On March 17, 2018 Zymeworks Inc. (NYSE/TSX: ZYME), a clinical-stage biopharmaceutical company developing multifunctional therapeutics, reported that presented preclinical data on ZW49, its lead bispecific antibody-drug conjugate candidate (ADC) and its ZymeLink ADC platform (Press release, Zymeworks, APR 17, 2018, View Source [SID1234525407]). As previously reported, Zymeworks expects to file an Investigational New Drug (IND) application this year in order to begin clinical trials with ZW49 for patients with HER2-expressing cancers.
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Abstract Number: 3914; ZW49, A HER2 Targeted Biparatopic Antibody Drug Conjugate for the Treatment of HER2 Expressing Cancers
Summary: ZW49, which incorporates Zymeworks’ Azymetric bispecific and ZymeLink ADC technology platforms, was shown to be active and well tolerated in a series of preclinical studies. The unique biparatopic (ability to simultaneously bind two distinct locations on a single target) properties of ZW49 enable highly efficient delivery of its cancer cell killing payload while its ZymeLink-enhanced tolerability allows higher doses to be administered leading to improved anti-tumor activity. In models of both high and low HER2-expressing cancers, administration of ZW49 resulted in complete regression of the tumors. Importantly, ZW49 was well tolerated in preclinical safety studies at the same exposure levels that demonstrated efficacy in tumor models, without the toxicities generally associated with this class of ADC payloads.
Abstract Number: 3912; Towards Development of Next Generation Biparatopic ADCs Using a Novel Linker-Toxin with Expanded Therapeutic Window
Summary: Many ADCs in development ultimately fail to demonstrate efficacy in clinical testing due to dose-limiting toxicities. Zymeworks’ approach to ADC development is focused on efficient payload delivery and improving tolerability to enable greater exposures at the tumor rather than the conventional approach of solely increasing ADC potency. Preclinical data demonstrate that ZymeLink improved the tolerability of ADCs against four known clinical targets compared to the corresponding ADC platforms used in clinical trials. This enabled ZymeLink ADC exposures of at least seven-fold higher than benchmark ADCs which translated to increased anti-tumor activity in preclinical models. Ongoing efforts are focused on evaluating biparatopic versions of these ZymeLink ADC candidates to expand the therapeutic window even further.
"Combining our complementary Azymetric and ZymeLink technology platforms gives us a foundation to create active and well tolerated ADCs," said Ali Tehrani, Ph.D., Zymeworks’ President & CEO. "ZW49 is the first of many of ADCs that we plan to develop as part of our diverse pipeline of new medicines to overcome the limitations of current therapies and ultimately, defeat cancer."
About ZW49
ZW49 is a biparatopic (a bispecific antibody that can simultaneously bind two non-overlapping epitopes on a single target) anti-HER2 ADC based on the same antibody framework as ZW25, Zymeworks’ lead clinical candidate being evaluated in a Phase 1 study, but armed with the company’s proprietary ZymeLink cytotoxic (potent cancer-cell killing) payload. ZW49 may mediate its therapeutic effect through a combination of mechanisms, including: increased HER2 receptor-antibody clustering and internalization leading to toxin-mediated cytotoxicity; increased binding and removal of HER2 protein from the cell surface; and potent effector function.
About Antibody-Drug Conjugates
Antibody-drug conjugates (ADC) are a class of anti-cancer therapies intended to precisely target tumor cells in order to avoid the significant toxicities routinely associated with cancer treatments while simultaneously improving their efficacy. An ADC is an antibody that is connected, or conjugated, to a small molecule drug. It has three critical components: the antibody for targeting of specific cells, the cytotoxin (or payload) being delivered to induce cancer cell death, and the linker, which connects the two components together.
About the ZymeLink Platform
The ZymeLink platform is a modular suite of site-specific conjugation technologies, customizable linkers, and proprietary cytotoxic payloads designed for the targeted delivery of therapeutics with optimal tolerability and efficacy. The ZymeLink platform is compatible with traditional antibodies and with the Azymetric platform and is intended to facilitate the development of next-generation therapeutics.
About the Azymetric Platform
The Azymetric platform enables the transformation of monospecific antibodies into bispecific antibodies, giving them the ability to simultaneously bind two different targets. Azymetric bispecific technology enables the development of multifunctional biotherapeutics that can block multiple signaling pathways, recruit immune cells to tumors, enhance receptor clustering degradation, and increase tumor-specific targeting. These features are intended to enhance efficacy while reducing toxicities and the potential for drug-resistance. Azymetric bispecifics have been engineered to retain the desirable drug-like qualities of naturally occurring antibodies, including low immunogenicity, long half-life and high stability. In addition, they are compatible with standard manufacturing processes with high yields and purity, potentially significantly reducing drug development costs and timelines.