealy Institute for Vaccine Sciences, Sealy Center for Structural
  • Hui Deng; Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
  • Hongjie Xia; Department of Biochemistry and Molecular Biology, Institute for Human Infection and Immunity, Sealy Institute for Vaccine Sciences, Sealy Center for Structural
  • Zou Jing; Department of Biochemistry and Molecular Biology, Institute for Human Infection and Immunity, Sealy Institute for Vaccine Sciences, Sealy Center for Structural
  • Birte K. Kalveram; Department of Biochemistry and Molecular Biology, Institute for Human Infection and Immunity, Sealy Institute for Vaccine Sciences, Sealy Center for Structural
  • Vineet D. Menachery; Department of Microbiology & Immunology, University of Texas Medical Branch, Galveston, TX, 77555, USA
  • Ningyan Zhang; Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
  • Julien Lescar; NTU Institute of Structural Biology and School of Biological Sciences, Nanyang Technological University, 636921, Singapore
  • Pei-Yong Shi; Department of Biochemistry and Molecular Biology, Institute for Human Infection and Immunity, Sealy Institute for Vaccine Sciences, Sealy Center for Structural
  • Zhiqiang An; Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
Preprint en En | PREPRINT-BIORXIV | ID: ppbiorxiv-478504
ABSTRACT
One major limitation of neutralizing antibody-based COVID-19 therapy is the requirement of costly cocktails to reduce antibody resistance. We engineered 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) increases antigen-binding and virus-neutralizing activities and spectrum against multiple SARS-CoV-2 variants including the Omicron, than the cocktail. X-ray crystallography and computational simulations reveal distinct neutralizing mechanisms for individual cocktail antibodies and suggest higher inter-spike crosslinking potentials by 14-H-06 than 14-crs-06. In mouse models of infections by SARS-CoV-2 and the Beta, Gamma, and Delta 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.
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Texto completo: 1 Colección: 09-preprints Base de datos: PREPRINT-BIORXIV Idioma: En Año: 2022 Tipo del documento: Preprint
Texto completo
Añadir a Mi BVS
Imprimir
XML
Buscar en Google
Texto completo: 1 Colección: 09-preprints Base de datos: PREPRINT-BIORXIV Idioma: En Año: 2022 Tipo del documento: Preprint