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 RETAININGTUMOR TARGETING PROPERTIES

Although monoclonal antibody (MoAb) therapy of the human malignant lym phomas has shown success in clinical trials, its full potential for th e treatment of hematologic malignancies has yet to be realized, To exp and the clinical potential of a promising human-mouse chimeric antihum an 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 evaluate d for in vitro cytotoxicity and in vivo tumor targeting. The glutamine synthetase gene amplification system was employed for high level expr ession of the recombinant fusion proteins. Antigenic specificity was c onfirmed by a competition radioimmunoassay against ARH-77 human myelom a cells. The activity of chCLL-1/GM-CSF was established by a colony fo rmation assay, and the bioactivity of chCLL-1/IL-2 was confirmed by su pporting the growth of an IL-2-dependent T-cell line, Antibody-depende nt cellular cytotoxicity against ARH-77 target cells demonstrated that both fusion proteins mediate enhanced tumor cell lysis by human monon uclear cells, Finally, biodistribution and imaging studies in nude mic e bearing ARH-77 xenografts indicated that the fusion proteins specifi cally 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 re agents for the treatment of B-cell malignancies. (C) 1997 by The Ameri can Society of Hematology.