Two MSLN-Targeted TCEs Halted: Zymeworks Terminates ZW171, Janssen Quietly Drops JNJ-79032421

This week, two mesothelin (MSLN)-targeted T cell engagers (MSLN TCE) encountered setbacks.

FirstZymeworks StopsMSLN TCE PipelineThe clinical development of ZW171; followed by Johnson & JohnsonMSLN TCE JNJ-79032421 has quietly exited the pipeline development.

September 2, 2025Zymeworks Announces Voluntary Halt of its Mesothelin (MSLN)-Targeted T-Cell Engager (MSLN-TCE）Clinical Development of ZW171.

ZW171 is a2+1 StructureMSLN TCE, with lower T-cell binding capacity, for high expressionMSLN tumor cells exhibit high cytotoxic activity but low expression.The tumor cell binding affinity of MSLN is relatively low.

According to the press release, stopThe decision for the clinical development of ZW171 is based on itsThe dose escalation portion of the Phase 1 clinical trial has completed the planned cohort study in patients with ovarian cancer and non-small cell lung cancer. After completing the planned dose escalation cohorts and determining the maximum tolerated dose, Zymeworks believes that further dose evaluation in the current trial is unlikely to support a benefit-risk profile consistent with the target product profile for single-agent therapy.

Although cytokine release syndrome was well-controlled in the Phase 1 study, dose-limiting toxicity remained associated withConsistency of Mesothelin-Related Targeted Non-Tumor Toxicity。

Participants currently enrolled in Phase 1 trials will continue to receive treatment based on the investigator's judgment, and participants who have stopped treatment will continue to undergo safety follow-up according to the study protocol.

What a pityZW171 Demonstrates Activity in Preclinical Studies, Another GenerationMSLN TCE thus clinically failed.

According toAccording to Oncologypipeline, Johnson & Johnson's JNJ-79032421 completed Phase 1 study for solid tumors in June 2025 and is no longer in Johnson & Johnson's R&D pipeline.

JNJ-79032421 has a 2+2 structure, utilizing dual-epitope blocking technology. The two MSLN-binding domains synergistically inhibit sMSLN interference while extending the half-life through Fc enhancement. It exhibits high-activity TCE properties, with optimized CD3 affinity gradients, achieving potent T-cell activation and controllable CRS in preclinical models.

Mesothelin (MSLN),It has become a popular target for tumor-targeted therapy research due to its high specific expression in various solid tumors, and is widely used in the development of various innovative drugs, including TCE, ADC and other innovative antibody drugs, as well as CAR-T cells.

But again becauseMSLNTableReaching some normal tissues,Soluble mesothelin interference and other issues,MSLN has also become the most challenging target for development. Multinational pharmaceutical companies such as Bayer, Roche, and Merck are all involved.Failed in MSLN-targeted drugs.

The development of MSLN TCE is also highlyChallenging. ByHarpoon Therapeutics' First-GenerationMSLN TCE PipelineHPN-536 was previously suspended from development due to lack of efficacy, primarily becauseHPN-536 and ShedMSLN binding, leading toInsufficient exposure affects efficacy.

And now,ZymeworksZW171 due toMesothelin-related targeted non-tumor toxicity issues lead to clinicalTermination, Johnson & JohnsonJNJ-79032421 has mysteriously exited the pipeline again.

There are currently a few more.MSLN TCE Pipeline is under development, including fromContextCT-95、Amgen's AMG 305.

References:

1.https://ir.zymeworks.com/news-releases/news-release-details/zymeworks-announces-decision-discontinue-clinical-development

2.https://ir.zymeworks.com/static-files/fa55ccc2-7b79-4880-b3a1-032d04698f2b

3. Never Quite Like the Youthful Journey《Johnson & Johnson MSLN TCE Withdraws from Pipeline》

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