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The Antibody Zalutumumab Inhibits Epidermal Growth Factor Receptor Signaling by Limiting Intra- and Intermolecular Flexibility

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The Antibody Zalutumumab Inhibits Epidermal Growth Factor Receptor Signaling by Limiting Intra- and Intermolecular Flexibility The antibody zalutumumab inhibits epidermal growth factor receptor signaling by limiting intra- and intermolecular flexibility Jeroen J. Lammerts van Bueren*, Wim K. Bleeker*, Annika Bra¨ nnstro¨ m†, Anne von Euler†, Magnus Jansson†, Matthias Peipp‡, Tanja Schneider-Merck‡, Thomas Valerius‡, Jan G. J. van de Winkel*§, and Paul W. H. I. Parren*¶ *Genmab, 3508 AD, Utrecht, The Netherlands; †Sidec, SE-164 40 Kista, Sweden; ‡Division of Nephrology and Hypertension, Christian-Albrecht-University, 24105 Kiel, Germany; and §Immunotherapy Laboratory, Department of Immunology, University Medical Centre Utrecht, 3584 EA, Utrecht, The Netherlands Edited by Michael Sela, Weizmann Institute of Science, Rehovot, Israel, and approved February 7, 2008 (received for review October 8, 2007) The epidermal growth factor receptor (EGFR) activates cellular intervene in EGFR signaling, as reflected by two classes of pathways controlling cell proliferation, differentiation, migration, anti-EGFR drugs that are currently used clinically: tyrosine and survival. It thus represents a valid therapeutic target for kinase inhibitors (TKIs) and monoclonal antibodies (mAbs). treating solid cancers. Here, we used an electron microscopy-based TKIs represent small-molecule inhibitors that block EGFR- technique (Protein Tomography) to study the structural rearrange- kinase activity by binding to the ATP-binding pocket, thereby ment accompanying activation and inhibition of native, individual, abrogating downstream EGFR signaling. The effects of TKI EGFR molecules. Reconstructed tomograms (3D density maps) seem to be primarily related to enzyme inhibition. showed a level of detail that allowed individual domains to be For mAbs, the mechanisms of action are more diverse and discerned. Monomeric, resting EGFR ectodomains demonstrated their relative contribution to antitumor activity is still being large flexibility, and a number of distinct conformations were investigated. Most EGFR mAbs bind to the EGFR ligand- observed. In contrast, ligand-activated EGFR complexes were de- binding domain and thereby compete with the ligand for recep- tected only as receptor dimers with ring-like conformations. Zalu- tor binding. The chimeric EGFR mAb cetuximab, for example, tumumab, a therapeutic inhibitory EGFR antibody directed against interacts with EGFR domain III and occludes the ligand-binding domain III, locked EGFR molecules into a very compact, inactive region. Cetuximab has been described to prevent the receptor conformation. Biochemical analyses showed bivalent binding of from adopting the extended conformation required for dimer- zalutumumab to provide potent inhibition of EGFR signaling. The ization by causing steric clashes between the antibody’s Fab structure of EGFR–zalutumumab complexes on the cell surface domain and domain I of the receptor (8). mAb-mediated EGFR visualized by Protein Tomography indicates that the cross-linking down-modulation is another mechanism that attenuates EGFR spatially separates the EGFR molecules’ intracellular kinase do- signaling. Antibody bivalency appeared to be an important mains to an extent that appears incompatible with the induction of prerequisite for this mechanism (9), although it was unclear how signaling. These insights into the mechanisms of action of receptor bivalent antibody binding of EGFR is compatible with EGFR inhibition may also apply to other cell-surface tyrosine kinase inactivation, without trans-autophosphorylation by the kinase receptors of the ErbB family. domains. Importantly, agonistic properties are frequently ob- served for mAbs directed against cell-surface receptors such as EGFR ͉ mechanism of action ͉ protein tomography IGFR, C-Met, CD28, or Fas (10–12). Our previous studies have shown that zalutumumab, a human pidermal growth factor receptor (EGFR) is a 180-kDa IgG1␬ EGFR antibody, potently inhibits tumor growth in xeno- Eglycoprotein receptor tyrosine kinase of the ErbB family (1). graft models by engaging two mechanisms of action (13). First, The receptor has several ligands with similar structures of which EGFR signaling is blocked. This was observed as a reduction in EGF and TGF-␣ are the most studied. Signaling via EGFR receptor phosphorylation and is most effective at saturating enhances processes responsible for cell growth and differentia- antibody concentrations. Second, antitumor effects are mediated tion, including promotion of proliferation, angiogenesis, cell by Fc-mediated ADCC. In the present work, we studied the migration, and inhibition of apoptosis. Activation of this growth molecular mechanisms via which zalutumumab inhibits EGFR factor receptor is tightly regulated by complex molecular mech- activation. First, we mapped the epitope of zalutumumab on anisms. Despite high levels of regulation, EGFR is frequently EGFR. Then, we used Protein Tomography to visualize EGFR abnormally activated in epithelial tumors, and overexpression of conformations in EGFR-overexpressing cells in its monomeric EGFR has been correlated with poor clinical prognosis (2). (resting) conformation, its EGF-stimulated conformation, and Crystallography studies of ErbB extracellular regions led to a its zalutumumab-inhibited conformation. This technique al- significant advance in our knowledge of how EGFR dimerization lowed us to observe cell membrane-localized EGFR molecules and activation is promoted by growth factor binding (3). Dimer- ization is mediated by ligand-induced receptor–receptor inter- actions, and a ‘‘dimerization arm’’ in a cysteine-rich domain II at Author contributions: J.J.L.v.B., W.K.B., J.G.J.v.d.W., and P.W.H.I.P. designed research; J.J.L.v.B., A.B., A.v.E., M.P., and T.S.-M. performed research; J.J.L.v.B., W.K.B., A.B., A.v.E., the dimer interface (4, 5) plays a critical role in this process. In M.J., T.V., J.G.J.v.d.W., and P.W.H.I.P. analyzed data; and J.J.L.v.B., W.K.B., A.B., J.G.J.v.d.W., the monomeric resting receptor (without ligand bound) this and P.W.H.I.P. wrote the paper. dimerization arm is buried intramolecularly by interaction with Conflict of interest statement: J.J.L.v.B., W.K.B., J.G.J.v.d.W., and P.W.H.I.P. are employees domain IV and thus appears to ‘‘autoinhibit’’ receptor dimer- of Genmab. A.B., A.v.E., and M.J. are employees of Sidec. J.G.J.v.d.W. has substantive ization (6). Activating ligands bridge two distinct binding sites on ownership of stock in Genmab BV. the receptor (in domains I and III) and induce domain rear- This article is a PNAS Direct Submission. rangement in the extracellular region of the receptor, leading to Freely available online through the PNAS open access option. homo- and/or heterodimerization and trans-autophosphoryla- ¶To whom correspondence may be addressed. E-mail: [email protected]. tion of the intracellular domain of the receptor (7) (Fig. 1). This article contains supporting information online at www.pnas.org/cgi/content/full/ Characterization of this complex mechanism of receptor ac- 0709477105/DCSupplemental. IMMUNOLOGY tivation has triggered the development of various strategies to © 2008 by The National Academy of Sciences of the USA www.pnas.org͞cgi͞doi͞10.1073͞pnas.0709477105 PNAS ͉ April 22, 2008 ͉ vol. 105 ͉ no. 16 ͉ 6109–6114 Fig. 1. Model for molecular mechanism of ligand-induced EGFR activation. EGFR domains are shown as a cartoon (domain I, blue; domain II, green; domain III, yellow; domain IV, red; intracellular tyrosine kinase domain, gray). (A) Most of the unliganded EGFR exists in an autoinhibited or tethered conformation, in which domains II and IV form an intramolecular interaction or tether. (B) In the remaining unliganded molecules, this tether is broken, and EGFR adopts a range of ‘‘untethered’’ conformations, some of which may be more extended. (C) Ligand binds preferentially to untethered molecules and interacts simultaneously with domains I and III, stabilizing the extended form in which domain II is exposed. (D) Dimerization is receptor-mediated and dominated by domain II interactions. In the dimer-complex, the intracellular kinase domains cross-phosphorylate residues in the C-terminal receptor tail. Adapted from ref. 8. at a level of detail not previously obtainable; i.e., where separate domain III (8), indicated both antibodies to compete with each protein domains could be discerned. Three-dimensional analyses other for binding (data not shown; n ϭ 3) by steric hindrance or of resting, EGF-bound, and zalutumumab-loaded EGFR pro- allosteric changes in the epitope. However, mAb 528 (another vide a unique view of the mechanisms via which EGFR mAbs EGFR antibody) blocked cetuximab but not zalutumumab bind- block EGFR activation and prevent EGFR tyrosine kinase ing to EGFR—suggesting overlapping but nonidentical epitopes. activation. Because zalutumumab does not bind murine EGFR (13), 7 of 17 nonhomologous amino acid residues within domain III of human Results EGFR were changed to the corresponding murine amino acid Bivalent Binding of Zalutumumab Without Activation of EGFR. Bind- residues by site-directed mutagenesis. These EGFR point- ing studies showed intact zalutumumab antibody to exhibit an mutants were used to fine-map the epitope of zalutumumab. An Ϸ 3-fold higher avidity for EGFR-expressing cells than its Fab additional point-mutant, K465E, which is known to affect cetux- fragment [EC50 intact IgG: 7 nM (C.I. 5–10); Fab: 19 nM (C.I. imab binding (14), was also included. The EGFR point-mutants 15–24)]. This difference indicates bivalent zalutumumab binding were transiently expressed in HEK293 cells, and zalutumumab to occur at the cell surface. Remarkably, this antibody-mediated binding to point-mutants was evaluated as compared with wild- cross-linking of EGFR did not result in EGFR activation, type human EGFR. EGFR point-mutants expression was veri- because we could not detect any induction of EGFR phosphor- fied by using a control mAb binding to EGFR domain II. Flow ylation in starved A431 cells using an ELISA (data not shown). Instead, zalutumumab effectively blocked EGF-induced EGFR cytometric analyses identified four amino acids that were critical activation in a cell-based EGFR phosphorylation assay with an for zalutumumab binding: K465, M467, K443, and S418 (Fig.
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