? This application to the FDA's Office of Orphan Products Development Grants Program requests funds to support a pilot open-label Exploratory IND Phase 1 imaging and biodistribution study to be performed at the University of Tennessee Graduate School of Medicine (UTGSM)/University of Tennessee Medical Center (UTMC), Knoxville, TN. It is designed to determine the human dosimetry and capability of the fibril-reactive murine monoclonal antibody Mu 11-1F4 labeled with I-124 to target amyloid deposits in organs or tissues of patients with AL amyloidosis. AL amyloidosis, a monoclonal plasma cell dyscrasia, is an illness associated with considerable morbidity that results from the pathologic deposition in vital organs of fibrils comprised of immunoglobulin light chain-related components and is presently incurable due to insufficient knowledge of disease pathogenesis, as well as limitations in diagnostic and therapeutic modalities. The radioisotope, I-124, will be furnished by IBA Molecular, Sterling, VA (DMF# 19434) and the vialed antibody (that has undergone the requisite pre-clinical pharmacology and toxicology testing) supplied by the National Cancer Institute-Frederick Cancer Research and Development Center's Biologic Resource Branch/Biopharmaceutical Development Program. The reagent will be radiolabeled in UTMC's Radiochemistry Facility and the final product (that has been assayed for purity, stability, detection of anti-fibril immunoreactivity, sterility, and non-pyrogenicity) provided to UTMC's Department of Nuclear Medicine for antibody administration and PET/CT scans. For dosimetry purposes, the first 3 patients will receive 74 MBq (2 mCi) of 124I-11-1F4 (there will be a 30-day interval between each study), after which the biodistribution data will be analyzed by a radiophysicist and this information sent to the FDA (Specific Aim 1). After approval by the Agency, the trial will be opened to include 20 subjects and, due to the heterogeneity of the disease and differences in amyloid fibril epitope expression, etc., if a known site of amyloid deposition is targeted in at least 4 of these individuals, another 10 will be placed on the protocol (Specific Aim 2). It also will be determined if the ability to image AL amyloid with 124I-Mu 11-1F4 is dependent on the primary structural features of the amyloidogenic precursor protein (Specific Aim 3). It is estimated that the study will require ~2 yrs, given the anticipated accrual rate of 2 patients per month. ? ? ?
AL amyloidosis, a monoclonal plasma cell dyscrasia, is an illness associated with considerable morbidity that results from the pathologic deposition in vital organs of fibrils comprised of immunoglobulin light chain-related components and is presently incurable due to insufficient knowledge of disease pathogenesis, as well as limitations in diagnostic and therapeutic modalities. This application, entitled """"""""Radioimaging of Patients with AL Amyloidosis using the Amyloid-Reactive Monoclonal Antibody Mu 11-1F4"""""""", addresses a critical need; namely, to provide an objective means to visualize and determine the extent of amyloid deposits in this patient population. Demonstration of the safety and targeting potential of 124I-11-1F4 would have important clinical implications in the care of patients with AL amyloidosis.
