title: Novel immunoconjugates comprised of streptonigrin and 17-amino-geldanamycin attached via a dipeptide-p-aminobenzyl-amine linker system.
abstract: Cytotoxic agents streptonigrin and 17-amino-geldanamycin were linked to monoclonal antibodies (mAbs), forming antibody-drug conjugates (ADCs) for antigen-mediated targeting to cancer cells. The drugs were conjugated with a linker construct that is labile to lysosomal proteases and incorporates a valine-alanine-p-aminobenzyl (PAB)-amino linkage for direct attachment to the electron-deficient amine functional groups present in both drugs. The resulting ADCs release drug following internalization into antigen-positive cancer cells. The drug linkers were conjugated to mAbs cAC10 (anti-CD30) and h1F6 (anti-CD70) via alkylation of reduced interchain disulfides to give ADCs loaded with 4 drugs/mAb. The streptonigrin ADCs were potent and immunologically specific on a panel of cancer cell lines in vitro and in a Hodgkin lymphoma xenograft model. We conclude that streptonigrin ADCs are candidates for further research, and that the novel linker system used to make them is well-suited for the conjugation of cytotoxic agents containing electron-deficient amine functional groups.
authors.affiliation: Seattle Genetics, Inc., Bothell, WA 98021, USA. pburke@seagen.com
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Burke
authors.forename: Brian E
authors.initials: BE
authors.lastname: Toki
authors.forename: David W
authors.initials: DW
authors.lastname: Meyer
authors.forename: Jamie B
authors.initials: JB
authors.lastname: Miyamoto
authors.forename: Kim M
authors.initials: KM
authors.lastname: Kissler
authors.forename: Martha
authors.initials: M
authors.lastname: Anderson
authors.forename: Peter D
authors.initials: PD
authors.lastname: Senter
authors.forename: Scott C
authors.initials: SC
authors.lastname: Jeffrey
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry; D016227:Benzoquinones / Q000138:chemical synthesis* / Q000737:chemistry; D001596:Benzylamines / Q000138:chemical synthesis / Q000737:chemistry*; D053282:CD27 Ligand / Q000378:metabolism; D045744:Cell Line, Tumor; D004151:Dipeptides / Q000138:chemical synthesis / Q000737:chemistry*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D018796:Immunoconjugates / Q000737:chemistry* / Q000494:pharmacology; D017730:Ki-1 Antigen / Q000378:metabolism; D047029:Lactams, Macrocyclic / Q000138:chemical synthesis* / Q000737:chemistry; D051379:Mice; D013308:Streptonigrin / Q000138:chemical synthesis* / Q000737:chemistry; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D016227:Benzoquinones; D001596:Benzylamines; D053282:CD27 Ligand; D004151:Dipeptides; D018796:Immunoconjugates; D017730:Ki-1 Antigen; D047029:Lactams, Macrocyclic; D013308:Streptonigrin; C001277:geldanamycin