Antibody-drug conjugates for the treatment of non-Hodgkin's lymphoma: target and linker-drug selection.
Antibody-drug conjugates (ADC), potent cytotoxic drugs covalently linked to antibodies via chemical linkers, provide a means to increase the effectiveness of chemotherapy by targeting the drug to neoplastic cells while reducing side effects. Here, we systematically examine the potential targets and linker-drug combinations that could provide an optimal ADC for the treatment for non-Hodgkin's lymphoma. We identified seven antigens (CD19, CD20, CD21, CD22, CD72, CD79b, and CD180) for potential treatment of non-Hodgkin's lymphoma with ADCs. ADCs with cleavable linkers mediated in vivo efficacy via all these targets; ADCs with uncleavable linkers were only effective when targeted to CD22 and CD79b. In target-independent safety studies in rats, the uncleavable linker ADCs showed reduced toxicity, presumably due to the reduced release of free drug or other toxic metabolites into the circulation. Thus, our data suggest that ADCs with cleavable linkers work on a broad range of targets, and for specific targets, ADCs with uncleavable linkers provide a promising opportunity to improve the therapeutic window for ADCs in humans.
Polson
Andrew G
AG
Genentech, Inc., South San Francisco, California, USA. polson@gene.com
Calemine-Fenaux
Jill
J
Chan
Pamela
P
Chang
Wesley
W
Christensen
Erin
E
Clark
Suzanna
S
de Sauvage
Frederic J
FJ
Eaton
Dan
D
Elkins
Kristi
K
Elliott
J Michael
JM
Frantz
Gretchen
G
Fuji
Reina N
RN
Gray
Alane
A
Harden
Kristin
K
Ingle
Gladys S
GS
Kljavin
Noelyn M
NM
Koeppen
Hartmut
H
Nelson
Christopher
C
Prabhu
Saileta
S
Raab
Helga
H
Ross
Sarajane
S
Slaga
Dion S
DS
Stephan
Jean-Philippe
JP
Scales
Suzie J
SJ
Spencer
Susan D
SD
Vandlen
Richard
R
Wranik
Bernd
B
Yu
Shang-Fan
SF
Zheng
Bing
B
Ebens
Allen
A
D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000276:immunology; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001402:B-Lymphocytes / Q000276:immunology; D003432:Cross-Linking Reagents / Q000008:administration & dosage / Q000493:pharmacokinetics; D005260:Female; D000922:Immunotoxins / Q000276:immunology / Q000493:pharmacokinetics / Q000494:pharmacology*; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy* / Q000276:immunology; D008453:Maytansine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D051379:Mice; D008813:Mice, Inbred ICR; D016513:Mice, SCID; D009842:Oligopeptides / Q000008:administration & dosage* / Q000493:pharmacokinetics; D051381:Rats; D013438:Sulfhydryl Compounds / Q000008:administration & dosage* / Q000493:pharmacokinetics; D023041:Xenograft Model Antitumor Assays
D015703:Antigens, CD; D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D000922:Immunotoxins; C488736:N(2')-deacetyl-N(2')-(3-mercapto-1-oxopropyl)maytansine; D009842:Oligopeptides; D013438:Sulfhydryl Compounds; C513576:monomethylauristatin F; D008453:Maytansine