Targeted Lymphoablation as an alternative to HSCT to cure T1D

项目摘要 由于胰岛素是1型糖尿病（T1 D）的唯一获批治疗方法， 儿童和成人患者需要明确的治愈方法。在美国，糖尿病目前影响14%的 所有年龄段的人口，它是第七大死亡原因，估计每年花费2370亿美元。 年，医疗系统。医学界已经认识到T1 D是一种自身免疫性疾病， 提出了不同的免疫治疗方法，然而，只有造血干细胞， 迄今为止，在用毒性化疗重置免疫系统后，HSCT显示出暂时的 恢复胰岛素的独立性。抗原特异性免疫疗法（Teplizumab）提供了部分 只有5-6%的患者显示出两年的胰岛素依赖性。AVM生物技术 (AVM)正在开发一种基于新型免疫调节制剂（AVM 0703）的T1 D新方法， 动员“增压”自然杀伤T细胞，安全清除自身反应性淋巴细胞， T1D I期活动的结果表明，AVM 0703单独给药可预防45%的糖尿病，或 在T1 D的NOD模型中，55%的小鼠的发病延迟20-31周。AVM 0703可能代表一个安全的 基于临床前小鼠数据，50%的患者可以选择独立的治疗方案， 胰岛素独立性窗口期为3-30年。如果复发，AVM 0703的安全性特征将允许 重复给药多达8次，目前FDA批准用于正在进行的复发性难治性 淋巴恶性肿瘤（NCT 04329728）。对于未显示缓解的患者，预计AVM 0703将加强 其他免疫疗法允许更广泛的T1 D患者实现胰岛素依赖性，例如， 与Teplizumab（抗CD 3）联合治疗。该SBIR第二阶段项目被设计为 随机、安慰剂对照的多中心临床前试验，以获得可靠的数据， AVM 0703和潜在伴随药物（如Teplizumab）的毒理学信息将加快IND 批准并为临床试验铺平道路。目标1中的活动旨在进行临床前给药- NOD小鼠在三种情况下的发现和作用机制研究：糖尿病前期、新发和已建立 糖尿病目标1的结果将用于确定关键疗效中使用的AVM 0703剂量 逆转新发糖尿病和已确诊糖尿病的研究，目的2和3。IND申请将 在项目结束时提交。

PROJECT SUMMARY With insulin being the only approved treatment of Type 1 Diabetes (T1D), there is a very large unmet medical need for a definitive cure for pediatric and adult patients. In the U.S., diabetes currently affects 14% of the population of all ages, and it is the seventh leading cause of death, with an estimated cost of $237 billion every year to the healthcare system. The medical community has recognized T1D as an autoimmune disease and proposed different immunotherapeutic approaches to cure it. However, only hematopoietic stem cell transplantation (HSCT) after reset of the immune system with toxic chemotherapy, has so far shown temporary restoration of insulin independence. Antigen-specific immunotherapies (Teplizumab) are offering partial therapeutic benefits with only 5-6% of the patients showing two-year insulin independence. AVM Biotechnology (AVM) is developing a new approach for T1D based on a novel immunomodulatory formulation (AVM0703) that mobilizes “Supercharged” Natural Killer T-Cells for safe removal of autoreactive lymphocytes responsible for T1D. Results from Phase I activities show that AVM0703 administered alone can prevent diabetes in 45%, or delay its onset by 20-31 weeks in 55% of mice in the NOD model of T1D. AVM0703 may represent a safe standalone curative option for 50% of the patients based on preclinical mouse data, providing them an expected window of insulin independence of 3-30 years. In case of relapse, the safety profile of AVM0703 will allow repetitive dosing up to 8 times as currently approved by the FDA for an ongoing clinical trial in relapsed refractory lymphoid malignancies (NCT04329728). For patients not showing remission, AVM0703 is expected to reinforce other immunotherapies allowing a wider range of T1D patients to achieve insulin independence, for instance, combinatorial therapy with Teplizumab (anti-CD3). This SBIR Phase II project has been designed as a randomized, placebo-controlled multi-center pre-clinical trial to obtain solid data which, with the already available toxicology information for AVM0703 and potential companion agents such as Teplizumab, will expedite IND approval and pave the way to clinical trials. Activities in Aim 1 will be directed to perform a pre-clinical dose- finding and mechanism of action study in NOD mice in three scenarios: pre-diabetic, new-onset, and established diabetes. Results from Aim 1 will be used to determine the AVM0703 dose to be used in the pivotal efficacy study for reversal of new-onset diabetes and established diabetes in Aims 2 and 3. An IND application will be filed at the end of the project.