A major challenge in the development of novel therapeutics is the precise localization and activation of drugs to specific areas in the body. Twenty years ago ‘click chemistry’, a simple yet powerful concept to tackle this challenge, was first coined by Hartmuth Kolb, M.G. Finn and Nobel prize winner Barry Sharpless. The term describes “an expanding set of powerful, selective, and modular ‘blocks’ that work reliably”1 to create new chemical compounds. In essence, it relies on a pair of molecules that will react only with each other, and not with any other molecules they encounter. If you were able to localize this reaction within the body, it would enable a much more selective targeting of active compounds. Several types of chemical reactions under the click chemistry umbrella already enable many biological applications, including those used in pharmaceutical research and the construction of novel therapeutics.
Shasqi is leading the development of therapeutics leveraging click chemistry to get active cancer treatments to tumors with its proprietary CAPACTM (Click Activated Protodrugs Against Cancer) platform. The technology is based on localizing a click chemistry reagent in the tumor area, which then activates a second agent, a systemically infused protodrug. When the two ‘click’, a powerful localized therapy is activated at the tumor, while keeping its systemic exposure levels below toxic thresholds.
Shasqi’s ongoing phase 1 trial shows that click chemistry works in a clinical setting, localizing 50 times more drug to the tumor than in the plasma. This finding validates the foundation of the CAPAC platform in humans and opens up an array of possibilities for future click chemistry-based therapies.
But what are those possibilities? How and where could click chemistry be used to create new therapies and improve upon the efficacy and safety of other cancer therapies?
Click chemistry can be applied to multiple drug classes, including small molecules, antibodies, and immune cell engagers. Click chemistry could enable the precise localization and activation of any of these therapies to the tumor site, thereby improving efficacy, minimizing side effects that are commonly associated with systemic exposure to potent drugs, and leading to better outcomes and quality of life for patients.
Here are some innovative ways in which click chemistry could be applied to existing technologies to improve outcomes for cancer patients:
Improving tolerability and efficacy of chemotherapies. Chemotherapy remains a mainstay of cancer treatment, but its systemic toxicities can limit dosing and reduce patients’ quality of life. Click chemistry can be applied to chemotherapies and highly potent cytotoxics, enabling higher dosing and drug exposure, and greater anti-tumor effects, with manageable toxicity levels.
Alternative to antibody-drug conjugates (ADCs). Conventional ADCs have a limited therapeutic index due to toxicities associated with the unintended systemic release of the cytotoxic payload. In addition, the requirement that an ADC be internalized for its payload to be released limits the choice of suitable tumor-associated antigens for ADC development. CAPAC does not require the antibody to be internalized, expanding the number of suitable antigens. Using click chemistry, antibodies that bind tumor-specific antigens can deliver a click reagent to the tumor. Once localized, the conjugate can activate the therapeutic protodrug only at the tumor. Separation of the targeting agent and the therapeutic payload allows the protodrug to be administered systemically at high levels minimizing the risk of dose-limiting toxicities.
Alternative to bispecific immune cell engagers. Conventional bispecific antibodies stimulate antitumor activity by localizing and activating immune cells in close proximity to tumor cells. However, use of bispecific antibodies is linked to potential toxicity including cytokine release syndrome, resulting from uncontrolled immune activation and release of inflammatory cytokines. A click chemistry approach enables two antibodies to be administered separately: the first antibody binds to tumor-specific antigens and localizes a click chemistry reagent at the tumor; the second antibody binds to immune effector cells, after which a click reaction brings the immune effector cells into close proximity with the cancer cell. Since the two antibodies are administered separately, it is possible to titrate immune activation and reduce the risk of an overactive immune response. Click chemistry will contribute to the future development of safe immune cell engagers with a broader range of tumor specificity.
Click chemistry can also be used to localize cytokines to cold tumors to activate an immune response, or radiotherapeutics to enhance cancer cell death and this is just the beginning.
Click chemistry has the potential to improve the utility and outcomes for many different treatment modalities. Almost any pharmaceutical agent with significant systemic side effects or a limited therapeutic window may benefit from utilizing a click chemistry approach to create novel, improved therapeutics.
To learn more about the future of click chemistry, visit www.shasqi.com/platform.
1Kolb, Finn, Sharpless, Angew. Chem. Int. Ed. 2001, 40, 2004-2021.