INA03, a potent transferrin-competitive antibody-drug conjugate against CD71, for a safer acute leukemia treatment.
Fiche publication
Date publication
avril 2024
Journal
Molecular cancer therapeutics
Auteurs
Membres identifiés du Cancéropôle Est :
Dr KOLODYCH Sergii, Dr KONIEV Sasha
Tous les auteurs :
Bratti M, Stubbs E, Kolodych S, Souchet H, Kelly L, Merlin J, Marchal M, Castellano R, Josselin E, Pasquer H, Benajiba L, Puissant A, Koniev O, Collette Y, Belanger C, Hermine O, Monteiro RC, Launay P
Lien Pubmed
Résumé
Innovative strategies to enhance efficacy and overcome drug resistance in hematologic cancers such as antibody-drug conjugates (ADCs) have shifted the paradigm of conventional care by delivering promising outcomes in cancer therapies with a significant reduction in the risk of relapse. The transferrin receptor 1, CD71, known to be overexpressed in malignant cells, is considered a potent anti-tumoral target. Therefore, we have developed an anti-CD71 ADC, INA03, a humanized antibody conjugated to the monomethyl auristatin E (MMAE) through a 3-arylpropiolonitrile-valine-citruline linker. In this study, we investigated both potency and safety of INA03, in competition with transferrin (Tf), the CD71's natural ligand, as a novel strategy to specifically target highly proliferative cells. The high expression of CD71 was confirmed on different leukemic cell lines, allowing INA03 to bind efficiently. Subsequently, INA03 rapidly internalizes into lysosomal compartments, where its cytotoxic drug is released following cathepsin-B cleavage. Downregulating CD71 expression using shRNA highlighted that INA03-induced cell death was dependent on CD71 density at the cell surface. INA03 intravenous treatment in acute leukemia mouse models significantly reduced tumor burden, increased mice survival and showed no residual disease compared to conventional chemotherapies. Since INA03 competes with the human Tf, a double knock-in (hCD71/hTf) competent mouse model was generated to mimic human pharmacokinetics and pharmacodynamics. INA03 administration in hCD71/hTf mice did not reveal, even at high doses, any improper toxicities. Hence, these data demonstrate promising pre-clinical efficacy and safety of INA03 and support its development as a novel acute leukemia treatment.
Référence
Mol Cancer Ther. 2024 04 20;: