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Discovery of solubilizing side chains for in vivo release of diverse drug classes using the Click Activated Protodrugs (CAP) platform

Award Number: R44TR004026
ORGANIZATION: NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/17/2022
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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Discovery of solubilizing side chains for in vivo release of diverse drug classes using the Click Activated Protodrugs (CAP) platform - Abstract Tambo is developing a platform to activate drugs at specific sites in the body, thus enhancing their efficacy while minimizing systemic toxicity and adverse drug events (ADEs). Most drugs distribute 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 healthy tissues. Each year, there are ~1.2 million reports of ADEs in the U.S., with overall costs of ADE-related morbidity and mortality thought to exceed $177 billion. ADEs also contribute to the 90% failure rate of drug candidates. Common prodrug approaches to overcome these critically limiting ADEs rely on biological or physiological factors, such as selected biomarkers, enzymatic activity, altered pH, or reactive oxygen species, which have found limited success due to inherent variability among patients. Tambo’s Click Activated Protodrugs (CAP) platform was designed to achieve higher concentrations of active drugs at specific pathological sites while minimizing systemic toxicity using an activation method independent of native biological processes; thus the approach is not affected by variations across patients. The platform also enables the reinvestigation and repurposing of drug candidates that may have previously been shelved due to off-target effects. A CAP therapeutic consists of 2 components: 1) a tetrazine (Tz)-modified activating agent that is not therapeutically active but is targeted to a disease site; and 2) a systemically administered trans-cyclooctene (TCO)-modified payload (a protodrug) with attenuated activity/toxicity. At the target site, the activating agent selectively and rapidly captures the protodrug via a bioorthogonal click chemistry reaction, followed by local release of the payload. One challenge the CAP platform has encountered is that the low solubility of certain protodrugs limits the feasible dose to subtherapeutic levels. To address this, the Phase I project successfully synthesized a selection of TCO-modified protodrugs carrying different solubilizing groups, including branched amino acids, linear PEG chains, and both positively and negatively charged groups. Solubility of a paclitaxel- based protodrug reached 16 mg/mL in an aqueous formulation buffer; free paclitaxel requires a toxic cremophor/ethanol mixture to be formulated. Solubility of an exatecan protodrug was similarly high, enabling high doses of each protodrug when tested in vivo. The protodrugs were tolerable in mice, and when the exatecan protodrug was tested in a murine tumor model with a biopolymer targeting agent carrying the activator, the tumors were completely eliminated. Phase II aims to further advance the CAP platform and to demonstrate its modularity by undertaking three specific aims: 1) synthesizing and characterizing protodrugs from novel therapeutic classes, 2) confirming in vitro and in vivo efficacy of developed protodrugs with a targeting agent, and 3) undertaking toxicology studies of a lead protodrug with a HER2-targeted activating agent. Phase II success will be defined by developing new protodrugs that translate to tissue-targeted efficacy and attenuated toxicity in vivo. Ultimately, the CAP platform could be used to develop better treatments for a wide range of disease indications.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $0 )
2026	2025	TAMBO, INC.	665 3RD ST	SAN FRANCISCO	CA	94107	SAN FRANCISCO	USA	National Center for Advancing Translational Sciences	000	3	3/26/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $1,209,827 )
2025	2025	TAMBO, INC.	665 3RD ST	SAN FRANCISCO	CA	94107	SAN FRANCISCO	USA	National Center for Advancing Translational Sciences	000	3	6/28/2025	NON-COMPETING CONTINUATION	$1,209,827
														Subtotal = $1,209,827

Issue Date FY: 2024 ( Subtotal = $929,651 )
2024	2024	TAMBO, INC.	665 3RD ST	SAN FRANCISCO	CA	94107	SAN FRANCISCO	USA	National Center for Advancing Translational Sciences	000	2	7/30/2024	COMPETING CONTINUATION	$929,651
														Subtotal = $929,651

Grand Total All Awards = $2,139,478

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Discovery of solubilizing side chains for in vivo release of diverse drug classes using the Click Activated Protodrugs (CAP) platform

Award Number: R44TR004026

ORGANIZATION: NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/17/2022

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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