Open AccessT cell-engaging BiTE antibodies specific for EGFR potently eliminate KRAS- and BRAF-mutated colorectal cancer cells
Author(s) -
Ralf Lutterbuese,
Tobias Raum,
Roman Kischel,
Patrick Hoffmann,
Susanne Mangold,
Benno Rattel,
Matthias Friedrich,
Oliver S. Thomas,
Grit Lorenczewski,
Doris Rau,
Evelyne Schaller,
Ines Herrmann,
Andreas Wolf,
Thomas Urbig,
Patrick A. Baeuerle,
Peter Kufer
Publication year - 2010
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.1000976107
Subject(s) - cetuximab , kras , antibody , monoclonal antibody , colorectal cancer , epidermal growth factor receptor , cancer research , medicine , cancer , egfr inhibitors , immunology
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.