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.