To evaluate in vivo efficacy of nonclinical surrogate PRX123 (PRX123s) – a dual amyloid beta (Aβ)/tau peptide vaccine against the N-terminus of Aβ and MTBR-tau – in a transgenic mouse model expressing human amyloid precursor protein (APP) and with aggressively high Aβ pathology.

Accumulation of Aβ plaque and tau tangles throughout the brain are hallmarks of Alzheimer’s disease (AD). Clinical evidence demonstrates that N-terminal anti-Aβ antibodies capable of robustly reducing Aβ plaques in the brains of patients with AD can slow cognitive decline. Nonclinical evidence indicates that anti-MTBR-tau antibodies can potentially suppress the pathogenic spatiotemporal spread of tau. It is therefore hypothesized that simultaneously disrupting these pathologic processes may increase therapeutic benefit beyond removal of Aβ plaques alone. Vaccines that target Aβ and tau may prevent or delay the clinical manifestation of AD by generating long-term polyclonal responses capable of intercepting both pathologic processes simultaneously. In in vitro studies, PRX123 generated robust immunogenic responses, producing antibodies that promote clearance of Aβ plaques and neutralization of MTBR-tau.

APP/PS1 (Thy1-hAPP*V717I/Thy1-hPS1*A246E) transgenic mice were vaccinated with PRX123s, beginning at 3.5 months old for 6 months.

PRX123s generated robust antibody titers capable of binding structural features indicative of Aβ plaques and tau tangles in post-mortem AD brain tissue at antibody concentrations expected to be reached in the brain (0.3% of plasma concentrations). Immunohistochemical analysis of brain tissue from vaccinated APP/PS1 mice demonstrated significant reduction in cortical Aβ plaques compared with a nonsense peptide control group. The degree of plaque clearance achieved with PRX123s immunization was similar to a plaque-clearing N-terminal monoclonal antibody, used as positive control.

These data demonstrate that PRX123 may generate high-quality antibody responses capable of clearing Aβ plaques at brain exposures that may be achievable in patients and support the continued development of PRX123 for the treatment and/or prevention of AD.