Raffaele Colombo: We always learn a lot from the publications of “unsuccessful” trials

Raffaele Colombo shared on X/Twitter:

“We always learn a lot from the publications of ‘unsuccessful’ trials.

MEDI7247 was an ADC targeting ASCT2, with a PBD (DAR2) conjugated to a site-specific Cys inserted after position S239 (C239i).

Half-life of both ADC and total mAb was very short (<24h)!

Visit the article website.

The SG3249 drug-linker is relative stable (similar to other MP-PEG8 linkers) and the stability was enhanced by the site selected for conjugation.

The poor PK likely derived from a combination of target sink and poor ADC properties (hydrophobicity)!

Visit the article website.

MEDI7247 antibody also contains a unique deamidation site, N102, located within the CDR, impacting the antibody binding to its target and, in turn, the cytotoxic potency and the pharmacology of the ADC.

Visit the article website.

Thrombocytopenia and neutropenia limited repeat dosing and dose-escalation phase was stopped early.

MTD was not established but <0.18 mg/kg Q3W, in line with other PBD ADCs (see here).

No correlation was observed between ASCT2 expression and clinical response.

While the ADC field has moved mainly away from PBD payloads, kudos to the authors for the nice and informative publication!”

Source: Raffaele Colombo/X

Raffaele Colombo, a  leading figure in the pharmaceutical industry is the Associate Director of Medicinal Chemistry at Zymeworks Inc.. His leadership and scientific acumen drive the discovery and optimization of novel drug candidates and advancing the treatment landscape for various diseases.