A conformation-specific, Fc-afucosylated anti-fibrillar medin antibody targeting cryptic cross-β epitopes clears age-...

IF a conformation-specific monoclonal antibody (anti-fibrillar medin mAb) engineered with afucosylated Fc for enhanced FcγRIII/FcγRIV engagement — targeting a cryptic cross-β spine epitope exposed exclusively on medin amyloid fibrils but sterically occluded in native MFG-E8 — is administered systemically (intraperitoneal or intravenous, 10–30 mg/kg, biweekly for 12 weeks) to aged (20–24 month) wild-type C57BL/6 mice (both sexes, representing the primary RMR2 target population with near-universal aortic medin burden),

THEN the following measurable outcomes will be observed:

1. ≥40% reduction in aortic medial medin amyloid burden (quantified by Congo red birefringence, anti-medin immunohistochemistry, and fibril density by cryo-EM of aortic sections)
2. ≥15% reduction in aortic pulse wave velocity (PWV), indicating restoration of medial elastic compliance
3. ≥20% improvement in endothelium-dependent vasodilation (acetylcholine-induced relaxation in ex vivo aortic ring assay)
4. Secondary reduction in cerebrovascular medin deposits and co-localised amyloid-β (Aβ) burden in cortical penetrating arterioles

BECAUSE the following causal chain operates:

1. Medin, a 50-amino acid fragment derived from the C2 domain of MFG-E8, accumulates as protease-resistant, insoluble extracellular amyloid fibrils in the tunica media of the aorta of virtually all humans over age 50, with deposits rising to 100% prevalence by the 9th decade — (medin present in ~97% of aged Caucasian aortas)[10.1073/pnas.96.15.8669]; (near-universal aortic accumulation confirmed histologically)[10.1038/labinvest.3780436]

2. These fibrils adopt a cross-β steric zipper conformation that buries residues present in native MFG-E8, thereby presenting fibril-specific epitopes accessible to a conformation-selective antibody without disrupting the efferocytosis function of full-length MFG-E8 — (steric zipper motifs within medin sequence identified as drivers of fibrillation)[10.1021/bi801276a] [SPECULATIVE: specific antibody epitope identity requires empirical mapping]

3. Systemically administered Fc-afucosylated anti-medin IgG reaches the adventitial-medial interface of large arteries, where FcγRIII/FcγRIV-expressing resident adventitial macrophages and recruited monocyte-derived phagocytes are activated by opsonised medin fibrils, initiating antibody-dependent cellular phagocytosis (ADCP) of the extracellular amyloid deposits — (proof-of-concept that anti-medin antibody administration reduces vascular medin deposits)[https://doi.org/10.1073/pnas.2011133117/-/DCSupplemental]; [SPECULATIVE: Fc-engineering enhancement of ADCP in aortic media has not been demonstrated for medin specifically; rationale drawn by analogy with lecanemab/anti-ATTR Fc-engineering literature cited in Evidence Set]

4. Removal of medin fibrils from the medial ECM relieves physical disruption of elastic lamellae, particularly the interaction with tropoelastin and fibrillin-1 that drives arteriosclerotic stiffening — (me...

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]