Generalizable Protodrug Characteristics for In Vivo Drug Release using the Click Activated Protodrugs (CAP) Platform

摘要- Tambo正在开发一种点击激活原药物(CAP)平台，以激活体内特定部位的药物， 在提高疗效的同时将全身毒性和不良药物事件(ADE)降至最低。该平台依赖于 可注射生物聚合物与弱化修饰原药的点击化学反应 活性/毒性。大多数药物都是系统地给药，并散布到全身。由于缺乏 由于病变部位的特殊性，需要高剂量才能达到有效的治疗浓度， 造成毒性和不良反应。2013年，仅在美国就有120万起ADE报告，相当于超过 占所有住院患者的5%。ADS也是90%的候选药物失败率的原因之一，因为 在目标部位达到治疗浓度或无法忍受的副作用，导致药物偏高 开发成本和价格。为了克服这些限制，开发了CAP平台以实现更高的 特定病理部位的活性药物浓度，同时将全身毒性降至最低。CAP由以下内容组成 两种成分：1)反式-环辛烯(TCO)修饰的活性/毒性减弱的原药； 可注射，四嗪(TZ)修饰的透明质酸钠(NaHA)生物聚合物。这种生物聚合物不具有治疗作用 活性，而不是通过4步过程激活体内的原药物而起作用。将生物聚合物注入 在病变部位局部给药，然后全身给药。在当地，生物聚合物 通过生物正交的“点击化学反应”选择性地快速捕获原药物，并释放 活性药物。通过这一平台，Tambo致力于改善老年糖尿病患者的治疗和生活质量 各种各样的医疗条件，包括肿瘤局部治疗，针对特定部位感染的抗生素，以及 局部抗炎治疗和疼痛控制。特别是，以阿霉素为基础的原药 使用CAP技术开发的晚期肉瘤患者的治疗目前正在进入一个阶段 1剂量递增临床试验(NCT04106492)。然而，对于其他一些迹象，尽管动物模型已经 显示出成功，该平台目前受到一些TCO修饰的原药物较差的溶解性的限制，甚至 在TCO中加入亲水性基团以改善原药的溶解度。这大大限制了 可以给药的原药物，并阻止充分利用原药物的减毒作用。因此，我们 提出通过以下几个目标提高平台的适用性：1)筛选候选解题 组内加用达托霉素原药。2)评价溶铅组(S)的泛化能力 适用于其他药物类别(如培西达替尼、曲安奈德)。3)确定最大耐受量(MTD) 在啮齿动物的AIMS 1和AIMS 2中开发的新的原药，并与母药进行比较以证实 毒性的减弱，以及通过血浆捕获和激活的药代动力学特征 取样。拟议的工作将导致一个先进的激活平台，提高原药物的溶解性 加强本已强大的改善治疗和减少不良反应的平台。

Abstract – Tambo is developing a Click Activated Protodrugs (CAP) platform to activate drugs at a specific site in the body, enhancing their efficacy while minimizing systemic toxicity and adverse drug events (ADEs). The platform relies on a click chemistry reaction between an injectable biopolymer and a modified protodrug with attenuated activity/toxicity. 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. In 2013, there were 1.2 million reports of ADEs in the U.S. alone, representing over 5% of all hospitalized patients. 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, leading to high drug development costs and prices. To overcome these limitations, the CAP platform was developed to achieve higher concentrations of active drugs at specific pathological sites while minimizing systemic toxicity. CAP consists of two components: 1) a trans-cyclooctene (TCO)-modified protodrug with attenuated activity/toxicity; and 2) an injectable, tetrazine (Tz)-modified sodium hyaluronate (NaHA) biopolymer. The biopolymer is not therapeutically active, but rather functions by activating the protodrug in the body in a 4-step process. The biopolymer is injected locally at a pathological site, followed by systemic administration of the protodrug. At the local site, the biopolymer selectively and rapidly captures the protodrug via a bioorthogonal “click chemistry” reaction and releases the active drug. Through this platform, Tambo seeks to improve the treatment and quality of life of patients with a wide variety of medical conditions, including tumor-localized therapy, antibiotics for site-specific infections, and localized anti-inflammatory therapy and pain management. In particular, the doxorubicin-based protodrug treatment for advanced sarcoma patients developed using the CAP technology is currently undergoing a Phase 1 dose escalation clinical trial (NCT04106492). For some other indications, however, while animal models have shown success, the platform is currently limited by the poor solubility of some TCO-modified protodrugs, even after adding hydrophilic groups to the TCO to improve protodrug solubility. This significantly limits the amount of protodrug that can be dosed, and prevents taking full advantage of the protodrugs’ attenuated toxicity. Thus, we propose to improve the applicability of the platform through the following aims: 1) Screen candidate solubilizing groups through addition to a daptomycin protodrug. 2) Assess generalizability of lead solubilizing group(s) by applying to other drug classes (e.g. pexidartinib, triamcinolone). 3) Determine maximum tolerated dose (MTD) of the new protodrugs developed in Aims 1 and 2 in rodents, and compare to parent drugs to confirm attenuation of toxicity, as well as characterize the pharmacokinetics of capture and activation through plasma sampling. The proposed work will result in an advanced activation platform with improved protodrug solubility characteristics, strengthening an already powerful platform for improving treatment and reducing ADEs.