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.

抽象的 - Tambo 正在开发点击激活原药 (CAP) 平台，以激活体内特定部位的药物， 该平台依赖于提高其疗效，同时最大限度地减少全身毒性和药物不良事件（ADE）。 关于可注射生物聚合物和具有减毒作用的修饰原药之间的点击化学反应 由于缺乏活性/毒性，大多数药物都是全身给药并扩散到全身。 病理部位的特异性，需要高剂量才能达到有效的治疗浓度， 导致毒性和 ADE 的情况 2013 年，仅在美国就有 120 万起 ADE 报告，超过 100 万份。 所有住院患者中 5% 的 ADE 也因无能力而导致了 90% 的候选药物失败率。 达到靶位点的治疗浓度或出现无法忍受的副作用，导致药物浓度过高 为了克服这些限制，开发了 CAP 平台以实现更高的开发成本和价格。 活性药物在特定病理部位的浓度，同时最大限度地减少全身毒性。 两种成分：1) 活性/毒性减弱的反式环辛烯 (TCO) 修饰的原药； 可注射的四嗪 (Tz) 改性透明质酸钠 (NaHA) 生物聚合物 该生物聚合物不具有治疗作用。 活性，而是通过四步过程激活体内的原药来发挥作用。 在病理部位进行局部治疗，然后在局部部位全身施用原药，即生物聚合物。 通过生物正交“点击化学”反应选择性地快速捕获原药并释放 通过这个平台，Tambo 致力于改善患有这种疾病的患者的治疗和生活质量。 各种各样的医疗状况，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管理，特别是基于阿霉素的原药。 使用 CAP 技术开发的针对晚期肉瘤患者的治疗目前正处于下一阶段 1 剂量递增临床试验（NCT04106492）然而，对于一些其他适应症，虽然动物模型有。 虽然取得了成功，但该平台目前受到一些 TCO 修饰的原药溶解度差的限制，甚至 在 TCO 中添加亲水基团以提高原药溶解度后，这显着限制了 TCO 的量。 可以给药的原药，并阻止充分利用原药的减弱毒性。 通过以下目标提高提案平台的适用性： 1）筛选候选增溶 通过添加达托霉素原药来评估铅增溶基团的普遍性。 适用于其他药物类别（例如培西达替尼、曲安西龙） 3) 确定最大耐受剂量 (MTD)。 在啮齿类动物中研究目标 1 和 2 中开发的新原药，并与母体药物进行比较以确认 毒性减弱，以及通过血浆捕获和激活的药代动力学特征 拟议的工作将产生一个具有改善的原药溶解度的先进激活平台。 特征，加强本已强大的平台，以改善治疗和减少不良事件。