A fibril-selective, IgG1-subclass anti-medin antibody targeting the cryptic C2-domain protofibril epitope in aged mic...
IF a conformation-selective, IgG1-subclass anti-medin monoclonal antibody engineered to bind a cryptic beta-sheet epitope within the C2-domain fibril core (residues 245–294 of MFG-E8) that is sterically occluded in soluble, monomeric MFG-E8 but fully exposed upon protofibrillar and fibrillar assembly — administered intravenously at 10 mg/kg biweekly for 6 months — is delivered to aged wild-type C57BL/6 mice (22–24 months, male and female),
THEN a ≥40% reduction in aortic medial medin aggregate burden (quantified by thioflavin-S histomorphometry and medin-specific ELISA of aortic lysate), a measurable decrease in pulse wave velocity (PWV; ≥15% reduction versus vehicle-aged controls), reduced endothelial oxidative stress (DHE fluorescence and nitric oxide bioavailability in aortic rings), and a secondary reduction in cerebral medin-seeded amyloid-β (Aβ) co-deposits in leptomeningeal vessels will be observed,
BECAUSE the following mechanistic chain is supported:
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Medin — a 50 amino acid fragment of MFG-E8 (residues 245–294) — accumulates as protease-resistant, insoluble extracellular aggregates in the aortic medial layer of aging wild-type mice, and these aggregates are absent in Mfge8 C2 knockout controls, establishing MFG-E8 as the obligate precursor and the C2-domain cleavage product as the pathogenic species (Medin aggregation and aortic amyloid in aging mice)[https://doi.org/10.1073/pnas.2011133117/-/DCSupplemental].
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Medin fibril deposition is mechanistically coupled to arterial stiffness and endothelial dysfunction; the aggregate-free vascular phenotype of Mfge8-deficient mice demonstrates that clearance of the amyloid species — not merely prevention of new deposition — is sufficient to protect vascular function, confirming that the accumulated aggregate is the damage unit requiring repair (Medin aggregation causes cerebrovascular dysfunction)[https://doi.org/10.1073/pnas.2011133117/-/DCSupplemental].
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Medin fibrils act as heterologous seeding templates for vascular Aβ aggregation via a cross-seeding mechanism; genetic deletion of Mfge8 in APP transgenic mice substantially reduces cerebral amyloid angiopathy load, establishing that clearance of peripheral medin deposits would disrupt an upstream driver of cerebrovascular Aβ pathology (Wagner et al., medin co-aggregates with vascular Aβ in AD)[https://doi.org/10.1038/s41586-022-05440-3].
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A conformation-selective IgG1 antibody targeting the fibril-exposed C2-domain epitope — analogous to the epitope-specificity design principle established for lecanemab's selectivity for Aβ protofibrils over monomeric APP — will bind medin aggregates with high affinity while exhibiting negligible affinity for soluble MFG-E8, thereby preserving MFG-E8's essential efferocytosis function (apoptotic cell clearance) and avoiding the functional autoimmunity that would result from indiscriminate MFG-E8 blockade (conformation-selective epitope strategy; WO2020161238A1)[https://doi.org/10.1073/pnas....
SENS category: GlycoSENS
Key references: • doi.org/10.1073/pnas.2011133117/-/DCSupplemental]. • doi.org/10.1038/s41586-022-05440-3]. • doi.org/10.1073/pnas.2011133117/-/DCSupplemental] • doi.org/10.1038/s41586-022-05440-3] • doi.org/10.1073/pnas.2011133117/-/DCSupplemental];