Human Monoclonal Antibody Combination against SARS Coronavirus: Synergy and Coverage of Escape Mutants

By J. T. ter Meulen, E. N. van den Brink, L. Poon, W. Marissen, C. S. Leung, F. Cox, C. Cheung, A. Bakker, Johannes A. Bogaards, E. van Deventer and 6 more. 2006

653 citations recorded by the source corpus.

Background Experimental animal data show that protection against severe acute respiratory syndrome coronavirus (SARS-CoV) infection with human monoclonal antibodies (mAbs) is feasible. For an effective immune prophylaxis in humans, broad coverage of different strains of SARS-CoV and control of potential neutralization escape variants will be required. Combinations of virus-neutralizing, noncompeting mAbs may have these properties. Methods and Findings Human mAb CR3014 has been shown to completely prevent lung pathology and abolish pharyngeal shedding of SARS-CoV in infected ferrets. We generated in vitro SARS-CoV variants escaping neutralization by CR3014, which all had a single P462L mutation in the glycoprotein spike (S) of the escape virus. In vitro experiments confirmed that binding of CR3014 to a recombinant S fragment (amino acid residues 318–510) harboring this mutation was abolished. We therefore screened an antibody-phage library derived from blood of a convalescent SARS patient for antibodies complementary to CR3014. A novel mAb, CR3022, was identified that neutralized CR3014 escape viruses, did not compete with CR3014 for binding to recombinant S1 fragments, and bound to S1 fragments derived from the civet cat SARS-CoV-like strain SZ3. No escape variants could be generated with CR3022. The mixture of both mAbs showed neutralization of SARS-CoV in a synergistic fashion by recognizing different epitopes on the receptor-binding domain. Dose reduction indices of 4.5 and 20.5 were observed for CR3014 and CR3022, respectively, at 100% neutralization. Because enhancement of SARS-CoV infection by subneutralizing antibody concentrations is of concern, we show here that anti-SARS-CoV antibodies do not convert the abortive infection of primary human macrophages by SARS-CoV into a productive one. Conclusions The combination of two noncompeting human mAbs CR3014 and CR3022 potentially controls immune escape and extends the breadth of protection. At the same time, synergy between CR3014 and CR3022 may allow for a lower total antibody dose to be administered for passive immune prophylaxis of SARS-CoV infection.

Subfields: Infectious Diseases, Molecular Biology, Radiology, Nuclear Medicine and Imaging

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Citations in the corpus

Elicitation of Potent Neutralizing Antibody Responses by Designed Protein Nanoparticle Vaccines for SARS-CoV-2 (2020, neutral): “…CR3022 is a weakly neutralizing Ab that binds to a conserved, cryptic epitope in the RBD that becomes accessible upon RBD opening but is distinct from the receptor binding motif (RBM), the surface of the RBD that interacts with ACE2 (Huo et al., 2020; ter Meulen et al., 2006; Yuan et al., 2020).”
Potent neutralizing antibodies from COVID-19 patients define multiple targets of vulnerability (2020, background): “In light of the rapid emergence of escape mutants in the RBD of SARS-CoV and MERS, monoclonal NAbs targeting other epitopes than the RBD are a welcome component of any therapeutic antibody cocktail (26, 27).”
Structural Basis for Potent Cross-Neutralizing Human Monoclonal Antibody Protection against Lethal Human and Zoonotic Severe Acute Respiratory Syndrome Coronavirus Challenge (2008, positive): “A cocktail of multiple MAbs was as capable of protecting against lethal challenge as the most potent individual MAbs, providing a strategy for minimizing the emergence of MAb escape mutants (2, 46).”
Complete mapping of mutations to the SARS-CoV-2 spike receptor-binding domain that escape antibody recognition (2020, positive): “The recombinant CR3022 antibody (rCR3022), was kindly provided by Neil King and Mike Murphy, University of Washington, Institute for Protein Design, based on the sequence reported by ter Meulen et al. (2006) .”
Neutralization of SARS-CoV-2 by Destruction of the Prefusion Spike (2020, positive): “…sterically and functionally independent of the well-established receptor-blocking neutralising antibody epitope there is considerable scope for therapeutic synergy between antibodies targeting the two epitopes (indeed this type of synergy has been described for SARS-CoV (Ter Meulen et al., 2006)).”
Naïve Human Antibody Libraries for Infectious Diseases (2018, background): “Aside from EBOV infections, antibody cocktails are also being applied in other viral infectious diseases such as rabies virus [194] , SARS coronavirus [195] , HIV [196] , hepatitis B virus [197] and other viruses [198] .”
From SARS to MERS, Thrusting Coronaviruses into the Spotlight (2019, background): “Host protease inhibitors Effective in mouse models [138] In vitro inhibition [138] Viral protease inhibitors In vitro inhibition [139] In vitro inhibition [140] Monoclonal and polyclonal antibodies Effective in mouse, ferrets, golden Syrian hamster [124, 141, 142] and non-human primate models [143, ”
Immunogenicity and structures of a rationally designed prefusion MERS-CoV spike antigen (2017, background): “A drawback of this approach is that coronaviruses can readily generate antibody-escape mutations in the RBD (23, 27, 28).”
A highly conserved cryptic epitope in the receptor-binding domains of SARS-CoV-2 and SARS-CoV (2020, background): “Together with the fact that CR3022 was isolated from a convalescent SARS patient (4), 124 these observations suggest that an antibody response can be elicited against this cryptic 125 epitope in SARS-CoV and possibly SARS-CoV-2.”