IF a conformation-selective anti-medin IgG1 monoclonal antibody — engineered with an Fc region bearing GASDALIE (S239D/A330L/I332E) mutations to enhance FcγRIII/FcγRIV engagement approximately 10-fold over wild-type IgG1 — and raised against a neo-epitope within the medin fibril surface (residues within the 245–294 fragment that are sterically buried within the C2 domain of native MFG-E8 but become surface-exposed only upon proteolytic release and fibrillization) is administered systemically (intraperitoneal injection, 10 mg/kg biweekly) to aged (20–22 month), male and female C57BL/6 wild-type mice carrying established aortic medial medin amyloid,

THEN the following will be observed after 24 weeks of treatment compared to age-matched vehicle-treated controls:

• ≥25% reduction in fibrillar medin burden within thoracic aorta sections (assessed by quantitative thioflavin-S histomorphometry and anti-medin immunofluorescence)
• ≥15% reduction in aortic pulse wave velocity (PWV, a direct measure of arterial stiffness)
• ≥20% reduction in co-deposited vascular amyloid-β (Aβ) in the cerebral vasculature (measured by anti-Aβ immunohistochemistry in cortical sections)
• Increased CD68⁺/CD206⁺ macrophage infiltration into the aortic medial layer, consistent with antibody-dependent cellular phagocytosis (ADCP) as the primary clearance mechanism

BECAUSE the following causal chain is supported mechanistically:

1. Medin (the 50-amino acid, 5.5 kDa C2-domain fragment of MFG-E8) accumulates in the internal elastic lamina of the aged aortic media as protease-resistant, insoluble extracellular amyloid fibrils in aged wild-type mice, morphologically confirmed by immuno-EM localization of MFG-E8 immunoreactivity to extracellular aggregates in aged but not young WT aorta (Medin aggregation causes cerebrovascular dysfunction in aging wild-type mice)[https://doi.org/10.1073/pnas.2011133117/-/DCSupplemental].

2. Fibrillization of medin structurally exposes a neo-epitope that is buried within the C2 domain of intact, circulating MFG-E8, analogous to the cryptic epitope mechanism of CAEL-101 (11-1F4) in AL amyloidosis, where the antibody exclusively recognizes immunoglobulin light chain in its misfolded, fibrillar conformation while sparing native immunoglobulin — a principle confirmed clinically to permit selective engagement without catastrophic on-target clearance of functional precursor protein (Edwards et al., Blood, 2016, cited in Evidence Set). An anti-medin antibody designed on this principle would exhibit a strong safety advantage over any strategy that inadvertently targets full-length MFG-E8, which is essential for efferocytosis and vascular homeostasis.

3. Medin fibrils exhibit a unique polypeptide fold under cryo-EM distinct from other amyloids (Fändrich et al., Nature Communications, 2021, cited in Evidence Set), and avidity-driven bivalent binding to the repetitive epitope array displayed along the fibril surface — the same principle underpinning lecane...

SENS category: GlycoSENS

Key references: • doi.org/10.1073/pnas.2011133117/-/DCSupplemental]. • doi.org/10.1073/pnas.2011133117/-/DCSupplemental] • doi.org/10.1073/pnas.2011133117/-/DCSupplemental];