CORE--THERAPEUTIC REAGENT EVALUATION, PRODUCTION AND NEW DRUG PERMIT CORE

Duke University, Durham NC

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): The role of Core 2 is twofold: 1) the preclinical evaluation and analysis of drugs, peptides, monoclonal reagents, derived constructs, and genetically modified antibody reagents for clinical application in terms of toxicity, stability, in vivo localization and therapeutic effect, generated in projects 1 , 3, and 4 of this SPORE; and 2) the preparation and submission of Investigational New Drug (IND) permit applications for all reagents of potential clinical utility. This Core provides a continuum from bench to clinical administration and assures the orderly progression and quality control of reagents in development that have characterized the development and implementation of our currently successful MAb reagents in Phase I and II clinical trials. The order of Aims below provides the developmental schema for reagents in the process of characterization all the way through to clinical application. The Functions/Specific Aims of Core 2 are as follows: Specific Aim 1. Pre-clinical development of intact, engineered, conjugated, and modified constructs of Mabs created in project 1 of this SPORE in terms of in vivo stability, localization, and therapeutic effect in immunocompetent and athymic rodent tumor xenograft models, both subcutaneous, intracranial, and intrathecal; Specific Aim 2. Pre-clinical analysis of derived drugs, peptides, and other moieties as described in Aim 1 for any reagents of promise identified in Projects 3 and 4; in vivo analysis of stability, localization, and specific cytocidal or cytotoxic effect; Specific Aim 3. Pre-clinical evaluation and quality certification of all reagents (drug, MAb, and derived constructs) generated in Projects 1, 3, and 4 of this SPORE. a. Quality control by performance of, or contract for, all assays for bacterial, fungal, viral, pyrogen, and DNA contamination, and general safety tests in vivo. b. Toxicity testing and analysis of drug, MAb-toxin conjugates, and nuclide-Mab conjugates, and their derivatives in animal models (normal and athymic rodents). c. Determination of the maximum tolerated doses (MTD) for all substances showing no toxicity and maximal stability and therapeutic effect in athymic and normal rat and mouse model systems (subcutaneous, intracranial, intrathecal, intratumoral CNS tumor xenografts). Specific Aim 4. Production of clinical grade reagents; and Specific Aim 5. Preparation and submission of IND permit applications for all proposed therapies developed in Projects 1, 3 and 4.