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

Abstract

IntroductionA 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.MethodsUB-311 is constructed with two synthetic Aβ1–14–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).ResultsUB-311 covers a diverse genetic background and facilitates strong immune response with high responder rate. UB-311 reduced the levels of Aβ1–42 oligomers, protofibrils, and plaque load in hAPP751 transgenic mice. Safe and well-tolerated UB-311 generated considerable site-specific (Aβ1–10) 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.DiscussionThe 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).

AJP001, a novel helper T‐cell epitope, induces a humoral immune response with activation of innate immunity when included in a peptide vaccine

“…1 For clinical application, chimeric peptide vaccines composed of a B-cell epitope and T-cell epitope have been developed instead of vaccines including large carrier proteins. 2 In this study, AJP001 showed a strong affinity for the haplotype of BALB/cA mice, and the antibody-producing efficiency of the AJP001 conjugate vaccine correlated with its affinity. In addition, binding affinity for human HLA-DR was predicted, and AJP001 revealed a strong binding affinity for HLA-DR alleles that are frequently found in the Japanese population (data not shown).…”

“…These B‐cell‐type peptide vaccines are required to be conjugated to large carrier proteins such as KLH . For clinical application, chimeric peptide vaccines composed of a B‐cell epitope and T‐cell epitope have been developed instead of vaccines including large carrier proteins . In this study, AJP001 showed a strong affinity for the haplotype of BALB/cA mice, and the antibody‐producing efficiency of the AJP001 conjugate vaccine correlated with its affinity.…”

“…However, this approach is fraught with difficulties in controlling the uniformity of the coupling process and provoking undesirable immune responses such as allergy and anaphylaxis. In recent years, chimeric peptide vaccines composed of B‐cell epitopes and T‐cell epitopes have been developed and studied in clinical trials to evaluate the effectiveness of these vaccines . In this strategy, the T‐cell epitope is MHC class II restricted; hence, it should be promiscuous or universal, allowing broad population coverage, and is required to include a helper T‐cell epitope to elicit specific T cells and humoral responses.…”

“…In recent years, chimeric peptide vaccines composed of B-cell epitopes and T-cell epitopes have been developed and studied in clinical trials to evaluate the effectiveness of these vaccines. [2][3][4] In this strategy, the T-cell epitope is MHC class II restricted; hence, it should be promiscuous or universal, allowing broad population coverage, and is required to include a helper T-cell epitope to elicit specific T cells and humoral responses. Furthermore, to efficiently induce antibody production via T-cell activation by vaccines, cotreatment with adjuvants contributes to the activation of an innate immune response to break down immune tolerance through the activation of Toll-Like Receptors (TLRs), Retinoic acid-Inducible Gene-I (RIG-I), or inflammasomes.…”

Membrane Active Peptides and Their Biophysical Characterization

“…Our group has also been focusing on combining the inhibitory properties of inhibitor peptides with CPPs [362]. Peptide vaccines (reviewed by Baig et al [363] have also gained interest in the immunotherapy of different types of cancer [364] such as breast cancer [365,366] or lung cancer [367], virally mediated diseases such as influenza [368], HPV [369,370], HIV and neurodegenerative diseases [363] such as Alzheimer's [371]. These peptide vaccines are frequently delivered as emulsions with adjuvants [372] to facilitate uptake across the membrane.…”