title: Influence of immunogenicity on the pharmacokinetics of BMS-191352, a Pseudomonas exotoxin immunoconjugate, in rats and dogs.
abstract: BMS-191352 is an immunotoxin construct of modified Pseudomonas exotoxin conjugated to a fragment of the BR96 monoclonal antibody. We have investigated the potential for immunogenicity of BMS-191352 and its influence on the pharmacokinetics in rats and dogs. BMS-191352 was administered intravenously at doses of 0.75, 1.5, and 3 mg m(-2) once every two days for a total of five doses in rats, and 1.2, 2.4, and 4.8 mg m(-2) once every three days for a total of five doses in dogs. Blood samples were collected on days 1 and 9 in rats, and on days 1, 7, and 13 in dogs to monitor pharmacokinetics and anti-BMS-191352 immune response. Plasma concentrations of BMS-191352 and serum anti-BMS-191352 antibody titre were determined using ELISA assays. Pharmacokinetics were assessed using a non-compartmental method. Anti-BMS-191352 antibodies were not observed in rats within the drug administration interval. In all dogs, except one, markedly higher anti-BMS-191352 antibody titres were observed on day 13 compared with days 1 and 7, and its magnitude was independent of BMS-191352 dose. The single dose kinetics of BMS-191352 in rats and dogs were linear and the drug exposures were generally dose proportional. Mean half-life, total body clearance, and volume of distribution were 1.74 h, 3.35 mL min(-1) m(-2), and 0.27 Lm(-2) in rats, respectively, and 4.27 h, 6.28 mL min(-1) m(-2), 1.19 L m(-2) in dogs, respectively. The multiple-dose (day 9) kinetics in rats were similar to the single-dose kinetics. In dogs, the disposition of BMS-191352 on day 7 was similar to that on day 1; however, there was a precipitous reduction in the systemic drug exposure (by 5- to 110-fold) and marked increase in drug clearance on day 13. These changes in the kinetics of BMS-191352 were attributed to the generation of anti-BMS-191352 antibodies. In the one dog that did not develop anti-BMS-191352 antibodies, the pharmacokinetics were unchanged. The pharmacokinetics of BMS-191352 may be perturbed due to an immune response thus restricting the therapeutic utility of the immunotoxin.
authors.affiliation: Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA.
authors.forename: B
authors.initials: B
authors.lastname: Damle
authors.forename: L
authors.initials: L
authors.lastname: Tay
authors.forename: C
authors.initials: C
authors.lastname: Comereski
authors.forename: W
authors.initials: W
authors.lastname: Warner
authors.forename: S
authors.initials: S
authors.lastname: Kaul
mesh_terms: D036002:ADP Ribose Transferases; D000818:Animals; D000911:Antibodies, Monoclonal; D000917:Antibody Formation; D001427:Bacterial Toxins; D004285:Dogs; D005098:Exotoxins; D018796:Immunoconjugates; D000922:Immunotoxins / Q000276:immunology / Q000493:pharmacokinetics*; D007262:Infusions, Intravenous; D011549:Pseudomonas / Q000737:chemistry*; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000493:pharmacokinetics*; D057127:Single-Chain Antibodies
chemical_list: D000911:Antibodies, Monoclonal; C115038:BMS-191352 protein, recombinant; D001427:Bacterial Toxins; D005098:Exotoxins; D018796:Immunoconjugates; D000922:Immunotoxins; D011993:Recombinant Fusion Proteins; D057127:Single-Chain Antibodies; D036002:ADP Ribose Transferases