| Autor: |
Doronina, Svetlana O, Toki, Brian E, Torgov, Michael Y, Mendelsohn, Brian A, Cerveny, Charles G, Chace, Dana F, DeBlanc, Ron L, Gearing, R Patrick, Bovee, Tim D, Siegall, Clay B, Francisco, Joseph A, Wahl, Alan F, Meyer, Damon L, Senter, Peter D |
| Předmět: |
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| Zdroj: |
Nature Biotechnology; Jul2003, Vol. 21 Issue 7, p778, 7p |
| Abstrakt: |
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[SUP+]) 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 greaterin vitro specificity and lowerin 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. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
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