FDA Approves Trials for ZW171: A Novel Bispecific Antibody for Hard-to-Treat Cancers

Zymeworks Inc. announced that the United States Food and Drug Administration (FDA) has cleared its investigational new drug (IND) application for ZW171. This novel bispecific antibody targets mesothelin-expressing cancers, such as ovarian and non-small cell lung cancer. ZW171 is designed to enhance tumor selectivity and improve safety. The company plans to initiate clinical trials in 2024.

Paul Moore, Chief Scientific Officer of Zymeworks, expressed enthusiasm about this significant milestone and emphasized that ZW171 is designed to overcome the limitations of current bispecific T-cell engagers by enhancing tumor selectivity and improving safety. "With promising preclinical results, ZW171 has the potential to provide a more effective and tolerable treatment option for patients with MSLN-expressing cancers, including ovarian cancer, non-small cell lung cancer, mesothelioma, and other cancers" he stated.

ZW171 represents a new class of cancer therapy known as 2+1 T-cell targeting bispecific antibodies. These are engineered to boost the body’s immune response against cancer cells without harming healthy tissues. The design involves dual binding: one part of the antibody binds to the mesothelin (MSLN) protein on cancer cells, while another part engages the CD3 receptor on T cells. This dual binding is expected to direct the body's immune T cells to attack the tumors more effectively.

The unique ‘2+1’ format of ZW171, which incorporates a novel low-affinity anti-CD3 binder, is specifically designed to enhance tumor targeting while reducing side effects like cytokine release syndrome (CRS)—a common complication with other immune therapies that can cause severe inflammatory symptoms.

Potential Across Various Cancers

Mesothelin is a protein found at high levels on the surface of several types of cancer cells, including ovarian cancer, non-small cell lung cancer, and mesothelioma, making it an attractive target for therapies. ZW171's ability to selectively engage T cells with cancer cells expressing mesothelin suggests a potential for high efficacy in these cancers

Promising Preclinical Results

Before reaching this stage, ZW171 showed promising results in preclinical studies, demonstrating potent anti-tumor activity. It preferentially killed cells overexpressing mesothelin while minimizing the activation of T cells that could affect normal tissues. This enhances the effectiveness of the treatment and improves safety.

Next Steps in Clinical Development

Zymeworks plans to initiate clinical development of ZW171 within 2024 and aims to advance additional product candidates as part of their '5 by 5' strategy over the next 24 months. The company also announced plans to file applications for regulatory permissions to start clinical studies for ZW171 in various non-US jurisdictions during the second half of 2024.

Developed using Zymeworks’ proprietary Azymetric™ and EFECT™ technologies, ZW171 has shown enhanced anti-tumor activity and safety in preclinical models. These technologies enable potent, selective killing of MSLN-overexpressing cells while minimising risks associated with on-target, off-tumour activity, peripheral T cell activation, and CRS (cytokine release syndrome).

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