Preclinical efficacy of an APOE targeted antibody for Alzheimer's disease

ABSTRACT We propose to challenge Alzheimer’s disease (AD) by modulating the interaction between Apolipoprotein E (ApoE) and glycosaminoglycans (GAGs) using therapeutic humanized antibodies. The founders of Epoch Biotech identified an individual that remained cognitively unimpaired until her seventies despite carrying a Presenilin-1 (PSEN1) mutation known to cause AD-related cognitive impairment at a median age of 44 years in the world’s largest population with autosomal dominant AD (ADAD) including over 1,200 PSEN1 mutation carriers. Clinical and positron emission tomography (PET) imaging studies of this subject showed extremely high amyloid but lower than expected for age tau burden and neurodegeneration. A comprehensive genetic analysis of this individual uncovered a homozygote rare variant in ApoE3 (R136S, traditionally known as the Christchurch variant) as the variant associated with the resistance to AD in this subject. Subsequently, our team and others have shown that the protective effect of the Christchurch mutation is generalizable to the broader population of patients with the ApoE4 risk variant. GAGs have been suggested to promote Aβ aggregation and neuronal uptake of extracellular tau; and ApoE binding may be necessary for some of these effects. The team at Schepens Eye Research Institute of Mass Eye and Ear (SERI/MEE) discovered that ApoE3Ch displayed a dramatic reduction in GAG binding ability with heparin when compared to other ApoE isoforms. SERI/MEE then developed an ApoE-targeted antibody (7C11) that binds to the region of ApoE corresponding to the Christchurch mutation that can mimic the effects of ApoECh in reducing GAG binding and the phosphorylation of tau. There is an urgent need for novel therapeutic options in the wake of the recent news that Aduhelm has now been discontinued and the reports of limited efficacy of Leqembi for slowing cognitive decline. Epoch Biotech was formed to commercialize the 7C11 antibody and capitalize on this approach as an entirely novel way to treat AD. In this Phase I STTR application, Epoch Biotech and SERI/MEEI propose to 1) characterize pharmacokinetics (PK) and biodistribution properties of humanized 7C11 and 2) test the preclinical efficacy of humanized 7C11 in a mouse model of tauopathy. Our goal is to demonstrate the feasibility of the humanized 7C11 antibody in preventing ApoE4/GAG interactions and reducing pTau levels, distinguishing it from current therapeutic approaches. In Phase II, we will commence IND-enabling toxicology studies in preparation for a Phase 1 clinical trial.