T cell-engaging BiTE antibodies specific for EGFR potently eliminate KRAS- and BRAF-mutated colorectal cancer cells.
Epidermal growth factor receptor (EGFR)-specific monoclonal antibodies predominantly inhibit colorectal cancer (CRC) growth by interfering with receptor signaling. Recent analyses have shown that patients with CRC with mutated KRAS and BRAF oncogenes do not profit from treatment with such antibodies. Here we have used the binding domains of cetuximab and pantitumumab for constructing T cell-engaging BiTE antibodies. Both EGFR-specific BiTE antibodies mediated potent redirected lysis of KRAS- and BRAF-mutated CRC lines by human T cells at subpicomolar concentrations. The cetuximab-based BiTE antibody also prevented at very low doses growth of tumors from KRAS- and BRAF-mutated human CRC xenografts, whereas cetuximab was not effective. In nonhuman primates, no significant adverse events were observed during treatment for 3 wk at BiTE serum concentrations inducing, within 1 d, complete lysis of EGFR-overexpressing cancer cells. EGFR-specific BiTE antibodies may have potential to treat CRC that does not respond to conventional antibodies.
Lutterbuese
Ralf
R
Micromet, 81477 Munich, Germany.
Raum
Tobias
T
Kischel
Roman
R
Hoffmann
Patrick
P
Mangold
Susanne
S
Rattel
Benno
B
Friedrich
Matthias
M
Thomas
Oliver
O
Lorenczewski
Grit
G
Rau
Doris
D
Schaller
Evelyne
E
Herrmann
Ines
I
Wolf
Andreas
A
Urbig
Thomas
T
Baeuerle
Patrick A
PA
Kufer
Peter
P
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011905:Genes, ras / Q000187:drug effects; D006801:Humans; D009154:Mutation / Q000187:drug effects; D009369:Neoplasms / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf; D012307:Risk Factors
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D066246:ErbB Receptors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D000068818:Cetuximab