Potent and specific antitumor effects of an anti-CD22-targeted cytotoxic ribonuclease: potential for the treatment of non-Hodgkin lymphoma

LL2, an anti-cDaa monoclonal antibody against B-cell lymphoma, was covalent ly linked to the amphibian ribonuclease, onconase, a member of the pancreat ic RNase A superfamily, LL2 increased in vitro potency (10 000-fold) and sp ecificity against human Daudi Burkitt lymphoma cells while decreasing syste mic toxicity of onconase. Monensin further increased potency of LL2-onconas e on Daudi cells (IC50, 20 and 1.5 pM, absence and presence of monensin, re spectively). A 1-hour exposure to LL2-onconase was sufficient to kill Daudi cells in culture. These favorable in vitro properties translated to signif icant antitumor activity against disseminated Daudi lymphoma in mice with s evere combined immunodeficiency disease. In mice inoculated with tumor cell s intraperitoneally (ip), LL2-onconase (100 mug 5 times ip every day) incre ased the life span of animals with minimal disease 200%. The life span of m ice with advanced disseminated Daudi lymphoma (tumor cells inoculated intra venously) was increased 135%, Mice injected with LL2-onconase tolerated a d ose as high as 300 mg/kg. Because both onconase and LL2 are in clinical tri als as cancer therapeutics, the covalently linked agents should be consider ed for treatment of non-Hodgkin lymphoma. (C) 2001 by The American Society of Hematology.