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Blood, 15 January 2001, Vol. 97, No. 2, pp. 528-535
NEOPLASIA
Potent and specific antitumor effects of an anti-CD22-targeted
cytotoxic ribonuclease: potential for the treatment of
non-Hodgkin lymphoma
Dianne L. Newton,
Hans J. Hansen,
Stanislaw M. Mikulski,
David M. Goldenberg, and
Susanna M. Rybak
From the SAIC Frederick, National Cancer
Institute-Frederick Cancer Research and Development Center, Frederick,
MD; Immunomedics Inc, Morris Plains NJ; Alfacell Corp, Bloomfield, NJ;
Garden State Cancer Center, Belleville, NJ; and Pharmaceutical
Experimental Therapeutics Section, Laboratory of Drug Discovery
Research and Development, Developmental Therapeutics Program, Division
of Cancer Treatment and Diagnosis, National Cancer Institute-Frederick
Cancer Research and Development Center, Frederick, MD.
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 (IC50, 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 µg 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.
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