By Hien Duong, MD, and Mikkael A. Sekeres, MD, MS

2009-12-06

Today’s Oral Session on erythropoiesis and paroxysmal nocturnal hemoglobinuria (PNH) (4:30 p.m. in rooms 220-222), moderated by Drs. Alan Schechter of the National Institutes of Health and James Palis of the University of Rochester, will feature several novel approaches to PNH and new treatment targets. Like the narrator in Robert Pirsig’s classic 1974 philosophical treatise, “Zen and the Art of Motorcycle Maintenance,” scientists in this session have relied on rational problem solving, rather than a romantic gestalt, to identify causes of and solutions to PNH-mediated hemolysis.

Dr. Ronald Taylor from the University of Virginia will discuss a novel monoclonal antibody (mAb), 3E7, and its chimeric humanized derivative H17, which block the alternative pathway of complement (APC) C3/C5 convertase, thus inhibiting hemolysis in PNH. Previously, eculizumab, a humanized mAb that binds C5 complement and prevents formation of the cytolytic membrane attack complex, was found to reduce hemolysis and thrombosis risk in PNH patients; these clinical successes led to FDA approval of eculizumab for PNH in 2007. However, a significant number of eculizumab-treated patients still have active hemolysis and remain transfusion-dependent.  It is thought that this persistent hemolysis is due to C3 opsonization, as eculizumab does not affect the APC pathway. Dr. Taylor will discuss whether mAb 3E7/H17 might provide another therapeutic option for patients who respond suboptimally to eculizumab.

Dr. Antonio M. Risitano, from Naples, Italy, will introduce TT30, a novel regulator of the APC, which can inhibit hemolysis of PNH erythrocytes. The investigators developed a modified Ham test that delayed hemolysis, thereby allowing for quantification of the effects of various regulators of complement on hemolysis on PNH erythrocytes. Using this model, C3 opsonization could be quantified and various inhibitors tested. TT30, a recombinant chimeric human fusion protein consisting of the iC3b/C3d-binding region of complement receptor 2 and functional domains of the APC regulator factor H (fH), significantly inhibited hemolysis. Using their modified Ham test, they showed that C3 opsonization continued to occur in PNH erythrocytes treated with eculizumab (as has been demonstrated clinically), but not with TT30. These findings illustrate another potential mechanism for blocking both intravascular and extravascular hemolysis in PNH by inhibiting the APC.

Dr. Regis Peffault de Latour from the National Institutes of Health will discuss another potential target for therapy in PNH:  the endoplasmic reticulum (ER) stress response. PNH is caused by a somatic mutation of the X-linked gene PIGA, which encodes a factor essential for stability of glycosylphosphatidylinositol-anchored proteins (GPI-APs). Unfolded GPI-APs are degraded intracellularly in the ER by proteasomes. Accumulation of misfolded proteins in mutant PNH cells is thought to activate the unfolded protein response (UPR) signaling cascade, which physiologically maintains the quality of newly synthesized proteins. UPR, then, could represent a new target for therapy in PNH. The investigators initially tested this theory using bortezomib, a potent proteasome inhibitor that is FDA-approved for treatment of multiple myeloma, and found that GPI-AP deficient cells of the type seen in PNH demonstrated significantly higher cytotoxicity in the presence of bortezomib than healthy cells. They confirmed this finding with two other proteasome inhibitors, MG132 and lactacystine, suggesting a method by which PNH cells might be eliminated.

As complex relationships among PNH erythrocytes, complement pathways, and the bone marrow environment continue to be discovered, new therapeutic strategies will be developed for improvement in patient outcomes. While there are still miles to go, the road ahead for research in PNH is an exciting one. And, of course, when riding your motorcycle down such roads, remember to always wear your helmet, lest you undergo accidental lysis.

Drs. Duong and Sekeres indicated no relevant conflicts of interest.

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