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Chimeric CLL-1 antibody fusion proteins containing granulocyte- macrophage
colony-stimulating factor or interleukin-2 with specificity for B-cell
malignancies exhibit enhanced effector functions while retaining tumor
targeting properties
JL Hornick, LA Khawli, P Hu, M Lynch, PM Anderson and AL Epstein
Department of Pathology, University of Southern California School of
Medicine, Los Angeles 90033, USA.
Although monoclonal antibody (MoAb) therapy of the human malignant
lymphomas has shown success in clinical trials, its full potential for the
treatment of hematologic malignancies has yet to be realized. To expand the
clinical potential of a promising human-mouse chimeric antihuman B-cell
MoAb (chCLL-1) constructed using the variable domains cloned from the
murine Lym-2 (muLym-2) hybridoma, fusion proteins containing
granulocyte-macrophage colony-stimulating factor (GM-CSF) (chCLL-1/GM-CSF)
or interleukin (IL)-2 (chCLL-1/IL-2) were generated and evaluated for in
vitro cytotoxicity and in vivo tumor targeting. The glutamine synthetase
gene amplification system was employed for high level expression of the
recombinant fusion proteins. Antigenic specificity was confirmed by a
competition radioimmunoassay against ARH- 77 human myeloma cells. The
activity of chCLL-1/GM-CSF was established by a colony formation assay, and
the bioactivity of chCLL-1/IL-2 was confirmed by supporting the growth of
an IL-2-dependent T-cell line. Antibody-dependent cellular cytotoxicity
against ARH-77 target cells demonstrated that both fusion proteins mediate
enhanced tumor cell lysis by human mononuclear cells. Finally,
biodistribution and imaging studies in nude mice bearing ARH-77 xenografts
indicated that the fusion proteins specifically target the tumors. These in
vitro and in vivo data suggest that chCLL-1/GM-CSF and chCLL-1/IL-2 have
potential as immunotherapeutic reagents for the treatment of B-cell
malignancies.
Volume 89,
Issue 12,
pp. 4437-4447,
06/15/1997
Copyright © 1997 by The American Society of Hematology
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