AMG 595, an Anti-EGFRvIII Antibody-Drug Conjugate, Induces Potent Antitumor Activity against EGFRvIII-Expressing Glioblastoma.
Epidermal growth factor receptor variant III (EGFRvIII) is a cancer-specific deletion mutant observed in approximately 25% to 50% of glioblastoma multiforme (GBM) patients. An antibody drug conjugate, AMG 595, composed of the maytansinoid DM1 attached to a highly selective anti-EGFRvIII antibody via a noncleavable linker, was developed to treat EGFRvIII-positive GBM patients. AMG 595 binds to the cell surface and internalizes into the endo-lysosomal pathway of EGFRvIII-expressing cells. Incubation of AMG 595 with U251 cells expressing EGFRvIII led to potent growth inhibition. AMG 595 treatment induced significant tumor mitotic arrest, as measured by phospho-histone H3, in GBM subcutaneous xenografts expressing EGFRvIII. A single intravenous injection of AMG 595 at 17 mg/kg (250 μg DM1/kg) generated complete tumor regression in the U251vIII subcutaneous xenograft model. AMG 595 mediated tumor regression in the D317 subcutaneous xenograft model that endogenously expresses EGFRvIII. Finally, AMG 595 treatment inhibited the growth of D317 xenografts orthotopically implanted into the brain as determined by magnetic resonance imaging. These results demonstrate that AMG 595 is a promising candidate to evaluate in EGFRvIII-expressing GBM patients.
Amgen Inc., Seattle, Washington. kjhamblett@comcast.net.
Kevin J
KJ
Hamblett
Amgen Inc., Seattle, Washington.
Carl J
CJ
Kozlosky
Amgen Inc., Seattle, Washington.
Sophia
S
Siu
Amgen Inc., South San Francisco, California.
Wesley S
WS
Chang
Amgen Inc., Seattle, Washington.
Hua
H
Liu
Amgen Inc., Burnaby, British Columbia, Canada.
Ian N
IN
Foltz
Amgen Inc., Seattle, Washington.
Esther S
ES
Trueblood
Amgen Inc., Seattle, Washington.
David
D
Meininger
Amgen Inc., Thousand Oaks, California.
Taruna
T
Arora
Amgen Inc., Thousand Oaks, California.
Brian
B
Twomey
Amgen Inc., Thousand Oaks, California.
Steven L
SL
Vonderfecht
Amgen Inc., Thousand Oaks, California.
Qing
Q
Chen
Amgen Inc., Thousand Oaks, California.
John S
JS
Hill
Amgen Inc., Seattle, Washington.
William C
WC
Fanslow
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D006801:Humans; D018796:Immunoconjugates / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology*; D007150:Immunohistochemistry; D007275:Injections, Intravenous; D008453:Maytansine / Q000031:analogs & derivatives / Q000276:immunology / Q000494:pharmacology; D008819:Mice, Nude; D016513:Mice, SCID; D009154:Mutation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
C000607290:AMG 595; D000911:Antibodies, Monoclonal; D018796:Immunoconjugates; D008453:Maytansine; D066246:ErbB Receptors