Antibody-dependent cell-mediated cytotoxicity effector-enhanced EphA2 agonist monoclonal antibody demonstrates potent activity against human tumors.
EphA2 is a receptor tyrosine kinase that has been shown to be overexpressed in a variety of human tumor types. Previous studies demonstrated that agonist monoclonal antibodies targeting EphA2 induced the internalization and degradation of the receptor, thereby abolishing its oncogenic effects. In this study, the in vitro and in vivo antibody-dependent cell-mediated cytotoxicity (ADCC) activity of EphA2 effector-enhanced agonist monoclonal antibodies was evaluated. With tumor cell lines and healthy human peripheral blood monocytes, the EphA2 antibodies demonstrated approximately 80% tumor cell killing. In a dose-dependent manner, natural killer (NK) cells were required for the in vitro ADCC activity and became activated as demonstrated by the induction of cell surface expression of CD107a. To assess the role of NK cells on antitumor efficacy in vivo, the EphA2 antibodies were evaluated in xenograft models in severe compromised immunodeficient (SCID) mice (which have functional NK cells and monocytes) and SCID nonobese diabetic (NOD) mice (which largely lack functional NK cells and monocytes). Dosing of EphA2 antibody in the SCID murine tumor model resulted in a 6.2-fold reduction in tumor volume, whereas the SCID/nonobese diabetic model showed a 1.6-fold reduction over the isotype controls. Together, these results demonstrate that the anti-EphA2 monoclonal antibodies may function through at least two mechanisms of action: EphA2 receptor activation and ADCC-mediated activity. These novel EphA2 monoclonal antibodies provide additional means by which host effector mechanisms can be activated for selective destruction of EphA2-expressing tumor cells.
Bruckheimer
Elizabeth M
EM
MedImmune, Inc., Gaithersburg, MD 20878, USA.
Fazenbaker
Christine A
CA
Gallagher
Sandra
S
Mulgrew
Kathy
K
Fuhrmann
Stacy
S
Coffman
Karen T
KT
Walsh
William
W
Ready
Shannon
S
Cook
Kim
K
Damschroder
Melissa
M
Kinch
Michael
M
Kiener
Peter A
PA
Woods
Rob
R
Gao
Changshou
C
Dall'Acqua
William
W
Wu
Herren
H
Coats
Steven
S
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000494:pharmacology; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects / Q000276:immunology*; D045744:Cell Line, Tumor; D005260:Female; D005838:Genotype; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000276:immunology; D007694:Killer Cells, Natural / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D052118:Lysosomal-Associated Membrane Protein 1 / Q000276:immunology; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D009369:Neoplasms / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D011110:Polymorphism, Genetic; D036104:Receptor, EphA2 / Q000819:agonists / Q000276:immunology* / Q000378:metabolism; D017452:Receptors, IgG / Q000235:genetics; D020349:Surface Plasmon Resonance; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; C080568:Fc gamma receptor IIA; D007141:Immunoglobulin Fc Fragments; D052118:Lysosomal-Associated Membrane Protein 1; D017452:Receptors, IgG; D036104:Receptor, EphA2