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，可以激活体内特定部位的药物，从而增强其疗效，同时 全身毒性和药物不良事件 (ADE) 大多数药物都是全身给药。 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 ADE。 仅在美国，每年就有大约 120 万份 ADE 报告，占所有报告的 5% 以上 住院患者的 ADE 相关发病率和死亡率的总成本预计超过 1770 亿美元。 由于无法达到治疗效果，ADE 还导致候选药物 90% 的失败率 为了克服这些关键限制，Shasqi 开发了目标部位的浓度或无法忍受的副作用。 设计了点击激活原药 (CAP) 平台，以在 CAP 包含一种针对特定病理部位的激活剂，同时最大限度地减少全身毒性。 向疾病部位和在目标部位系统施用的原药，激活剂。 通过生物正交点击化学反应选择性地快速捕获原药，然后进行局部捕获 第一代 CAP 系统使用注射透明质酸钠 (NaHA)。 生物聚合物作为活化剂，阿霉素（Dox）作为原药，该系统目前正在测试中。 在可注射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。 尚未观察到，即使每个周期的剂量高达传统 Dox 摩尔当量的 12 倍。 展示了 CAP 平台在限制 Shasqi 现在寻求的药物相关毒性方面的惊人有效性。 开发第二代 (Gen2) 平台，其中包含抗原靶向版本的激活剂 能够在多个位点局部激活原药，包括注射无法到达的位置。 Shasqi 通过进行 I 期等效研究证明了该技术的概念 通过 HER2 靶向原药，在 HER+ 胃癌模型中实现依赖性肿瘤消退 对于这一直接二期项目，Shasqi 将进一步推进化疗单甲基奥瑞他汀 E (MMAE)。 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 体内药物缀合物，2) 确认所选缀合物与 TCO-MMAE 在同基因 HER2+ 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，以及 4) GLP HER2 Fab-Tz 的原药生产和细胞系开发，以实现毒理学研究。 将鉴定用于 Shasqi Gen2 CAP 的新型抗原靶向结构，并将推进初始产品 这将有助于更好地了解平台中的抗原靶向激活剂， 未来可用于开发针对其他适应症的定点治疗，包括抗生素 用于特定部位感染、自身免疫以及局部抗炎和疼痛管理。