In vitro and in vivo characterization of MDX-1401 for therapy of malignant lymphoma.

Abstract

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 (EC(50)) 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.

• Authors: Pina M Cardarelli, Maria-Cristina Moldovan-Loomis, Ben Preston, Amelia Black, David Passmore, Tseng-Hui Chen, Sharline Chen, Jie Liu, Michelle R Kuhne, Mohan Srinivasan, Albert Assad, Alison Witte, Robert F Graziano, David J King
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 15 Issue 10 Pg. 3376-83 (May 15 2009) ISSN: 1078-0432 [Print] United States
• PMID: 19401346 (Publication Type: Journal Article)

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Carbohydrates
• FCGR3A protein, human
• Ki-1 Antigen
• MDX-1401
• Receptors, IgG
• Fucose

Topics

• Animals
• Antibodies, Monoclonal (chemistry, immunology, pharmacology)
• Antibodies, Monoclonal, Humanized
• Antibody Affinity (drug effects, immunology)
• Antibody-Dependent Cell Cytotoxicity (drug effects)
• Binding Sites, Antibody (immunology)
• CHO Cells
• Carbohydrates (chemistry, immunology)
• Cell Line, Tumor
• Cricetinae
• Cricetulus
• Dose-Response Relationship, Drug
• Fucose (chemistry, immunology)
• Humans
• Ki-1 Antigen (immunology)
• Lymphoma (drug therapy, immunology, pathology)
• Male
• Mice
• Mice, SCID
• Receptors, IgG (chemistry, immunology)
• Xenograft Model Antitumor Assays