Design, synthesis, and biological evaluation of antibody-drug conjugates comprised of potent camptothecin analogues.
Antibody-drug conjugates (ADCs) were prepared with potent camptothecin analogues attached to monoclonal antibodies (mAbs) via dipeptide or glucuronide-based linkers. Aniline-containing camptothecin analogues were employed to provide a site of linker attachment via carbamate bonds that would be stable in circulation. The camptothecin analogues, 7-butyl-10-amino-camptothecin and 7-butyl-9-amino-10,11-methylenedioxy-camptothecin, are generally 10-1000 times more potent than camptothecin. Dipeptide and glucuronide drug linkers were employed containing self-immolative spacers that release drug following lysosomal degradation upon ADC internalization into antigen-positive cell lines. The camptothecin drug linkers were conjugated to three antibodies: chimeric BR96, chimeric AC10, and humanized 1F6, which bind to the Lewis-Y antigen on carcinomas, CD30 on hematologic malignancies, and CD70 present on hematologic malignancies and renal cell carcinoma, respectively. ADCs bearing the potent camptothecin analogue, 7-butyl-9-amino-10,11-methylenedioxy-camptothecin, were highly potent and immunologically specific on a panel of cancer cell lines in vitro, and efficacious at well-tolerated doses in a renal cell carcinoma xenograft model.
Burke
Patrick J
PJ
Seattle Genetics, Inc., 21823 30th Drive SE, Bothell, Washington 98021, USA. pburke@seagen.com
Senter
Peter D
PD
Meyer
David W
DW
Miyamoto
Jamie B
JB
Anderson
Martha
M
Toki
Brian E
BE
Manikumar
Govindarajan
G
Wani
Mansukh C
MC
Kroll
David J
DJ
Jeffrey
Scott C
SC
D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry* / Q000276:immunology; D000918:Antibody Specificity; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D002166:Camptothecin / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D015195:Drug Design; D004355:Drug Stability; D006801:Humans; D018796:Immunoconjugates / Q000737:chemistry* / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D051379:Mice; D008807:Mice, Inbred BALB C
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D018796:Immunoconjugates; D002166:Camptothecin