On April 10, 2021 Zymeworks Inc. (NYSE: ZYME), a clinical-stage biopharmaceutical company developing multifunctional biotherapeutics, reported five presentations at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting (Press release, Zymeworks, APR 10, 2021, View Source [SID1234577826]). The presentations highlight preclinical data that reveal new insights into the unique mechanisms of action of lead clinical candidate, zanidatamab, introduce Zymeworks’ fourth therapeutic platform, ProTECT, and describe two new preclinical assets focused on the cytokine, IL-12, and the immune-oncology target, 4-1BB.
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Presentations are now available to registrants of the AACR (Free AACR Whitepaper) Annual Meeting and will also be archived on the Zymeworks website.
Zanidatamab Presentations
Super-resolution imaging studies of zanidatamab: providing insights into its bispecific mode of action
Abstract: 1032
Session Category: Experimental and Molecular Therapeutics
Session Title: Cellular Responses to Anticancer Drugs
The bispecific antibody zanidatamab’s (ZW25’s) unique mechanisms of action and durable anti-tumor activity in HER2-expressing cancers
Abstract: 1005
Session Category: Experimental and Molecular Therapeutics
Session Title: Cellular Responses to Anticancer Drugs
Zanidatamab, Zymeworks’ lead clinical candidate, is currently enrolling in a pivotal trial for refractory HER2-amplified biliary tract cancer (HERIZON-BTC-01) as well as several Phase 2 trials for HER2-expressing gastroesophageal and breast cancers. Zanidatamab is a bispecific antibody that simultaneously binds two distinct sites on HER2 resulting in multiple mechanisms of action. Research presented today at AACR (Free AACR Whitepaper) continues to demonstrate that zanidatamab induces the formation of HER2 receptor clusters and receptor internalization resulting in their downregulation, inhibits growth factor-dependent and -independent tumor cell proliferation, and potently activates the immune system via antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). New findings from this research have revealed that zanidatamab can form complexes with HER2 with distinct higher order geometry on the cell surface. The potential for zanidatamab-induced HER2 localization may promote C1q engagement and is consistent with the additional finding that zanidatamab has the unique ability to promote complement dependent cytotoxicity (CDC). This was not observed with either of the HER2-targeted monospecific antibodies, trastuzumab and pertuzumab, or their combination and may contribute to zanidatamab’s promising clinical activity.
"In addition to the broad clinical validation of zanidatamab, we continue to value ongoing research designed to better understand its unique biparatopic mechanisms of action," said Ali Tehrani, Ph.D., Zymeworks’ President & CEO. "These findings provide important insights for our clinical development strategy and support our goal of developing zanidatamab in earlier lines of therapy where the combination of trastuzumab and pertuzumab are the backbone of the current standard of care."
ProTECT Presentation
ProTECT, a novel antibody platform for integrating tumor-specific immune modulation and enhancing the therapeutic window of targeted multispecific biologics
Abstract: 924
Session Category: Experimental and Molecular Therapeutics
Session Title: Antibody Technologies
The ProTECT platform is the first conditionally-active antibody technology that can simultaneously address both ends of the therapeutic window by potentially reducing toxicity and increasing efficacy. Functional, natural heterodimers (e.g. PD-1/PD-L1) are introduced to sterically block antigen binding outside the tumor. As a result, therapeutics utilizing ProTECT have limited activity in normal healthy tissue, avoiding on-target, off-tumor toxicities. Once in the tumor microenvironment, proteases cleave and release one half of the functional block activating both the targeting antibody and the immunomodulatory function. The resulting activated multifunctional therapeutic enables immune modulation in concert with antigen binding, leading to an overall increase in the therapeutic window through selective tumor activity and enhanced potency. This platform is also transferable with minimal engineering so it can be easily applied to different therapeutic targets. Data presented today at AACR (Free AACR Whitepaper) showcase the utility of the ProTECT platform for the generation of a first-in-class CD3-redirecting multispecific that also comprises PD-L1 checkpoint blockade.
IL-12 and 4-1BB Presentations
Increasing the therapeutic index of IL-12 by engineering for tumor-specific protease activation
Abstract: 1788
Session Category: Immunology
Session Title: Modifiers of the Tumor Microenvironment
IL-12 is a cytokine produced by innate immune cells that potently stimulates anti-tumor cytotoxic T cell, T helper cell, and natural killer cell-mediated immunity. The use of IL-12 as a therapeutic approach has historically been limited by systemic toxicity observed in clinical trials, and current approaches to address this toxicity have focused on reducing the potency of IL-12, which may also limit its anti-tumor activity. To broaden the therapeutic window of this highly potent cytokine, systemic IL-12 activity was blocked with an anti-IL-12 antibody which was designed to be cleaved and released by proteases in the tumor microenvironment. Data presented at AACR (Free AACR Whitepaper) show that the therapeutic window of IL-12 may be increased by the combination of antibody blockade and cytokine modifications that synergize to localize activity to the tumor.
Understanding the geometry and valency of bispecific antibodies in the optimization of tumor-dependent activation of 4-1BB
Abstract: 1737
Session Category: Immunology
Session Title: Immunomodulatory Agents and Interventions
4-1BB is a receptor expressed on the surface of tumor-infiltrating T cells that when activated, can enhance T cell function leading to tumor regression. Unfortunately, the clinical development of several 4-1BB targeting antibodies has been plagued by dose-limiting liver toxicity and subsequent lack of anti-tumor activity. To address this liability, multiple formats of 4-1BB x TAA (tumor associated antigen) bispecific candidates were developed to identify those that could selectively activate T cells within the tumor microenvironment. A promising bispecific format with bivalent 4-1BB targeting and monovalent TAA targeting demonstrated the highest potential for tumor selectivity across several different TAAs and was subsequently evaluated in an in vivo xenograft model where it showed robust anti-tumor activity.
"The presentations highlighted at the AACR (Free AACR Whitepaper) Annual Meeting showcase Zymeworks’ proprietary protein engineering capabilities and how they are being used to develop solutions for a broad set of therapeutic modalities," said Tony Polverino, Ph.D., Executive Vice President, Early Development and Chief Scientific Officer of Zymeworks. "Leveraging different approaches to achieve tumor selective activity, from the functional block of the ProTECT platform, to the antibody block used in our IL-12 cytokine candidates, to the use of format and valency in our 4-1BB program, we’ve demonstrated several versatile ways to increase the therapeutic window of our drug candidates. We continue to exploit these approaches along with our bispecific, antibody-drug conjugate, and immunomodulatory platforms to build a diverse therapeutic pipeline."
About Zanidatamab
Zanidatamab is a bispecific antibody, based on Zymeworks’ Azymetric platform, that can simultaneously bind two non-overlapping epitopes of HER2, known as biparatopic binding. This unique design results in multiple mechanisms of action including dual HER2 signal blockade, increased binding, and removal of HER2 protein from the cell surface, and potent effector function leading to encouraging antitumor activity in patients. Zymeworks is developing zanidatamab in multiple Phase 1, Phase 2, and pivotal clinical trials globally as a targeted treatment option for patients with solid tumors that express HER2. The FDA has granted Breakthrough Therapy designation for zanidatamab in patients with previously treated HER2 gene-amplified Biliary Tract Cancer (BTC), and two Fast Track designations to zanidatamab, one as a single agent for refractory BTC and one in combination with standard of care chemotherapy, for first-line gastroesophageal adenocarcinoma (GEA). These designations mean zanidatamab is eligible for Accelerated Approval, Priority Review and Rolling Review, as well as intensive FDA guidance on an efficient drug development program. Zanidatamab has also received Orphan Drug designations for the treatment of biliary tract, gastric and ovarian cancers, as well as Orphan Drug designation for the treatment of gastric cancer from the European Medicines Agency.