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Monovalent Antibody Design and Mechanism of Action of Onartuzumab, a MET Antagonist with Anti-Tumor Activity As a Therapeutic Ag

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Monovalent Antibody Design and Mechanism of Action of Onartuzumab, a MET Antagonist with Anti-Tumor Activity As a Therapeutic Ag Monovalent antibody design and mechanism of PNAS PLUS action of onartuzumab, a MET antagonist with anti-tumor activity as a therapeutic agent Mark Merchanta,1,2, Xiaolei Mab,2,3, Henry R. Maunc,2, Zhong Zhenga,2,4, Jing Penga, Mally Romeroa,5, Arthur Huangd,6, Nai-ying Yanga, Merry Nishimuraa, Joan Grevee, Lydia Santellc, Yu-Wen Zhangf, Yanli Suf, Dafna W. Kaufmanf, Karen L. Billecig, Elaine Maih, Barbara Moffatg,7, Amy Limi, Eileen T. Duenasi, Heidi S. Phillipsa, Hong Xiangj, Judy C. Youngh, George F. Vande Woudef, Mark S. Dennisd, Dorothea E. Reillyk, Ralph H. Schwalla,8, Melissa A. Starovasnikb, Robert A. Lazarusc, and Daniel G. Yansurad Departments of aTranslational Oncology, bStructural Biology, cEarly d e Discovery Biochemistry, Antibody Engineering, Biomedical Imaging, fi gProtein Chemistry, hBiochemical and Cellular Pharmacology, iPurification Signi cance Development, jPharmacokinetic and Pharmacodynamic Sciences, and kEarly Stage Cell Culture, Genentech, Inc., South San Francisco, CA 94080; and Therapeutic antibodies have revolutionized the treatment of hu- fLaboratory of Molecular Oncology, Van Andel Research Institute, Grand Rapids, MI 49503 man disease. Despite these advances, antibody bivalency limits their utility against some targets. Here, we describe the de- Edited by Richard A. Lerner, The Scripps Research Institute, La Jolla, CA, and velopment of a one-armed (monovalent) antibody, onartuzumab, approved June 3, 2013 (received for review February 15, 2013) targeting the receptor tyrosine kinase MET. While initial screening Binding of hepatocyte growth factor (HGF) to the receptor tyrosine of bivalent antibodies produced agonists of MET, engineering kinase MET is implicated in the malignant process of multiple can- them into monovalent antibodies produced antagonists instead. cers, making disruption of this interaction a promising therapeutic We explain the structural basis of the mechanism of action with strategy. However, targeting MET with bivalent antibodies can the crystal structure of onartuzumab antigen-binding fragment in β mimic HGF agonism via receptor dimerization. To address this lim- complex with MET and HGF- . These discoveries have led to an itation, we have developed onartuzumab, an Escherichia coli- additional antibody-based therapeutic option and shed light on derived, humanized, and affinity-matured monovalent monoclo- the underpinnings of HGF/MET signaling. nal antibody against MET, generated using the knob-into-hole technology that enables the antibody to engage the receptor in Author contributions: M.M. and R.H.S. designed research; X.M., H.R.M., Z.Z., J.P., M.R., A.H., N.-y.Y., M.N., J.G., L.S., Y.-W.Z., Y.S., D.W.K., K.L.B., E.M., H.S.P., H.X., J.C.Y., G.F.V.W., M.S.D., a one-to-one fashion. Onartuzumab potently inhibits HGF binding M.A.S., and R.A.L. performed research; B.M., A.L., E.T.D., D.E.R., and D.G.Y. contributed new and receptor phosphorylation and signaling and has antibody-like reagents/analytic tools; M.M., X.M., H.R.M., Z.Z., J.P., M.R., A.H., N.-y.Y., M.N., J.G., L.S., pharmacokinetics and antitumor activity. Biochemical data and Y.-W.Z., Y.S., D.W.K., K.L.B., E.M., B.M., A.L., E.T.D., H.S.P., H.X., J.C.Y., G.F.V.W., M.S.D., a crystal structure of a ternary complex of onartuzumab anti- D.E.R., R.H.S., M.A.S., R.A.L., and D.G.Y. analyzed data; M.M., X.M., H.R.M., Z.Z., J.P., M.R., A.H., N.-y.Y., M.N., J.G., L.S., Y.-W.Z., Y.S., D.W.K., K.L.B., E.M., B.M., A.L., E.T.D., H.S.P., H.X., gen-binding fragment bound to a MET extracellular domain frag- J.C.Y., G.F.V.W., M.S.D., D.E.R., R.H.S., M.A.S., R.A.L., and D.G.Y. wrote the paper; M.M. led the ment, consisting of the MET Sema domain fused to the adjacent project and conceived in vitro and in vivo antibody assessment studies; X.M., H.R.M., M.A.S., Plexins, Semaphorins, Integrins domain (MET Sema-PSI), and the and R.A.L. planned or carried out biochemical experiments and determined the crystal struc- β fi ture of onartuzumab Fab with MET Sema-PSI and HGF-β; Z.Z. performed extensive in vitro HGF -chain demonstrate that onartuzumab acts speci cally by fi α β assessment of onartuzumab; J.P. and M.R. conducted in vivo ef cacy and PK/PD studies; A.H. blocking HGF -chain (but not -chain) binding to MET. These data performed cloning and generation of monovalent monoclonal antibodies; N.-y.Y. carried out suggest a likely binding site of the HGF α-chain on MET, which in vitro assessment of onartuzumab; M.N., J.G., and H.S.P. performed the U-87 MG orthotopic when dimerized leads to MET signaling. Onartuzumab, therefore, tumor model; L.S. performed competition binding studies of onartuzumab Fab with HGF represents the founding member of a class of therapeutic mono- proteins; Y-W.Z., Y.S., and G.F.V.W. conducted studies in hHGFtg-SCID mice; K.L.B. performed MET KIRA assays; E.M. and J.C.Y. carried out assays to assess HGF binding to MET and assess- valent antibodies that overcomes limitations of antibody biva- ment of onartuzumab PK; H.X. performed PK work; B.M., A.L., E.T.D., and D.E.R. developed the lency for targets impacted by antibody crosslinking. purification methods for onartuzumab; M.S.D. humanized and affinity-matured OA5D5 to generate onartuzumab; R.H.S. initiated the anti-MET project and oversaw the initial assessment of onartuzumab; D.G.Y. developed the monovalent antibody platform based upon the “knob” scatter factor | HGFR | MetMAb | OA5D5 and “hole” heterodimerization technology; and D.W.K. performed the in vitro growth and study preparation and analysis for the NCI-H596 efficacy studies. onoclonal antibodies (mAbs) have revolutionized our ar- Conflict of interest statement: All authors except Y.-W.Z., Y.S., D.W.K., and G.F.V.W. are Msenal of modern medicines (1). They allow target speci- or were employees of Genentech, Inc., at the time when they performed the work pre- sented in this manuscript. ficity that generally results in negligible off-target side effects. MEDICAL SCIENCES Despite the influx of antibodies into the clinic, limitations still This article is a PNAS Direct Submission. remain with respect to selected targets. In particular, receptor Freely available online through the PNAS open access option. tyrosine kinases (RTKs) are generally activated by binding to Data deposition: The atomic coordinates have been deposited in the Protein Data Bank, their respective ligands that dimerize or oligomerize RTKs, www.pdb.org (PDB ID code 4K3J). leading to kinase autoactivation (2, 3). This structural interplay 1To whom correspondence should be addressed. E-mail: [email protected]. between ligand and receptor is challenging for therapeutic 2M.M., X.M., H.R.M., and Z.Z. contributed equally to this work. antibodies because their bivalent nature can dimerize and ago- 3Present address: Department of Structural Chemistry, Novartis Institutes for Biomedical nize rather than antagonize their intended target. We describe Research, Emeryville, CA 94608. a class of therapeutics with the generation of a mAb that is 4Present address: Foster City, CA 94404. monovalent against its target, the MET RTK. This unique an- 5Present address: Department of Pharmacology, Celgene, Inc., San Diego, CA 92121. tibody, onartuzumab (MetMAb, or the anti-MET monovalent 6Present address: Laboratory of Circuit and Behavioral Physiology, RIKEN Brain Science monoclonal antibody), consists of a single humanized and af- Institute, Wako-shi, Saitama 351-0198, Japan. finity-matured antigen-binding fragment (Fab) fused to a com- 7Retired. plete constant domain fragment (Fc) engineered to assemble in 8Deceased August 26, 2005. “ ” “ ” Escherichia coli through the use of knob and hole mutations This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. in the CH3 domain within the Fc (4). This design has enabled 1073/pnas.1302725110/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1302725110 PNAS | Published online July 23, 2013 | E2987–E2996 Downloaded by guest on September 25, 2021 large-scale production of a functional monovalent antibody that consisting of a murine/human chimeric IgG1 with only one 5D5 effectively antagonizes hepatocyte growth factor (HGF)/MET Fab arm, we sought to overcome the short half-life of a Fab while signaling. eliminating the bivalent binding inherent in a full-length IgG MET signaling is initiated by binding to its cognate ligand HGF. (Fig. 1D). Protein was generated in E. coli by coexpression of the HGF is secreted as a single-chain ligand (pro-HGF) that is pro- chimeric 5D5 light chain, chimeric full-length heavy chain with teolytically processed to generate a disulfide-linked α/β-heterodimer. or without a human Fc chain starting at the hinge region. When The α-chain comprises an N-terminal plasminogen family, apple only full-length heavy and light chains were coexpressed, the domain, and nematode protein (PAN) domain, followed by four antibody fragments assembled a bivalent full-length antibody of Kringle domain repeats and the β-chain contains a C-terminal ∼150 kDa (Fig. 1E, lane 1). Inclusion of an expression construct trypsin-like serine protease domain (5). Although both pro-HGF encoding a nonmutated Fc chain with full-length heavy and light and HGF α/β-heterodimer (mature HGF) bind MET with high chains produced a monovalent antibody of expected size (∼100 affinity (6, 7), signaling is elicited only by cleaved HGF.
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