Zymeworks Showcases Preclinical Data on ADC Programs at EORTC-NCI-AACR Conference

Zymeworks Inc., a clinical-stage biotechnology firm specializing in the development of innovative biotherapeutics, has recently unveiled significant preclinical data for its two promising antibody-drug conjugate (ADC) candidates, ZW220 and ZW251. These findings were presented at the European Organisation for Research and Treatment of Cancer-National Cancer Institute-American Association for Cancer Research (EORTC-NCI-AACR) Conference in Barcelona.

Paul Moore, Ph.D., Chief Scientific Officer at Zymeworks, expressed his enthusiasm about the unveiled preclinical data. He emphasized the potential of these ADC candidates, which incorporate Zymeworks’ proprietary payload, ZD06519, to address critical unmet needs in oncology. Moore highlighted the potential of these programs to enhance treatment options beyond the current standards, offering new hope for patients with challenging cancers where therapeutic progress has been limited.

The oral presentation titled “ZW220, a NaPi2b-directed topoisomerase I inhibitor Antibody-Drug Conjugate, demonstrates compelling preclinical activity in NSCLC, ovarian and uterine cancer models, with a favorable toxicology profile in non-human primates,” focused on ZW220. This ADC has shown promising preclinical activity and a favorable toxicology profile, supporting its potential for an investigational new drug (IND) submission in the first half of 2025.

ZW220 has demonstrated efficacy, tolerability, and a unique mechanism of action. Featuring a novel, moderate potency TOPO1i payload with strong bystander activity, ZW220 is beneficial for tumors with low and heterogeneous NaPi2b expression. It also offers a differentiated safety profile compared to other ADCs currently in clinical development. Animal studies have shown high tolerability, with maximum tolerated doses (MTDs) of ≥90 mg/kg in non-human primates and ≥200 mg/kg in rats. This suggests the potential for high doses in humans. ZW220's low drug-antibody ratio (DAR) and moderate stability provide a good balance of stability, tolerability, and anti-tumor activity while potentially minimizing antibody-driven toxicities. Its strong internalizing antibody enables efficient cellular trafficking and tissue penetration, potentially improving anti-tumor activity even at lower NaPi2b levels.

A poster titled “ZW251, a novel glypican-3-targeting antibody-drug conjugate bearing a topoisomerase I inhibitor payload, demonstrates compelling preclinical activity in hepatocellular carcinoma models” featured ZW251. This ADC has shown strong preclinical activity in hepatocellular carcinoma (HCC) models, supporting an IND submission in the second half of 2025.

ZW251 holds promise as a new treatment option for HCC patients, potentially improving upon the current standard of care. It has demonstrated significant anti-tumor activity across various HCC models, including those with lower and heterogeneous GPC3 expression. Designed with a DAR of four, ZW251 balances tolerability and broad anti-tumor effectiveness. In non-human primates, ZW251 displayed significant tolerability at doses up to 120 mg/kg, suggesting the possibility of high initial dosing in human trials. As an ADC, ZW251 offers flexibility in treatment strategies, potentially serving as a standalone therapy or in combination with existing treatments.

ZW220 targets NaPi2b-expressing non-small cell lung cancer (NSCLC) and ovarian cancers, featuring Zymeworks’ proprietary TOPO1i-payload technology. The NaPi2b-targeting antibody was developed in-house and selected for its favorable binding profile and enhanced internalization properties. This enables targeting both high- and low-NaPi2b-expressing tumors. The antibody in ZW220 is Fc-silenced to minimize potential off-target toxicities. ZW220 has shown anti-tumor activity in patient-derived xenograft models and robust growth inhibition in 3D spheroid models of these cancers. The bystander effect of the TOPO1i payload may help address NaPi2b heterogeneity across these cancers. ZW220 is well-tolerated in non-human primates and rats, reaching maximum tolerated doses of ≥90 mg/kg and ≥200 mg/kg, respectively. Zymeworks plans to submit an IND and non-U.S. applications for ZW220 in the first half of 2025.

ZW251, designed for glypican 3 (GPC3)-expressing HCC, incorporates the same Zymeworks proprietary bystander-active TOPO1i payload used in ZW220. Preclinical studies have shown anti-tumor activity in multiple HCC models with varying levels of GPC3 expression. GPC3 is over-expressed in most HCC patients, making it an appealing ADC target. In non-human primate studies, ZW251 displayed significant tolerability at doses up to 120 mg/kg, suggesting the potential for high initial dosing in human trials. Zymeworks plans to submit an IND and non-U.S. applications for ZW251 in the second half of 2025.

Zymeworks Inc. is a global clinical-stage biotechnology company dedicated to discovering, developing, and commercializing novel biotherapeutics. Its mission is to make a significant difference in the lives of people with difficult-to-treat cancers and other diseases. Zymeworks leverages its therapeutic platforms and drug development engine to engineer and develop differentiated antibody-based therapeutic candidates.