A phase 1B trial of humanized monoclonal antibody M195 (anti-CD33) in myeloid leukemia: specific targeting without immunogenicity.
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.
Caron
P C
PC
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York NY 10021.
Jurcic
J G
JG
Scott
A M
AM
Finn
R D
RD
Divgi
C R
CR
Graham
M C
MC
Jureidini
I M
IM
Sgouros
G
G
Tyson
D
D
Old
L J
LJ
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*; D015703:Antigens, CD / Q000032:analysis* / Q000276:immunology; D015214:Antigens, Differentiation, Myelomonocytic / Q000032:analysis* / Q000276:immunology; D005260:Female; D006801:Humans; D007951:Leukemia, Myeloid / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D063268:Sialic Acid Binding Ig-like Lectin 3; D014018:Tissue Distribution
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; C571163:CD33 protein, human; C571165:Cd33 protein, mouse; D063268:Sialic Acid Binding Ig-like Lectin 3