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

使用点击激活原药 (CAP) 平台进行体内药物释放的可推广原药特征

• 批准号: 10383848
• 负责人: Maksim Royzen
• 金额: $ 30.02万
• 依托单位: TAMBO, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-17 至 2023-12-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10383848
• 关键词: Adverse Drug Experience Report; Adverse drug event; Alkanesulfonates; Ammonium; Animal Model; Anti-Inflammatory Agents; Antibiotics; Antineoplastic Agents; Area; Attenuated; Bacterial Infections; Biological Models; Biopolymers; Cell Culture Techniques; Characteristics; Chemistry; Clinical Trials; Cyclooctenes; Daptomycin; Data; Disease; Dose; Doxorubicin; Drug Kinetics; FDA approved; Failure; Focal Infection; Future; Generations; Injectable; Injections; Kinetics; Lead; Legal patent; Local Therapy; Maximum Tolerated Dose; Measures; Medical; Morbidity - disease rate; Pain management; Parents; Pathologic; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Plasma; Price; Process; Quality of life; Reaction; Rodent; Safety; Sampling; Site; Sodium Hyaluronate; Solid Neoplasm; Solubility; Specificity; Steroids; Technology; Therapeutic; Therapeutic Uses; Toxic effect; Toxicity Attenuation; Translating; Triamcinolone; Vancomycin; Work; aqueous; attenuation; base; carboxylate; clinical candidate; cost; design; drug candidate; drug development; hydrophilicity; improved; in vivo; mortality; polyol; preclinical efficacy; prevent; sarcoma; screening; side effect; small molecule; success; sugar; systemic toxicity; therapeutically effective; tumor

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.

摘要-- Tambo正在开发一种点击激活原型药物（CAP）平台，以激活体内特定部位的药物， 增强其功效，同时最小化全身毒性和药物不良事件（ADE）。该平台依靠 关于可注射生物聚合物和具有减毒作用的改性原型药物之间的点击化学反应 活性/毒性。大多数药物是全身给药，并扩散到全身。由于缺乏 由于对病理部位的特异性，需要高剂量以达到有效的治疗浓度， 导致中毒和ADE 2013年，仅美国就有120万份ADE报告，超过 5%的住院患者。ADE也导致了90%的候选药物失败率， 以在靶部位达到治疗浓度或产生不可耐受的副作用，导致高药物浓度。 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 在特定的病理部位的活性药物浓度，同时最大限度地减少全身毒性。CAP包括 两种组分：1）具有减弱的活性/毒性的反式-环辛烯（TCO）-修饰的原型药物;和2） 可注射四嗪（Tz）改性透明质酸钠（NaHA）生物聚合物。生物聚合物不是治疗性的 活性，而是通过在4步过程中激活体内的原型药物来发挥作用。生物聚合物被注入 在病理部位局部给药，然后全身给予原型药物。在当地，生物聚合物 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， 活性药物通过这个平台，Tambo寻求改善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，针对部位特异性感染的抗生素， 局部抗炎治疗和疼痛管理。特别地，基于阿霉素的原型药物 使用CAP技术开发的晚期肉瘤患者的治疗目前正在进行一个阶段 1项剂量递增临床试验（NCT 04106492）。然而，对于其他一些适应症，尽管动物模型具有 尽管该平台已经取得了成功，但目前该平台受到一些TCO修饰的原型药物溶解度差的限制， 在向TCO中加入亲水基团以提高原型药物溶解度之后。这大大限制了 这是因为可以给药的前药的毒性降低，并且阻止充分利用前药的减弱的毒性。因此我们 建议通过以下目标提高平台的适用性：1）筛选候选溶解 通过添加到达托霉素原型药物中，2)通过以下方式评估铅增溶基团的普遍性 适用于其他药物类别（例如pexidartinib、曲安西龙）。3)确定最大耐受剂量（MTD） 在啮齿类动物中开发的目标1和2中的新原型药物，并与母体药物进行比较，以确认 毒性衰减，以及通过血浆表征捕获和活化的药代动力学 取样.拟议的工作将导致一个先进的激活平台，提高原型药物的溶解度 这些措施旨在加强一个已经强大的平台，以改善治疗和减少ADE。