Canada-based Zymeworks, a clinical-stage biopharmaceutical company, has entered into a licensing agreement that grants Iconic Therapeutics non-exclusive rights to the company’s proprietary ZymeLink™ antibody-drug conjugate (ADC) platform for the development of its ICON-2 Tissue Factor ADC for cancer.

The proprietary conjugation platform includes a suite of novel protein site-specific conjugation technologies and customizable cleavable and non-cleavable linkers that is compatible with a variety of small molecule therapeutics. The platform ensures the production of homogeneous drug products while maintaining systemic stability and following internalization, enabling the efficient release of the cytotoxic payload to target cells.

Tissue factor
Tissue factor is a 47-kDa membrane-bound cell surface receptor. It is also known as thromboplastin, coagulation factor III (fIII) or CD142. As a naturally-occurring protein in humans tissue factor plays an important role in the coagulation cascade, a complex set of processes that produce a blood clot in response to an injury.

The expression of tissue factor is restricted to the cells that are not in direct contact with blood, such as pericytes, fibroblasts and smooth muscle cells, which are localized in the sub-endothelial vessel wall and sequestered from circulating coagulation factor VII (fVII), the natural ligand for tissue factor.

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When tissue factor is overexpressed, however, it causes inflammation and an abnormal growth of blood vessels called angiogenesis, which often produce undesirable consequences for patients. Overexpression of tissue factor plays a pivotal role in multiple diseases, including wet age-related macular degeneration (AMD) and cancer.

Because of the critical role of tissue factor in the underlying pathology, several biopharmaceutical companies have attempted to develop therapeutics that target and inhibit tissue factor overexpression. Although tissue factor is a relatively well understood target for drug development, a number of therapies have proven challenging to develop because of safety concerns.

Overexpression of tissue factor on tumors, on tumor vasculature and in the tumor microenvironment is a key attribute of multiple solid tumors. When aberrantly expressed in solid tumors, tissue factor been associated with poor prognosis.

Based on its high expression in a broad range of solid tumors combined with a  rapid internalization, tissue factor is considered a suitable target for an ADC.

The only active clinical development program known to be targeting tissue factor is using an ADC and showing evidence of clinical activity. However, some studies investigating this agent have shown dose limiting adverse events caused by interference with coagulation.

The investigational program involves TF-011-vcMMAE, an ADC under development for the treatment of solid tumors composed of a human tissue factor specific antibody (TF-011), a protease cleavable valine-citrulline (vc) linker and the microtubule disrupting agent monomethyl auristatin E (MMAE). [1][2][3]

By contrast, scientists at Iconic have demonstrated that an alternative antibody does not interfere with blood clotting while achieving outstanding activity in difficult to treat xenografts and patient-derived xenograft (PDX) models. Given these advantages, Iconic plans to address several high unmet needs tumors.

The company expects their their novel ADC will enter formal IND-enabling studies in 2019.

The collaboration between the companies announced today is the first collaboration leveraging the ZymeLink platform and represents Zymeworks’ third technology platform licensed to a collaborator.

Under the terms of the agreement, Zymeworks will be eligible to receive development and commercial milestone payments and tiered royalties on worldwide net sales. The agreement also provides Zymeworks co-promotion rights with increased royalties for products developed using the Iconic ADC program. If Iconic out-licenses the program, in lieu of co-promotion rights, Zymeworks will receive a share of the revenue Iconic receives from any partners as well as tiered royalties on worldwide net sales.

Further validation
“We believe this first ZymeLink licensing deal provides further validation of our novel ADC technology, which is already being used in Zymeworks’ own clinical candidate, ZW49, a bispecific anti-HER2 ADC being developed for several indications characterized by HER2 expression, including breast and gastric cancers, that have progressed or are refractory to existing HER2-targeted therapies, and other HER2 expressing solid tumors.” said Ali Tehrani, Ph.D., President and Chief Executive Officer of Zymeworks.

“Historically, traditional ADC development has been plagued by a number of challenges related to toxicity and efficacy. Our research has shown that we have the capacity to significantly enhance exposure and tolerability, broadening the therapeutic window and leading to potentially safer and more efficacious therapeutic candidates.”

“Zymeworks’ technology provides properties and capabilities we believe will enhance and leverage Iconic’s Tissue Factor platform,” noted William Greene, MD., Iconic’s Chief Executive Officer.

“Having evaluated several alternatives, we are confident that we can develop a truly differentiated ADC with ZymeLink. Tissue factor is an important target in solid tumors, and we believe the combination of our best-in-class antibodies with Zymeworks’ next generation payload technology will deliver an ADC with enhanced safety and efficacy with the potential to be an important addition to the cancer armamentarium. We [expect that we will be able to progress] ICON-2 to the clinic in 2020 and more broadly, to further developing our pipeline of therapeutic approaches to targeting tissue factor mediated diseases.”

[1] Breij EC, de Goeij BE, Verploegen S, Schuurhuis DH, Amirkhosravi A, Francis J, et al. An antibody-drug conjugate that targets tissue factor exhibits potent therapeutic activity against a broad range of solid tumors.Cancer Res. 2014 Feb 15;74(4):1214-26. doi: 10.1158/0008-5472.CAN-13-2440. Epub 2013 Dec 26.
[2] Förster Y, Meye A, Albrecht S, Schwenzer B. Tissue factor and tumor: clinical and laboratory aspects. Clin Chim Acta. 2006;364(1-2):12-21.
[3] Cocco E, Varughese J, Buza N, et al. Expression of tissue factor in adenocarcinoma and squamous cell carcinoma of the uterine cervix: implications for immunotherapy with hl-con1, a factor VII-IgGFc chimeric protein targeting tissue factor. BMC Cancer. 2011;11:263.

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