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

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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.