Retinoic acid-induced CD38 antigen as a target for immunotoxin-mediated killing of leukemia cells.
A major obstacle in the successful delivery of antibody-based therapeutics to tumor cells is the heterogeneity of target antigen expression. We reported previously that retinoic acid (RA) is a potent and selective inducer of the cell-surface antigen CD38 in myeloid leukemia cells. The purpose of this study was to determine whether the RA-induced CD38 antigen could be a target for an anti-CD38-based immunotoxin to induce selective killing of leukemia cells. The combination of RA and the anti-CD38 gelonin immunotoxin induced a synergistic killing of leukemia cells. Thus, coculture of myeloid leukemia cells and cell lines with as little as 1 nM RA in the presence of immunotoxin induced substantial killing (>90%) of leukemia cell clones. More importantly, the blasts of myeloid leukemia patients, irrespective of their morphological and phenotypic features, also responded to the RA and immunotoxin combination when cultured ex vivo. A similar synergistic effect between RA and immunotoxin was observed against a multidrug-resistant variant subline of HL-60 cells. However, another variant of HL-60 cells, HL-60R, in which the retinoid receptor function has been abrogated by a trans-dominant-negative mutation, exhibited complete resistance to the immunotoxin-induced killing effect in the presence or absence of RA. Our results suggest that RA combined with anti-CD38-based therapeutic agent may offer exciting opportunities for the treatment of myeloid leukemias despite their multiplicity of genetic and clinical varieties.
Mehta
Kapil
K
Department of Bioimmunotherapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA. kmehta@mdanderson.org
Ocanas
Larry
L
Malavasi
Fabio
F
Marks
John W
JW
Rosenblum
Michael G
MG
D036541:ADP-ribosyl Cyclase / Q000096:biosynthesis* / Q000627:therapeutic use; D051997:ADP-ribosyl Cyclase 1; D000911:Antibodies, Monoclonal / Q000737:chemistry; D015703:Antigens, CD / Q000096:biosynthesis* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D018432:Drug Resistance, Multiple; D018922:HL-60 Cells; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D000922:Immunotoxins / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use*; D007938:Leukemia / Q000628:therapy*; D008562:Membrane Glycoproteins; D009154:Mutation; D010940:Plant Proteins / Q000737:chemistry; D054789:Ribosome Inactivating Proteins, Type 1; D014212:Tretinoin / Q000378:metabolism / Q000494:pharmacology*
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000970:Antineoplastic Agents; D018076:DNA, Complementary; D000922:Immunotoxins; D008562:Membrane Glycoproteins; D010940:Plant Proteins; D054789:Ribosome Inactivating Proteins, Type 1; D014212:Tretinoin; C025674:GEL protein, Gelonium multiflorum; D036541:ADP-ribosyl Cyclase; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1