Immunotherapeutic for ATTR/AL Cardiac Amyloidosis

Cardiac amyloidosis is characterized by myocardial accumulation of protein fibrils in the heart and the most common types are wild-type and hereditary transthyretin (ATTR) and light-chain (AL) amyloidosis. It is a severe, progressive and often lethal disorder. We believe it is possible to develop a pan amyloid therapeutic that can treat all cardiac amyloidosis and can target patients irrespective of whether they have AL, wild-type or mutant ATTR amyloidosis. We have identified a novel family of synthetic, polybasic peptides that specifically detect a unique version of heparan sulfate in amyloid deposits and binds to the surface of diverse protein amy- loid fibrils (Fig 1). Heparan sulfate, which is a major and ubiquitous component of all amyloid deposits is struc- turally distinct from the heparan sulfate normally found in the extra-cellular matrix. It is present in amyloid in a much higher density and is hypersulfated, and can therefore be specifically targeted. The peptides, p5 and the elongated form p5+14, were shown to bind to amyloid deposits in vitro and in vivo in a murine model. A radio- labeled version designated 124I-p5+14, is currently being developed as a pan-amyloid imaging agent for the detection, quantification and monitoring of multi-organ amyloidosis including cardiac amyloidosis in human subjects.We propose to develop and characterize a humanized version of the p5 antibody-fusion (termed hIgp5), in which the p5 peptide is fused directly to the humanized antibody light chain. The new antibody-peptide fu- sion construct will be quantitatively evaluated in various in vitro ATTR and AL amyloid binding studies. Addi- tionally, we will employ florescence based methods of measuring their ability to induce uptake of amyloid in vitro. Mice bearing localized fluorescent human amyloidomas, which can be non-invasively monitored by opti- cal imaging, will be used for in vivo studies.Our goal is to develop a pan amyloidosis therapeutic agent to 1) bind all types of amyloid 2) leverage multiple binding sites 3) remain highly specific 4) serve as a backbone for therapeutics and 5) utilize for imag- ing as a disease biomarker and a biomarker to monitor outcomes from therapeutic intervention. Our research strategy could lead to a pan amyloid antibody therapeutic that is highly effective in clearing amyloid fibrils from the heart and a trailblazer to a transformative therapy for cardiac amyloidosis patients.Cardiac amyloidosis is a devastating disease characterized by the deposition of protein fibrils mainly ATTR and AL in the heart causing it to fail and leading ultimately to death. Despite decades of research and improvements in patient survival rates, they remain invariably fatal due to the inability to effectively diagnose and remove tissue amyloid. Therefore, our goal is to develop a drug that can target all amyloid or a pan amyloid therapeutic that can target both ATTR and AL thereby providing new hope for patients with these diseases.