Radioimmunotherapy with an antibody to HPV16 E6 oncoprotein is effective in experimental cervical tumor expressing low levels of E6

Purpose: HPV16 is associated with similar to 50% of all cervical cancers worldwide. The E6 and E7 genes of oncogenic HP V types, such as HP V16, are necessary for the HP V transforming function and tumorogenesis making them ideal targets for novel treatments. Radioimmunotherapy employs systemically administered radiolabeled monoclonal antibodies (mAbs) that bind to tumor-associated antigens. Previously we demonstrated in mice that radioimmunotherapy targeting viral antigens with mAb to HP V16 E6 suppressed CasKi cervical tumors expressing high levels of E6 (similar to 600 copies of HP V per cell). However, that study opened the question whether radioimmunotherapy can suppress the growth of cervical tumors with low E6 and E7 expression, such as may be seen in patients. Experimental Design: We evaluated the expression of E6 in patients' tumors and in the SiHa cell line expressing low levels of E6 and E7 (1-2 copies of HP V per cell) and found them comparable. We initiated SiHa tumors in nude mice, radiolabeled C1P5 mAb to E6 with a beta-emitter 188-Rhenium (Re-188) and treated tumor-bearing mice with: (1) 200 mu Ci Re-188-C1P5 alone; (2) proteasome inhibitor MG132 alone; (3) MG132 followed by 200 mu Ci Re-188-C1P5; (4) unlabeled C1P5; (5) 200 mu Ci Re-188-18B7 (isotype-matching control mAb); (6) no treatment. Re-188-C1P5 alone and in combination with MG-132 significantly retarded tumor growth compared to all control groups. Conclusions: Our data demonstrate the possibility to suppress tumor growth by targeting viral antigens even in cervical tumors with low E6 expression and provide additional evidence for the potential usefulness of radioimmunotherapy targeting HPV-related antigens in the clinic.