Abstract 2525: JL1 is a cell surface molecule of acute leukemia blasts: Potential for targeted immunotherapy

Abstract

Abstract Background: Acute leukemia in adults is associated with poor prognosis, with many patients suffering from treatment-resistant relapse. Novel targeted therapies are needed. JL1 was identified as an extracellular glycoform of the cell surface protein sialophorin (CD43). We tested monoclonal antibodies (mAbs) specific for JL1 that are not immunoreactive to the common form of CD43. We characterized JL1 expression in primary acute leukemia blasts and explored the therapeutic potential of these antibodies against acute leukemia. Methods: Fresh peripheral blood or bone marrow aspirate samples from acute leukemia patients, healthy donors, or leukemia cell lines were used for expression studies by flow cytometry (FC) with a monoclonal antibody against JL1. Immunohistochemistry (IHC) was also performed on normal human tissues. A saporin-conjugated anti-JL1 mAb was used to evaluate the proliferation-inhibition and apoptosis-induction against leukemia cell lines in vitro and primary acute leukemia cells ex vivo. A mouse engraftment model with primary acute leukemia cells was established to investigate the in vivo effect of the JL1 mAb. Results: By IHC, JL1 expression was found in normal human thymocytes FC showed that JL1 was not detectable on normal peripheral blood cells (n=3). FC assay of acute leukemia blasts showed that 85.7% (18 of 20 acute myeloid leukemia and 6 of 8 acute lymphoblastic leukemia) of cases expressed JL1. A saporin-conjugated anti-JL1 mAb was capable of mediating dose-dependent proliferation-inhibition and apoptosis-induction in CEM-7 leukemia cells. The effect of proliferation-inhibition of anti-JL1-saporin on different cell lines appears to be related to JL-1 expression level. Preliminary data also shows this toxin-conjugated mAb displayed effects of 1) proliferation-inhibition on primary JL1+ acute leukemia blasts while control antibody-saporin had no detectable activity; 2) inhibition of colony formation of primary leukemia cells in a soft agar assay. A SCID/CEM-7 xenograft mouse model indicates that JL1 mAb treatment prolongs survival. We are currently testing the in vivo efficacy of JL1-saporin conjugate in primary acute leukemia blast-engrafted NSG mouse model. Conclusion: JL1 is a cell surface antigen expressed in majority of acute leukemia blasts while it is not detectable in normal human blood cells. JL1 mAbs are capable of inhibiting proliferation and mediating apoptosis in cell lines and primary acute leukemia cells when mAb is conjugated to saporin. Mouse xenograft data demonstrates the anti-tumor potential of JL1 mAb in vivo. Taken together, these data suggest that JL1 is a promising target in the treatment of acute leukemia. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2525. doi:1538-7445.AM2012-2525