Evaluating the\nSynergistic Effects of Multi-Epitope\nNanobodies on BA.2.86 Variant Immune Escape

Addressing the frequent emergence\nof SARS-CoV-2 mutant strains\nrequires therapeutic approaches with innovative neutralization mechanisms.\nThe targeting of multivalent nanobodies can enhance potency and reduce\nthe risk of viral escape, positioning them as promising drug candidates.\nHere, the synergistic mechanisms of the two types of nanobodies are\ninvestigated deeply. Our research revealed that the Fu2-1-Fu2-2 system\nexhibited significant synergy, whereas the Sb#15-Sb#68 system demonstrated\nantagonism, in which entropy was the dominant contributor to antagonism.\nConformational analysis further demonstrated that the presence of\na monomeric nanobody influenced the flexibility of residues near other\nepitopes, thereby affecting the overall synergy of the systems. Moreover,\nwe identified that changes in the hydrogen bond network and the charge\nof residues played a critical role in the binding between nanobodies\nand spike. We hope this study will provide novel insights into the\ndevelopment of multivalent nanobody combinations.