Engaging antiviral antibodies for tumor therapy using bispecific adapter proteins

Treatment of solid tumors using oncolytic adenoviruses is a promising approach to achieve selective tumor cell killing, reduction of tumor immunosuppression and induction of anti-tumor immune responses. However, this treatment also triggers strong humoral immune responses against the adenoviral vector, thus limiting viral spread and the efficacy of repeat administrations.

Here, we investigated whether these anti-adenoviral antibodies can be exploited for cancer therapy by means of tumor-specific retargeting. We established bispecific adapter molecules consisting of a tumor-specific ligand (directed against targets such as polysialic acid or carcinoembryonic antigen) and a viral domain, derived from the adenoviral capsid protein hexon, which is capable of binding substantial amounts of anti-adenoviral IgGs. In adenovirus pre-challenged mice, systemic adapter application inhibited tumor growth and significantly prolonged survival in several syngeneic, subcutaneous tumor models established with CMT64 lung carcinoma, MC38 colon carcinoma, and B16F10 melanoma cells as well as in a transgenic model of orthotopically grown liver cancer. Antibody retargeting effectively inhibited metastases as shown in a murine model of CMT64 lung colonies. Analyses of tumor infiltrating cells and subsequent depletion experiments in the MC38 model revealed NK-cells and CD8 T-cells as essential mediators of adapter-mediated tumor growth inhibition. Furthermore, we could show that adapter treatment leads to a systemic induction of tumor antigen-specific CD8 T-cells in a NK cell-dependent manner. Finally, antibody retargeting following an intratumoral treatment of MC38 tumors with an oncolytic adenovirus resulted in enhanced therapeutic efficacy compared to virotherapy alone, including complete tumor remissions and long-term tumor free survival.

Our data demonstrate that retargeting of antiviral antibodies using bispecific adapter molecules is a promising new approach for cancer immunotherapy and significantly improves the therapeutic potential of an oncolytic virotherapy.