The failure of Celldex’s anti-gpNMB antibody-drug conjugate glembatumumab vedotin was seen by some as the death knell for this mechanism. Not so, clinicaltrials.gov shows: the registry has just revealed that Pfizer has advanced PF-08046033, an ADC with the same target, into its first-in-human study.
It appears that the two projects’ antibodies are at the very least extremely similar, and it's clear that their payloads differ only slightly. PF-08046033 uses a “novel” auristatin S, where glemba-V employed the more typical monomethyl auristatin E (MMAE), which is best known as the payload on Pfizer’s Seagen-derived blockbuster Adcetris.
A poster due to be presented at this weekend’s AACR meeting makes the distinction clear, stating that glemba-V’s early signs of efficacy were marred by dose-limiting toxicities, most of which were “likely driven by the released MMAE payload”. In contrast, auristatin S is engineered to be less permeable than MMAE, a feature that could widen PF-08046033’s therapeutic window.
The poster also discloses that PF-08046033 uses the human IgG1 anti-gpNMB antibody hCR011. Glemba-V used a fully human MAb coded CR011, so it appears that the antigen-targeting ends of glemba-V and PF-08046033 are extremely similar, and might even be identical.
The phase 1 solid tumour study, which clinicaltrials.gov says began at the start of this month, should show whether PF-08046033 might overcome the setback of glemba-V, discontinued in 2018 after failing a phase 2 trial in breast cancer. Celldex had licensed the linker and payload used in glemba-V from Seagen, which since 2023 has been owned by Pfizer.
Either way, it’s clear that gpNMB, a transmembrane protein thought to be upregulated in several cancers, is a fairly untested target. OncologyPipeline reveals only one other clinical-stage project apart from PF-08046033, and that’s a Car-T therapy in a protocol designed by Health Canada for a single patient with alveolar soft part sarcoma.
Recently disclosed first-in-human studies*
Another highly unusual target that features in the latest first-in-human study initiations is DYRK2, where Tasly has advanced the DYRK2/CDK4/6 inhibitor TSL2109. DYRK2 is a conserved enzyme that acts as a key regulator of cell cycle progression, apoptosis and protein degradation, and no other inhibitors appear to be in development.
Meanwhile, two companies that might soon have marketed drugs on their hands, Immunome and Ideaya, are branching out. Immunome’s gamma secretase inhibitor varegacestat is to be filed shortly, but in the meantime the company is starting a human trial of an anti-FAP radioconjugate; several companies, including Novartis, are working on FAP inhibition.
Ideaya this week reported a clinical success with its pan-PKC inhibitor darovasertib, and had already announced the dosing of the first patients in phase 1 trials of four new pipeline projects: the KAT6/7 inhibitor IDE574, PRMT5 inhibitor IDE892, anti-DLL3 ADC IDE849, and anti-B7-H3 x PTK7 ADC IDE034. Though the last began in February, its entry has just appeared on clinicaltrials.gov.
