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

Chang Yi Wang; Pei-Ning Wang; Ming-Jang Chiu; Connie L Finstad; Feng Lin; Shugene Lynn; Yuan-Hung Tai; Xin De Fang; Kesheng Zhao; Chung-Ho Hung; Yiting Tseng; Wen-Jiun Peng; Jason Wang; Chih-Chieh Yu; Be-Sheng Kuo; Paul A Frohna

doi:10.1016/j.trci.2017.03.005

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

Alzheimers Dement (N Y). 2017 Apr 14;3(2):262-272. doi: 10.1016/j.trci.2017.03.005. eCollection 2017 Jun.

Authors

Chang Yi Wang^{1

2

3}, Pei-Ning Wang⁴, Ming-Jang Chiu⁵, Connie L Finstad¹, Feng Lin¹, Shugene Lynn², Yuan-Hung Tai², Xin De Fang¹, Kesheng Zhao¹, Chung-Ho Hung¹, Yiting Tseng³, Wen-Jiun Peng², Jason Wang², Chih-Chieh Yu³, Be-Sheng Kuo¹, Paul A Frohna³

Affiliations

¹ United Biomedical, Inc. (UBI), Hauppauge, NY, USA.
² United Biomedical Inc., Asia (UBI-Asia), Hsinchu, Taiwan.
³ United Neuroscience, Inc. (UNS), Hsinchu, Taiwan.
⁴ Department of Neurology, Taipei Veterans General Hospital, Taipei, Taiwan.
⁵ Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan.

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.

Associated data

ClinicalTrials.gov/NCT02551809