MAb S309 for COVID-19

MAb S309 may be beneficial for COVID-19 according to the studies below. COVID-19 involves the interplay of 500+ viral and host proteins and factors providing many therapeutic targets. Scientists have proposed 11,000+ potential treatments. c19early.org analyzes 210+ treatments. We have not reviewed mAb S309 in detail.
Mackin et al., Fc-engineered antibodies enhance protection against SARS-CoV-2 lung infection and inflammation, mBio, doi:10.1128/mbio.00557-26
ABSTRACT As the SARS-CoV-2 pandemic progressed, many monoclonal antibodies (mAbs) that neutralized infection against initial strains lost potency against later variants due to the accumulation of mutations in the spike protein. Nonetheless, some mAbs, including the parent of the therapeutically used sotrovimab, S309, remained protective in animals against Omicron variants despite reduced neutralizing potential, with inhibitory activity likely sustained by Fc-mediated effector functions. Here, we identify Fc variants of S309 that confer enhanced protection against SARS-CoV-2 infection in a humanized Fcγ receptor transgenic (Hu-FcγR Tg) mouse model of infection. Versions of S309 that are afucosylated (AFUC) and contain a G236A (GA) mutation in the Fc region showed increased binding to FcγRs IIA, IIIA, and IIIB and enhanced phagocytic activity in cell culture-based assays. Treatment with S309-GA-AFUC resulted in less viral burden, inflammation, and pulmonary ventilatory dysfunction in the lungs of Hu-FcγR Tg mice challenged with SARS-CoV-2 strains compared to the parental S309 mAb or a variant lacking Fc effector functions (S309-GRLR). The enhanced protection in the lung conferred by S309-GA-AFUC required trafficking of CCR2-expressing monocytes to reduce SARS-CoV-2 viral burden and lung injury. Flow cytometry and RNA sequencing analyses showed that compared to the parental S309 mAb, S309-GA-AFUC treatment reduced the inflammatory state and induced a reparative transcriptional signature in monocytes and interstitial macrophages. Overall, our findings demonstrate that Fc engineering to increase antibody binding to activating FcγRs can strengthen effector functions, shape myeloid transcriptional profiles, and enhance protection against SARS-CoV-2 infection in vivo . IMPORTANCE Although therapeutic antibodies had success in protecting vulnerable individuals from severe COVID-19 during the early stages of the pandemic, many lost effectiveness as SARS-CoV-2 accumulated mutations that compromised neutralizing activity. Our experiments show that antibody protection against SARS-CoV-2 strains can be enhanced by genetically engineering the Fc region or altering its N-linked glycosylation to improve interactions with FcγRs on host immune cells. Modified versions of S309, the parent of the clinically used sotrovimab antibody, more effectively reduce viral burden and inflammation in the lung and shape protective transcriptional responses, which, together, result in improved lung ventilatory function and outcome after SARS-CoV-2 infection. Thus, antibody engineering can serve as a strategy to enhance therapeutic activity against rapidly evolving viruses with the potential to escape neutralization.
Alshahrani et al., Frustration Landscapes of Broadly Neutralizing SARS-CoV-2 Spike Antibodies Targeting Conserved Epitopes Reveal Energetic Logic of Escape-Proof and Escape-Prone Mechanisms, bioRxiv, doi:10.64898/2026.04.02.716254
Abstract The continued evolution of SARS-CoV-2 has enabled escape from most monoclonal antibodies, yet a subset of broadly neutralizing antibodies targeting three newly identified super-conserved RBD epitopes—SCORE-A, SCORE-B, and SCORE-C—retains remarkable activity against even the most recent JN.1-derived sublineages. Here we employed an integrated computational framework combining conformational dynamics, mutational scanning, MM-GBSA binding energetics, and frustration profiling to dissect the molecular mechanisms by which XGI antibodies achieve broad neutralization and resistance to immune escape. Structural analysis revealed that all three SCORE epitopes share a common architecture: a highly conserved, minimally frustrated core that provides stable anchoring, flanked by peripheral regions that accommodate antibody-specific variations. Conformational dynamics showed that SCORE-A antibodies (XGI-183) rigidify the lateral epitope while leaving the RBM partially mobile; SCORE-B antibodies (XGI-198, XGI-203) clamp the RBM apex, directly blocking ACE2; and SCORE-C antibodies (XGI-171) allosterically loosen the RBM loop, impairing receptor engagement indirectly. Mutational scanning identified a hierarchical hotspot organization where primary hotspots (e.g., K356, T500, Y380, T385) are evolutionarily constrained and minimally frustrated, while secondary hotspots (e.g., V503, Y508, S383) are neutrally frustrated and represent the principal sites of immune-driven mutations. MM-GBSA decomposition revealed that van der Waals-driven hydrophobic packing dominates binding, with electrostatic interactions providing auxiliary stabilization. Critically, frustration analysis demonstrated that immune escape hotspots reside precisely in zones of neutral frustration—“energetic playgrounds” that permit mutational exploration without destabilizing the RBD—while minimally frustrated cores are evolutionarily locked. The comparative analysis of conformational versus mutational frustration distributions revealed a unifying principle: aligned neutral frustration yields permissive, escape-prone interfaces; decoupling enables targeting of constrained cores; and convergence of minimal frustration in both distributions creates invulnerable interfaces. These findings establish that broad neutralization arises not from ultra-high-affinity anchors but from strategic energy distribution across rigid, evolutionarily informed interfaces, providing a roadmap for designing next-generation therapeutics that target the invulnerable cores of viral surface proteins.