Preclinical and clinical development of an anti-kappa free light chain mAb for multiple myeloma.

Monoclonal antibodies (mAb) have had tremendous success in treating a variety of cancers over the past twenty years. Yet despite their widespread clinical use, which includes treatments for haematological malignancies, there are still no approved mAb therapies for multiple myeloma (MM). This is likely to change within the next few years with a number of mAb therapies being assessed in late stage clinical trials, most notably, the anti-CS-1 mAb, elotuzumab, and the anti-CD38 mAb, daratumumab, which are currently being evaluated in Phase III clinical trials for MM.

Cell membrane associated free kappa light chains are found on a subset of tonsil and in vitro-derived plasmablasts.

The monoclonal antibody, MDX-1097, is currently progressing through clinical trials as a possible therapy for multiple myeloma. MDX-1097 targets a cell membrane bound form of free immunoglobulin kappa light chain (FκLC), termed kappa myeloma antigen (KMA), which is found on the surface of malignant plasma cells. The clinical potential of MDX-1097 highlights the need to characterise the expression of its cognate antigen, KMA, in normal tissue.

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

We have described the presence of cell-membrane-associated κFLCs (free immunoglobulin light chains) on the surface of myeloma cells. Notably, the anti-κFLC mAb (monoclonal antibody) MDX-1097 is being assessed in clinical trials as a therapy for κ 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.

The ability to interact with cell membranes suggests possible biological roles for free light chain.

During antibody synthesis, immunoglobulin light chains are produced in excess of heavy chains and, as a consequence, can be secreted by plasma cells as free light chains (FLC). Thus, FLC were considered to be a by-product of immunoglobulin synthesis, lacking any biological function or relevance. However, mounting evidence suggests that FLC are bioactive molecules.

Characterization of a unique conformational epitope on free immunoglobulin kappa light chains that is recognized by an antibody with therapeutic potential.

The murine mAb, K-1-21, recognizes a conformational epitope expressed on free Ig kappa light chains (FκLCs) and also on cell membrane-associated FκLCs found on kappa myeloma cells. This has led to the development of a chimeric version of K-1-21, MDX-1097, which is being assessed in a Phase II clinical trial for the treatment of multiple myeloma. The epitope recognized by K-1-21 is of particular interest, especially in the context that it is not expressed on heavy chain-associated light chains such as in an intact Ig molecule.