AACR 2025 preview – new preclincal approaches abound

Well-known mechanisms such as TIGIT blockade might be set to hog the limelight at next month’s AACR meeting, but a look at the preclinical highlights reveals plenty of new approaches too.

Some of these involve novel targets like Ly6E, which is hit by Zymeworks’ ADC ZW327, while Zai Lab and Sotio are both taking aim at LRRC15, the former helped by a recent technology deal with MediLink. KAT6, which is in the spotlight after a recent Pfizer breast cancer reshuffle, will also feature, courtesy of Olema, one of the few clinical-stage contenders in this space.

The only other Ly6E project to have been studied, according to OncologyPipeline, was Roche and Seagen’s RG7841; however, phase 1 development was halted in 2016. In LRRC15 AbbVie abandoned its contender, samrotamab vedotin, and all the other players are currently preclinical.

TREM1 and TREM2 are also targets without much competition. TREM2 will be represented at AACR by iTeos, whose EOS-215 recently hit the clinic, and TREM1 by Singlomics and SignaBlok, which appear to be taking diametrically opposed approaches with an agonistic antibody and a small-molecule inhibitor respectively.

Selected preclinical trial presentations at AACR

More familiar targets will also be in focus, judging by the list of AACR abstracts, the titles of which were revealed on Tuesday after market. Claudin6, where BioNTech’s Car-T was recently joined by ADCs from Torl and Daiichi Sankyo, could see more competition from ADC Therapeutics’ ADCT-242. According to OncologyPipeline, the only other Claudin6 ADC in development is Axcynsis’s AT03-65, with phase 1 due to begin in April.

Others are taking a new angle on established targets; for example, Zymeworks has a DLL3-targeting trispecific T-cell engager, ZW209. The company must hope that this could surpass Amgen’s approved drug Imdelltra by incorporating CD28 co-stimulation, though such attempts haven’t met with much success. Roche is taking a similar approach in DLL3: RO7616789, incorporating 4-1BB co-stimulation, recently completed phase 1.

Cytokine-based therapies have also failed to live up to their initial hype, but there’s still activity here, and Zai Lab just unveiled a PD-1-targeted IL-12 known as ZL-1222 that will feature at AACR, alongside a rival project from Innovent, IBI3026.

The hope is that cytokine activity can be targeted to tumour cells, reducing toxicity; there are a couple of other such dual PD-1/IL-12 approaches, from AskGene Pharma and Bonum Therapeutics, but according to OncologyPipeline all are preclinical.

AACR takes place in Chicago on 25-30 April.