CORE--INVESTIGATIONAL NEW DRUG AND MONOCLONAL ANTIBODY PERMIT APPLICATION

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Core 1 furnishes: 1) the preclinical evaluation of drugs and monoclonal reagents for the preparation of Investigational New Drug (IND) applications and 2) the continued generation and development of new, and the establishment and characterization of genetically modified antibodies for clinical application. The preparation of IND applications includes the establishment of biologic specificity, the performance of all FDA mandated assays for bacterial, fungal, viral, pyrogen, and DNA contamination, and general safety tests. Two Phase I clinical studies are in progress under permits BBIND 2692 and BBIND 3344; these trials are evaluating the efficacy and lack of toxicity of the intrathecal and intracystic administration of the MAbs 81C6 and Mel-14 in patients with gliomas, metastatic malanoma; or other brain tumors. The second role of Core 1 is to provide a continual source of reagents for IND application and Phase I trial. Three areas are being pursued: 1) chimerization of anti-glioma MAbs; 2) preclinical evaluation of drugs and MAb conjugates in athymic rat xenograft model systems to allow intraarterial and intrathecal modes of administration; and 3) development and de novo production of new reagents for glioma and medulloblastoma. MAb chimerization. Murine MAbs in Phase I trial, 81C6 and Mel-14, have been chimerized by genomic cloning, transfected into an SP2/0 expression system, purified, demonstrated to retain specificity and an equal to or greater affinity than the parental murine molecule and localize in athymic mouse subcutaneous xenograft models. Enhanced plasma half-life and greater localization in percent dose/gm and localization indices were observed, as was decreased dehalogenation. Alternate methods of chimerization are being explored for these and all other candidate reagents, with regard to human framework desired, maximally productive cell expression systems, and site-directed mutagenesis. Model systems for reagent development. We have developed and applied two model systems in the athymic rat for the evaluation of intraarterial or intrathecal compartmental therapy. Tumor xenograft models include glioma (D54 MG), medulloblastoma (D341 Med), carcinoma (A431), and rhabdomyosarcoma (TE- 671). Currently, we are evaluating intraarterial and intrathecal administration of melphalan to glioma and medulloblastoma xenografts; the intrathecal therapy of carcinoma with MAb-Pseudomonas toxin conjugates; and the efficacy of alpha-emitting nuclide-MAb conjugates (211AT) to intracranial tumors and leptomeningeal disease. Development of new antiglioma and anti-medulloblastoma reagents. Additional candidate molecules for diagnostic, imaging or therapeutic targeting have been identified. Currently, the only MAb demonstrated to be of value in the compartmental therapy of medulloblastoma is the anti-L1 MAb UJ181.4, the continued use of which has been compromised by its inherent low secretion rate. We are optimizing this mAb for Phase I studies by chimerization. We propose the production of reagents to the multi-epitopic L1 molecule for therapeutic application and determination of its role in medulloblastoma cell aggregation and adhesion to leptomeningeal matrix.