Light chain of a public SARS-CoV-2 class-3 antibody modulates neutralization against Omicron
Anamika Patel,
Sanjeev Kumar,
Lilin Lai,
Meredith Keen,
Rajesh Valanparambil,
Chennareddy Chakravarthy,
Zane Laughlin,
Filipp Frank,
Narayanaiah Cheedarla,
Hans P. Verkerke,
Andrew S. Neish,
John D. Roback,
Carl W. Davis,
Jens Wrammert,
Amit Sharma,
Rafi Ahmed,
Mehul S. Suthar,
Kaja Murali-Krishna,
Anmol Chandele,
Eric Ortlund
Affiliations
Anamika Patel
Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322, USA
Sanjeev Kumar
ICGEB-Emory Vaccine Center, International Center for Genetic Engineering and Biotechnology, New Delhi 110067, India; Department of Pediatrics, Division of Infectious Diseases, Emory University School of Medicine, Emory University, Atlanta, GA 30322, USA; Emory Vaccine Center, Emory University, Atlanta, GA 30322, USA
Lilin Lai
Department of Pediatrics, Division of Infectious Diseases, Emory University School of Medicine, Emory University, Atlanta, GA 30322, USA; Emory Vaccine Center, Emory University, Atlanta, GA 30322, USA
Meredith Keen
Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322, USA
Rajesh Valanparambil
Department of Microbiology and Immunology, Emory University School of Medicine, Emory University, Atlanta, GA 30322, USA; Emory Vaccine Center, Emory University, Atlanta, GA 30322, USA
Chennareddy Chakravarthy
Department of Microbiology and Immunology, Emory University School of Medicine, Emory University, Atlanta, GA 30322, USA; Emory Vaccine Center, Emory University, Atlanta, GA 30322, USA
Zane Laughlin
Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322, USA
Filipp Frank
Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322, USA
Narayanaiah Cheedarla
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA
Hans P. Verkerke
Department of Pathology, Brigham and Women’s Hospital, Boston, MA, USA
Andrew S. Neish
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA
John D. Roback
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA
Carl W. Davis
Department of Microbiology and Immunology, Emory University School of Medicine, Emory University, Atlanta, GA 30322, USA; Emory Vaccine Center, Emory University, Atlanta, GA 30322, USA
Jens Wrammert
Department of Pediatrics, Division of Infectious Diseases, Emory University School of Medicine, Emory University, Atlanta, GA 30322, USA; Emory Vaccine Center, Emory University, Atlanta, GA 30322, USA
Amit Sharma
Structural Parasitology Group, International Center for Genetic Engineering and Biotechnology, New Delhi 110067, India
Rafi Ahmed
Department of Microbiology and Immunology, Emory University School of Medicine, Emory University, Atlanta, GA 30322, USA; Emory Vaccine Center, Emory University, Atlanta, GA 30322, USA
Mehul S. Suthar
Department of Pediatrics, Division of Infectious Diseases, Emory University School of Medicine, Emory University, Atlanta, GA 30322, USA; Department of Microbiology and Immunology, Emory University School of Medicine, Emory University, Atlanta, GA 30322, USA; Emory Vaccine Center, Emory University, Atlanta, GA 30322, USA
Kaja Murali-Krishna
ICGEB-Emory Vaccine Center, International Center for Genetic Engineering and Biotechnology, New Delhi 110067, India; Department of Pediatrics, Division of Infectious Diseases, Emory University School of Medicine, Emory University, Atlanta, GA 30322, USA; Emory Vaccine Center, Emory University, Atlanta, GA 30322, USA; Corresponding author
Anmol Chandele
ICGEB-Emory Vaccine Center, International Center for Genetic Engineering and Biotechnology, New Delhi 110067, India; Corresponding author
Eric Ortlund
Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322, USA; Corresponding author
Summary: The pairing of antibody genes IGHV2-5/IGLV2-14 is established as a public immune response that potently cross-neutralizes SARS-CoV-2 variants, including Omicron, by targeting class-3/RBD-5 epitopes in the receptor binding domain (RBD). LY-CoV1404 (bebtelovimab) exemplifies this, displaying exceptional potency against Omicron sub-variants up to BA.5. Here, we report a human antibody, 002-S21B10, encoded by the public clonotype IGHV2-5/IGLV2-14. While 002-S21B10 neutralized key SARS-CoV-2 variants, it did not neutralize Omicron, despite sharing >92% sequence similarity with LY-CoV1404. The structure of 002-S21B10 in complex with spike trimer plus structural and sequence comparisons with LY-CoV1404 and other IGHV2-5/IGLV2-14 antibodies revealed significant variations in light-chain orientation, paratope residues, and epitope-paratope interactions that enable some antibodies to neutralize Omicron but not others. Confirming this, replacing the light chain of 002-S21B10 with the light chain of LY-CoV1404 restored 002-S21B10’s binding to Omicron. Understanding such Omicron evasion from public response is vital for guiding therapeutics and vaccine design.
