IND, REGULATORY AND BIOINFORMATICS

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Seeinstructions): Core A. IND, Regulatory, and Bioinformatics Core. Darell D. Signer, M.D., Ph.D., Core Leader Core A integrates the development, certification, pre-clinical evaluation, biostatistical and regulatory aspects of reagents that will be evaluated in the SRC and separately funded grants. Specifically, Core A provides: 1) continued development and certification of new reagents directed against targets identified by gene mining approaches in separately funded grants and the establishment and characterization of genetically modified antibodies, immunotoxins, and vaccine antigens in the form of peptides or RNA for clinical application; 2) preparation of IND applications and maintenance of regulatory compliance for all reagents generated in this SRC or in separately funded grants; and 3) coordinated informatic and statistical oversight and analysis during the design and conduct of the pre-clinical and clinical studies outlined in the SRC and in separately funded grants. This Core will focus on two areas: 1) chimerization, fragment engineering, biochemical and genomic production and pre-clinical evaluation of monoclonal antibody and immunotoxin constructs in athymic rodent models for intracerebal and intrathecal compartmental therapy, and 2) in vitro characterization and pre-clinical toxicity evaluation of vaccine strategies consisting of conjugated peptides and RNA-loaded dendritic cells in immunocompetent syngeic murine astrocytoma models. Reagents will be developed, refined, or advanced to clinical trial that target EGFR/EGFRvlll, GP240/hmwCSPG, GPNMB, MRP3, and gangliosides 3'-isoLM1 and 3',6'-isoLD1. The requisite methodology for the generation of scFv diabodies, minibodies, and CH2 domain-deleted F(ab')2 MAbs for improved penetration, blood clearance, and lack of glomerular trapping is available in this Core. A large repertoire of large and small animal models that mimic human CMS disease and available administration routes (e.g. i.t. and i.e.) for preclinical evaluation of stability, localizing ability, immunologic, and tumoristatic or tumoricidal effect of developed agents is also available in this Core. We have multiple agents currently ready for testing and several others that should matriculate during the first year. This level of familiarity with these agents makes Core A a natural hub for IND preparation, statistical oversight, and the development and application of Nautilus and Oracle databases as well. RELEVANCE (Seeinstructions): This Core provides the statistical analysis to ensure proper design and interpretation of all experiments performed in this SRC. Experiments performed in this Core will ensure the quality and safety of all reagents produced within this SRC before clinical use. Finally, this Core provides the infrastructure to collect clinical data and to properly catalog, store and retrieve valuable clinical specimens.