Identification of specific immune responses in monoclonal gammopathy of undetermined significance with therapeutic implications

Abstract

8103 Background: Monoclonal gammopathy of undetermined significance (MGUS) is a benign condition with only 30% patients developing symptomatic multiple myeloma (MM). The events leading to the transformation from MGUS to MM remain unclear, however several evidences have supported the idea that immune surveillance play a role in preventing progression. Therefore, identification of antigenic targets with immune response in MGUS may provide insight into disease biology and immune-based therapeutic applications. Methods: Using the Serological identification of antigen by Recombinant Expression cloning (SEREX) technique, we have screened a MM cDNA library with 3 MGUS patients sera. Results: We have identified 11 gene products with an antibody response in MGUS. The response appeared to be directed against intracellular proteins involved in apoptosis (SON, Hip1), DNA and RNA binding proteins (KIAA0530, GPATC4), signal transduction regulators (AKAP11), developmental proteins (OFD1), transcriptional co-repressors (IRF2BP2), protein of the ubiquitin-proteosome pathways (PSMC1). We have further analyzed frequency of antibody response against these antigens in additional 26 MGUS sera, 10 newly diagnosed, 11 post-transplant remission and 12 relapsed MM patients and 25 normal donors. Whereas an antibody response was observed against OFD1 (20.6%), KIAA0530 (10.3%), AKAP11 (10.3%) and GPATC4 (6.8%) in MGUS patients, no responses were observed in normal donors or MM patients except against OFD1 in 3 post transplant patients. We have further focused our studies on OFD1, a developmentally expressed Hedgehog (Hh)-pathway-related protein with most frequent antibody response. We have previously showed that Hh-pathway genes are involved in development of MGUS. Our microarray analysis showed that OFD1 and other Hh pathway-related genes (Sonic, Smothened, Patched, Gli-1 and Gli-3) are selectively expressed in MM cell lines and primary cells. We have further evaluated a specific inhibitor of Hh- pathway, Cyclopamine, in MM and observed an inhibition of the proliferation in 5 MM cell lines with an IC50 between 13 - 20 μM. Conclusion: We have confirmed a specific immune response in MGUS and have identified a novel therapeutic target for treatment of MM. No significant financial relationships to disclose.