NOVEL TUMOR ANTIGEN FOR ANTIBODY TARGETING

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DESCRIPTION: Monoclonal antibodies (MoAb) have clinical potentials for the diagnosis and therapy of human cancers. Using the MoAb 3F8 directed at ganglioside GD2, and human neuroblastoma as the tumor model, the investigator has demonstrated over the last 13 years that MoAb can be successfully integrated into multimodality curative strategies. MoAb can target both radiation and immune effector functions effectively at minimal residual disease. With a single MoAb - antigen system, more than 50 percent of patients with metastatic neuroblastoma are expected to be long term survivors whereas none survived 2 decades ago. Late relapses after 3 years are now rare, and late effects from antibody treatment minimal. Analogous to combination chemotherapy, the investigator expects the efficacy of MoAb approach to be further amplified if a panel of clinically useful MoAbs is available. The relative lack of appropriate targets among pediatric embryonal, mesenchymal and brain tumors has greatly limited the development of antibody-based strategies. These tumors include rhabdomyosarcoma (RMS), osteosarcoma (OS), Ewing's/PNET (ES), desmoplastic small round cell tumor (DSRT), brain tumors and other sarcomas in the pediatric/adolescent age group. Following an extensive screening of their neuroblastoma MoAb inventory, the investigators have identified a novel MoAb 8H9 with a broad spectrum of reactivity against human neuroectodermal, mesenchymal, and epithelial tumors. This MoAb has no cross reactivity with normal blood or marrow cells, brain, brainstem, spinal cord, normal organs except for faint staining of the cytoplasm of adrenal cortex, pancreas and liver. Antigen expression is homogenous among positive tumors and remains unmodulated at 37 degrees C following MoAb binding. 8H9 is effective in purging tumors from blood or marrow stem cells. When radiolabeled, 8H9 retains immunoreactivity and targets effectively to human neuroblastoma and rhabdomyosarcoma xenografts. Intravenous and intrathecal injections of 8H9 has no side effects in cynomolgus monkeys. In this grant application the investigator proposes to define the biodistribution of 131-I-8H9 in patients with RMS, OS, ES, DSRT, brain tumors and other soft tissue sarcomas. They will test the sensitivity and specificity of this antibody in detecting tumors when compared to conventional radiographic studies. The pharmacokinetics of this antibody when given intravenously and the amount of 8H9 deposited in tumors versus normal organs will be carefully defined. This information is critical for radioimmunotherapy as well as future antibody-based targeted therapies.