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Lilly joins the folate receptor arena

Lilly’s Mablink acquisition challenges Genmab’s move for ProfoundBio.

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 for an undisclosed fee. 

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*

ProjectMechanismCompanyTrialScheduled start
TT125-802CBP/p300 inhibitorTolremo TherapeuticsSolid tumours7 Nov 2023
GT307TIL therapyGrit BiotechnologySolid tumours18 Apr 2024
QLC1101KRAS G12D inhibitorQilu PharmaceuticalKRAS G12D+ve solid tumours25 Apr 2025
AMT-676Anti-CDH17 ADCMultitude TherapeuticsSolid tumours9 May 2024
CDR404Mage-A4 T-cell engagerCDR-LifeHLA-A*02:01, Mage-A4 +ve solid tumours15 May 2024
APL-5125Undisclosed**Apollo TherapeuticsSolid tumoursMay 2024
ETX-19477PARG inhibitor858 TherapeuticsSolid tumoursMay 2024
LY4170156/ MBK-103Anti-FRα ADCLilly (ex Mablink)FRα+ve solid tumoursMay 2024
Debio 4228GnRH antagonistDebiopharmMetastatic prostate cancerJun 2024
FTL008.16Anti-5T4 x 4-1BB bispecific MAbSound BiopharmaceuticalsSolid tumoursJun 2024
TB511CD18 fusion proteinTwinpig BiolabSolid tumours, +/- KeytrudaOct 2024
BAH243βA-T87Q-globin-encoding lentiviral gene therapyEssen BiotechSickle cell disease10 Nov 2024

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