Pharmacokinetics and antitumor activity of a bivalent disulfide-stabilized Fv immunotoxin with improved antigen binding to erbB2.
We have generated a stable bivalent Fv molecule [(dsFv)2] of the anti-erbB2 monoclonal antibody e23 in which the V(H) and V(L) domains of the Fv are linked to each other by a disulfide bond and the two Fvs are connected by a 15-amino acid linker (T. K. Bera et al., J. Mol. Biol., 281: 475-483, 1998). The e23 (dsFv)2 molecule is linked to a truncated form of Pseudomonas exotoxin (PE38) to generate a bivalent disulfide-stabilized immunotoxin e23 (dsFv)2-PE38. Compared to the monovalent immunotoxin, the (dsFv)2 immunotoxin showed greatly increased cytotoxicity to four cancer cell lines expressing low levels of erbB2 but not to four other cell lines with high erbB2 expression. e23 (dsFv)2-PE38 was administered i.v. to mice, and its half-life was determined. The t(1/2)alpha and t(1/2)beta were 20 and 325 min, respectively, whereas the corresponding values for the monovalent dsFv immunotoxin were shorter, 6 and 52 min. The antitumor activities of the monovalent and bivalent immunotoxin were compared using mice bearing A431 tumors. Despite the fact that e23 (dsFv)2-PE38 was 13-fold more active than e23 dsFv-PE38 on A431 cells in cell culture, its antitumor activity in mice was <2-fold that of the monovalent immunotoxin. These data show that a large increase in avidity does not always lead to an increase in cytotoxic activity. Furthermore, in one of the cases in which cytotoxic activity in vitro was greatly enhanced, there was only a small increase in antitumor activity.
Bera
T K
TK
Laboratory of Molecular Biology, National Cancer Institute, NIH, Bethesda, Maryland 20892-4255, USA.
Viner
J
J
Brinkmann
E
E
Pastan
I
I
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D005098:Exotoxins / Q000008:administration & dosage*; D005260:Female; D007140:Immunoglobulin Fab Fragments / Q000008:administration & dosage* / Q000276:immunology; D000922:Immunotoxins / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000276:immunology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology*; D013440:Sulfides
D000911:Antibodies, Monoclonal; D005098:Exotoxins; D007140:Immunoglobulin Fab Fragments; D000922:Immunotoxins; D018719:Erb-b2 Receptor Tyrosine Kinases; D013440:Sulfides