Light chain amyloidosis (AL) is the most common form of systemic amyloid disease, with an estimated 4,500 new cases each year in the US. AL is a complex plasma cell-related disease characterized by the formation of insoluble, immunologically-inert protein fibrils composed of misfolded monoclonal immunoglobulin light chain components Extracellular amyloid fibrils can deposit in any organ or tissue causing loss of function, morbidity, and, ultimately, death. Despite decades of active research and increased understanding of pathological mechanisms, AL remains incurable, and the prognosis for patients is poor with a median survival of less than 3 years. Effective clinical management of patients with AL requires, in addition to chemotherapy, removal of destructive tissue amyloid so that organ function can be allowed to recover. A proven method of amyloid removal is opsonization of the deposits by using amyloid-reactive antibodies. Although promising, preliminary results from two ongoing clinical trials of anti-AL amyloid antibodies indicate that they may be effective in only approximately 50% of patients. To address this deficiency we have developed a strategy that uses a novel bifunctional ?peptope? ? that combines a pan-amyloid-reactive peptide and a linear epitope sequence ? to enhance the efficacy and extend the utility of current immunotherapeutic antibodies, such as the chimeric reagent, 11-1F4. In this proposal, we will evaluate and characterize a peptope comprised of the amyloid-reactive peptide p5+14 and a high affinity epitope (0.3 nM) recognized by 11-1F4. Using a battery of quantitative in vitro binding assays as well as in vivo dual-energy SPECT imaging and tissue biodistribution studies, we will quantify the efficacy of peptope-mediated amyloid targeting of the 11-1F4 antibody. Finally, we will investigate, using mouse models of systemic and localized amyloidosis, the ability of peptope-antibody immunotherapy to induce amyloid removal in vivo. We anticipate that this novel, two-stage opsonizing immunotherapy will enhance the efficacy of 11-1F4-based therapy in patients with AL and potentially extend the utility of this antibody to other forms of systemic amyloid disease. AL amyloidosis remains a devastating and incurable disease. The goal of this application is to develop bifunctional peptides that simultaneously bind amyloid and the 11-1F4 monoclonal antibody to generate a novel immunotherapy for AL amyloidosis. This approach will complement and extend current antibody-based therapies for amyloid removal, thereby restoring organ function and securing long term survival and remission for patients with AL.
Light chain (AL) amyloidosis is a devastating disease characterized by the deposition of protein fibrils, known as amyloid, in body organs and tissues, causing a loss of function and ultimately death. Removal of the amyloid would permit organs to recover and regain their function providing positive clinical benefit for patients. Therefore, we will develop a new and creative approach to enhance and expand current antibody-based methods for treating AL patients that will allow the body to more effectively ?dissolve? amyloid deposits, thereby providing new hope for patients with the disease.
|Wall, Jonathan S; Williams, Angela D; Foster, James S et al. (2018) Bifunctional amyloid-reactive peptide promotes binding of antibody 11-1F4 to diverse amyloid types and enhances therapeutic efficacy. Proc Natl Acad Sci U S A 115:E10839-E10848|