Core 1 provides : 1) preclinical evaluation and analysis of drugs and monoclonal reagents requisite for eventual clinical trial, 2) continued development of new reagents directed against targets identified by gene mining approaches in separately funded grants, and establishment and characterization of genetically modified antibody reagents for clinical application; and 3) preparation of IND applications for all reagents generated in this SRC or in separately funded grants. Preclinical evaluation includes the performance of all requisite certification assays for all reagents (drug, MAb, chimeric MAb molecules, constructs and conjugates) generated in the SRC, and currently supports Phase I/II trials elaborated in Project 4. The developmental role of Core 1 is to generate new or modified reagents for clinical application as described in Aim 1. Three areas are being pursued: 1) chimerization, fragment engineering, and biochemical and genomic production of MAb conjugates/constructs; 2) evaluation of drugs and antibody conjugates in athymic rodent models (subcutaneous (sc), intracranial (ic), and intrathecal (ith); neoplastic meningitis); and 3) preclinical characterization and development of reagents generated in other funded grants for compartmental therapy. MAb engineering. In addition to the successful chimerization of the MAbs in Phase I/II trials (81C6 and derivatives), we now have available the requisite methodology for the generation of diabodies, minibodies, and CH2 domain-deleted F(ab')2 MAbs for improved penetration, blood clearance, and/or lack of glomerular trapping for both direct therapeutic application and elicitation of cell mediated reactivity. In vivo models for CNS neoplasia therapy. Central to development of reagents is the consistent preclinical evaluation of stability, localizing ability, and tumoristatic or tumoricidal effect in models mimicking human CNS disease. We constantly refine our large repertoire (sc, ic, ith) of available models in athymic rats with new disease models (ependymoma) and new administration routes; e.g. it and ic with convection enhanced delivery methods, for preclinical assessment of specificity, efficacy, and lack of toxicity. Most unique to this program is the leptomeningeal meningitis model in athymic rats which allows not only establishment of CNS tumors with subarachnoid spread, but the ith administration of therapeutic reagents. Development of glioma-targeting reagents generated in separately funded grants. MAb reagents vs GPNMB, MRP3, SSTR2A, and glioma-associated gangliosides 3'-isoLM1 and 3',6'-isoLD1, generated under separate funding, will undergo preclinical evaluation under the auspices of this core.
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