INTRACEREBRAL BISPECIFIC LIGAND-ANTIBODY CONJUGATE INCREASES SURVIVALOF ANIMALS BEARING ENDOGENOUSLY ARISING BRAIN-TUMORS

Bispecific antibodies capable of simultaneously binding a tumor surfac e antigen and the T-cell receptor/CD3 complex ave capable of inducing polyclonal immune effector cells to destroy targeted tumor cells. Bisp ecific antibody immunotherapies have shown some promise against tumors of hematopoietic origin such as lymphomas, but use of bispecific anti bodies for the treatment of solid tumors has been less fully explored, To test the preclinical potential of bispecific antibody therapy agai nst an endogenously arising solid brain tumor, we have utilized a nove l variation of conventional bispecific antibodies, referred to as bisp ecific ligand-antibody conjugates, to target choroid plexus tumors, Th e bispecific ligand-antibody conjugate described in this study is a ch emical conjugate between an anti-CD3 monoclonal antibody (MAb) and fol ic acid, the ligand for a high-affinity surface receptor expressed on the surface of choroid plexus tumors, SV11 mice transgenic for SV40 la rge T antigen and its promoter develop solid choroid plexus tumors in the brain. We demonstrate that choroid plexus tumor cells are suscepti ble in vitro to cytolysis mediated by cytotoxic T cells in the presenc e of the bispecific ligand-antibody conjugate in a folate-inhibitable manner. Adoptive immunotherapy studies demonstrate the potential benef its of the bispecific ligand-antibody conjugate in vivo. The bispecifi c conjugate is capable of retaining adoptively transferred T lymphocyt es specifically within tumor tissue for periods of up to at least I we ek. Further, following intracerebro-ventricular injection of bispecifi c conjugate and splenocytes containing activated cytotoxic T cells, T cells were observed to penetrate to interior regions of the tumor. A s ingle treatment of adoptively delivered activated effecters and bispec ific conjugate into the brain ventricles was insufficient to produce s ignificant increases in survival of SV11 mice, but repeated treatment through indwelling cannulas prolonged survival of animals treated with activated effecters and bispecific ligand-antibody conjugate compared to animals treated with activated effectors or saline alone. Our resu lts demonstrate that the SV11 model may be useful for preclinical eval uation and optimization of bispecific ligand-antibody conjugate treatm ents of solid tumors. (C) 1998 Wiley-Liss, Inc.