Biotherapy of B-cell precursor leukemia by targeting genistein to CD19-associated tyrosine kinases.
B-cell precursor (BCP) leukemia is the most common form of childhood cancer and the second most common form of acute leukemia in adults. Human BCP leukemia was treated in a severe combined immunodeficient mouse model by targeting of the tyrosine kinase inhibitor Genistein (Gen) to the B cell-specific receptor CD19 with the monoclonal antibody B43. The B43-Gen immunoconjugate bound with high affinity to BCP leukemia cells, selectively inhibited CD19-associated tyrosine kinases, and triggered rapid apoptotic cell death. At less than one-tenth the maximum tolerated dose more than 99.999 percent of human BCP leukemia cells were killed, which led to 100 percent long-term event-free survival from an otherwise invariably fatal leukemia. The B43-Gen immuno-conjugate might be useful in eliminating leukemia cells in patients who have failed conventional therapy.
Uckun
F M
FM
Department of Therapeutic Radiology-Radiation Oncology, University of Minnesota, Minneapolis 55455.
Evans
W E
WE
Forsyth
C J
CJ
Waddick
K G
KG
Ahlgren
L T
LT
Chelstrom
L M
LM
Burkhardt
A
A
Bolen
J
J
Myers
D E
DE
D000818:Animals; D000911:Antibodies, Monoclonal; D015703:Antigens, CD / Q000276:immunology*; D018941:Antigens, CD19; D000944:Antigens, Differentiation, B-Lymphocyte / Q000276:immunology*; D017209:Apoptosis; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000378:metabolism; D019833:Genistein; D018796:Immunoconjugates / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007529:Isoflavones / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D017254:Leukemic Infiltration; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D051379:Mice; D016513:Mice, SCID; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D014018:Tissue Distribution; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D018941:Antigens, CD19; D000944:Antigens, Differentiation, B-Lymphocyte; D004273:DNA, Neoplasm; D018796:Immunoconjugates; D007529:Isoflavones; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)