Design, synthesis, and biological evaluation of antibody-drug conjugates comprised of potent camptothecin analogues

Bioconjug Chem. 2009 Jun;20(6):1242-50. doi: 10.1021/bc9001097.


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.

MeSH terms

  • Animals
  • Antibodies, Monoclonal / chemistry*
  • Antibodies, Monoclonal / immunology
  • Antibody Specificity
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology*
  • Camptothecin / chemistry*
  • Camptothecin / pharmacology*
  • Cell Line, Tumor
  • Drug Design
  • Drug Stability
  • Humans
  • Immunoconjugates / chemistry*
  • Immunoconjugates / pharmacology*
  • Inhibitory Concentration 50
  • Mice
  • Mice, Inbred BALB C


  • Antibodies, Monoclonal
  • Antineoplastic Agents
  • Immunoconjugates
  • Camptothecin