Click-to-Release

OUR TECHNOLOGY

Enabling universal, chemically controlled, on-target activation of antibody-drug conjugates (ADCs) and immunomodulators, as well as off-target deactivation of radiopharmaceuticals

While there has been incredible progress in recent years, the impact of many systemic therapies has been limited by their therapeutic index – the measure of the effective dose that can be administered to a patient relative to the drug’s safety in the body.

Tagworks has built a unique technology known as Click-to-Release, based on its invention of the pyridazine elimination reaction, so far the only bioorthogonal cleavage reaction that is selective and fast enough for clinical use in vivo. After its discovery, the team further developed the chemistry into a broadly applicable platform technology for systemic therapies.

Click-to-Release can capture the therapeutic potential of highly potent systemic therapies in multiple ways, including:

By enabling their safe delivery to the tumor microenvironment and their controlled on-target activation, as with ADCs and masked immunomodulators, increasing on-target efficacy.
By enabling off-target deactivation of radioimmunotherapy, by selective cleavage and renal clearance of the radiolabel from freely circulating radioimmunotherapeutics, decreasing dose-limiting toxicity in the bone marrow.

How our Technology Works

Click-to-Release is based on the sequential administration of a pair of molecules that only react (click) with each other, but not with any other molecule they encounter. One molecule comprises a trans-cyclooctene (TCO) linker bound to a payload and the other molecule is a tetrazine, which acts as the trigger. When the TCO linker and tetrazine trigger click together, a follow-on reaction is triggered that instantaneously releases the payload bound to the TCO linker.

Our platform is compatible with small molecules, peptides, and larger biomolecules, such as antibodies and antibody fragments, and covers a wide range of toxin and immunomodulator classes. It can be used to release a payload from a targeting agent to unmask and activate a payload in the body, or to clear a payload from non-target tissues. This technology offers fast, universal & temporally controlled release that does not rely on currently used biological drug release mechanisms (e.g. proteases), thereby potentially increasing the application scope and therapeutic index for several therapeutic modalities. In addition, the chemically controlled release is designed to make therapies such as ADCs safer, due to the stability of the linker in the absence of the trigger.

Tagworks is initially leveraging its approach to expand the number of ADC targets. In addition to the lead ADC program, TGW101, the pipeline includes discovery phase programs in ADCs and radiopharmaceuticals.

Tagworks has a broad IP estate on the Click-to-Release reaction, covering wide range of chemical and application scope. In addition, Tagworks owns a broad IP portfolio on in vivo Click Conjugation (for pre-targeted radioimmunotherapy).

Click-Cleavable ADCs: The Opportunity

ADCs have long held great promise as powerful, highly targeted cancer therapies. The limitation of today’s conventional ADCs is that they rely on suitable internalizing targets, which are not necessarily expressed by every cancer type and cancer cell. Our ADC therapy, however, does not depend on internalizing targets as it is based on chemically controlled release of the payload in the tumor micro-environment, thereby killing heterogenous tumors where not every cell expresses the target. In addition, the stability of the linker in the absence of the trigger has the potential to allow a further improved therapeutic index. Importantly, our unique approach to targeting non-internalizing receptors also offers the opportunity to address a whole new cancer target landscape, especially in solid tumors.

Tagworks’ platform represents an opportunity to expand both the therapeutic index and reach of these therapies to additional tumor types, and to make a truly transformative impact on patients not served by existing therapies.

Click-Cleavable ADCs

Click-Cleavable Radiotherapeutics

The main challenge for radioimmunotherapy is the long blood circulation of the radiolabeled antibodies, leading to high radiation doses to the bone marrow, limiting the dose that can be safely administered, thereby limiting the therapeutic effect. To overcome this, Tagworks is employing the Click-to-Release platform for the selective liberation and renal clearance of the radiolabel from freely circulating antibody once sufficient radiolabeled antibody has localized in the tumor cells.

This off-target deactivation approach is designed to improve target-blood ratios of radiolabeled antibodies targeted to efficiently internalizing receptors. After sufficient tumor binding and internalization has occurred, the trigger is injected, which is not cell-permeable and will therefore only cleave the linker of the freely circulating antibody, resulting in rapid clearance of the cleaved radioactive fragment through the kidneys and a boost of the tumor-blood ratio. Tagworks discovery program includes a click-cleavable radioimmunotherapeutic for HER2-positive breast cancer.