UB-311, a novel UBITh® amyloid β peptide vaccine for mild Alzheimer's disease Alzheimer's & Dementia: Translational Research & Clinical Interventions 3 (2017) 262-272
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 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). Results UB-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. 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).
Introduction The amyloid β (Aβ) peptide, central to the "Amyloid Cascade Hypothesis," is thought to be the pivot for the onset and progression of Alzheimer's disease (AD), and the toxic forms of oligomers and fibrils are suggested to be responsible for the death of synapses and neurons that leads the pathology of AD and dementia [[1], [2]]. Although recent findings may suggest a dual protective/damaging role for Aβ peptides in AD pathology [[3], [4]], a successful disease-modifying therapy for AD will include products that affect the disposition of Aβ in the brain [5], in which the immunotherapeutic strategy has drawn much attention since the first active immunotherapy was investigated in mice in 1999 [6]. AN-1792 vaccine [[7], [8]], using aggregated full-length Aβ1–42 peptide as immunogen associated with a Th1 adjuvant (QS-21; saponin), was the first immunotherapy tested in AD patients, which generated anti-Aβ antibody responses in <25% of patients with improved memory and decreased level of tau protein in the cerebral spinal fluid of a small subset of patients [[7], [8]], thus providing encouraging results for development of new Aβ vaccines. AN-1792 was discontinued because of acute meningoencephalitis symptoms in 6% of patients, likely caused by autoreactive T-cell activation and Aβ-reactive T-cell infiltration into the central nervous system [7]. Several second-generation Aβ-targeting vaccines were subsequently designed to minimize Aβ-related T-cell inflammation. These include the following: ACC-001 using Aβ1–7 peptide conjugated to diphtheria toxoid protein [9], CAD106 using Aβ1–6 peptide coupled to Qβ virus-like particle [10], V950 using multivalent Aβ1–15 conjugated to a carrier unknown [11], and affitopes AD01 and AD02 using Aβ mimetics (six amino acids) conjugated to KLH [12]. These vaccines induced variable anti-Aβ antibody titers and responder rates, with most of the immune response directed toward the large carrier molecules. To date, these and related vaccines have not presented convincing clinical efficacy data [13]. Development of AD02, ACC-001, and V950 vaccines have been discontinued for reasons unclear [14]. CAD106, currently in clinical phase-III trial, has completed two phase-II trials reporting acceptable safety and tolerability and evoking a strong serological responses in 80% of patients, and brain PET imaging was suggestive of target engagement [[15], [16]]. Aβ is the principal target of late-stage development programs with relatively few agents in clinical trials for AD, suggesting a need to amplify the drug discovery ecosystem [17]. We describe in this report a novel design of the UBITh® platform-based, fully synthetic Aβ1–14 peptide vaccine (UB-311), preclinical characterization, and a first-in-human (FIH) phase-I clinical study which enrolled 19 patients with mild-to-moderate AD. UB-311 comprises two Aβ1–14–targeting peptides (B-cell epitopes), each linked to different helper T-cell peptide epitopes (UBITh®) as a chimeric peptide to maximize immunogenicity, which is formulated in a Th2-biased delivery system to minimize T-cell inflammatory reactivity. The UB-311 vaccine was safe and well-tolerated, generating strong site-specific (Aβ1–10) antibodies in all patients. Of note, a subgroup of mild AD patients (Mini–Mental State Examination [MMSE] ≥20) showed a positive trend toward cognition improvement.
Posts
No comments:
Post a Comment