Dipeptide-based highly potent doxorubicin antibody conjugates.
Highly potent and novel derivatives of doxorubicin were linked to monoclonal antibodies (mAbs) for site-specific drug delivery. Drug linker 5 consisted of a dipeptide linker attached directly to the daunosamine nitrogen of the n-butyldiacetate doxorubicin derivative 2a. Upon hydrolysis of the peptide linker and acetate groups, the free daunosamine nitrogen is able to form the highly potent 2-pyrrolinodoxorubicin (3a). The second approach involved the use of an oxazolidine carbamate (13) to mask an activating aldehyde group until proteolytic hydrolysis releases 3a. Both drug linkers were shown to be substrates for the lysosomal enzyme cathepsin B. Each molecule was conjugated to the mAbs c1F6 (anti-CD70) and cAC10 (anti-CD30) to give potent drug conjugates against renal cell carcinoma and anaplastic large cell lymphoma cell lines, respectively. The activities were immunologically selective, since antigen negative cell lines were much less sensitive to treatment with the drug conjugates. The approaches described here for attaching highly potent doxorubicin derivatives to mAbs are novel and allow for control of drug stability while covalently bound to the delivery agent.
Jeffrey
Scott C
SC
Department of Chemistry, Seattle Genetics, 21823 30th Drive SE, Bothell, WA 98021, USA. sjeffrey@seagen.com
Nguyen
Minh T
MT
Andreyka
Jamie B
JB
Meyer
Damon L
DL
Doronina
Svetlana O
SO
Senter
Peter D
PD
D000951:Antigens, Neoplasm / Q000187:drug effects / Q000276:immunology; D001665:Binding Sites; D002292:Carcinoma, Renal Cell / Q000188:drug therapy*; D045744:Cell Line, Tumor; D004151:Dipeptides / Q000737:chemistry*; D004317:Doxorubicin / Q000031:analogs & derivatives / Q000737:chemistry*; D016503:Drug Delivery Systems / Q000379:methods; D004354:Drug Screening Assays, Antitumor; D004355:Drug Stability; D006801:Humans; D006868:Hydrolysis; D000922:Immunotoxins / Q000737:chemistry* / Q000494:pharmacology*; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy*; D008968:Molecular Conformation; D013329:Structure-Activity Relationship
D000951:Antigens, Neoplasm; D004151:Dipeptides; D000922:Immunotoxins; D004317:Doxorubicin