title: Development of potent monoclonal antibody auristatin conjugates for cancer therapy.
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.
authors.affiliation: Seattle Genetics, Inc., 21823 30th Dr. SE, Bothell, Washington 98021, USA.
authors.forename: Svetlana O
authors.initials: SO
authors.lastname: Doronina
authors.forename: Brian E
authors.initials: BE
authors.lastname: Toki
authors.forename: Michael Y
authors.initials: MY
authors.lastname: Torgov
authors.forename: Brian A
authors.initials: BA
authors.lastname: Mendelsohn
authors.forename: Charles G
authors.initials: CG
authors.lastname: Cerveny
authors.forename: Dana F
authors.initials: DF
authors.lastname: Chace
authors.forename: Ron L
authors.initials: RL
authors.lastname: DeBlanc
authors.forename: R Patrick
authors.initials: RP
authors.lastname: Gearing
authors.forename: Tim D
authors.initials: TD
authors.lastname: Bovee
authors.forename: Clay B
authors.initials: CB
authors.lastname: Siegall
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Francisco
authors.forename: Alan F
authors.initials: AF
authors.lastname: Wahl
authors.forename: Damon L
authors.initials: DL
authors.lastname: Meyer
authors.forename: Peter D
authors.initials: PD
authors.lastname: Senter
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000737:chemistry* / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use*; D002478:Cells, Cultured / Q000187:drug effects; D016503:Drug Delivery Systems / Q000379:methods; D004355:Drug Stability; D006801:Humans; D000922:Immunotoxins / Q000009:adverse effects / Q000737:chemistry / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D009842:Oligopeptides / Q000009:adverse effects / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use*; D011485:Protein Binding; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D000922:Immunotoxins; D009842:Oligopeptides; C105791:soblidotin