Abstract 5344: The contribution of unlabeled antibodies to intracellular antigens to efficacy of radioimmunotherapy in experimental metastatic melanoma and cervical cancer
Authors: Dadachova Ekaterina , Phaeton Rebecca , Revskaya Ekaterina , Jiang Zewei , Bryan Ruth A. , Goldberg Gary L. , Casadevall Arturo 
Published: February 2011

Introduction: Radioimmunotherapy (RIT) targeting intracellular antigens released in rapidly growing tumors as a result of a cellular turnover is an attractive modality for treatment of aggressive solid tumors. We are developing RIT for metastatic melanoma and HPV-related cervical cancer by targeting the intracellular antigens melanin and E6 oncoprotein, respectively, with radiolabeled specific antibodies (mAbs). In prior studies we observed that administration of unlabeled mAbs to melanin and E6 alone to tumor-bearing mice caused retardation of tumor growth.

Objective: To investigate the immunological mechanisms by which unlabeled mAbs to intracellular antigens melanin and E6 oncoprotein contribute to the efficacy of RIT of melanoma and cervical cancer.

Methods: The CasKi human cervical tumors and A2058 human metastatic melanoma tumors were induced in female nude mice and when the tumors diameter reached 0.5-0.7 cm, the mice with cervical tumors were treated with C1P5 mAb (IgG1 isotype) to E6 or isotype-matching control mAbs, or left untreated; and mice with melanoma tumors were given 6D2 mAb (IgM isotype) to melanin or isotype matching control mAbs; or left untreated. The tumor growth was monitored for 30 days. On day 5 and 10 post-treatment 4 mice out of each group were sacrificed and their tumors analyzed for C3 complement by Western blot and immunohistochemistry (IHC). On day 10 the tumors were analyzed by flow cytometry for the infiltration by inflammatory cells.

Results: There was significant retardation of melanoma and cervical tumor growth during the observation period by 6D2 mAb to melanin and C1P5 mAb to E6 compared with untreated controls (P&lt;0.05). For both types of tumors the isotype-matching control mAbs had the same in magnitude effect on the tumor growth as specific mAbs (P&gt;0.05). On days 5 and 10 C3 complement deposition was observed by Western blot and IHC in specific and non-specific mAbs-treated tumors but not in the untreated controls. The expression of C3 was more prominent on day 10. On day 10 there was infiltration of mAb-treated melanoma and cervical tumors by CD45+, CD4+ and CD8+ inflammatory cells with their levels being 30-100% greater than in untreated tumors.

Conclusions: Our results of the treatment of melanoma and cervical tumors with unlabeled mAbs to intracellular antigens suggest that these mAbs can initiate complement dependent toxicity (CDC) and antibody dependent cellular toxicity (ADCC). The effect of mAbs did not depend on a mAb specificity for a particular antigen. It appeared to be dependent on the affinity of the Fc portion of mAbs for C1q molecule (CDC case) or for the Fc receptors on inflammatory cells (ADCC case). Further investigation of the contribution of unlabeled mAbs to efficacy of RIT will help to design effective treatment regiments for patients with metastatic melanoma and cervical cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5344.