Antibody-guided localized activation of bioorthogonal protodrugs via click chemistry

通过点击化学抗体引导生物正交原药的局部激活

• 批准号: 10760737
• 负责人: Jesse Mischa McFarland
• 金额: $ 78.17万
• 依托单位: SHASQI, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10760737
• 关键词: Acceleration; Adverse Drug Experience Report; Adverse drug event; Anti-Inflammatory Agents; Antibiotics; Antibodies; Antibody-drug conjugates; Antigen Targeting; Antigens; Area; Attenuated; Autoimmune Diseases; Autoimmunity; Biology; Biopolymers; Breast Cancer Model; Cancer Model; Cell Line; Chemistry; Clinic; Conjugating Agent; Cyclooctenes; Cysteine; Development; Disease; Dose; Dose Limiting; Doxorubicin; Drug Kinetics; ERBB2 gene; Effectiveness; Engineering; Failure; Future; Generations; Hospitalization; Infection; Injectable; Injections; Local Therapy; Location; Lysine; Medical; Modality; Morbidity - disease rate; Pain management; Pathologic; Patients; Pharmaceutical Preparations; Phase; Price; Quality of life; Reaction; Risk Reduction; Schedule; Site; Sodium Hyaluronate; Solid Neoplasm; Specificity; Sprague-Dawley Rats; Structure; System; Technology; Testing; Therapeutic; Time; Toxic effect; Toxicity Attenuation; Toxicology; Xenograft Model; advanced system; cohort; cost; design; drug candidate; drug development; improved; in vivo; malignant stomach neoplasm; manufacture; mortality; novel; side effect; success; systemic toxicity; therapeutically effective; tumor

Abstract Shasqi is developing a platform to activate drugs at a specific site in the body, thus enhancing their efficacy while minimizing systemic toxicity and adverse drug events (ADEs). Most drugs are administered systemically and spread throughout the body. Due to lack of specificity for the pathological site, high doses are required to achieve effective therapeutic concentrations, causing toxicity and ADEs at sites of the body where they are not needed. Each year, there are approximately 1.2 million reports of ADEs in the U.S. alone, representing over 5% of all hospitalized patients. The overall costs of ADE-related morbidity and mortality are thought to exceed $177 billion. ADEs also contribute to the 90% failure rate of drug candidates due to the inability to achieve therapeutic concentrations at the target site or intolerable side effects. To overcome these critical limitations, Shasqi designed the Click Activated Protodrugs (CAP) platform to achieve higher concentrations of active drugs at specific pathological sites while minimizing systemic toxicity. CAP consists of an activating agent that is targeted to a disease site and a protodrug that is administered systematically. At the target site, the activating agent selectively and rapidly captures the protodrug via a bioorthogonal click chemistry reaction, followed by local release of active drug. The first-generation CAP system used an injectable sodium hyaluronate (NaHA) biopolymer as the activating agent and doxorubicin (Dox) for the protodrug. This system is now being tested in a Phase 2a trial in patients with injectable solid tumors. Over 8 dose escalation cohorts, a dose-limiting toxicity has not been observed, even at doses up to 12-times the molar equivalent of conventional Dox per cycle. This demonstrates the striking effectiveness of the CAP platform at limiting drug-related toxicities. Shasqi now seeks to develop a second-generation (Gen2) platform with an antigen-targeted version of the activating agent to enable local activation of the protodrug at multiple sites, including locations not reachable by injection. As a proof of concept of this technology, Shasqi has demonstrated through conducting Phase I-equivalent studies the dose- dependent tumor regression in a HER+ gastric cancer model through HER2-targeting of a protodrug of the chemotherapeutic monomethyl auristatin E (MMAE). For this Direct to Phase II project Shasqi will further advance this system by undertaking four specific aims: 1) developing and testing novel HER2-targeted activating agent conjugates in vivo, 2) confirming efficacy of selected conjugate with TCO-MMAE in a syngeneic HER2+ breast cancer model, 3) performing pharmacokinetic (PK) studies and dosing optimization, and 4) GLP manufacturing of protodrug and cell line development for HER2 Fab-Tz to enable toxicology studies. These aims will identify novel antigen-targeted structures for use in Shasqi’s Gen2 CAP and will advance an initial product toward the clinic. This will provide a better understanding of the antigen-targeted activating agents in the platform, which could be used in the future to develop site-directed treatments for other indications, including antibiotics for site-specific infections, autoimmunity, and localized anti-inflammatory and pain management.

摘要 Shasqi正在开发一个平台，以激活体内特定部位的药物，从而提高其功效， 最大限度地减少全身毒性和药物不良事件（ADE）。大多数药物是全身给药， 遍布全身由于缺乏对病理部位的特异性，需要高剂量来实现 有效治疗浓度，在不需要的身体部位引起毒性和ADE。 每年，仅在美国就有大约120万例ADE报告，占所有ADE报告的5%以上。 住院病人。据认为，与ADE相关的发病率和死亡率的总成本超过1770亿美元。 ADE还导致90%的候选药物失败率，因为无法实现治疗性 目标部位的浓度或难以忍受的副作用。为了克服这些严重的限制，Shasqi 设计了点击激活的原型药物（CAP）平台，以实现更高浓度的活性药物， 同时最大限度地减少全身毒性。CAP由一种活化剂组成， 到疾病部位和系统给药的原型药物。在靶部位，活化剂 通过生物正交点击化学反应，选择性地和快速地捕获原型药物，然后局部 释放活性药物。第一代CAP系统使用可注射透明质酸钠（NaHA） 生物聚合物作为活化剂，阿霉素（Dox）作为原型药物。该系统目前正在测试中， 一项在注射性实体瘤患者中进行的2a期试验。超过8个剂量递增队列，剂量限制性毒性 甚至在剂量高达每循环常规Dox摩尔当量的12倍时也没有观察到。这 证明了CAP平台在限制药物相关毒性方面的显著有效性。沙斯奇现在寻求 开发具有抗原靶向形式的活化剂的第二代（Gen 2）平台， 能够在多个位点局部激活原型药物，包括注射不能到达的位置。以证明你 Shasqi通过进行I期等效研究证明了该技术的剂量- 在HER+胃癌模型中通过HER 2-靶向本发明的前药的依赖性肿瘤消退 化疗单甲基澳瑞他汀E（MMAE）。对于这个直接到第二阶段项目，Shasqi将进一步 通过承担四个具体目标来推进该系统：1）开发和测试新的HER 2靶向激活 体内药物缀合物，2）确认选定的TCO-MMAE缀合物在同基因HER 2+中的功效 乳腺癌模型，3）进行药代动力学（PK）研究和剂量优化，和4）GLP 用于HER 2 Fab-Tz的原型药物和细胞系开发的制造，以实现毒理学研究。这些目标 将确定用于Shasqi的Gen 2 CAP的新型抗原靶向结构，并将推进初始产品 去诊所这将提供对平台中的抗原靶向活化剂的更好理解， 这在未来可以用于开发其他适应症的定点治疗，包括抗生素 用于部位特异性感染、自身免疫和局部抗炎和疼痛管理。