TROP2 remains hot

Two separate antibody-drug conjugates targeting TROP2 are entering human trials for the first time, showing continued interest in this antigen, likely spurred by AstraZeneca/Daiichi Sankyo’s datopotamab deruxtecan and Merck & Co/Kelun’s sacituzumab tirumotecan.

Only one of the new entrants, OBI Pharma’s OBI-992, is a purely TROP2-targeting molecule; the other, Biocytogen’s DM001, hits EGFR as well as TROP2. The new entries have been revealed in the latest listings on the clinicaltrials.gov registry, which also feature Adicet’s shot at a cell therapy against CD70, and Teva’s return to PD-1 blockade after many years’ absence.

OBI Pharma’s OBI-992 uses a topoisomerase 1 inhibitor payload but is said to have high serum stability and a broad therapeutic index, with the aim of improving safety over other topo-based ADCs. These pharmacokinetic attributes were shown in a preclinical poster presented at April’s AACR meeting, so now OBI will be hoping to demonstrate this clinically.

Meanwhile, dato-dxd is in two phase 3 studies combining it with Astra’s anti-EGFR drug Tagrisso (Tropion-Lung14 and 15), and the aim behind Biocytogen’s DM001 might be simply to combine the two mechanisms in one molecule. OncologyPipeline reveals few other industry projects that have activity at TROP2 as well as EGFR.

A completely different approach is taken by the private US company Myeloid Therapeutics, whose MT-302 comprises lipid nanoparticles delivering mRNA that encodes an in vivo Car against TROP2. Now, clinicaltrials.gov reveals, Myeloid is entering phase 1 with a second such in vivo Car, MR-303, which targets GPC3; that antigen was thrust into the spotlight by results of AbelZeta’s Car-T therapy C-CAR031 at ASCO.

Recently disclosed first-in-human studies*

Note: *projects newly listed on the clinicaltrials.gov database between 26 and 28 Jun 2024.

It was about 18 years ago, at the dawn of the PD-(L)1 revolution, that Teva first worked on PD-1 blockade, in a collaboration with CureTech covering the molecule CT-011, later named pidilizumab. However, that work led nowhere, with the deal being terminated in 2013, and PD-1 was subsequently found not to be pidilizumab’s primary target.

Fast forward another 10 years, and Teva’s May 2023 “pivot to growth” presentation revealed another anti-PD-1 project, TEV-56278. It’s this that has now entered a phase 1 trial as monotherapy or in combination with Keytruda.

TEV-56278 combines activity on PD-1 with IL-2, and the possible need to give it with Keytruda suggests that hitting PD-1 is a means of delivering IL-2 to PD-1-positive T cells, rather than to exert PD-1 blocking activity. A similar approach is being taken by Anaveon’s ANV600, a non-blocking PD-1 x IL-2Rβ/γ fusion protein that’s also entering the clinic this month.

Meanwhile, in cell therapy Adicet is taking the anti-CD70 gamma-delta Car-T project ADI-270 into its first-in-human kidney cancer trial. ADI-270 is Adicet’s second clinical gamma-delta Car-T therapy, after the CD20-targeting ADI-001 struggled to deliver on its initial promise.

One problem about targeting CD70 with a T-cell therapy is the risk of fratricide, owing to this antigen’s transient presence on T cells themselves. For this reason Allogene’s allogeneic Car-T therapy ALLO-316, for instance, is designed to mask the presence of CD70 on the surface of the Car-T cells.

ADI-270 is said to be “armoured” against alloreactive host T cells, but appears to have no mechanism specifically against fratricide. Despite this, ADI-270 cells have preclinically been expanded “without indications of fratricide”, according to May’s ASGCT poster; now Adicet must repeat the trick in the clinic.