Amyloid Light-chain (AL) amyloidosis is a rare disease characterized by the formation and deposition of insoluble fibrillary proteins (amyloid) in extracellular spaces of tissues and organs resulting in severe structural and functional organ damage. Currently, treatment of patients with AL amyloidosis is limited to anti-plasma cell chemotherapy to reduce or eliminate the amyloidogenic light chain producing cells. Although the development of new agents has improved survival, the prognosis is still poor due to accumulation of pathologic fibrillar deposits and the resultant loss of vital organ function. In an effort to induce rapid removal of amyloid fro the body, Dr. Solomon developed a murine monoclonal anti-light chain antibody (designated 11-1F4) that is specific for light-chain amyloid fibrils. Moreover, administration of this agent into mice with induced subcutaneous tumors composed of human AL amyloid led to elimination, i.e., amyloidolysis, of the pathologic material with no apparent untoward side effects. To facilitate its use in humans, the murine mAb 11-1F4 has been chimerized under the auspices of the National Cancer Institute's Biological Resource Branch Developmental Therapeutic Program and amounts of GMP-grade chimeric (Ch) mAb 11-1F4 have been produced that are sufficient for a Phase 1a/1b therapeutic clinical trial. The clinical trial proposes to (1) define the MTD and safety of (Ch) Ab 11-1F4 in a Phase 1a study; (2) determine the safety, tolerance and possible clinical benefit of the MTD of (Ch) Ab 11-1F4 in a Phase 1b study; and (3) determine the serum levels of (Ch) mAb 11-1F4 in treated patients by enzyme-linked immunosorbent assay (ELISA) when given as a single intravenous infusion (Phase 1a) or as a series of four weekly intravenous infusions (Phase 1b). Proof of the efficacy of AL-fibril-specific mAb treatment would be an adjunct (in combination with anti-plasma cell drugs) in the treatment of patients with AL amyloidosis and may lead to improved medical management of this incurable and fatal disease.
AL Amyloidosis is an orphan disease characterized by the deposition of amyloid consisting of misfolded light chain fibrils, which leads if untreated, to organ failure. Dr. Solomon's group developed an (Ch) mAb 11-1F4 antibody that directly targets existing amyloid and potentially leads to the clearance of the amyloid. We plan to test the (Ch) mAb 11-1F4 antibody in a clinical trial to determine the safety, tolerance, pharmacokinetics, and clinical benefit. Positive findings from our trial showing a decrease in amyloid body burden will provide a complete new and promising treatment option for this devastating disease.
| Li, Shirong; Fu, Jing; Wang, Hui et al. (2018) IMiD compounds affect CD34+ cell fate and maturation via CRBN-induced IKZF1 degradation. Blood Adv 2:492-504 |
