Serotherapy of B-cell neoplasms with anti-B4-blocked ricin: a phase I trial of daily bolus infusion.
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.
Division of Tumor Immunology, Dana-Farber Cancer Institute, Boston, MA 02115.
M L
ML
Grossbard
A S
AS
Freedman
J
J
Ritz
F
F
Coral
V S
VS
Goldmacher
L
L
Eliseo
N
N
Spector
K
K
Dear
J M
JM
Lambert
W A
WA
Blättler
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D015703:Antigens, CD / Q000276:immunology*; D018941:Antigens, CD19; D000944:Antigens, Differentiation, B-Lymphocyte / Q000276:immunology*; D002051:Burkitt Lymphoma / Q000628:therapy*; D002478:Cells, Cultured; D004341:Drug Evaluation; D006801:Humans; D000922:Immunotoxins / Q000008:administration & dosage* / Q000009:adverse effects; D066298:In Vitro Techniques; D007518:Isoantibodies / Q000378:metabolism; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000628:therapy*; D008107:Liver Diseases / Q000209:etiology; D016131:Lymphocyte Subsets / Q000276:immunology; D016393:Lymphoma, B-Cell / Q000628:therapy*; D051379:Mice; D012276:Ricin / Q000737:chemistry*; D012709:Serum Albumin / Q000378:metabolism
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D018941:Antigens, CD19; D000944:Antigens, Differentiation, B-Lymphocyte; D000922:Immunotoxins; D007518:Isoantibodies; D012709:Serum Albumin; D012276:Ricin