9arv
CryoEM structure of AMETA-A3
Structural highlights
DiseaseIGHM_HUMAN Autosomal agammaglobulinemia. The disease is caused by mutations affecting the gene represented in this entry.[1] FunctionIGHM_HUMAN IgM antibodies play an important role in primary defense mechanisms. They have been shown to be involved in early recognition of external invaders like bacteria and viruses, cellular waste and modified self, as well as in recognition and elimination of precancerous and cancerous lesions. The membrane-bound form is found in the majority of normal B-cells alongside with IgD. Membrane-bound IgM induces the phosphorylation of CD79A and CD79B by the Src family of protein tyrosine kinases. It may cause death of cells by apoptosis. It is also found in soluble form, which represents about 30% of the total serum immunoglobulins where it is found almost exclusively as a homopentamer. After the antigen binds to the B-cell receptor, the secreted form is secreted in large amounts.[2] Publication Abstract from PubMedPathogens constantly evolve and can develop mutations that evade host immunity and treatment. Addressing these escape mechanisms requires targeting evolutionarily conserved vulnerabilities, as mutations in these regions often impose fitness costs. We introduce adaptive multi-epitope targeting with enhanced avidity (AMETA), a modular and multivalent nanobody platform that conjugates potent bispecific nanobodies to a human immunoglobulin M (IgM) scaffold. AMETA can display 20+ nanobodies, enabling superior avidity binding to multiple conserved and neutralizing epitopes. By leveraging multi-epitope SARS-CoV-2 nanobodies and structure-guided design, AMETA constructs exponentially enhance antiviral potency, surpassing monomeric nanobodies by over a million-fold. These constructs demonstrate ultrapotent, broad, and durable efficacy against pathogenic sarbecoviruses, including Omicron sublineages, with robust preclinical results. Structural analysis through cryoelectron microscopy and modeling has uncovered multiple antiviral mechanisms within a single construct. At picomolar to nanomolar concentrations, AMETA efficiently induces inter-spike and inter-virus cross-linking, promoting spike post-fusion and striking viral disarmament. AMETA's modularity enables rapid, cost-effective production and adaptation to evolving pathogens. Adaptive multi-epitope targeting and avidity-enhanced nanobody platform for ultrapotent, durable antiviral therapy.,Xiang Y, Xu J, McGovern BL, Ranzenigo A, Huang W, Sang Z, Shen J, Diaz-Tapia R, Pham ND, Teunissen AJP, Rodriguez ML, Benjamin J, Taylor DJ, van Leent MMT, White KM, Garcia-Sastre A, Zhang P, Shi Y Cell. 2024 Oct 21:S0092-8674(24)01143-7. doi: 10.1016/j.cell.2024.09.043. PMID:39447570[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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