The cationic small molecule GW4869 is cytotoxic to high phosphatidylserine-expressing myeloma cells.

We have discovered that a small cationic molecule, GW4869, is cytotoxic to a subset of myeloma cell lines and primary myeloma plasma cells. Biochemical analysis revealed that GW4869 binds to anionic phospholipids such as phosphatidylserine - a lipid normally confined to the intracellular side of the cell membrane. However, interestingly, phosphatidylserine was expressed on the surface of all myeloma cell lines tested (n = 12) and 9/15 primary myeloma samples. Notably, the level of phosphatidylserine expression correlated well with sensitivity to GW4869. Inhibition of cell surface phosphatidylserine exposure with brefeldin A resulted in resistance to GW4869. Finally, GW4869 was shown to delay the growth of phosphatidylserine-high myeloma cells in vivo. To the best of our knowledge, this is the first example of using a small molecule to target phosphatidylserine on malignant cells. This study may provide the rationale for the development of phosphatidylserine-targeting small molecules for the treatment of surface phosphatidylserine-expressing cancers.

A parasite-derived 68-mer peptide ameliorates autoimmune disease in murine models of Type 1 diabetes and multiple sclerosis.

Helminth parasites secrete molecules that potently modulate the immune responses of their hosts and, therefore, have potential for the treatment of immune-mediated human diseases. FhHDM-1, a 68-mer peptide secreted by the helminth parasite Fasciola hepatica, ameliorated disease in two different murine models of autoimmunity, type 1 diabetes and relapsing-remitting immune-mediated demyelination. Unexpectedly, FhHDM-1 treatment did not affect the proliferation of auto-antigen specific T cells or their production of cytokines. However, in both conditions, the reduction in clinical symptoms was associated with the absence of immune cell infiltrates in the target organ (islets and the brain tissue). Furthermore, after parenteral administration, the FhHDM-1 peptide interacted with macrophages and reduced their capacity to secrete pro-inflammatory cytokines, such as TNF and IL-6. We propose this inhibition of innate pro-inflammatory immune responses, which are central to the initiation of autoimmunity in both diseases, prevented the trafficking of autoreactive lymphocytes from the periphery to the site of autoimmunity (as opposed to directly modulating their function per se), and thus prevented tissue destruction. The ability of FhHDM-1 to modulate macrophage function, combined with its efficacy in disease prevention in multiple models, suggests that FhHDM-1 has considerable potential as a treatment for autoimmune diseases.

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. In this study, we have analysed the expression of KMA on B cell subsets found in tonsils, peripheral blood and bone marrow. We found KMA expression on a small population of tonsillar and in vitro derived plasmablasts. In contrast, no KMA expression was observed on peripheral blood or bone marrow resident B cell subsets. This study yields important insights into the possible subsets of B cells that might be depleted as a result of an immunotherapy targeting KMA.