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Antibody Affinity Governs the Inhibition of SARS-CoV-2 Spike/ACE2 Binding in Patient Serum


Fiedler, Sebastian; Piziorska, Monika A; Denninger, Viola; Morgunov, Alexey S; Ilsley, Alison; Malik, Anisa Y; Schneider, Matthias M; Devenish, Sean R A; Meisl, Georg; Kosmoliaptsis, Vasilis; Aguzzi, Adriano; Fiegler, Heike; Knowles, Tuomas P J (2021). Antibody Affinity Governs the Inhibition of SARS-CoV-2 Spike/ACE2 Binding in Patient Serum. ACS Infectious Diseases, 7(8):2362-2369.

Abstract

The humoral immune response plays a key role in suppressing the pathogenesis of SARS-CoV-2. The molecular determinants underlying the neutralization of the virus remain, however, incompletely understood. Here, we show that the ability of antibodies to disrupt the binding of the viral spike protein to the angiotensin-converting enzyme 2 (ACE2) receptor on the cell, the key molecular event initiating SARS-CoV-2 entry into host cells, is controlled by the affinity of these antibodies to the viral antigen. By using microfluidic antibody-affinity profiling, we were able to quantify the serum-antibody mediated inhibition of ACE2–spike binding in two SARS-CoV-2 seropositive individuals. Measurements to determine the affinity, concentration, and neutralization potential of antibodies were performed directly in human serum. Using this approach, we demonstrate that the level of inhibition in both samples can be quantitatively described using the dissociation constants (KD) of the binary interactions between the ACE2 receptor and the spike protein as well as the spike protein and the neutralizing antibody. These experiments represent a new type of in-solution receptor binding competition assay, which has further potential applications, ranging from decisions on donor selection for convalescent plasma therapy, to identification of lead candidates in therapeutic antibody development, and vaccine development.

Abstract

The humoral immune response plays a key role in suppressing the pathogenesis of SARS-CoV-2. The molecular determinants underlying the neutralization of the virus remain, however, incompletely understood. Here, we show that the ability of antibodies to disrupt the binding of the viral spike protein to the angiotensin-converting enzyme 2 (ACE2) receptor on the cell, the key molecular event initiating SARS-CoV-2 entry into host cells, is controlled by the affinity of these antibodies to the viral antigen. By using microfluidic antibody-affinity profiling, we were able to quantify the serum-antibody mediated inhibition of ACE2–spike binding in two SARS-CoV-2 seropositive individuals. Measurements to determine the affinity, concentration, and neutralization potential of antibodies were performed directly in human serum. Using this approach, we demonstrate that the level of inhibition in both samples can be quantitatively described using the dissociation constants (KD) of the binary interactions between the ACE2 receptor and the spike protein as well as the spike protein and the neutralizing antibody. These experiments represent a new type of in-solution receptor binding competition assay, which has further potential applications, ranging from decisions on donor selection for convalescent plasma therapy, to identification of lead candidates in therapeutic antibody development, and vaccine development.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Institute of Neuropathology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Scopus Subject Areas:Health Sciences > Infectious Diseases
Uncontrolled Keywords:COVID-19
Language:English
Date:13 August 2021
Deposited On:16 Jun 2021 12:50
Last Modified:25 Jun 2024 01:40
Publisher:American Chemical Society (ACS)
ISSN:2373-8227
OA Status:Closed
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1021/acsinfecdis.1c00047
PubMed ID:33876632