Epratuzumab-SN-38: a new antibody-drug conjugate for the therapy of hematological malignancies
Menée sur des lignées cellulaires de leucémies et de lymphomes ainsi qu'à l'aide de xénogreffes, cette étude évalue l'efficacité antitumorale de l'epratuzumab-SN-38, un nouveau conjugué anticorps-médicament
We previously found that slowly internalizing antibodies conjugated with SN-38 could be used successfully when prepared with a linker that allows ~50% of the IgG-bound SN-38 to dissociate in serum every 24 h. In this study, the efficacy of SN-38 conjugates prepared with epratuzumab (rapidly internalizing) and veltuzumab (slowly internalizing), humanized anti-CD22 and anti-CD20 IgG, respectively, was examined for the treatment of B-cell malignancies. Both ADCs had similar nanomolar activity against a variety of human lymphoma/leukemia cell lines, but SN-38's slow release compromised potency discrimination in vitro, even against an irrelevant conjugate. When SN-38 was stably linked to the anti-CD22 conjugate, its potency was reduced 40- to 55-fold. Therefore, further studies were performed only with the less-stable, slowly dissociating, linker. In vivo, similar anti-tumor activity was found between CD22 and CD20 ADCs in mice bearing Ramos xenografts, even though Ramos expressed 15-fold more CD20 than CD22, suggesting that the internalization of the epratuzumab-SN-38 conjugate (Emab-SN-38) enhanced its activity. Emab-SN-38 was more efficacious than a non-binding, irrelevant IgG-SN-38 conjugate in vivo, eliminating a majority of well-established Ramos xenografts at non-toxic doses. In vitro and in vivo studies showed Emab-SN-38 could be combined with unconjugated veltuzumab for a more effective treatment. Thus, Emab-SN-38 is active in lymphoma and leukemia at doses well below toxic levels, and therefore represents a new promising agent with therapeutic potential alone or combined with anti-CD20 antibody therapy.
http://mct.aacrjournals.org/content/early/2011/10/28/1535-7163.MCT-11-0632.abstract