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Serotherapy of B-cell neoplasms with anti-B4-blocked ricin: a phase I trial
of daily bolus infusion
ML Grossbard, AS Freedman, J Ritz, F Coral, VS Goldmacher, L Eliseo, N Spector, K Dear, JM Lambert and WA Blattler
Division of Tumor Immunology, Dana-Farber Cancer Institute, Boston, MA
02115.
Anti-B4-blocked Ricin (Anti-B4-bR) is an immunotoxin comprised of the
anti-B4 monoclonal antibody (MoAb) and the protein toxin "blocked ricin."
The anti-B4 MoAb is directed against the B-lineage-restricted CD19 antigen
expressed on more than 95% of normal and neoplastic B cells. Blocked ricin
is an altered ricin derivative that has its nonspecific binding eliminated
by chemically blocking the galactose binding domains of the B chain. In
vitro cytotoxicity studies demonstrate that the IC37 of Anti-B4-bR is 2 x
10(-11) mol/L compared with 4 x 10(-12) mol/L for native ricin. A phase I
dose escalation clinical trial was conducted in 25 patients with refractory
B-cell malignancies. Anti-B4-bR was administered by daily 1-hour bolus
infusion for 5 consecutive days at doses ranging from 1 microgram/kg/d to
60 micrograms/kg/d. Serum levels above 1 nmol/L were achieved transiently
in the majority of patients treated at the maximum tolerated dose of 50
micrograms/kg/d for 5 days for a total dose of 250 micrograms/kg. The
dose-limiting toxicity was defined by transient, reversible grade 3
elevations in hepatic transaminases, without impaired hepatic synthetic
function. Minor toxicities included transient hypoalbuminemia,
thrombocytopenia, and fevers. Human antimouse antibody and human anti-ricin
antibody were detected in nine patients. One complete response, two partial
responses, and eight mixed or transient responses were observed. These
results show the in vitro and in vivo cytotoxicity of Anti-B4-bR and
indicate that this immunotoxin can be administered as a daily bolus
infusion for 5 days with tolerable, reversible toxicity.
Volume 79,
Issue 3,
pp. 576-585,
02/01/1992
Copyright © 1992 by The American Society of Hematology
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