UB-311, a novel UBITh® amyloid β peptide vaccine for mild Alzheimer's disease

Abstract

Introduction: A novel amyloid β (Aβ) synthetic peptide vaccine (UB-311) has been evaluated in a first-in-human trial with patients of mild-to-moderate Alzheimer's disease. We describe translational research covering vaccine design, preclinical characterization, and phase-I clinical trial with supportive outcome that advances UB-311 into an ongoing phase-II trial.

Methods: UB-311 is constructed with two synthetic Aβ_1-14-targeting peptides (B-cell epitope), each linked to different helper T-cell peptide epitopes (UBITh^®) and formulated in a Th2-biased delivery system. The hAPP751 transgenic mouse model was used to perform the proof-of-concept study. Baboons and macaques were used for preclinical safety, tolerability, and immunogenicity evaluation. Patients with mild-to-moderate Alzheimer's disease (AD) were immunized by intramuscular route with 3 doses of UB-311 at weeks 0, 4, and 12, and monitored until week 48. Safety and immunogenicity were assessed per protocol, and preliminary efficacy was analyzed by Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), Mini-Mental State Examination (MMSE), and Alzheimer's Disease Cooperative Study-Clinician's Global Impression of Change (ADCS-CGIC).

Results: UB-311 covers a diverse genetic background and facilitates strong immune response with high responder rate. UB-311 reduced the levels of Aβ_1-42 oligomers, protofibrils, and plaque load in hAPP751 transgenic mice. Safe and well-tolerated UB-311 generated considerable site-specific (Aβ_1-10) antibodies across all animal species examined. In AD patients, UB-311 induced a 100% responder rate; injection site swelling and agitation were the most common adverse events (4/19 each). A slower rate of increase in ADAS-Cog from baseline to week 48 was observed in the subgroup of mild AD patients (MMSE ≥ 20) compared with the moderate AD subgroup, suggesting that UB-311 may have a potential of cognition improvement in patients with early stage of Alzheimer's dementia.

Discussion: The UBITh^® platform can generate a high-precision molecular vaccine with high responder rate, strong on-target immunogenicity, and a potential of cognition improvement, which support UB-311 for active immunotherapy in early-to-mild AD patients currently enrolled in a phase-II trial (NCT02551809).

Keywords: Alzheimer's disease; Amyloid β vaccine; FIH clinical trial; UB-311; UBITh® platform.

Fig. 1

Patient disposition and study design. The first-in-human (FIH) clinical trial enrolled 19 patients (50–80 years old) with mild-to-moderate Alzheimer's disease in a 24-week interventional study, and all 19 subjects received three UB-311 vaccine doses by intramuscular injection (300-μg immunogen peptide) at 0, 4, and 12 weeks and completed the treatment study (identifier no.: NCT00965588). After the first five subjects passed the safety evaluation at week 48, the remaining 14 subjects enrolled in and completed a 24-week observational extension study added to the end of the interventional study to monitor long-term safety, tolerability, immunogenicity, and efficacy (identifier no.: NCT01189084).

Fig. 2

Serum anti-Aβ antibody titers assayed by ELISA and preferable targeted Aβ species visualized by dot plot after UB-311 immunization in AD patients. (A) Mean antibody response during the 24-week interventional study (solid line) in 19 AD patients treated with UB-311; 14 of 19 patients (dashed line) were followed up in an additional 24-week observational study, whose mean ADAS-Cog score was 4.9 (improvement). The mean baseline titer (pretreatment) was 1.0 log₁₀; and 4 weeks after last vaccine boost at week 16, the titer peaked at 2.7 log₁₀ (range: 1.8–3.7 log₁₀). At week 48, all patients had decreasing but still positive antibody titers, measured by Aβ_1–28 ELISA test. At week 16, serum samples recognized Aβ_1–42 monomers (B) and oligomers (C); preimmune serum samples collected at week 0 had anti-Aβ_1–42 antibody levels below quantification limit (not shown on log scale), except subjects P109 (monomer) and P108 (oligomer). (D) At week 16, analysis of serum dot plot (left panel), flanked by the positive control 6E10 mAb, reveals that the vaccine-induced anti-Aβ antibodies bind preferentially to Aβ fibrils, followed by oligomers, and the least to monomers; the densitometric measures (right panel) for the three Aβ species are the mean scales from three representative AD subjects, P105, P108, and P206. Abbreviations: AD, Alzheimer's disease; ADAS-Cog, Alzheimer's Disease Assessment Scale–Cognitive Subscale; ELISA, enzyme-linked immunosorbent assay.

Fig. 3

Mean change over time in ADAS-Cog and MMSE scores by age, MMSE at baseline, or gender. For assessment of ADAS-cog and MMSE scores, UB-311-treated patients were stratified by (A and D) age in years (<60 and ≥60), (B and E) MMSE score (<20 and ≥ 20), or (C and F) gender (male and female). A positive change from baseline in ADAS-Cog score represents cognitive deterioration. For MMSE, a negative change indicates deterioration. Error bars are standard error. (B) MMSE score (<20 and ≥20); *P < .0002 for the difference in the rate of disease progression. Abbreviations: ADAS-Cog, Alzheimer's Disease Assessment Scale–Cognitive Subscale; MMSE, Mini–Mental State Examination.