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Development of potent monoclonal antibody auristatin conjugates for cancer therapy

An Erratum to this article was published on 01 August 2003

Abstract

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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Acknowledgements

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). https://doi.org/10.1038/nbt832

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