Formation of assemblies on cell membranes by secreted proteins: Molecular studies of free lambda light chain aggregates found on the surface of myeloma cells

We have described the presence of cell-membrane-associated kappa FLCs (free immunoglobulin light chains) on the surface of myeloma cells. Notably, the anti-kappa FLC mAb (monoclonal antibody) MDX-1097 is being assessed in clinical trials as a therapy for kappa light chain isotype multiple myeloma. Despite the clinical potential of anti-FLC mAbs, there have been limited studies on characterizing membrane-associated FLCs at a molecular level. Furthermore, it is not known whether lambda FLCs can associate with cell membranes of myeloma cells. In the present paper, we describe the presence of lambda FLCs on the surface of myeloma cells. We found that cell-surface-associated lambda FLCs are bound directly to the membrane and in an aggregated form. Subsequently, membrane interaction studies revealed that lambda FLCs interact with saturated zwitterionic lipids such as phosphatidylcholine and phosphatidylethanolamine, and using automated docking, we characterize a potential recognition site for these lipids. Atomic force microscopy confirmed that membrane-associated lambda FLCs are aggregated. Given the present findings, we propose a model whereby individual FLCs show modest affinity for zwitterionic lipids, with aggregation stabilizing the interaction due to multivalency. Notably, this is the first study to image FLCs bound to phospholipids and provides important insights into the possible mechanisms of membrane association by this unique myeloma surface antigen.