Mean tumor weights with 95% confidence intervals and the weights of individual tumors are shown. HeyA8-luc cells in an EphA2-specific manner. In orthotopic mouse models, treatment with 1C1-mcMMAF inhibited tumor growth by 85%C98% compared with that in control mice (eg, for excess weight of HeyA8 tumors, 1C1-mcMMAF = 0.05 g and control = 1.03 g; difference = 0.98 g, 95% ML 171 confidence interval [CI] = 0.40 to 1 1.58 g; = .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; = .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%; = .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%; < .001) and of mouse endothelial cells (eg, 1C1-mcMMAF vs ML 171 control, mean 2.8% vs 0.4% apoptotic endothelial cells; difference = 2.4%, 95% CI = 1.4% to 4.6%; = .034). Conclusion The 1C1-mcMMAF immunoconjugate experienced antitumor activity in preclinical models of ovarian carcinoma. CONTEXT AND CAVEATS Prior knowledgeEphA2 is usually a receptor tyrosine kinase that is overexpressed in many human cancers but is usually absent or expressed at low levels in normal epithelial tissues. Study designThe antitumor activity of an immunoconjugate made up of an anti-EphA2 monoclonal antibody (1C1) linked to a chemotherapeutic agent (monomethyl auristatin phenylalanine [MMAF]) through a noncleavable linker maleimidocaproyl (mc) was analyzed in ovarian malignancy cell lines and ovarian tumor models in mice. ContributionThe 1C1-mcMMAF immunoconjugate experienced antitumor activity in ovarian malignancy cell lines and preclinical models of ovarian malignancy. ImplicationsAdditional preclinical investigations into the antitumor activity of 1C1-mcMMAF and its security are warranted. LimitationsThe 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 carried out in cultured cell lines and in mouse models that used immunodeficient mice, and so results may not necessarily translate into human patients with ovarian malignancy. From your Editors Ovarian malignancy is the most common cause of death from a gynecologic malignancy (1). Although most patients with advanced-stage ovarian malignancy will pass away of the disease, more than 70% have a favorable initial response to surgery and chemotherapy and a substantial fraction will respond to second-line therapies (2,3). Systemic chemotherapy is usually widely used but is frequently associated with intolerable side effects (4). Given the high mortality rate of ovarian malignancy, new therapies are urgently needed to target the tumor while sparing normal tissues. Monoclonal antibodies may be a potential type of new therapy. Human and chimeric monoclonal antibodies (including bevacizumab, rituximab, trastuzumab, alemtuzumab, and cetuximab) have been shown to be highly selective therapeutic brokers for malignancy (5). Immunoconjugates made up of a monoclonal antibody and a chemotherapeutic agent provide another approach to selectively deliver toxins or cytotoxic brokers to various types of malignancy, including gemtuzumab ozogamicin, 90Y-labeled ibritumomab tiuxetan, and 131I-labeled ML 171 tositumomab (6). An TSPAN11 ideal target for such an immunoconjugate would be a molecule that is expressed at much higher levels in the tumor than in normal tissues or expressed in tumor tissue but not in normal tissue. Such a target may be the EphA2 receptor, which is usually overexpressed by many human cancers ML 171 including ovarian, lung, prostate, colorectal, melanoma, and brain malignancies but is usually expressed at low levels in only some normal epithelial tissues including kidney, lung, colon, and bladder (7C10). EphA2 overexpression has been associated with poor prognosis in patients with ovarian, esophageal, and renal cancers. It is thought that EphA2 overexpression prospects to mislocalization and loss of contact with the ephrin ligands, leading to an increase in adhesions ML 171 between cells.