In vitro and In vivo Characterization of MDX-1401 for Therapy of Malignant Lymphoma.
Clin Cancer Res. 2009 Apr 28
Cardarelli PM, Moldovan-Loomis MC, Preston B, Black A, Passmore D, Chen TH, Chen S, Liu J, Kuhne MR, Srinivasan M, Assad A, Witte A, Graziano RF, King DJ.
Authors' Affiliations: Departments of Cell Biology and Pharmacology, Protein Chemistry, and Biochemistry, Medarex, Sunnyvale, California; Department of Research Management, Medarex, Milpitas, California; Clinical Department and Department of Discovery Research, Medarex, Bloomsbury, New Jersey; and AnaptysBio, San Diego, California.
PURPOSE:
This study was undertaken to evaluate the effects of MDX-1401, a nonfucosylated fully human monoclonal antibody that binds to human CD30, and to determine whether it exhibits greater in vitro and in vivo activity than its parental antibody.
EXPERIMENTAL DESIGN:
Assays measuring antibody binding to CD30-expressing cells and FcgammaRIIIa (CD16) transfectants as well as antibody-dependent cellular cytotoxicity (ADCC) were conducted. Antitumor activity was determined using a Karpas-299 systemic model.
RESULTS:
The binding of MDX-1401 to CD30 antigen was identical to fucose-containing parental anti-CD30 antibody (MDX-060). In contrast, MDX-1401 showed increased binding affinity to FcgammaRIIIa-transfected cells resulting in increased effector function. MDX-1401 greatly improved ADCC activity as evidenced by a decrease in half-maximal effective concentration (EC50) and an increase in maximum cell lysis when compared with MDX-060. Increased ADCC activity was observed among a panel of cell lines, including one with very low CD30 antigen expression in which parental antibody failed to induce any detectable ADCC. MDX-1401 activity with all FcgammaRIIIa polymorphic variants, including less active Phe/Phe158 and Phe/Val158 effector cells, was shown. Furthermore, MDX-1401 was efficacious in inhibiting tumor growth in CD30(+) lymphoma xenografts.
CONCLUSIONS:
The low doses of antibody required for ADCC activity irrespective of donor genotype, the ability to mediate ADCC in target cells expressing low levels of CD30, and increased in vivo efficacy support the development of MDX-1401 for treatment of malignant lymphoma. |
