Evaluation of CD38 as Target for Immunotherapy in Multiple Myeloma

We have read with interest the report of Goldmacher et al.’ They describe the construction of an anti-CD38 imunotoxin (IT) by conjugating CD38 monoclonal antibody (MoAb) HB7 to blocked ricin. The resulting IT shows potent killing of plasma cell lines, whereas only low toxicity is observed for hematopoietic precursor cells (HPC). Therefore, they conclude that this HB7-blocked ricin may have clinical utility for ex vivo and in vivo therapy of multiple myeloma (MM). We agree with the notice that CD38 is strongly expressed on malignant (and normal) plasma cells, but differ in opinion about the side effects of an anti-CD38 IT. These side effects relate to reactivity with HPC as well as with nonlymphoid tissue. Our research group is also engaged in the development of an MoAb based therapy for MM. We performed a selection procedure with a panel of 12 different plasma cell reactive MoAbs, including four CD38 MoAbs: ID5 (IgM), 6B10 (IgM), and 7A6 (IgG2a) from R. van Lier (Amsterdam, The Netherlands) and also HB7 (IgG1) from M. Cooper (Birmingham, AL). For ex vivo use, we used as major criterium (besides reactivity with malignant cells) the absence of reactivity with HPC to avoid interference with blood cell repopulation of the treated bone marrow. Goldmacher et all correctly mention that the pluripotent HPC are crucial for a long-term (sustained) marrow recovery. These cells are CD38 MoAbs and rabbit complement (Table 1). Depletion of CD38’ cells resulted in a complete eradication of GM-CFU cells and a practically complete one of BFU-E cells. No effect was seen with the MoAbs alone (data not shown). Whereas the quantitive difference between our results and those of Goldmacher et al’ might relate to a different density of CD38 or a possible different IT-induced internalization of CD38 on HPC than on plasma cells, it certainly enforces the caution that the toxicity they saw with their anti-CD38 IT is a specific one indeed. The importance of a bone marrow purging protocol for MM may be restricted by the recent progress in the application of peripheral HPC pheresis and transplantation. Therefore, Goldmacher et all rightly envisage as well an eventual in vivo therapy. An additional criterium to reactivity with hematopoietic precursors for such in vivo use is the absence of crossreactivity with other tissues, an item not discussed or tested by Goldmacher et al.’ Indeed, sufficient data are lacking in the literature so far. We have tested the crossreactivity of CD38 MoAb with different tissues using indirect three-step immunoperoxidase staining. Tissues involved included spleen, stomach, duodenum, esophagus, tonsil, thyroid gland, liver, lung, kidney, heart, muscle, skin, thymus, brain, lymph node, skin immunocytoma, and nasopharynx plasmacytoma. Plasma cells at various locations