Therapy of patients with T-cell lymphomas and leukemias using an anti-CD7 monoclonal antibody-ricin A chain immunotoxin.
Anti-CD7-dgA, DA7, consists of deglycosylated ricin A chain coupled to a mouse monoclonal anti-human CD7 antibody. This study determined the maximally tolerated dose (MTD) of this immunotoxin administered as a one hour infusion over five days to 11 patients with T-cell lymphoma (>30% CD7+ malignant cells). The MTD was 0.2 mg/kg/day or 1 mg/kg/120 hours (maximal toxicity grade 3) with vascular leak syndrome (VLS) as dose-limiting toxicity (DLT). Predictors of severe VLS included age and absence of circulating lymphoma cells. Two partial responses and one minimal response were seen. Patients with minimal lymphoma burden or T-cell large granular lymphocyte (LGL) leukemia showed the best responses. The mean maximal serum concentration of immunotoxin at the MTD was 2.5 ug/ml. The mean alpha-phase half-life was 1.5 hours and the mean beta-phase half-life was 8 hours. Repeated dosing had minimal effects on either peak serum immunotoxin concentrations or serum half-lives. While human antimouse antibodies were observed, they were low in concentration (<55 ng/ml). Human anti-ricin antibody was elevated in one patient (190 ng/ml). VLS presented with hypoalbuminemia, dyspnea, pulmonary edema, aphasia, and peripheral edema and cleared over a two week period. Serum fibronectin levels were measured in three patients and were very low in one patient who developed VLS. No specific binding of DA7 immunotoxin was seen with vascular endothelium in various human tissues.
Frankel
A E
AE
Department of Medicine, Medical University of South Carolina, Charleston, USA.
Laver
J H
JH
Willingham
M C
MC
Burns
L J
LJ
Kersey
J H
JH
Vallera
D A
DA
D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use; D000912:Antibodies, Neoplasm / Q000096:biosynthesis / Q000097:blood; D019011:Antigens, CD7 / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004730:Endothelium, Vascular / Q000378:metabolism; D005260:Female; D005353:Fibronectins / Q000097:blood; D006801:Humans; D000922:Immunotoxins / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007262:Infusions, Intravenous; D015458:Leukemia, T-Cell / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D016399:Lymphoma, T-Cell / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D012276:Ricin / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*
D000911:Antibodies, Monoclonal; D000912:Antibodies, Neoplasm; D019011:Antigens, CD7; D005353:Fibronectins; D000922:Immunotoxins; D012276:Ricin