Pharmacokinetics and biodistribution of the antitumor immunoconjugate, cantuzumab mertansine (huC242-DM1), and its two components in mice.
The humanized monoclonal antibody maytansinoid conjugate, cantuzumab mertansine (huC242-DM1) that contains on average three to four linked drug molecules per antibody molecule was evaluated in CD-1 mice for its pharmacokinetic behavior and tissue distribution, and the results were compared with those of the free antibody huC242. The pharmacokinetics in blood were similar for (125)I-labeled conjugate and antibody with terminal half-lives of 154 and 156 h, respectively. Pharmacokinetic analysis using an enzyme-linked immunosorbent assay (ELISA) method, which measures intact conjugate in plasma samples revealed a faster clearance for the conjugate corresponding to a half-life of 42.2 h. This faster clearance is explained as the result of clearance from circulation and concomitant clearance of drug from circulating conjugate through linker cleavage. An antibody-specific ELISA allowed the determination of the clearance rate of the antibody component from circulation. The drug clearance rate from circulating conjugate was then calculated as the difference between the clearance of the conjugate and the clearance of the antibody component and found to be about three times that of the antibody component. The above results were confirmed with a conjugate, huC242-[(3)H]DM1, where the linked DM1 drugs carried a stable tritium label. Tissue distribution studies with (125)I-labeled conjugate and antibody showed antibody-like behavior for the conjugate; the antibody of the conjugate did not distribute or bind significantly to any solid tissue.
Xie
Hongsheng
H
ImmunoGen, Inc, Cambridge, MA 02139, USA. hongsheng.xie@immunogen.com
Audette
Charlene
C
Hoffee
Mary
M
Lambert
John M
JM
Blättler
Walter A
WA
D000818:Animals; D000906:Antibodies / Q000378:metabolism; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D018796:Immunoconjugates / Q000493:pharmacokinetics*; D007457:Iodine Radioisotopes; D008453:Maytansine / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D051379:Mice; D014018:Tissue Distribution; D014316:Tritium
D000906:Antibodies; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D018796:Immunoconjugates; D007457:Iodine Radioisotopes; D014316:Tritium; D008453:Maytansine; C483240:cantuzumab mertansine