Pfizer takes on Merck in a new checkpoint

Pfizer might have been beaten by Merck & Co in the original checkpoint inhibitor arena, PD-(L)1 blocking, but this hasn’t stopped it from trying again. Pfizer is about to go into human trials with a bispecific antibody against LILRB1 and LILRB2 – targets also known as ILT2 and ILT4 respectively, where Merck & Co is a prominent contender.

Other new clinical entrants, according to the latest listings on the clinicaltrials.gov registry, include BeiGene’s first NK cell engager, and a Pol theta inhibitor from Moma Therapeutics, which will challenge GSK in this synthetic lethality mechanism.

LILRB or ILT

Pfizer’s PF-07826390 hits both LILRB1 and LILRB2 (ILT2 and ILT4), which are expressed on myeloid cells in the tumour microenvironment and are implicated in suppressing the body’s anti-tumour immune response. It’s hoped that hitting these targets could help overcome PD-(L)1 resistance.

According to OncologyPipeline, the only other player with a similarly acting clinical-stage bispecific is NGM Biopharmaceuticals, whose NGM707 has yielded an 11% ORR in combination with Keytruda in a phase 1 solid tumour trial, with more data from the same study imminent.

But the biggest contender here is Merck, which licensed the anti-ILT4 MAb MK-4830 from Agenus in 2014; phase 2 trials are ongoing. Agenus also has a wholly owned anti-ILT2 MAb, AGEN1571.

Pfizer is testing its candidate as monotherapy and alongside its subcutaneous PD-1 inhibitor sasanlimab in metastatic solid tumours including NSCLC, colorectal cancer and renal cell carcinoma.

NK cells & synthetic lethality

Meanwhile, BeiGene is making a first attempt as NK cell engagement with BGB-B3227, which targets Muc1. With this modality the company is going up against Affimed, an NK cell engager specialist that has fallen out of favour with investors.

Another NK cell project has also hit the clinic: Base Therapeutics’ NK520. Base editing is said to be a more precise version of Crispr/Cas9, and Base Therapeutics claims to have a next-generation technology it calls AccuBase that, it says, could reduce off-target effects. Now it needs to prove this in humans, with two Chinese trials having started in July.

Synthetic lethality has been a hot sector, and the latest project to start human testing here is Moma Therapeutics’ Pol theta inhibitor MOMA-313. A big rival here is GSK, which has licensed GSK4524101 from Ideaya Biosciences.

The only other companies with active clinical-stage Pol theta inhibitors, according to OncologyPipeline, are Artios Pharma, with ART6043, and Varsity Pharmaceuticals, with novobiocin (VP-006).

Mystery projects

An unusual first-in-human project is AstraZeneca’s AZD5492 – a subcutaneous trispecific antibody that binds to CD20, CD8 and the T-cell receptor.

Other assets are more mysterious still, with no target details available for Novartis’s ITU512 or Bristol Myers Squibb’s BMS-986484.

ITU512, which is being developed for sickle cell disease, could be the WIZ degrader that Novartis has long been promising to take into the clinic. WIZ is a repressor of fetal haemoglobin, and increasing fetal haemoglobin is the aim of various sickle cell therapies including Vertex and Crispr Therapeutics gene edited therapy Casgevy.

Meanwhile, BMS-986484 might be a bispecific targeting CD40 and FAP, based on keywords on the clinicaltrils.gov entry. Roche has been a key proponent of FAP, having had several attempts here; that group’s current contender is RG7827, a FAP/4-1BB-targeting fusion protein.

Recently disclosed first-in-human studies*

Note: *projects newly listed on the clinicaltrials.gov database between 6 and 9 August 2024.