Refocusing the immune system to react with human tumors by targeting human lymphocytes with bispecific antibodies

Recent studies have established that crosslinking triggering sites on an immune cell, such as CD3 or FcR, to antigens on target cells with redirect the target-cell specificity of the immune cell. We are testing whether the human immune system can be refocused against human tumors with bifunctional antibodies produced by chemically crosslinking monoclonal antibodies against CD3 and tumor antigens with SPDP. The tumor model consists of immunodeficient (athymic) mice injected i.p. with a human ovarian cell line, OVCAR 3. Mice are treated 4-6 days later, after tumor growth has been established, with i.p. injections of human PBL from normal donors and bifunctional antibodies. Tumor growth is assessed by the amount of tumor cells and cell-free tumor antigen recovered in peritoneal lavage fluid 15 days after tumor injection. Relative to lymphocytes alone, bifunctional antibodies (including Fab preparations) increase the % of tumor-free mic from about 20 to 60%. A variety of controls show that both the bifunctional antibodies and the lymphocytes are required for the anti-tumor effect. Thus, heterocrosslinked antibodies can greatly enhance the anti-tumor activity in human PBL and may provide a new immunotherapeutic approach for treating human cancer.