EphA2 immunoconjugate as molecularly targeted chemotherapy for ovarian carcinoma.

Abstract

BACKGROUND:

EphA2 is overexpressed in many types of human cancer but is absent or expressed at low levels in normal epithelial tissues. We investigated whether a novel immunoconjugate containing an anti-EphA2 monoclonal antibody (1C1) linked to a chemotherapeutic agent (monomethyl auristatin phenylalanine [MMAF]) through a noncleavable linker maleimidocaproyl (mc) had antitumor activity against ovarian cancer cell lines and tumor models.

METHODS:

Specificity of 1C1-mcMMAF was examined in EphA2-positive HeyA8 and EphA2-negative SKMel28 ovarian cancer cells by antibody binding and internalization assays. Controls were phosphate-buffered saline (PBS), 1C1, or control IgG-mcMMAF. Viability and apoptosis were investigated in ovarian cancer cell lines and tumor models (10 mice per group). Antitumor activities were tested in the HeyA8-luc and SKOV3ip1 orthotopic mouse models of ovarian cancer. Endothelial cells were identified by use of immunohistochemistry and anti-CD31 antibodies. All statistical tests were two-sided.

RESULTS:

The 1C1-mcMMAF immunoconjugate specifically bound to EphA2-positive HeyA8 cells but not to EphA2-negative cells and was internalized by HeyA8 cells. Treatment with 1C1-mcMMAF decreased the viability of HeyA8-luc cells in an EphA2-specific manner. In orthotopic mouse models, treatment with 1C1-mcMMAF inhibited tumor growth by 85%-98% compared with that in control mice (eg, for weight of HeyA8 tumors, 1C1-mcMMAF = 0.05 g and control = 1.03 g; difference = 0.98 g, 95% confidence interval [CI] = 0.40 to 1.58 g; P = .001). Even in bulkier disease models with HeyA8-luc cells, 1C1-mcMMAF treatment, compared with control treatment, caused regression of established tumors and increased survival of the mice (eg, 1C1-mcMMAF vs control, mean = 60.6 days vs 29.4 days; difference = 31.2 days, 95% CI = 27.6 to 31.2 days; P = .001). The antitumor effects of 1C1-mcMMAF therapy, in SKOV3ip1 tumors, for example, were statistically significantly related to decreased proliferation (eg, 1C1-mcMMAF vs control, mean = 44.1% vs 55.8% proliferating cells; difference = 11.7%, 95% CI = 2.45% to 20.9%; P = .01) and increased apoptosis of tumor cells (eg, 1C1-mcMMAF vs control, mean = 8.6% vs 0.9% apoptotic cells; difference = 7.7%, 95% CI = 3.8% to 11.7%; P < .001) and of mouse endothelial cells (eg, 1C1-mcMMAF vs control, mean 2.8% vs 0.4% apoptotic endothelial cells; difference = 2.4%, 95% CI = 1.4% to 4.6%; P = .034).

CONCLUSION:

The 1C1-mcMMAF immunoconjugate had antitumor activity in preclinical models of ovarian carcinoma.

• Authors: Jeong-Won Lee, Hee Dong Han, Mian M K Shahzad, Seung Wook Kim, Lingegowda S Mangala, Alpa M Nick, Chunhua Lu, Robert R Langley, Rosemarie Schmandt, Hye-Sun Kim, Shenlan Mao, John Gooya, Christine Fazenbaker, Dowdy Jackson, David A Tice, Charles N Landen, Robert L Coleman, Anil K Sood
• Journal: Journal of the National Cancer Institute (J Natl Cancer Inst) Vol. 101 Issue 17 Pg. 1193-205 (Sep 02 2009) ISSN: 1460-2105 [Electronic] United States
• PMID: 19641174 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Antineoplastic Agents
• Immunoconjugates
• Oligopeptides
• Platelet Endothelial Cell Adhesion Molecule-1
• Proliferating Cell Nuclear Antigen
• Receptor, EphA2
• monomethyl auristatin E

Topics

• Animals
• Antibodies, Monoclonal (pharmacology)
• Antineoplastic Agents (pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Blotting, Western
• Cell Line, Tumor
• Cell Survival (drug effects)
• Female
• Fluorescent Antibody Technique
• Humans
• Immunoconjugates (pharmacology, therapeutic use)
• Immunohistochemistry
• In Situ Nick-End Labeling
• Mice
• Oligopeptides (pharmacology, therapeutic use)
• Ovarian Neoplasms (drug therapy, immunology)
• Platelet Endothelial Cell Adhesion Molecule-1 (analysis)
• Proliferating Cell Nuclear Antigen (analysis)
• Receptor, EphA2 (analysis, antagonists & inhibitors, immunology)
• Xenograft Model Antitumor Assays