Antibody-guided localized activation of bioorthogonal protodrugs via click chemistry

摘要 沙斯基正在开发一个平台，在体内的特定位置激活药物，从而增强它们的疗效，同时 将全身毒性和不良药物事件(ADE)降至最低。大多数药物都是系统地给药，而且 扩散到全身。由于缺乏对病变部位的特异性，需要高剂量才能实现 有效的治疗浓度，在不需要它们的身体部位造成毒性和ADE。 每年，仅在美国就有大约120万起ADE报告，占总数的5%以上 住院病人。与ADE相关的发病率和死亡率的总成本被认为超过1770亿美元。 ADS也是90%的候选药物失败率的原因之一，因为无法实现治疗 目标部位的药物浓度或无法忍受的副作用。为了克服这些关键限制，沙斯基 设计点击激活原药物(CAP)平台，以实现更高浓度的活性药物 特定的病理部位，同时将全身毒性降至最低。CAP由靶向激活剂组成 一种疾病部位和一种系统地给药的原药。在目标位置，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物，然后局部 活性药物的释放。第一代CAP系统使用可注射玻璃酸钠(NaHA) 生物聚合物作为活化剂，阿霉素(Dox)作为原药。该系统目前正在进行测试 在可注射实体肿瘤患者中进行的2a期试验。超过8个剂量递增队列，具有剂量限制性毒性 没有观察到，即使在每周期高达传统Dox摩尔等价物12倍的剂量下也是如此。这 展示了CAP平台在限制与药物有关的毒性方面的显著有效性。沙斯基现在正在寻找 开发具有抗原靶向的激活剂版本的第二代(Gen2)平台 使原药物能够在多个地点局部激活，包括无法通过注射到达的地点。作为证据 在这项技术的概念中，沙斯基已经通过进行第一阶段-等效研究论证了剂量- HER+胃癌模型中HER2靶向原药的肿瘤消退作用 化疗单甲基金雀异黄素E(MMAE)。对于这个直通二期的项目，沙斯基将进一步 通过承担四个具体目标来推进该系统：1)开发和测试新的HER2靶向激活 药物在体内的结合物，2)证实所选择的结合物与TCO-MMAE在同基因HER2+中的有效性 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制造原药和开发细胞系，以进行毒理学研究。这些目标 将确定新的抗原靶向结构用于沙斯基的Gen2 CAP，并将推出初步产品 朝诊所走去。这将提供对平台中的抗原靶向激活剂的更好的理解， 未来可用于开发包括抗生素在内的其他适应症的定点治疗 适用于特定部位的感染、自身免疫以及局部抗炎和疼痛治疗。

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.