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.
