Arthritis & Rheumatism, Volume 60,
October 2009 Abstract Supplement
The 2009 ACR/ARHP Annual Scientific Meeting
Philadelphia October 16-21, 2009.
A Nonfucosylated Human Antibody to CD19 with Potent B-Cell Depletive Activity for Treatment of Autoimmune Diseases
Cardarelli1, Pina M., Blanset2, Diann, Rao-Naik1, Chetana, Witte1, Alison, Preston1, Ben, Chen1, Sharline, Yellin2, Michael J.
CD19 represents an attractive B-cell target for the treatment of autoimmune diseases with a number of potential advantages over CD20-directed therapies. Studies to characterize the in vitro and in vivo activities of a novel anti-CD19 antibody, MDX-1342, have been undertaken.
A human anti-CD19 antibody was expressed in fucosyltransferase-deficient CHO cells to generate nonfucosylated MDX-1342. Assays measuring antibody binding to CD19-expressing cells and FcgRIIIa (CD16) transfectants as well as antibody-dependent cell-mediated cytotoxicity (ADCC) were conducted. In vivo B-cell depletion was monitored in cynomolgus monkeys following a single intravenous dose of MDX-1342. Flow cytometry was carried out by standard methods.
Binding of MDX-1342 to human CD19-expressing cells was similar to its fucosylated counterpart. However, nonfucosylated MDX-1342 exhibited increased affinity for FcgRIIIa-Phe158 and FcgRIIIa-Val158 receptors and enhanced effector cell function, as demonstrated by increased potency and efficacy in antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis assays. MDX-1342 displayed low nanomolar binding to cynomolgus monkey CD19 and demonstrated increased affinity for cynomolgus monkey FcgRIIIa. Administration of MDX-1342 at 1 mg/kg in cynomolgus monkeys resulted in a 90% depletion of circulating B cells while parental anti-CD19 antibody induced approximately 50% depletion of B cells. Furthermore, the duration of B-cell depletion was longer for MDX-1342 compared to parental mAb. The ability of MDX-1342 to deplete cynomolgus monkey B cells was compared to rituximab. The extent and duration of B-cell depletion was similar for MDX-1342 and rituximab, despite higher levels of CD20 antigen on B cells, although the kinetics of depletion appeared to be initially more rapid with rituximab. B-cell repletion was documented in animals treated with both B cell-specific antibodies and there was no effect of treatment on serum IgG or IgM levels. Preliminary data available from an ongoing Phase 1 study of MDX-1342 in subjects with active rheumatoid arthritis (RA) despite treatment with methotrexate demonstrates potent B-cell depletion with single-dose (10 or 30 mg) administration of MDX-1342. Flow cytometric analysis showed that the CD20-CD27+CD38+ plasmablasts, a cell population implicated in the pathogenesis of RA and systemic lupus erythematosus and known to be unaffected by anti-CD20-directed monoclonal antibodies, were also depleted in these human subjects.
MDX-1342 is a promising anti-CD19 antibody with enhanced effector function. Clinical studies of MDX-1342 in patients with RA are ongoing.
To cite this abstract, please use the following information:
Cardarelli, Pina M., Blanset, Diann, Rao-Naik, Chetana, Witte, Alison, Preston, Ben, Chen, Sharline, et al; A Nonfucosylated Human Antibody to CD19 with Potent B-Cell Depletive Activity for Treatment of Autoimmune Diseases [abstract]. Arthritis Rheum 2009;60 Suppl 10 :692