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Mesothelin lives on

Work targeting mesothelin, and some other antigens that have hitherto disappointed, continues.

Mesothelin has few clinical success to its credit, with Takeda the latest to pull the plug on work on this tumour-associated antigen. Nevertheless, biopharma continues to invest in it, and the latest clinical trial listings reveal two anti-mesothelin assets, from Johnson & Johnson and UTC Therapeutics, starting human studies for the first time.

Also new to the clinic are BeiGene’s CDK2 inhibitor – a field gaining significant traction of late – Aprea’s attempt at inhibiting Wee1, and an anti-CTLA-4 MAb from GigaGen. CTLA-4 and mesothelin are both well-known targets, but J&J and GigaGen appear to be taking a novel tack with the hope of improving on competitors’ earlier work.

In a December investor presentation J&J listed JNJ-79032421 among preclinical assets it would soon take into phase 1, and the first-in-human study began this month, according to The project is a T-cell engaging MAb against mesothelin, but J&J describes its target as mrMSLN.

mrMSLN stands for membrane-region mesothelin, and work on it was spurred by the finding that mesothelin shedding is a major obstacle to successful targeting of this antigen. The NCI developed a MAb that targeted mesothelin and bound next to the cell membrane at its protease-sensitive region, inhibiting its shedding, and presumably JNJ-79032421 follows a similar principle.

China’s UTC Therapeutics is taking a more typical shot at mesothelin with the Car-T therapy UCMYM802, which has started phase 1 in mesothelin-positive solid tumours.


Meanwhile, GigaGen says its anti-CTLA-4 MAb GIGA-564 differs from the likes of Yervoy and Imjudo by specifically depleting T regulatory cells in the tumour microenvironment but not blocking the binding of CTLA-4 to B7 ligands.

GigaGen is a US start-up that since 2021 has been wholly owned by the blood products company Grifols; an initial 44% GigaGen stake cost Grifols $35m in 2017, and the remainder was acquired for a further $80m. The characteristics of GIGA-564 are designed to increase efficacy and reduce toxicity – a known problem of CTLA-4 blockade.


Recently disclosed first-in-human studies*

ProjectMechanismCompanyTrialScheduled start
UCMYM802Anti-mesothelin Car-TUTC TherapeuticsMesothelin +ve solid tumours1 Jan 2024
VIO-01/ OX425Pan-DDR decoyValerio Therapeutics (FKA Onxeo)Breast cancer or HRRm/HRD+ve solid tumours10 Jan 2024
KK2269Undisclosed bispecific MAbKyowa KirinSolid tumours25 Jan 2024
JNJ-79032421/ JNJ-2421Anti-mesothelin T-cell engagerJohnson & JohnsonSolid tumours5 Feb 2024
ReT01 ACTUnknownAeonvital BiomedicineSolid tumours18 Feb 2024
BG-68501/ ETX-197CDK2 inhibitorBeiGene (ex Ensem)Solid tumours19 Feb 2024
GM103Oncolytic virusGeneMedicineSolid tumours29 Feb 2024
SPX-303Anti-LILRB2 x PD-L1 bispecific MAbSparX BiotechSolid tumoursFeb 2024
GIGA-564Anti-CTLA-4 MAbGigaGen (Grifols)Solid tumoursMar 2024
APR-1051Wee1 inhibitorApreaSolid tumoursJun 2024

Note: *projects newly listed on the database between 13 and 20 Feb 2024.


Development of inhibitors of CDK2 has been gaining traction, based on the finding that this kinase subtype could act as a resistance mechanism arising in response to treatment with CDK4/6 inhibitors like Kisqali, Verzenio and Ibrance.

The most advanced industry projects belong to Pfizer and Blueprint Medicines, and the space has seen an uptick in deal activity. One of these deals was between BeiGene and the private US biotech Ensem Therapeutics last November, and now BeiGene has taken the result of this tie-up, a CDK2 inhibitor coded BG-68501, into its first phase 1 trial. 

Finally, synthetic lethality has continued to attract interest, though one such approach, Wee1 inhibition, has been abandoned by AstraZeneca, which had once been its biggest proponent. Despite this, the micro-cap Aprea is starting phase 1 with its Wee1 inhibitor APR-1051, which will thus become its second clinical-stage pipeline asset, after the ATR inhibitor ATRN-119.

Unfortunately for Aprea, ATR blockade has also seen significant setbacks. Aprea was once focused on the p53 protein, sometimes called the guardian of the genome, but the failure in 2021 of its p53 reactivator eprenetapopt destroyed its share price, and the group is now worth just $20m.