Naive and radiolabeled antibodies to E6 and E7 HPV-16 oncoproteins show pronounced antitumor activity in experimental cervical cancer

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From: Immunotherapy(Vol. 7, Issue 6)
Publisher: Future Medicine Ltd.
Document Type: Report
Length: 6,233 words
Lexile Measure: 1810L

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Author(s): R Phaëton aff1 , J Gutierrez aff1 , Z Jiang aff2 , RG Karabakhtsian aff3 , J Albanese aff3 , J Sunkara aff3 , DR Fisher aff4 , GL Goldberg aff1 , E Dadachova [*] aff2

Keywords:

188 Rhenium; apoptosis; complement cytotoxicity; E6 and E7 oncoproteins; HPV16 positive cervical cancer; p53 expression; radioimmunotherapy; retinoblastoma

It has been well established and is universally accepted that cervical cancer is caused by Human Papilloma Virus, HPV [1,2 ]. Molecular epidemiologists have been able to trace strains of HPV back to the prehistoric era noting conservation of the viral epitopes for over 200,000 years [3 ]. Throughout the course of time the preservation of the active oncogenic portions of the virus, the reliance of malignant transformation on early oncogenes expression has remained the same; namely of the E6 and E7 viral oncogenes [4 ]. Persistence of HPV infection leads to the malignant change of normal cervical epithelium to cancer. In concert with other factors such as loss of heterozygosity, E6 oncogene deregulates the p53 pathway, while E7 deregulates retinoblastoma gene (Rb ) [5 ]. In spite of the profound reduction in incidence of cervical cancer due to Papanicolaou screening and initiation of HPV vaccination, cervical cancer remains a pandemic with more than 85% of the global burden of disease occurring in developing countries and claims more than 275,000 lives annually (WHO, 2011). In early stages of cervical cancer, surgery can be curative, however, when cancer is metastatic at the time of a patient presentation or is recurrent, treatment options are limited.

Our approach to address this limitation is the development of radioimmunotherapy (RIT) to target the viral specific oncoproteins of HPV-induced cervical cancer by labeling monoclonal antibodies (mAbs) to E6 or E7 oncoproteins, the products of E6 and E7 expression, with a radionuclide which emits cytotoxic radiation, such as 188 Rhenium (188 Re) [6 ]. To access the intranuclearly located target E6 and E7 oncoproteins, this approach initially relies on tumor necrosis that occurs as the tumor outgrows its blood supply causing the release of intranuclear contents into the interstitial spaces where it becomes accessible to mAbs while further damage is being mediated via beta-emission of a radionuclide. Our previous studies focused on RIT targeting E6 oncoprotein. We have demonstrated the ability of a mAb C1P5 which is specific for HPV-16 E6 to target E6 antigen in experimental cervical cancer models with both high and low HPV copy numbers [ 7,8 ]. We observed abrogation of xenografted cervical tumors in nude mice by 188 Re-labeled C1P5 mAb to E6 and a surprising effect of tumor growth inhibition in the unlabeled C1P5 mAb treatment group.

The molecular arrangement of E7 oncogene is intricately linked to another early gene E2 in the HPV genome and although the relative expression in actual human tumors (and commercially available cell lines) is blunted compared with E6 as shown in [9 ], the impact of the linkage might render targeting it with RIT equally efficacious. In our previous studies we detected E7 expression by western blot analysis...

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Gale Document Number: GALE|A422428335