ENGINEERED ANTI-CD38 MONOCLONAL-ANTIBODIES FOR IMMUNOTHERAPY OF MULTIPLE-MYELOMA

Multiple myeloma is a malignancy of plasma cells for which there is no effective treatment. To develop an immunotherapeutic agent, we have r aised a high affinity mAb (AT13/5) against CD38, one of the few well-c haracterized surface Ags present on myeloma cells. Since murine monocl onals have many disadvantages as human therapeutics, we prepared two e ngineered forms of the Ab: a CDR-grafted humanized IgG1 and a chimeric FabFc(2) (mouse Fab cross-linked to two human gamma(1) Fc). To retain affinity in the humanized Ab, a number of changes were required to th e human framework regions of the heavy chain. In particular, through s ystematic mutagenesis and computer modeling, we identified a critical interaction between the side chains of residues 29 and 78, which may b e important for the humanization of other Abs. The properties of the h umanized IgG1 and FabFc(2) constructs were compared in a series of in vitro tests. Both constructs efficiently directed Ab-dependent cellula r cytotoxicity against CD38-positive cell lines, but C was activated o nly poorly. Neither construct caused down-modulation of CD38, nor did they affect the NADase activity of CD38. Despite their differing struc tures, both Abs showed similar activity in most assays, although the h umanized IgG1 was more potent at inducing monocyte cytotoxicity. These data represent the first direct comparison of CDR-grafted and chimeri c FabFc(2) forms of the same Ab, and offer no support for the perceive d advantages of the FabFc(2). These Abs show promise for therapy of mu ltiple myeloma and other diseases involving CD38-positive cells.