Safety/Tolerability/Immunogenicity of first-in-human Aβ DNA vaccine, AV-1959D Phase 1 trials in early-stage AD subjects: based on IND18953 cleared by FDA.

首个人类 Aβ DNA 疫苗的安全性/耐受性/免疫原性，AV-1959D 在早期 AD 受试者中的 1 期试验：基于 FDA 批准的 IND18953。

• 批准号: 10340654
• 负责人: Michael G Agadjanyan
• 金额: $ 268.07万
• 依托单位: INSTITUTE FOR MOLECULAR MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-15 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10340654
• 关键词: AN-1792; Aducanumab; Adverse event; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Antibodies; Antibody Formation; Antibody titer measurement; Attenuated; B-Lymphocyte Epitopes; B-Lymphocytes; Binding; Biological Markers; Blood; Brain; Clinical; Clinical Data; Clinical Trials; Control Groups; DNA Vaccines; Data; Detection; Disease; Dose; Double-Blind Method; Early Intervention; Elderly; Enzyme-Linked Immunosorbent Assay; Epitopes; Ethics; Future; Genetic Polymorphism; Goals; Helper-Inducer T-Lymphocyte; Hepatitis B; Human; Immune response; Immunize; Immunotherapeutic agent; Immunotherapy; Impaired cognition; Inflammation; Influenza; Injections; Interferon Type II; Laboratories; MHC Class II Genes; Measures; Memory; Methods; Monkeys; Monoclonal Antibodies; Nucleic Acids; Oryctolagus cuniculus; PADRE 45; Participant; Passive Immunotherapy; Pathologic; Pathologic Processes; Pathology; Patients; Peptides; Peripheral Blood Mononuclear Cell; Persons; Phase; Physical Examination; Placebo Control; Placebos; Positron-Emission Tomography; Preparation; Preventive; Preventive measure; Preventive treatment; Preventive vaccine; Publishing; Randomized; Reporting; Risk; Safety; Self Tolerance; Senile Plaques; Serum; Target Populations; Test Result; Testing; Tetanus Toxin; Therapeutic; Time; U-Series Cooperative Agreements; Vaccinated; Vaccination; Vaccine Clinical Trial; Vaccinee; Vaccines; active method; autoreactivity; base; cognitive function; cost; cost effective; design; enzyme linked immunospot assay; first-in-human; follow-up; human monoclonal antibodies; immunogenic; immunogenicity; immunosenescence; intravenous injection; meetings; mouse model; multidisciplinary; non-demented; novel marker; older patient; patient population; peptide B; peripheral blood; phase 1 study; phase I trial; prevent; primary outcome; programs; prophylactic; response; retinal S antigen peptide M; safety testing; secondary outcome; synthetic peptide; tau Proteins; tau aggregation; treatment arm; vaccine evaluation; vaccine strategy; vaccine trial

Project Summary Recent data from clinical trials with humanized or fully human mAbs targeting Aβ suggest that immunotherapy could clear/reduce brain amyloid plaques and even slow cognitive decline in vaccinated subjects when initiated as a preventive measure. However, passive immunotherapy with even the most effective anti-Aβ mAb is not practical and cost-effective as a preventive measure in healthy subjects due to the need for frequent (monthly) administrations of high concentrations (~800mg IV injections/each time) of this immunotherapeutic in a substantial patient population. At the same time, high doses of mAb frequently (~30%) induce ARIA-E and ARIA- H. In contrast, AD vaccine, similar to the vast majority of vaccines in general, could be very effective when used as a preventive/early intervention measure. Today, only limited results are available from ACC001, CAD106, and UB311 epitope vaccine clinical trials, but fortunately, comprehensive data on AN-1792 are published. These data demonstrated that the AN-1792 vaccine has induced antibodies specific to N-terminus of amyloid in ~19% immunized AD patients without causing ARIA-E and ARIA-H abnormalities. Importantly the follow-up analysis revealed that even after 14 years post-vaccination, the vaccinated subjects were plaque-free, and there was a significant inverse correlation between peripheral blood anti-Aβ antibody titers and the plaque counts. Despite the reduction of Aβ pathology, vaccination did not improve cognitive functions likely due to tau pathology buildup. These data support our long-standing proposal of starting anti-Aβ vaccination with AV-1959D as a prophylactic measure in subjects at risk for AD to inhibit/reduce oligomerization of Aβ and delay downstream pathological processes. However, based on an ethical imperative raised by the FDA during our pre-IND meeting, they recommended us to test our Aβ vaccine AV-1959D in participants with early-stage AD patients prior to initiating the preventive trials in asymptomatic people at risk of MCI/AD. Therefore, here we propose to initiate a Phase 1 safety trial with the first-in-human Aβ DNA vaccine, AV-1959D in early-stage MCI/AD patients based on FDA cleared IND18953 developed under an NIA cooperative agreement (U01 AG048310). Importantly, our vaccine strategy differs from all previous or current vaccines tested in clinical trials, as our approach is based on the very immunogenic and proprietary MultiTEP platform designed for human use and aimed to (i) overcome self- tolerance by inducing Th cell responses to MultiTEP, but not to self-Aβ epitopes; (ii) diminish variability of immune responses due to HLA diversity in humans; (iii) augment anti-Aβ antibody production through activation of both naïve and pre-existing memory Th cells, especially beneficial for elderly patients with immunosenescence. Therefore, in Phase 1 trials, the first-in-human MultiTEP-based DNA vaccine targeting Aβ1-11 B cell epitope should be safe and should induce therapeutically sufficient titers of anti-Aβ antibodies in an appreciable number of vaccinated early stage AD subjects. Our future program includes preventive vaccine trial in asymptomatic people at risk of MCI/AD using only the most immunogenic and safe dose of AV-1959D.

项目总结