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


METHODS
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.
Cardarelli
Pina M
PM
Department of Cell Biology and Pharmacology, Medarex, Sunnyvale, CA 94089, USA. pcardarelli@medarex.com
Moldovan-Loomis
Maria-Cristina
MC
Preston
Ben
B
Black
Amelia
A
Passmore
David
D
Chen
Tseng-Hui
TH
Chen
Sharline
S
Liu
Jie
J
Kuhne
Michelle R
MR
Srinivasan
Mohan
M
Assad
Albert
A
Witte
Alison
A
Graziano
Robert F
RF
King
David J
DJ
D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000915:Antibody Affinity / Q000187:drug effects / Q000276:immunology; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects; D001666:Binding Sites, Antibody / Q000276:immunology; D016466:CHO Cells; D002241:Carbohydrates / Q000737:chemistry / Q000276:immunology; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D005643:Fucose / Q000737:chemistry / Q000276:immunology; D006801:Humans; D017730:Ki-1 Antigen / Q000276:immunology; D008223:Lymphoma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D016513:Mice, SCID; D017452:Receptors, IgG / Q000737:chemistry / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D002241:Carbohydrates; C496124:FCGR3A protein, human; D017730:Ki-1 Antigen; C542433:MDX-1401; D017452:Receptors, IgG; D005643:Fucose