CD133/prominin-1 is a potential therapeutic target for antibody-drug conjugates in hepatocellular and gastric cancers.
CD133/prominin-1 is a pentaspan transmembrane glycoprotein overexpressed in various solid tumours including colorectal and glioblastomas. CD133 was found here to be highly expressed in >or=50% of pancreatic, gastric and intrahepatic cholangiocarcinomas. Quantitative flow cytometric analysis showed that a panel of established hepatocellular, pancreatic and gastric cancer cell lines expressed CD133 at levels higher than normal epithelial cells or bone marrow progenitor cells. A murine anti-human CD133 antibody (AC133) conjugated to a potent cytotoxic drug, monomethyl auristatin F (MMAF), effectively inhibited the growth of Hep3B hepatocellular and KATO III gastric cancer cells in vitro with IC(50) values of 2-7 ng ml(-1). MMAF induced apoptosis in the cancer cells as measured by caspase activation. The anti-CD133-drug conjugate (AC133-vcMMAF) was shown to internalise and colocalised with the lysosomal marker CD107a in the sensitive cell lines. In contrast, in the resistant cell line Su.86.86, the conjugate internalised and colocalised with the caveolae marker, Cav-1. Addition of ammonium chloride, an inhibitor of lysosomal trafficking and processing, suppressed the cytotoxic effect of AC133-vcMMAF in both Hep3B and KATO III. Anti-CD133-drug conjugate treatment resulted in significant delay of Hep3B tumour growth in SCID mice. Anti-CD133 antibody-drug conjugates warrant further evaluation as a therapeutic strategy to eradicate CD133+ tumours.
Seattle Genetics Inc., 21823 30th Drive Southeast, Bothell, WA 98021, USA. lsmith@seagen.com
L M
LM
Smith
A
A
Nesterova
M C
MC
Ryan
S
S
Duniho
M
M
Jonas
M
M
Anderson
R F
RF
Zabinski
M K
MK
Sutherland
H-P
HP
Gerber
K L
KL
Van Orden
P A
PA
Moore
S M
SM
Ruben
P J
PJ
Carter
D000071916:AC133 Antigen; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D015703:Antigens, CD / Q000096:biosynthesis; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004067:Digestive System Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D006023:Glycoproteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D022781:Hepatocytes; D006801:Humans; D006825:Hybridomas; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism; D010455:Peptides / Q000037:antagonists & inhibitors*; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000378:metabolism
D000071916:AC133 Antigen; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000970:Antineoplastic Agents; D006023:Glycoproteins; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse