Broadening sarbecovirus neutralization with bispecific antibodies combining distinct conserved targets on the receptor binding domain

• Main Authors: Denise Guerra (Author), Laura Radić (Author), Mitch Brinkkemper (Author), Meliawati Poniman (Author), Lara van der Maas (Author), Jonathan L. Torres (Author), Andrew B. Ward (Author), Kwinten Sliepen (Author), Janke Schinkel (Author), Rogier W. Sanders (Author), Marit J. van Gils (Author), Tim Beaumont (Author)
• Format: Book
• Published: Taylor & Francis Group, 2024-12-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 10.1080/21645515.2024.2388344; 2164-554X; 2164-5515
• Keywords: SARS-CoV-2; variants; sarbecoviruses; bispecific antibodies; cross-reactivity; breadth; Immunologic diseases. Allergy; RC581-607; Therapeutics. Pharmacology; RM1-950
• Source: Human Vaccines & Immunotherapeutics, Vol 20, Iss 1 (2024)

Monoclonal neutralizing antibodies (mAbs) are considered an important prophylactic against SARS-CoV-2 infection in at-risk populations and a strategy to counteract future sarbecovirus-induced disease. However, most mAbs isolated so far neutralize only a few sarbecovirus strains. Therefore, there is a growing interest in bispecific antibodies (bsAbs) which can simultaneously target different spike epitopes and thereby increase neutralizing breadth and prevent viral escape. Here, we generate and characterize a panel of 30 novel broadly reactive bsAbs using an efficient controlled Fab-arm exchange protocol. We specifically combine some of the broadest mAbs described so far, which target conserved epitopes on the receptor binding domain (RBD). Several bsAbs show superior cross-binding and neutralization compared to the parental mAbs and cocktails against sarbecoviruses from diverse clades, including recent SARS-CoV-2 variants. BsAbs which include mAb COVA2-02 are among the most potent and broad combinations. As a result, we study the unknown epitope of COVA2-02 and show that this mAb targets a distinct conserved region at the base of the RBD, which could be of interest when designing next-generation bsAb constructs to contribute to a better pandemic preparedness.