Regeneron keeps up its co-stimulatory crusade

Trying to harness co-stimulatory domains hasn’t always gone smoothly, but one of the biggest proponents of this approach, Regeneron, isn’t about to throw in the towel: the company is soon to start clinical development of its latest contender, the anti-CD38 x CD28 bispecific antibody REGN7945.

The most recent first-in-human study listings on the clinicaltrials.gov registry also reveal a project from AP Biosciences using a different co-stimulatory domain, 4-1BB, while degraders, projects against synthetic lethality targets, and bispecific antibodies targeting Claudin6 also feature.

More co-stimulatory candidates

Adding co-stimulatory domains to cancer therapies is designed to help activate T cells and bolster efficacy; however, the jury is still out on this broad approach, with Inhibrx discontinuing its anti-PD-L1 x 4-1BB INBRX-105 and Roche canning a CD19 x CD28 bispecific, RG6333, this year.

This hasn’t stopped others from persevering with co-stimulatory projects, and Regeneron is more exposed than most. Still, the group told ApexOnco at the recent ESMO meeting that it was confident about this strategy in general, and CD28 as its co-stimulatory domain of choice.

With REGN7945, though, the company is trying to go better than an already very successful therapy, namely Johnson & Johnson/Genmab’s anti-CD38 MAb Darzalex. This high bar could explain why no other CD38 x CD28 projects are in clinical development, according to OncologyPipeline.

Meanwhile, AP’s AP402 will become the second anti-HER2 x 4-1BB asset to reach humans, joining Yuhan’s YH32367.

Degrader determination

Degraders represent another approach that has largely fallen flat, but this hasn’t put off Pierre Fabre and Recursion Pharmaceuticals, with projects against cMet and RBM39 respectively; the latter is a target related to CDK12.

cMet is a crowded space, but Recursion is the first RBM39-targeting asset to hit the clinic; however, a search of OncologyPipeline reveals that Seed Therapeutics could also take its degrader ST-00937 into human trials next year.

Synthetic lethality mechanisms such as Wee1 and PKMYT1 have also had their ups and downs, but Acrivon, whose clinicaltrials.gov listing for ACR-2316 recently went live, isn’t the only group to combine both modalities in one molecule: Schrödinger took its similarly acting SGR-3515 into the clinic in June.

Meanwhile, another synthetic lethality target, Pol theta, is seeing increasing interest, and the latest entrant here is SynRx Therapeutics, with SYN818. Others going after this space include GSK, via a deal with Ideaya, Artios Pharma, Moma Therapeutics, Repare and Varsity Pharmaceuticals.

Claudin6 is yet another troubled target, and the latest clinical trials listings show two relevant assets here: Astellas’s bispecific ASP1893 and Third Arc Bio’s T-cell engager ARC101.

There are now nine projects against Claudin6 in clinical development by industry, according to OncologyPipeline; the most advanced are Car-Ts (BioNTech’s BNT211) and ADCs (Torl Biotherapeutics’ TORL-1-23 and Daiichi’s DS-9606a).

Data on all three were presented at ESMO in September, with efficacy looking similar between BNT211 and TORL-1-23, and DS-9606a lagging, although dose escalation with the last of these continues.

Recently disclosed first-in-human studies*

Note: *projects newly listed on the clinicaltrials.gov database between 30 Oct and 8 Nov 2024.