T Cell-engaging BiTE Antibodies Specific for EGFR Potently Eliminate KRAS- and BRAF-mutated Colorectal Cancer Cells

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2010 Jul 10

PMID 20616015

Citations 71

Authors

Ralf Lutterbuese

Tobias Raum

Roman Kischel

Patrick Hoffmann

Susanne Mangold

Benno Rattel

Matthias Friedrich

Oliver Thomas

Grit Lorenczewski

Doris Rau

Evelyne Schaller

Ines Herrmann

Andreas Wolf

Thomas Urbig

Patrick A Baeuerle

Peter Kufer

Affiliations

Soon will be listed here.

Abstract

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.

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