Focused on antibody-based cancer therapies, Zymeworks (NYSE:ZYME) believes bi- and multi-specific antibodies offer significant potential in oncology. Such therapies could provide new biological avenues for cancer treatment and extend immunotherapy to patients with few options. The FDA has approved three bispecific antibodies, and more than one hundred others are in development across the industry.
Zymeworks has a multi-pronged strategy related to multi-specific antibodies. In addition to its lead drug candidates, zanidatamab (ZW25) and ZW49, the company has developed a series of technology platforms to assist with in-house development and partnerships.
“We want to take information and lessons learned from our clinical trials and apply that back to the next generation of therapies that we develop,” said Zymeworks executive vice president and chief scientific officer Tony Polverino.
Zymeworks’ first platform for therapeutic antibodies, Azymetric, enables binding to multiple locations on one or more targets to offer novel mechanisms of action. The company and some of its collaborators have “derived a lot of benefit” from the platform, Polverino said.
Three more platforms grew out of Azymetric, including Zymelink, EFECT and, most recently, ProTECT. “All of them utilize the understandings that we’ve generated from Azymetric but have added functionality,” Polverino explained.
The company recently announced that Janssen has dosed the first patient with JNJ-78278343, a bispecific antibody developed using Zymeworks’ Azymetric and EFECT platforms.
EFECT introduces mutations into the fragment crystallizable (Fc) domain that can regulate the degree of binding to Fc-gamma receptors. As a result, the company “can enhance interactions with different immune cells,” Polverino said. “We can decrease interactions with immune cells, and we can enhance the oligomerization of antibodies as a result of those mutations,” he explained. “We thought it was critical to dial in different immune components and to regulate activation versus inhibition.”
Zymelink is the company’s internal linker-toxin platform. While the company was aware that antibody-drug conjugates (ADCs) were beginning to demonstrate the potential of targeted therapeutics in oncology, there were still challenges. “We wanted to address one of the pitfalls of the early design elements for ADCs — the inherent instability of some of those early platform ideas,” Polverino said. Therefore, the company’s platform was designed to maximize the stability of the linker-toxin to the antibody. As a result, it can deliver as much payload as possible to the target cells without releasing it systemically, Polverino said.
ZW49, a HER2-targeted antibody-drug conjugate for HER2-expressing cancers, resulted from the application of the Zymelink platform to zanidatamab, which is a HER2-targeted bispecific antibody. “ZW49 is unique in that it utilizes a biparatopic binder using Azymetric to HER2,” Polverino said. “ZW49 also utilizes our normal linker toxin platform to deliver toxins directly to HER2-expressing cells.”
A traditional antibody has two binding arms targeted towards a given antigen. “They are coupled to a Fc domain that interacts with the immune system,” Polverino said. Azymetric can introduce mutations that enhance the ability of those two different arms to come together. Azymetric is unique in the flexibility it offers in terms of tweaking the binding arms. “You need those two arms to come together homogeneously and to express and behave as similarly as possible to a traditional IgG-type molecule,” Polverino said. The Azymetric platform offers such functionality. “We think it’s best-in-class for creating bispecific-type molecules,” he said.
Filed Under: clinical trials, Drug Discovery, Oncology