Abstract 4573: Inhibition of tumor growth by human IgM-isotype monoclonal antibody to ganglioside GD2

Abstract

Abstract Monoclonal antibody, MORAb-028, a human IgM derived from patients with melanoma, specifically binds to tumor cell surface ganglioside-GD2 with high specificity, and kills GD2-expressing target cells via complement-mediated cytotoxicity (CDC). This CDC-mediated anti-tumor activity of MORAb-028 has been confirmed in vitro using various GD2-expressing tumor cells in presence of rat sera. In the present study, intraperitoneal (i.p) and intratumoral (i.t.) treatment models in nude rats were developed to investigate in vivo anti-tumor activity of MORAb-028. These compartmental models provide an in vivo system to monitor IgM anti-tumor activity that has not been possible in previous studies due to the rodent poly-Ig-Receptor (PIgR) that is able to sequester systemically administered hIgM in the liver thereby lowering serum IgM steady-state levels that in turn lowers distribution of IgM to targeted tumors. In the present study, murine EL4-luc2 cells that express high levels of GD2 were engineered to express a luciferase-reporter-gene enabling in vivo bioluminescent detection for monitoring tumor status. These cells were used in two different models to test the ability of MORAb-028 to impact tumor growth. An i.p. model was developed whereby tumor cells were injected directly into the peritoneal cavity of nude rats followed immediately by a single i.p. dose of MORAb-028 at 3mg/kg, a dose that has showed activity in vitro. Tumor progression was monitored by bioluminescence using IVIS living imaging system. On day 24 post treatment, a significant reduction in tumor progression was observed in the MORAb-028-treated animals in comparison to the control. Only minimal tumor growth (∼3 to 5 mm3) was observed in MORAb-028-treated animals in contrast to control animals, in which tumor occupied the entire peritoneal cavity. In a second model EL-4-luc cells were implanted subcutaneously and antibody was directly administered to palpable tumors. Here, a single intratumoral injection of MORAb-028 was administered into established (300-400 mm3) tumors. Results showed that MORAb-028 treatment significantly inhibited tumor growth and eradicated nearly the entire tumor in ∼30% of the animals. Six days post treatment the tumor volume in MORAb-028-treated animals was ∼250 mm3, whereas the tumor volume was >1500mm3 in control animals. Animals with eradicated tumors showed no sign of recurrence at day 30 when the study was terminated. These data indicate that MORAb-028 is a potent agent to treat GD2-positive tumors in rat models. These results also suggest that this antibody may be useful in clinical applications for the treatment of GD2-positive human cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4573. doi:10.1158/1538-7445.AM2011-4573