Zymeworks Inc. announced 11 presentations including new data from the Company's clinical and preclinical development-stage programs at the 2023 American Association for Cancer Research Annual Meeting being held in Orlando, Florida. Presentation Highlights: ZW191, a novel FRa-targeting antibody-drug conjugate bearing a topoisomerase 1 inhibitor payload: Human folate receptor alpha (FRa) is a glycosyl-phosphatidylinositol-linked membrane protein. Expression of FRa is rare in normal tissue, but frequently elevated in several solid tumour types including epithelial ovarian cancer, endometrial cancer and lung adenocarcinoma.

ZW191 is an antibody-drug conjugate (ADC) targeting FRa comprised of a novel fully humanized IgG1 antibody covalently conjugated to a novel topoisomerase 1 inhibitor ZD06519, a camptothecin derivative, via endogenous interchain cysteines with a drug to antibody ratio (DAR) of eight. The linker in ZW191 consists of a maleimidocaproyl anchor and a glycyl glycyl phenylalanyl glycine-aminomethyl protease-cleavable sequence. Upon target binding and receptor-mediated internalization of ZW191, intracellular release of bystander-active ZD06519 induces cell death of FRa positive cells and FRa negative cells through bystander-mediated killing.

Key Results: • ZW191 exhibited a compelling preclinical activity profile that supports potential activity in targeting FRa-high/mid/low ovarian cancers. • ZW191 demonstrated strong responses in FRa-low expressing PDX models, indicating potential activity in other oncology indications with lower levels of FRa. • ZW191 displayed favorable pharmacokinetics (PK) and is well tolerated in non-human primates (NHP) at exposure levels above those projected to be efficacious.

ZW171, a T cell-engaging, bispecific antibody for the treatment of mesothelin-expressing solid tumors: Mesothelin (MSLN) is a glycosylphosphatidylinositol-linked membrane glycoprotein that is overexpressed in many cancer indications, including pancreatic, mesothelioma, and ovarian, for which there is a high unmet medical need. While MSLN-targeting agents have shown early signs of clinical activity, there remains a need for therapies with improved safety and efficacy. T cell engager (TCE) therapies have exhibited clinical utility against hematological malignancies but have shown limited success against solid tumors due to dose-limiting toxicities associated with risk of cytokine release syndrome (CRS) and on-target off-tumor effects.

To improve the therapeutic intervention of MSLN-expressing tumors, Zymeworks utilized proprietary technologies based on the company's Azymetric™ and EFECT™ platforms as well as focused engineering strategies to generate a panel of MSLN-targeting TCEs with a variety of formats, geometries, and paratope affinities. ZW171 was selected for development from this panel based on its enhanced anti-tumor activity and safety. Key Results: • ZW171 induced potent preferential killing of MSLN-overexpressing target cells and stimulated MSLN-dependent T cell activation, mitigating the risk of on-target off-tumor toxicity and peripheral T cell activation and CRS.

• ZW171 exhibited potent tumor growth inhibition in MSLN-expressing tumor models and was well tolerated in cynomolgus monkeys up to a single dose of 30 mg/kg. • Data suggest that ZW171 could overcome the issues impeding the success of other TCEs developed to treat solid tumors and provide the therapeutic rationale to support the development of ZW171 for the treatment of MLSN-expressing tumors. ZW251, a novel glypican-3-targeting antibody-drug conjugate bearing a topoisomerase 1 inhibitor payload: Glypican-3 (GPC3) is a membrane-associated proteoglycan that is specifically up-regulated in a substantial proportion of patients with hepatocellular carcinoma (HCC)4, the most common type of liver cancer.

Liver cancer is a major cause of death in many countries, and the number of people diagnosed with liver cancer is expected to rise5. ZW251 is an ADC consisting of a topoisomerase 1 inhibitor payload conjugated to an antibody targeting GPC3. Topoisomerase 1 inhibiting ADCs have demonstrated wide clinical benefit in solid tumors and ZW251 aims to apply this against a target expressed in hepatocellular carcinoma (HCC), a disease with high unmet need and limited treatment options.

Key Results: • ZW251 exhibited robust anti-tumor activity in a large panel of HCC cell line-derived xenograft (CDX)and PDX models at both DAR 4 and DAR 8. • Anti-tumor activity (tumor growth inhibition > 50%) for ZW251 was evident in 82% of models with GPC3 H-score > 200 and 50-75% of models with GPC3 H-score • No mortality was observed in a repeat dose NHP toxicology study with doses up to 60 mg/kg (DAR 8) or 120 mg/kg (DAR 4). • ZW251 is a potentially first-in class glypican-3 targeting ADC.