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Anti-CD38-blocked ricin: an immunotoxin for the treatment of multiple
myeloma [see comments]
VS Goldmacher, LA Bourret, BA Levine, RA Rasmussen, M Pourshadi, JM Lambert and KC Anderson
ImmunoGen, Inc, Cambridge, MA 02139.
We report the development of a potent anti-CD38 immunotoxin capable of
killing human myeloma and lymphoma cell lines. The immunotoxin is composed
of an anti-CD38 antibody HB7 conjugated to a chemically modified ricin
molecule wherein the binding sites of the B chain have been blocked by
covalent attachment of affinity ligands (blocked ricin). Conjugation of
blocked ricin to the HB7 antibody has minimal effect on the apparent
affinity of the antibody and no effect on the ribosome-inactivating
activity of the ricin A-chain moiety. Four to six logs of CD38+ tumor cell
line kill was achieved at concentrations of HB7-blocked ricin in the range
of 0.1 to 3 nmol/L. Low level of toxicity for normal bone marrow (BM)
granulocyte-macrophage colony- forming units (CFU-GM), burst-forming
units-erythroid (BFU-E), colony- forming
units-granulocyte/erythroid/monocyte/macrophage (CFU-GEMM) cells was
observed. Greater than two logs of CD38+ multiple myeloma cells were
depleted from a 10-fold excess of normal BM mononuclear cells (BMMCs) after
an exposure to HB7-blocked ricin under conditions (0.3 nmol/L) that were
not very toxic for the normal BM precursors. HB7- blocked ricin was tested
for its ability to inhibit protein synthesis in fresh patients' multiple
myeloma cells and in normal BMMCs isolated from two healthy volunteers;
tumor cells from four of five patients were 100-fold to 500-fold more
sensitive to the inhibitory effect of HB7-blocked ricin than the normal BM
cells. HB7 antibody does not activate normal resting peripheral blood
lymphocytes, and HB7-blocked ricin is not cytotoxic toward these cells at
concentrations of up to 1 nmol/L. The potent killing of antigen-bearing
tumor cells coupled with a lack of effects on peripheral blood T cells or
on hematopoietic progenitor cells suggests that HB7-blocked ricin may have
clinical utility for the in vivo or in vitro purging of human multiple
myeloma cells.
Volume 84,
Issue 9,
pp. 3017-3025,
11/01/1994
Copyright © 1994 by The American Society of Hematology
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