Characterization of human monoclonal antibodies that neutralize multiple poliovirus serotypes.
Following the eradication of wild poliovirus (PV), achieving and maintaining a polio-free status will require eliminating potentially pathogenic PV strains derived from the oral attenuated vaccine. For this purpose, a combination of non-cross-resistant drugs, such as small molecules and neutralizing monoclonal antibodies (mAbs), may be ideal. We previously isolated chimpanzee and human mAbs capable of neutralizing multiple PV types (cross-neutralization). Here, we describe three additional human mAbs that neutralize types 1 and 2 PV and one mAb that neutralizes all three types. Most bind conformational epitopes and have unusually long heavy chain complementarity determining 3 domains (HC CDR3). We assessed the ability of the mAbs to neutralize A12 escape mutant PV strains, and found that the neutralizing activities of the mAbs were disrupted by different amino acid substitutions. Competitive binding studies further suggested that the specific mAb:PV interactions that enable cross-neutralization differ among mAbs and serotypes. All of the cloned mAbs bind PV in the vicinity of the "canyon", a circular depression around the 5-fold axis of symmetry through which PV recognizes its cellular receptor. We were unable to generate escape mutants to two of the mAbs, suggesting that their epitopes are important for the PV life cycle. These data indicate that PV cross-neutralization involves binding to highly conserved structures within the canyon that binds to the cellular receptor. These may be facilitated by the long HC CDR3 domains, which may adopt alternative binding configurations. We propose that the human and chimpanzee mAbs described here could have potential as anti-PV therapeutics.
Lankenau Institute for Medical Research, 100 E. Lancaster Ave., Wynnewood, PA 19096, USA.
Rama Devudu
RD
Puligedda
Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA.
Diana
D
Kouiavskaia
Lankenau Institute for Medical Research, 100 E. Lancaster Ave., Wynnewood, PA 19096, USA.
Fetweh H
FH
Al-Saleem
Lankenau Institute for Medical Research, 100 E. Lancaster Ave., Wynnewood, PA 19096, USA.
Chandana Devi
CD
Kattala
Lankenau Institute for Medical Research, 100 E. Lancaster Ave., Wynnewood, PA 19096, USA.
Usman
U
Nabi
Lankenau Institute for Medical Research, 100 E. Lancaster Ave., Wynnewood, PA 19096, USA.
Hamid
H
Yaqoob
Department of Biotechnology, College of Science & Technology, Andhra University, Visakhapatnam 530 003, Andhra Pradesh, India.
V Sandeep
VS
Bhagavathula
Lankenau Institute for Medical Research, 100 E. Lancaster Ave., Wynnewood, PA 19096, USA.
Rashmi
R
Sharma
Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA. Electronic address: Konstantin.Chumakov@fda.hhs.gov.
Konstantin
K
Chumakov
Lankenau Institute for Medical Research, 100 E. Lancaster Ave., Wynnewood, PA 19096, USA. Electronic address: dessain@limr.org.
Scott K
SK
Dessain
D000328:Adult; D000368:Aged; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D057134:Antibodies, Neutralizing / Q000276:immunology*; D000914:Antibodies, Viral / Q000276:immunology*; D000956:Antigens, Viral / Q000276:immunology; D000939:Epitopes / Q000276:immunology; D006801:Humans; D008875:Middle Aged; D009500:Neutralization Tests / Q000379:methods; D002679:Pan troglodytes / Q000276:immunology / Q000821:virology; D011051:Poliomyelitis / Q000276:immunology* / Q000517:prevention & control / Q000821:virology; D017955:Poliovirus / Q000276:immunology*; D065288:Serogroup
D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D000956:Antigens, Viral; D000939:Epitopes
Circulating vaccine derived poliovirus (cVDPV); Cross-neutralization; Human immunity; Immune deficiency associated vaccine derived poliovirus (iVDPV); Monoclonal antibody; Neutralization; Polio eradication; Poliovirus