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Volume 12
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10.3390/biomedicines12030642
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Article

Broad Epitope Coverage of Therapeutic Multi-Antibody Combinations Targeting SARS-CoV-2 Boosts In Vivo Protection and Neutralization Potency to Corner an Immune-Evading Virus

by
Ilse Roodink
*,
Maartje van Erp
,
Andra Li
,
Sheila Potter
,
Sander M. J. van Duijnhoven
,
Milou Smits
,
Arthur J. Kuipers
,
Bert Kazemier
,
Bob Berkeveld
,
Ellen van Geffen
,
Britte S. de Vries
,
Danielle Rijbroek
,
Bianca Boers
,
Sanne Meurs
,
Wieger Hemrika
,
Alexandra Thom
,
Barry N. Duplantis
,
Roland A. Romijn
,
Jeremy S. Houser
,
Jennifer L. Bath
and
Yasmina N. Abdiche
add Show full author list remove Hide full author list
ImmunoPrecise Antibodies Ltd., 4837 Amber Valley Parkway, Suite 11, Fargo, ND 58104, USA
*
Author to whom correspondence should be addressed.
Biomedicines 2024, 12(3), 642; https://doi.org/10.3390/biomedicines12030642
Submission received: 22 June 2023 / Revised: 5 March 2024 / Accepted: 8 March 2024 / Published: 13 March 2024
(This article belongs to the Section Drug Discovery, Development and Delivery)
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Abstract

Therapeutic antibodies (Abs) which act on a broader range of epitopes may provide more durable protection against the genetic drift of a target, typical of viruses or tumors. When these Abs exist concurrently on the targeted antigen, several mechanisms of action (MoAs) can be engaged, boosting therapeutic potency. This study selected combinations of four and five Abs with non- or partially overlapping epitopes to the SARS-CoV-2 spike glycoprotein, on or outside the crucial receptor binding domain (RBD), to offer resilience to emerging variants and trigger multiple MoAs. The combinations were derived from a pool of unique-sequence scFv Ab fragments retrieved from two SARS-CoV-2-naïve human phage display libraries. Following recombinant expression to full-length human IgG1 candidates, a biolayer interferometric analysis mapped epitopes to bins and confirmed that up to four Abs from across the bins can exist simultaneously on the spike glycoprotein trimer. Not all the bins of Abs interfered with the spike protein binding to angiotensin converting enzyme 2 (ACE2) in competitive binding assays, nor neutralized the pseudovirus or authentic virus in vitro, but when combined in vivo, their inclusion resulted in a much stronger viral clearance in the lungs of intranasally challenged hamsters, compared to that of those treated with mono ACE2 blockers. In addition, the Ab mixtures activated in vitro reporter cells expressing Fc-gamma receptors (FcγRs) involved in antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP). The best four-Ab combination neutralized seventeen variants of concern from Wuhan-Hu1 to Omicron BA.4/BA.5 in vitro.
Keywords: antibody-dependent cellular effects; bio-engineering; COVID-19; multi-antibody combination; neutralizing antibodies; resilient efficacy; SARS-CoV-2 antibody-dependent cellular effects; bio-engineering; COVID-19; multi-antibody combination; neutralizing antibodies; resilient efficacy; SARS-CoV-2

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MDPI and ACS Style

Roodink, I.; van Erp, M.; Li, A.; Potter, S.; van Duijnhoven, S.M.J.; Smits, M.; Kuipers, A.J.; Kazemier, B.; Berkeveld, B.; van Geffen, E.; et al. Broad Epitope Coverage of Therapeutic Multi-Antibody Combinations Targeting SARS-CoV-2 Boosts In Vivo Protection and Neutralization Potency to Corner an Immune-Evading Virus. Biomedicines 2024, 12, 642. https://doi.org/10.3390/biomedicines12030642

AMA Style

Roodink I, van Erp M, Li A, Potter S, van Duijnhoven SMJ, Smits M, Kuipers AJ, Kazemier B, Berkeveld B, van Geffen E, et al. Broad Epitope Coverage of Therapeutic Multi-Antibody Combinations Targeting SARS-CoV-2 Boosts In Vivo Protection and Neutralization Potency to Corner an Immune-Evading Virus. Biomedicines. 2024; 12(3):642. https://doi.org/10.3390/biomedicines12030642

Chicago/Turabian Style

Roodink, Ilse, Maartje van Erp, Andra Li, Sheila Potter, Sander M. J. van Duijnhoven, Milou Smits, Arthur J. Kuipers, Bert Kazemier, Bob Berkeveld, Ellen van Geffen, and et al. 2024. "Broad Epitope Coverage of Therapeutic Multi-Antibody Combinations Targeting SARS-CoV-2 Boosts In Vivo Protection and Neutralization Potency to Corner an Immune-Evading Virus" Biomedicines 12, no. 3: 642. https://doi.org/10.3390/biomedicines12030642

APA Style

Roodink, I., van Erp, M., Li, A., Potter, S., van Duijnhoven, S. M. J., Smits, M., Kuipers, A. J., Kazemier, B., Berkeveld, B., van Geffen, E., Vries, B. S. d., Rijbroek, D., Boers, B., Meurs, S., Hemrika, W., Thom, A., Duplantis, B. N., Romijn, R. A., Houser, J. S., ... Abdiche, Y. N. (2024). Broad Epitope Coverage of Therapeutic Multi-Antibody Combinations Targeting SARS-CoV-2 Boosts In Vivo Protection and Neutralization Potency to Corner an Immune-Evading Virus. Biomedicines, 12(3), 642. https://doi.org/10.3390/biomedicines12030642

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