Potent anti-tumor effects of an anti-CD24 ricin A-chain immunotoxin in vitro and in a disseminated human Burkitt's lymphoma model in SCID mice.
A new anti-CD24 immunotoxin (IT), SWA11.dgA, was constructed by coupling the MAb SWA11 via the bivalent linker SMPT to deglycosylated ricin A-chain (dgA). The effects of SWA11.dgA were evaluated in vitro against the B-precursor leukemia cell line REH, the non-B-non-T acute lymphoblastic leukemia cell line NALM-6 and the Burkitt's lymphoma cell lines BL-2 and BL-38. Binding of SWA11 to the CD24 antigen was assessed by flow cytometry demonstrating high affinity of the MAb for all cell lines tested. SWA11.dgA inhibited the protein synthesis of BL-38, NALM-6, REH and BL-2 cells by 50% at concentrations (IC50) of 4.0 x 10(-11) M, 6.0 x 10(-11) M, 8.0 x 10(-11) M and 3.0 x 10(-9) M, respectively. SWA11.dgA was subsequently used for the treatment of disseminated human BL-38 Burkitt's lymphoma in a newly developed SCID mouse model. The mean survival time (MST) of BL-38-bearing SCID mice was extended from 23 days in untreated controls to more than 230 days when 6 microg SWA11.dgA was applied intraperitoneally one day after tumor challenge. All of the animals achieved continuous complete remissions. SCID mice treated with SWA11.dgA 4 days after tumor cell challenge or a reduced dose of SWA11.dgA (67%) also had a significantly extended MST (45.0 and 51.4 days, respectively, as compared to 22.7 and 23.1 days in the controls). We conclude that SWA11.dgA might be of potential use for the treatment of lymphoma in man.
Schnell
R
R
Department of Medicine I, University of Cologne, Germany.
Katouzi
A A
AA
Linnartz
C
C
Schoen
G
G
Drillich
S
S
Hansmann
M L
ML
Schiefer
D
D
Barth
S
S
Zangemeister-Wittke
U
U
Stahel
R A
RA
Diehl
V
V
Engert
A
A
D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D002051:Burkitt Lymphoma / Q000628:therapy*; D051927:CD24 Antigen; D002470:Cell Survival; D006801:Humans; D000922:Immunotoxins / Q000627:therapeutic use*; D007938:Leukemia / Q000276:immunology; D008562:Membrane Glycoproteins; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D012276:Ricin / Q000008:administration & dosage*; D016019:Survival Analysis; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D015703:Antigens, CD; D051927:CD24 Antigen; C497889:CD24 protein, human; C497890:Cd24a protein, mouse; D000922:Immunotoxins; D008562:Membrane Glycoproteins; D012276:Ricin