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.

抽象的 Shasqi正在开发一个平台来激活体内特定部位的药物，从而提高其效率 最小化全身毒性和不良药物事件（ADE）。大多数药物是系统地给药的， 散布在整个身体中。由于缺乏病理部位的特异性，需要高剂量才能实现 有效的治疗浓度，在不需要的身体部位引起毒性和AD。 每年，仅在美国就有大约120万份ADE的报告，占所有ADE的5％以上 住院的患者。认为与ADE相关的发病率和死亡率的总成本超过1770亿美元。 由于无法实现治疗，ADE还导致候选药物的90％失败率 目标部位或可抗副作用的浓度。为了克服这些关键局限性，Shasqi 设计了点击激活的原始果（CAP）平台，以实现更高浓度的活性药物 特定的病理部位，同时最大程度地减少全身毒性。 CAP由针对的激活剂组成 到系统施用的疾病部位和原始果。在目标部位，激活剂 通过生物正交点击化学反应有选择地，快速地捕获原始果，然后是局部 释放活性药物。第一代帽系统使用了可注射的钠钠（NAHA） 生物聚合物作为原生糖的活化剂和阿霉素（DOX）。该系统现在正在测试 可注射实体瘤患者的2A期试验。超过8剂量升级队列，剂量限制毒性 也没有观察到，即使在每周循环的摩尔等效摩尔等效的摩尔等效剂量最多为12倍时也没有观察到。这 证明了CAP平台在限制与药物有关的毒性方面具有惊人的有效性。 Shasqi现在正在寻找 开发具有抗原针对激活剂的抗原靶向版本的第二代（GEN2）平台 在多个位点启用局部激活原始剂，包括注射无法达到的位置。作为证明 关于这项技术的概念，Shasqi通过进行I阶段等效研究证明了剂量 她的+胃癌模型中的依赖性肿瘤回归是通过靶标的靶标的 化学治疗单甲基甲氨酸蛋白E（MMAE）。直接到II阶段项目Shasqi将进一步 通过实现四个具体目标来推进该系统：1）开发和测试新型Her2靶向激活 代理在体内共轭，2）确认选定的与TCO-MMAE在Syngeneic HER2+中的效率 乳腺癌模型，3）进行药代动力学（PK）研究和剂量优化，4）GLP 为HER2 Fab-TZ的原始果和细胞系开发制造，以实现毒理学研究。这些目标 将识别出新型的抗原靶向结构，用于在Shasqi的Gen2 Cap中使用，并将推进初始产品 走向诊所。这将更好地理解平台中以抗原为目标的激活剂， 将来可以用来开发针对其他适应症的现场定向治疗方法，包括抗生素 用于特定地点的感染，自身免疫性以及局部抗炎和疼痛管理。