Year: 2022
Type: preprint
Abstract: Traditional Y-shaped IgG topologies restrict conventional multispecific antibodies by imposing steric constraints that hinder target binding and stability. To overcome this, we engineered tetrahedral antibodies, a multispecific class that non-covalently self-assembles via two hinge-integrated collectrin-like domains (CLDs). This non-planar, tetrapartite architecture coordinates up to six unobstructed Fab, Fc, and extracellular domains. Parallel to the clinical translation of our dual-Fc anti-CD19/CD20 tetrahedral antibody for systemic lupus erythematosus (SLE), we evaluated an anti-SARS-CoV-2 candidate that exhibited in vivo efficacy in non-human primates. Furthermore, we demonstrate functional FcγR binding cooperativity across the dual-Fc domains of anti-CD19/CD20 tetrahedral antibodies, while introducing an interface disulfide bond into the CLD dimer increases structural stability as evidenced by effectively abolishing CLD dynamic dissociation and resolving the dissociation equilibrium into discrete, stable quaternary states. These findings establish tetrahedral architectures as a robust, translatable multispecific platform.
Authors: Daniel J. Capon, Larisa A. Troitskaya, Marina E. Fomin, Malcolm L. Gefter, Ursula Edman, Brendon Frank, Benjamin Z. Capon, Jing Jin, Rachel Martinelli, Ginger A. Ferguson, Ramona Vestweber, Cheila Rocha, Berit Roshani, Victor Corman, Christian Drosten, Nadine Krüger, Stefan Pöhlmann, Graham Simmons, Nelson L.S. Chan
Institutions: Vitalant Research Institute, Boise Bible College, Idaho Geological Survey, German Primate Center, Humboldt-Universität zu Berlin, German Center for Infection Research, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Freie Universität Berlin, Charité – Universitätsmedizin Berlin, University of Göttingen
Language: English
Subfield: Radiology, Nuclear Medicine and Imaging
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W4220688320