Novel immunoconjugates comprised of streptonigrin and 17-amino-geldanamycin attached via a dipeptide-p-aminobenzyl-amine linker system.
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.
Burke
Patrick J
PJ
Seattle Genetics, Inc., Bothell, WA 98021, USA. pburke@seagen.com
Toki
Brian E
BE
Meyer
David W
DW
Miyamoto
Jamie B
JB
Kissler
Kim M
KM
Anderson
Martha
M
Senter
Peter D
PD
Jeffrey
Scott C
SC
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
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