Journal of the National Cancer Institute Advance Access originally published online on July 29, 2009
JNCI Journal of the National Cancer Institute 2009 101(17):1193-1205; doi:10.1093/jnci/djp231
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© The Author 2009. Published by Oxford University Press.
ARTICLES |
EphA2 Immunoconjugate as Molecularly Targeted Chemotherapy for Ovarian Carcinoma
Affiliations of authors: Department of Gynecologic Oncology (J-WL, HDH, MMKS, SWK, LSM, AMN, CL, RS, H-SK, CNL, RLC, AKS) and Department of Cancer Biology (RRL, AKS), University of Texas M.D. Anderson Cancer Center, Houston, TX; Department of Obstetrics and Gynecology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea (J-WL); Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, TX (MMKS); Department of Pathology, Cheil General Hospital and Women’s Healthcare Center, Kwandong University College of Medicine, Seoul, Korea (H-SK); MedImmune, Gaithersburg, MD (SM, JG, CF, DJ, DT)
Correspondence to: Anil K. Sood, MD, Department of Gynecologic Oncology and Department of Cancer Biology, The University of Texas M.D. Anderson Cancer Center, 1155 Herman Pressler, Unit 1352, Houston, TX 77030 (e-mail: asood{at}mdanderson.org).
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.
| CONTEXT AND CAVEATS Prior knowledge EphA2 is a receptor tyrosine kinase that is overexpressed in many human cancers but is absent or expressed at low levels in normal epithelial tissues. Study design The antitumor activity of an immunoconjugate containing an anti-EphA2 monoclonal antibody (1C1) linked to a chemotherapeutic agent (monomethyl auristatin phenylalanine [MMAF]) through a noncleavable linker maleimidocaproyl (mc) was studied in ovarian cancer cell lines and ovarian tumor models in mice. Contribution The 1C1-mcMMAF immunoconjugate had antitumor activity in ovarian cancer cell lines and preclinical models of ovarian cancer. Implications Additional preclinical investigations into the antitumor activity of 1C1-mcMMAF and its safety are warranted. Limitations The activity of 1C1-mcMMAF that has actually been delivered into a solid tumor mass has not been studied. Unexpected toxicities in future research cannot be ruled out, especially to EphA2-expressing normal tissues or cells. Analyses in this study were done in cultured cell lines and in mouse models that used immunodeficient mice, and so results may not necessarily translate into human patients with ovarian cancer. From the Editors
|
Manuscript received October 2, 2008; revised June 3, 2009; accepted June 23, 2009.
Related Article in JNCI
CiteULike 
Connotea 
Del.icio.us What's this?
J Natl Cancer Inst 2009 101: 1159.