Lilly joins the folate receptor arena

Genmab, which last month bought the private biotech ProfoundBio for $1.8bn, now has a new clinical-stage competitor in the shape of Lilly. ProfoundBio’s lead project is the folate receptor alpha (FRα) targeting ADC rinatabart sesutecan, and Lilly has just taken the similarly acting LY4170156 into phase 1.

The study has just been revealed on the clinicaltrials.gov registry, along with several other first-in-human initiations. Other new projects include yet another KRAS G12D inhibitor, from Qilu, and attempts to buck the negative trends in 4-1BB activation and MAGE-A4 targeting.

FRα resurgence

The most prominent FRα-targeting ADC is AbbVie’s approved product Elahere, gained through last year’s $10.1bn takeout of ImmunoGen. However, plenty of others are vying for a piece of this target, including Sutro, which has luveltamab tazevibulin and has notably not been acquired. 

Luvelta-T and Elahere both use a tubulin inhibitor payload, while ProfoundBio and now Lilly have opted for the currently more fashionable topoisomerase 1 inhibitor. Lilly gained LY4170156 via its purchase of Mablink last October; in its 2023 annual report it disclosed that $257m was written off to account for the acquired Mablink R&D. 

Other big hitters developing Frα-targeting ADCs include Eisai and Bristol Myers Squibb, with the tubulin inhibitor-based farletuzumab ecteribulin, and AstraZeneca with AZD5335, which employs a topoisomerase 1 inhibitor.

Crowded vs novel

Talking of crowded areas, China’s Qilu is the latest to get into KRAS G12D inhibition, with QLC1101. 

Meanwhile, privately held Multitude Therapeutics is going after a more novel target with AMT-676, an ADC that hits cadherin-17 (CDH17), a protein thought to be involved in gastric cancers. However, Boehringer Ingelheim recently quietly dropped its anti-CDH17 x Trail-R2 bispecific antibody BI 905711.

Multitude is gunning for another novel target, CDH6, with the OnCusp-partnered CUSP06, but the rest of its pipeline looks more familiar: incidentally, its lead project is an FRα-directed ADC, AMT-151.

Another approach that has run into difficulties is activating the 4-1BB co-stimulatory pathway to enhance activity against another target. But Sound Biopharmaceuticals believes that this still has legs, with its anti-5T4 x 4-1BB bispecific another new entrant to the clinic. The group isn’t the only one to keep the faith with 4-1BB, but according to OncologyPipeline Alligator Bioscience's Aptevo-partnered ALG.APV-527 is the only other project that also acts on 5T4; phase 1 readout with this has been delayed from late 2023 to the second half of this year.

Mage-A4 has also had its ups and downs, and the latest to try its luck here is CDR-Life, with the T-cell engager CDR404. Roche earlier scrapped a similarly acting project, RO7444973, while much of the other work in this arena has been on engineered T-cell receptors, with Adaptimmune awaiting a US approval verdict by 4 August on its contender afami-cel. 

Grit Biotechnology might be hoping to follow in the footsteps of Iovance with its tumour-infiltrating lymphocyte contender GT307; however, a look at OncologyPipeline shows plenty of others are trying to do the same.

Recently disclosed first-in-human studies*

Notes: *projects newly listed on the clinicaltrials.gov database between 2 and 10 May ; **could be CK2α inhibitor, based on AACR 2024 poster.

This story has been updated to include the Mablink acquisition price.