ABSTRACT
SARS-CoV-2, the virus responsible for COVID-19, has caused a global pandemic. Antibodies can be powerful biotherapeutics to fight viral infections. Here, we use the human apoferritin protomer as a modular subunit to drive oligomerization of antibody fragments and transform antibodies targeting SARS-CoV-2 into exceptionally potent neutralizers. Using this platform, half-maximal inhibitory concentration (IC50) values as low as 9 × 10-14 M are achieved as a result of up to 10,000-fold potency enhancements compared to corresponding IgGs. Combination of three different antibody specificities and the fragment crystallizable (Fc) domain on a single multivalent molecule conferred the ability to overcome viral sequence variability together with outstanding potency and IgG-like bioavailability. The MULTi-specific, multi-Affinity antiBODY (Multabody or MB) platform thus uniquely leverages binding avidity together with multi-specificity to deliver ultrapotent and broad neutralizers against SARS-CoV-2. The modularity of the platform also makes it relevant for rapid evaluation against other infectious diseases of global health importance. Neutralizing antibodies are a promising therapeutic for SARS-CoV-2.
Subject(s)
Antibodies, Monoclonal/pharmacology , Antibodies, Neutralizing/immunology , Antibodies, Viral/chemistry , SARS-CoV-2/immunology , Animals , Antibodies, Monoclonal/chemistry , Antibodies, Monoclonal/genetics , Antibodies, Monoclonal/immunology , Antibodies, Neutralizing/chemistry , Antibodies, Viral/immunology , Antibody Specificity , Apoferritins/chemistry , Biological Availability , Epitope Mapping , Humans , Immunoglobulin G/immunology , Male , Mice, Inbred BALB C , Mice, Inbred C57BL , Protein Engineering/methods , Protein Subunits/chemistry , Spike Glycoprotein, Coronavirus/immunology , Tissue DistributionABSTRACT
INTRODUCTION: Adjuvants are critical components of vaccines to improve the quality and durability of immune responses. Molecular adjuvants are a specific subclass of adjuvants where ligands of known immune-modulatory receptors are directly fused to an antigen. Co-stimulation of the B cell receptor (BCR) and immune-modulatory receptors through this strategy can augment downstream signaling to improve antibody titers and/or potency, and survival in challenge models. AREAS COVERED: C3d has been the most extensively studied molecular adjuvant and shown to improve immune responses to a number of antigens. Similarly, tumor necrosis superfamily ligands, such as BAFF and APRIL, as well as CD40, CD180, and immune complex ligands can also improve humoral immunity as molecular adjuvants. EXPERT OPINION: However, no single strategy has emerged that improves immune outcomes in all contexts. Thus, systematic exploration of molecular adjuvants that target B cell receptors will be required to realize their full potential as next-generation vaccine technologies.