Misfolded and aggregated immunoglobulin kappa and lambda light chains (AL amyloid)

Misfolded and aggregated immunoglobulin kappa and lambda light chains are the primary pathogenic drivers of AL amyloidosis, a systemic disorder characterized by the extracellular deposition of amyloid fibrils in vital organs (Merlini et al., 2018). These light chains are produced by clonal plasma cells and undergo conformational changes that lead to the formation of toxic oligomers and insoluble fibrils, causing progressive organ damage, particularly in the heart and kidneys (Gertz, 2020). Therapeutic strategies targeting these aggregates involve monoclonal antibodies designed to recognize specific epitopes exposed only in the misfolded state (Sanchorawala et al., 2023). By binding to these targets, the drugs aim to neutralize proteotoxicity and stimulate the immune-mediated clearance of existing amyloid deposits (Vaxman & Gertz, 2020). This approach complements traditional chemotherapy, which focuses on reducing the production of precursor light chains by targeting the underlying plasma cell dyscrasia.

Other names

Amyloid light chainsAL fibrilsMonoclonal free light chainsMisfolded FLCsImmunoglobulin light chain aggregates

Monoclonal antibodies bind to cryptic epitopes exposed on misfolded or aggregated light chains, facilitating their clearance by macrophages and neutralizing soluble toxic oligomers (Sanchorawala et al., 2023; Vaxman & Gertz, 2020).