Poster presented at the American College of Toxicology (ACT) 2023 Annual Meeting
Josée Hue-Perron1, Noémie Luong1, Lisa Ivanschitz1, Nathalie Bellocq2, Léo Marx2, Ulf Andersson1
1Debiopharm, Chemin Messidor 5-7, CH-1002 Lausanne, Switzerland
2Debiopharm Research and Manufacturing, Rue du Levant 146, CH-1920 Martigny, Switzerland
Summary
Antibody drug conjugates (ADCs) represent an attractive method to deliver cytotoxic payloads into tumor cells while reducing systemic toxicities. To improve efficacy, increasing the DAR (drug–antibody ratio) is an appealing approach, although lipophilicity of such constructions can lead to unselective uptake. Non-specific linker cleavage is also associated with off-target toxicity. We have developed the MultilinkTM technology, which allows rapid and specific intracellular cleavage of a hydrophilic linker, resulting in efficient payload release from the ADCs.
We investigated the toxicology profiles in mouse of two ADCs targeting CD37. Both ADCs carry the cytotoxic payload DM1; one with a non-cleavable thioether linker (Debio 1562; DAR3.5) and the other with our MultilinkTM linker (Debio 1562M; DAR8). Both ADCs demonstrated a toxicity profile expected with DM1, such as hematologic abnormalities, infusion reactions and hepatic lesions. Despite higher DAR, there were fewer toxicities with the MultilinkTM ADC, and a trend to lower severity of histopathological lesions. Notably, there were no hemorrhage or degeneration in the sciatic nerve when compared to the thioether conjugated-ADC, which suggests reduced risk of peripheral neuropathy. Unconjugated MultilinkTM-DM1 linker (quenched with cysteine) was not associated with any signs of toxicity. When evaluated in xenograft efficacy mouse AML models, the MultilinkTM ADC demonstrated significantly better tumor regression.