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The murine mAb, K-1-21, recognizes a conformational epitope expressed on free Ig kappa light chains (FkappaLCs) and also on cell membrane-associated FkappaLCs 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. Using epitope excision techniques we have localized the K-1-21 epitope to a region spanning residues 104-110 of FkappaLC. This short strand of residues links the variable and constant domains, and is a flexible region that adopts different conformations in FkappaLC and heavy chain-associated light chain. We tested this region using site-directed mutations and found that the reactivity of K-1-21 for FkappaLC was markedly reduced. Finally, we applied in silico molecular docking to generate a model that satisfied the experimental data. Given the clinical potential of the Ag, this study may aid the development of next generation compounds that target the membrane form of FkappaLC expressed on the surface of myeloma plasma cells.