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In vivo efficacy and toxicity of a single-chain immunotoxin targeted to
CD40
JA Francisco, GJ Schreiber, CR Comereski, LE Mezza, GL Warner, TJ Davidson, JA Ledbetter and CB Siegall
Molecular Immunology Department, Bristol-Myers Squibb Pharmaceutical
Research Institute, Seattle, WA 98121, USA.
G28-5 sFv-PE40 is a single-chain immunotoxin targeted to CD40, which is
highly expressed on human hematologic malignancies, including non-
Hodgkin's lymphoma, B-lineage leukemias, multiple myeloma, and Hodgkin's
disease, as well as certain carcinomas. In vitro analysis showed that this
monovalent immunotoxin had a binding affinity of 3 nmol/L, within 15-fold
of the bivalent parental monoclonal antibody. G28-5 sFv-PE40 was stable
when incubated in mouse serum at 37 degrees C for 6 hours and cleared from
the circulation of mice with a half-life of 16.7 minutes. This immunotoxin
was effective in treating human Burkitt's lymphoma xenografted SCID mice
with complete responses, defined by an asymptomatic phenotype for greater
than 120 days, obtained at doses of 0.13 to 0.26 mg/kg. The efficacy of
treatment was dependent on the schedule used, with every three days for
five injections being the most effective tested. The toxicity of G28-5 sFv-
PE40 was examined in SCID mice, rats, and monkeys, with the maximum
tolerated dose being 0.48, 1.0, and 1.67 mg/kg, respectively. Comparative
immunohistology showed that the G28-5 specificity was qualitatively similar
between human and monkey tissue. In summary, G28- 5 sFv-PE40 was effective
at inducing complete antitumor responses in lymphoma xenografted mice at
doses that were well tolerated in mice, rats, and monkeys.
Volume 89,
Issue 12,
pp. 4493-4500,
06/15/1997
Copyright © 1997 by The American Society of Hematology
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