Development of potent monoclonal antibody auristatin conjugates for cancer therapy

  • An Erratum to this article was published on 01 August 2003


We describe the in vitro and in vivo properties of monoclonal antibody (mAb)-drug conjugates consisting of the potent synthetic dolastatin 10 analogs auristatin E (AE) and monomethylauristatin E (MMAE), linked to the chimeric mAbs cBR96 (specific to Lewis Y on carcinomas) and cAC10 (specific to CD30 on hematological malignancies). The linkers used for conjugate formation included an acid-labile hydrazone and protease-sensitive dipeptides, leading to uniformly substituted conjugates that efficiently released active drug in the lysosomes of antigen-positive (Ag+) tumor cells. The peptide-linked mAb-valine-citrulline-MMAE and mAb-phenylalanine-lysine-MMAE conjugates were much more stable in buffers and plasma than the conjugates of mAb and the hydrazone of 5-benzoylvaleric acid-AE ester (AEVB). As a result, the mAb-Val-Cit-MMAE conjugates exhibited greater in vitro specificity and lower in vivo toxicity than corresponding hydrazone conjugates. In vivo studies demonstrated that the peptide-linked conjugates induced regressions and cures of established tumor xenografts with therapeutic indices as high as 60-fold. These conjugates illustrate the importance of linker technology, drug potency and conjugation methodology in developing safe and efficacious mAb-drug conjugates for cancer therapy.

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Figure 1: Structures of drugs and mAb-drug conjugates.
Figure 2: Conjugate characteristics.
Figure 3: Conjugate stability in human and mouse plasma.
Figure 4: In vitro cytotoxicity.
Figure 5: In vivo therapeutic efficacy of the conjugates in immunocompromised mice with subcutaneous human tumor xenografts.


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This work was supported in part by Grant 1R43 CA 88583-01A1 from the National Cancer Institute. We acknowledge George Robert Pettit, Nathan Ihle and Perry Fell for useful discussions, and Nick Vincent-Maloney, Starr Rejniak and Jennifer Haugen for experimental assistance.

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Correspondence to Peter D Senter.

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Doronina, S., Toki, B., Torgov, M. et al. Development of potent monoclonal antibody auristatin conjugates for cancer therapy. Nat Biotechnol 21, 778–784 (2003).

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