Biotherapy for xenografted human central nervous system leukemia in mice with severe combined immunodeficiency using B43 (anti-CD19)-pokeweed antiviral protein immunotoxin.
The study of central nervous system (CNS) leukemia has been hampered by the lack of a suitable animal model. We report that severe combined immunodeficiency (SCID) mice invariably develop rapidly progressive fatal CNS leukemia within 3 weeks after intravenous injection of NALM-6 pre-B acute lymphoblastic leukemia (ALL) cells. Colonization of the dura mater and subarachnoid space, usually of the distal spinal cord with occasional extension into the Virchow-Robin spaces of blood vessels subjacent to the meninges, followed involvement of bone marrow in the skull, vertebrae, and, occasionally, the appendicular skeleton. Occult CNS leukemia was detectable by polymerase chain reaction amplification of human DNA as early as 8 days postinoculation of leukemia cells. We used this in vivo model of human CNS leukemia to examine the therapeutic efficacy and toxicity of intrathecally administered B43 (anti-CD19)-pokeweed antiviral protein (PAP), an anti-B-lineage ALL immunotoxin directed against the pan-B-cell antigen CD19/Bp95. Intrathecal therapy with B43 (anti-CD19)-PAP immunotoxin at nontoxic dose levels significantly improved survival of SCID mice and was superior to intrathecal methotrexate therapy.
Gunther
R
R
Department of Therapeutic Radiology-Radiation Oncology, University of Minnesota, Minneapolis, USA.
Chelstrom
L M
LM
Tuel-Ahlgren
L
L
Simon
J
J
Myers
D E
DE
Uckun
F M
FM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000627:therapeutic use; D015703:Antigens, CD / Q000276:immunology*; D018941:Antigens, CD19; D000944:Antigens, Differentiation, B-Lymphocyte / Q000276:immunology*; D001812:Blood-Brain Barrier; D001853:Bone Marrow / Q000473:pathology; D002465:Cell Movement; D002490:Central Nervous System / Q000473:pathology*; D004273:DNA, Neoplasm / Q000032:analysis; D004353:Drug Evaluation, Preclinical; D000922:Immunotoxins / Q000008:administration & dosage / Q000627:therapeutic use*; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007278:Injections, Spinal; D017254:Leukemic Infiltration / Q000188:drug therapy*; D008578:Meninges / Q000473:pathology*; D008727:Methotrexate / Q000627:therapeutic use; D051379:Mice; D016513:Mice, SCID; D009699:N-Glycosyl Hydrolases; D009368:Neoplasm Transplantation; D009360:Neoplastic Cells, Circulating; D010940:Plant Proteins / Q000008:administration & dosage / Q000627:therapeutic use*; D016133:Polymerase Chain Reaction; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000473:pathology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000473:pathology; D054789:Ribosome Inactivating Proteins, Type 1; D013047:Specific Pathogen-Free Organisms; D014183:Transplantation, Heterologous
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D018941:Antigens, CD19; D000944:Antigens, Differentiation, B-Lymphocyte; D004273:DNA, Neoplasm; D000922:Immunotoxins; D010940:Plant Proteins; D054789:Ribosome Inactivating Proteins, Type 1; D009699:N-Glycosyl Hydrolases; C024275:pokeweed antiviral protein; D008727:Methotrexate