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正在开发一个点击激活的原始果（CAP）平台，以激活体内特定部位的药物， 提高其效率，同时最大程度地减少全身毒性和不良药物事件（ADE）。平台依靠 在可注射的生物聚合物和改良的原始果之间的单击化学反应中 活动/毒性。大多数药物全身服用并分布在整个身体中。由于缺乏 对病理部位的特异性，需要高剂量才能达到有效的治疗浓度， 引起毒性和ADE。 2013年，仅在美国就有120万份ADE的报告，代表 所有住院患者中有5％。由于无法，ADE还导致了候选药物的90％失败率 在目标部位或可实现副作用的治疗浓度，导致药物较高 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 活性药物在特定病理部位的浓度，同时最大程度地减少全身毒性。帽子由 两个组成部分：1）反式环链烯（TCO）改性的原始果具有减毒活性/毒性； 2） 可注射的四嗪（TZ）修饰的氢钠钠（NAHA）生物聚合物。生物聚合物在治疗上没有 活跃，而是通过在4步过程中激活体内的原始液体来发挥作用。注入生物聚合物 局部在病理部位，然后是系统性给予原始剂。在当地地点，生物聚合物 通过生物正交的“点击化学”反应有选择地，快速地捕获原始果，并释放 活性药物。通过这个平台，Tambo试图改善患者的治疗和生活质量 各种各样的医疗状况，包括肿瘤定位疗法，用于特定部位感染的抗生素和 局部抗炎疗法和疼痛管理。特别是，基于阿霉素的质子果 目前正在使用CAP技术开发的高级肉瘤患者的治疗 1剂量升级临床试验（NCT04106492）。但是，对于其他一些迹象，虽然动物模型具有 该平台显示出成功，目前受到某些TCO修饰的原始果的溶解度的限制，甚至 在将亲水组添加到TCO中以改善质子可溶性。这显着限制了 可以给予剂量的原始果，并防止充分利用原果的毒性减弱。那，我们 通过以下目的提高平台的适用性：1）筛选候选人溶解 通过添加Daptomycin Protodrug组。 2）评估铅可溶性组的概括性 适用于其他药物类别（例如pexidartinib，triamcinolone）。 3）确定最大耐受剂量（MTD） 在啮齿动物中的目标1和2中开发的新的质子中，并与父母进行比较以确认 毒性的衰减以及通过等离子体捕获和激活的药代动力学特征 采样。拟议的工作将导致一个高级激活平台，并具有改进的原始液体可溶性 特征，增强了已经强大的平台，用于改善治疗和减少ADE。