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A phase 1B trial of humanized monoclonal antibody M195 (anti-CD33) in
myeloid leukemia: specific targeting without immunogenicity
PC Caron, JG Jurcic, AM Scott, RD Finn, CR Divgi, MC Graham, IM Jureidini, G Sgouros, D Tyson and LJ Old
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York NY
10021.
This trial studied the biodistribution, pharmacology, toxicity,
immunogenicity, and biologic characteristics of a trace-labeled, anti-
CD33, humanized monoclonal antibody M195 (Hu-M195) in patients with
relapsed and refractory myeloid leukemia. Hu-M195 is a computer- modeled,
"complementarity-determining region-grafted," IgG1, humanized version of
M195. M195 is a murine monoclonal antibody that reacts with CD33, a 67-kD
glycoprotein expressed on early myeloid progenitor cells and myeloid
leukemia (acute myelogenous leukemia and chronic myelogenous leukemia)
cells, but not normal stem cells. 131I-murine- M195 has already shown
significant ability to cytoreduce patients with relapsed or refractory
myeloid leukemias. Hu-M195 has higher avidity than the original mouse
monoclonal antibody and, unlike murine M195, has the capability to mediate
antibody-dependent cellular cytotoxicity against leukemia targets. Thirteen
patients with relapsed or refractory myelogenous leukemia were treated with
Hu-M195 at 4 levels of 0.5, 1.0, 3.0, and 10.0 mg/m2 in a phase I trial.
Patients received a total of 6 doses per patient over 18 days. Two patients
were retreated for a total of 12 doses. The first dose of Hu-M195 was
trace-labeled with 131I to allow detailed pharmacokinetic and
biodistribution studies by serial sampling of blood, radioimmunoassays of
cells, and whole-body gamma- camera imaging. Cumulative total doses of up
to 216 mg of Hu-M195 were administered safely. Reversible fever and rigors
were observed after infusion at the highest dose levels. The entire bone
marrow was specifically and clearly imaged within hours after infusion,
with optimal biodistribution occurring at the 3 mg/m2 level. Adsorption of
Hu-M195 onto targets in vivo was demonstrated by flow cytometry; near
saturation of available sites occurred at the 3 mg/m2 dose level. Plasma
and whole body half lives were 38 and 51 hours, respectively, which may
reflect continual replenishment of target sites on new leukemia cells.
131I-Hu-M195 was rapidly internalized into the target cells in vivo within
1 hour. Human antihuman antibody responses were not observed. In
conclusion, Hu-M195 can be administered safely in multiple doses, without
significant toxicity or any evidence of immunogenicity, and can localize
rapidly and efficiently to the bone marrow in patients with myeloid
leukemias. Additional phase II trials with this agent alone or in
combination with cytokines or isotopes are warranted at the optimal
biologic dose.
Volume 83,
Issue 7,
pp. 1760-1768,
04/01/1994
Copyright © 1994 by The American Society of Hematology
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