Zymeworks becomes the latest mesothelin dropout

Mesothelin has long looked like a dead end, and Zymeworks put another nail in this target’s coffin on Tuesday with the discontinuation of its T-cell engager ZW171. The project, which had been in a phase 1 trial in mesothelin-expressing tumours, was scuppered by “on-target, off-tumour toxicity”.

A look at OncologyPipeline shows only a handful of mesothelin-targeting T-cell engagers, and things have gone quiet on one of the few clinical-stage projects, Johnson & Johnson’s JNJ-79032421. However, a couple of groups are persevering, including Context Therapeutics, which is due early data on CT-95 next year, and Molecular Partners, which has two shots at this target.

Evercore ISI's Jonathan Miller applauded Zymeworks' decision to pull the plug on ZW171 early, but the company's stock still closed down 5% on Tuesday. 

Failures

Many have tried hitting mesothelin, commonly using Car-T, but with little success, with expression in healthy tissues leading to toxicity. Zymeworks didn’t say what side effects it had seen with ZW171, but Miller cited pleuritis/pericarditis and acute pulmonary injury as issues previously observed with mesothelin-targeting projects.

Another problem is that mesothelin is commonly shed into the pleural fluid and blood, creating a “sink” within tumours and narrowing the therapeutic window.

J&J had hoped to solve this with JNJ-2421, which was designed to bind to membrane-region mesothelin, presumably avoiding shed mesothelin. However, there has been no word yet on a phase 1 trial completed in June, and the project is no longer listed in J&J’s pipeline. It seems that this approach did no better than the others.

The most advanced T-cell engager player now is Context, which paid just $3.8m for Link Therapeutics’ CT-95. A phase 1 study in various solid tumours associated with mesothelin expression is under way, with dose-escalation data expected in mid-2026.

Mesothelin-targeting T-cell engagers 

Note: *targets membrane-region MSLN; **anti-esothelin x EpCAM x CD3 x CD2 switch darpin. Source: OncologyPipeline.

Meanwhile, Molecular Partners is developing two preclinical mesothelin-targeting projects, the most advanced of which is the darpin radioconjugate MP0726. Darpins (designed ankyrin repeat proteins) use protein-based binding molecules, instead of antibodies, and the company believes that its asset selectively binds membrane-bound mesothelin without being affected by shed mesothelin. First clinical data are due next year.

Further behind is a so-called switch darpin designed to activate T cells only in the presence of cells co-expressing mesothelin and EpCAM that, the company hopes, could help avoid activation in healthy tissue. That project also incorporates CD2 co-stimulation.

As for Zymeworks, that company’s lead wholly owned project is the anti-folate receptor alpha (FRα) ADC ZW191, which unlike AbbVie’s similarly acting drug Elahere uses a topoisomerase 1 inhibitor payload. Initial clinical data with ZW191 are due late this year or early next.

Zymeworks also has various projects set to enter the clinic soon, including the GPC3-targeting ADC ZW251, and the DLL3 x CD28-targeting trispecific T-cell engager ZW209.

The company this year “paused” development of a NaPi2b-targeting ADC, ZW220, but apparently still has hopes to partner this asset, according to Miller.