Probing Affinity, Avidity, Anticooperativity, and Competition in Antibody and Receptor Binding to the SARS-CoV-2 Spike by Single Particle Mass Analyses

Yin, Victor; Lai, Szu-Hsueh; Caniels, Tom G.; Brouwer, Philip J.M.; Brinkkemper, Mitch; Aldon, Yoann; Liu, Hejun; Yuan, Meng; Wilson, Ian A.; Sanders, Rogier W.; Gils, Marit J. van; Heck, Albert J. R.

doi:10.1021/acscentsci.1c00804

Cited by 23 publications

(22 citation statements)

References 60 publications

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“…In addition, factors such as avidity and (anti-) cooperativity are known to also influence binding between full-length IgG1 and the S-protein 22 , 23 . In any case, these binding differences between antibody clones are an important feature to consider when selecting antibodies for further development into biotherapeutics.…”

Section: Discussionmentioning

confidence: 99%

Discriminating cross-reactivity in polyclonal IgG1 responses against SARS-CoV-2 variants of concern

et al. 2022

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Existing assays to measure antibody cross-reactivity against different SARS-CoV-2 spike (S) protein variants lack the discriminatory power to provide insights at the level of individual clones. Using a mass spectrometry-based approach we are able to monitor individual donors’ IgG1 clonal responses following a SARS-CoV-2 infection. We monitor the plasma clonal IgG1 profiles of 8 donors who had experienced an infection by either the wild type Wuhan Hu-1 virus or one of 3 VOCs (Alpha, Beta and Gamma). In these donors we chart the full plasma IgG1 repertoires as well as the IgG1 repertoires targeting the SARS-CoV-2 spike protein trimer VOC antigens. The plasma of each donor contains numerous anti-spike IgG1 antibodies, accounting for <0.1% up to almost 10% of all IgG1s. Some of these antibodies are VOC-specific whereas others do recognize multiple or even all VOCs. We show that in these polyclonal responses, each clone exhibits a distinct cross-reactivity and also distinct virus neutralization capacity. These observations support the need for a more personalized look at the antibody clonal responses to infectious diseases.

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Section: Discussionmentioning

confidence: 99%

Discriminating cross-reactivity in polyclonal IgG1 responses against SARS-CoV-2 variants of concern

et al. 2022

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“…Previous studies comparing full IgGs with single Fabs suggest that RBD-targeting NAbs COVA1-16 and COVA1-18 need bivalency for strong binding and neutralization 17,44,45 . To corroborate these results and determine the influence of bivalency on binding and neutralization potency of all NAb candidates, we produced additional "dead arm" bsAbs by combining COVA-16, COVA2-02 and COVA2-15 with HCV-specific HC84.26.…”

Section: Cova Rbd Antibodies Rely On Avidity For Strong Bindingmentioning

confidence: 99%

Bispecific antibodies combine breadth, potency, and avidity of parental antibodies to neutralize sarbecoviruses

Radić

Sliepen

Yin

et al. 2022

Preprint

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SARS-CoV-2 mutational variants evade humoral immune responses elicited by vaccines and current monoclonal antibody (mAb) therapies. Novel antibody-based treatments will thus need to exhibit broad neutralization against different variants. Bispecific antibodies (bsAbs) combine the specificities of two distinct antibodies into one antibody taking advantage of the avidity, synergy and cooperativity provided by targeting two different epitopes. Here we used controlled Fab-arm exchange (cFAE), a versatile and straightforward method, to produce bsAbs that neutralize SARS-CoV and SARS-CoV-2 variants, including Omicron and its subvariants, by combining potent SARS-CoV-2-specific neutralizing antibodies with broader but less potent antibodies that also neutralize SARS-CoV. We demonstrate that the parental IgG's rely on avidity for their neutralizing activity by comparing their potency to bsAbs containing one irrelevant "dead" Fab arm. We used single particle mass photometry to measure formation of antibody:spike complexes, and determined that bsAbs increase binding stoichiometry compared to corresponding cocktails, without a loss of binding affinity. The heterogeneous binding pattern of bsAbs to spike (S), observed by negative-stain electron microscopy and mass photometry provided evidence for both intra- and inter-spike crosslinking. This study highlights the utility of cross-neutralizing antibodies for designing bivalent or multivalent agents to provide a robust activity against circulating variants, as well as future SARS-like coronaviruses.

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“…That each clone shows a unique binding pattern can be caused by the unique binding epitopes of the IgG clones in their interactions with the S-protein, leading to that some clones are more affected by specific mutations (17, 18). In addition, factors such as avidity and (anti-) cooperativity are known to also influence binding between full-length IgG1 and the S-protein (19, 20). In any case, these binding differences between antibody clones are an important feature to consider when selecting antibodies for further development into biotherapeutics.…”

Section: Discussionmentioning

confidence: 99%

IgG1 responses following SARS-CoV-2 infection are polyclonal and highly personalized, whereby each donor and each clone displays a distinct pattern of cross-reactivity against SARS-CoV-2 variants

Rijswijck

Bondt

Hoek

et al. 2022

Preprint

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Using a recently introduced efficient mass spectrometry-based approach we monitored in molecular detail the IgG1 clonal responses in individual donors' IgG1 clonal responses in molecular detail, examining SARS-CoV-2 spike-protein-specific IgG1 repertoires. We monitored the plasma clonal IgG1 profiles of 8 donors (4 male and 4 female) who had recently experienced an infection by either the wild type Wuhan Hu-1 virus or one of 3 VOCs (Alpha, Beta and Gamma). In these donors we charted the full plasma IgG1 repertoires as well as the IgG1 repertoires targeting the SARS-CoV-2 spike protein trimer as antigen. We observed that shortly after infection in between <0.1% to almost 10% of all IgG1 antibody molecules present in plasma did bind to the spike protein. Each donor displayed a unique plasma IgG1 repertoire, but also each donor displayed a unique and polyclonal antibody response against the SARS-CoV-2 spike-protein variants. Our analyses revealed that certain clones exhibit (alike) binding affinity towards all four tested spike-protein variants, whereas other clones displayed strong unique mutant-specific affinity. We conclude that each infected person generates a unique polyclonal response following infection, whereby some of these clones can bind multiple viral variants, whereas other clones do not display such cross-reactivity. In general, by assessing IgG1 repertoires following infection it becomes possible to identify and select fully matured human plasma antibodies that target specific antigens, and display either high specificity or cross-reactivity versus mutated versions of the antigen, which will aid in selecting antibodies that may be developed into biotherapeutics.

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Probing Affinity, Avidity, Anticooperativity, and Competition in Antibody and Receptor Binding to the SARS-CoV-2 Spike by Single Particle Mass Analyses

Cited by 23 publications

References 60 publications

Discriminating cross-reactivity in polyclonal IgG1 responses against SARS-CoV-2 variants of concern

Discriminating cross-reactivity in polyclonal IgG1 responses against SARS-CoV-2 variants of concern

Bispecific antibodies combine breadth, potency, and avidity of parental antibodies to neutralize sarbecoviruses

IgG1 responses following SARS-CoV-2 infection are polyclonal and highly personalized, whereby each donor and each clone displays a distinct pattern of cross-reactivity against SARS-CoV-2 variants

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