In vivo efficacy and toxicity of a single-chain immunotoxin targeted to CD40.
G28-5 sFv-PE40 is a single-chain immunotoxin targeted to CD40, which is highly expressed on human hematologic malignancies, including non-Hodgkin's lymphoma, B-lineage leukemias, multiple myeloma, and Hodgkin's disease, as well as certain carcinomas. In vitro analysis showed that this monovalent immunotoxin had a binding affinity of 3 nmol/L, within 15-fold of the bivalent parental monoclonal antibody. G28-5 sFv-PE40 was stable when incubated in mouse serum at 37 degrees C for 6 hours and cleared from the circulation of mice with a half-life of 16.7 minutes. This immunotoxin was effective in treating human Burkitt's lymphoma xenografted SCID mice with complete responses, defined by an asymptomatic phenotype for greater than 120 days, obtained at doses of 0.13 to 0.26 mg/kg. The efficacy of treatment was dependent on the schedule used, with every three days for five injections being the most effective tested. The toxicity of G28-5 sFv-PE40 was examined in SCID mice, rats, and monkeys, with the maximum tolerated dose being 0.48, 1.0, and 1.67 mg/kg, respectively. Comparative immunohistology showed that the G28-5 specificity was qualitatively similar between human and monkey tissue. In summary, G28-5 sFv-PE40 was effective at inducing complete antitumor responses in lymphoma xenografted mice at doses that were well tolerated in mice, rats, and monkeys.
Francisco
J A
JA
Molecular Immunology Department, Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, WA 98121, USA.
Schreiber
G J
GJ
Comereski
C R
CR
Mezza
L E
LE
Warner
G L
GL
Davidson
T J
TJ
Ledbetter
J A
JA
Siegall
C B
CB
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity; D000951:Antigens, Neoplasm / Q000276:immunology*; D000970:Antineoplastic Agents / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D002051:Burkitt Lymphoma / Q000188:drug therapy* / Q000276:immunology; D019013:CD40 Antigens / Q000276:immunology*; D004334:Drug Administration Schedule; D005098:Exotoxins; D005260:Female; D006801:Humans; D000922:Immunotoxins / Q000276:immunology / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D014018:Tissue Distribution; D014183:Transplantation, Heterologous
D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D019013:CD40 Antigens; D005098:Exotoxins; C106497:G28-5 sFv-PE40; D000922:Immunotoxins