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Tumor-Specific Inhibition of Membrane-Bound Complement Regulatory Protein Crry with Bispecific Monoclonal Antibodies Prevents Tumor Outgrowth in a Rat Colorectal Cancer Lung Metastases Model

Departments of ¹ Pathology and ² Surgery, Leiden University Medical Center, Leiden, The Netherlands, and ³ Department of Molecular Biology, Nagoya City University, Graduate School of Medical Science, Nagoya, Japan

Membrane-bound complement regulatory proteins (mCRP) inhibit complement-mediated tumor cell eradication in vitro and in vivo. Immunotherapy of cancer with monoclonal antibodies (mAbs) that activate complement might be hampered by expression of mCRP on tumor cells. An important strategy to improve mAb immunotherapy can be blocking or overwhelming mCRP at the tumor cells surface in a tumor-specific manner. In our study, we investigated the feasibility of this approach in vivo using bispecific mAbs (bi-mAbs). This study, performed in a syngeneic lung metastases model of rat (WAG/Rij) colorectal cancer, showed that modulation of mCRP on tumor cells resulted in significantly decreased tumor outgrowth. Opsonization of tumor cells with a bi-mAb directed against a tumor-associated antigen and rat mCRP Crry (MG4_2a*5I2) almost completely prevented the outgrowth of lung tumors (0–7 tumors/rat; n = 17). Opsonization with mAb-cobra venom factor conjugates significantly reduced the number of lung tumors (23–59 tumors; n = 12) compared with the unconjugated MG4_2a (175–246 tumors; n = 17; P = 0.008 and 0.014, respectively). The effect of MG4_2a*5I2 was shown to be caused by increased complement activation due to inhibition of Crry. Moreover, prophylactic treatment with MG4_2a*5I2 or MG4_2a showed comparable results (3–24 and 215–472 tumors, P = 0.02; n = 6) as observed with pre-opsonized tumor cells without noticeable side effects, despite binding of MG4_2a*5I2 to endothelium and leukocytes. These results demonstrate that Crry inhibits complement-mediated tumor cell eradication by immunotherapeutic mAbs and show that tumor-specific inhibition of complement regulatory proteins using bi-mAbs can significantly improve mAb-mediated immunotherapy.

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