Potent and specific antitumor effects of an anti-CD22-targeted cytotoxic ribonuclease: potential for the treatment of non-Hodgkin lymphoma.
LL2, an anti-CD22 monoclonal antibody against B-cell lymphoma, was covalently linked to the amphibian ribonuclease, onconase, a member of the pancreatic RNase A superfamily. LL2 increased in vitro potency (10 000-fold) and specificity against human Daudi Burkitt lymphoma cells while decreasing systemic toxicity of onconase. Monensin further increased potency of LL2-onconase on Daudi cells (IC(50), 20 and 1.5 pM, absence and presence of monensin, respectively). A 1-hour exposure to LL2-onconase was sufficient to kill Daudi cells in culture. These favorable in vitro properties translated to significant antitumor activity against disseminated Daudi lymphoma in mice with severe combined immunodeficiency disease. In mice inoculated with tumor cells intraperitoneally (ip), LL2-onconase (100 microg 5 times ip every day) increased the life span of animals with minimal disease 200%. The life span of mice with advanced disseminated Daudi lymphoma (tumor cells inoculated intravenously) was increased 135%. Mice injected with LL2-onconase tolerated a dose as high as 300 mg/kg. Because both onconase and LL2 are in clinical trials as cancer therapeutics, the covalently linked agents should be considered for treatment of non-Hodgkin lymphoma.
Newton
D L
DL
SAIC Frederick, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, MD 21702-1201, USA.
Hansen
H J
HJ
Mikulski
S M
SM
Goldenberg
D M
DM
Rybak
S M
SM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D015703:Antigens, CD / Q000276:immunology; D000944:Antigens, Differentiation, B-Lymphocyte / Q000276:immunology; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D015815:Cell Adhesion Molecules; D016923:Cell Death / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004355:Drug Stability; D005260:Female; D006801:Humans; D000922:Immunotoxins / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity; D007700:Kinetics; D037102:Lectins; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D023421:Models, Animal; D009368:Neoplasm Transplantation; D010179:Pancreas / Q000201:enzymology; D012260:Ribonucleases / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D051918:Sialic Acid Binding Ig-like Lectin 2; D015996:Survival Rate; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; D000970:Antineoplastic Agents; C497867:CD22 protein, human; C497868:Cd22 protein, mouse; D015815:Cell Adhesion Molecules; D000922:Immunotoxins; D037102:Lectins; D051918:Sialic Acid Binding Ig-like Lectin 2; C095913:bectumomab; D012260:Ribonucleases; C058703:ranpirnase