A novel antibody engineering strategy for making monovalent bispecific heterodimeric IgG antibodies by electrostatic steering mechanism

Journal of Biological Chemistry

Volumn 290, Issue 12, 2015, Pages 7535-7562

  Liu, Zhi ^a,c   Leng, Esther C ^a,d   Gunasekaran, Kannan ^a,d   Pentony, Martin ^a,c   Shen, Min ^a,c   Howard, Monique ^a,c   Stoops, Janelle ^a,c   Manchulenko, Kathy ^a,d   Razinkov, Vladimir ^a,c   Liu, Hua ^b,c   Fanslow, William ^b,c   Hu, Zhonghua ^a,c   Sun, Nancy ^a,c   Hasegawa, Haruki ^a,c   Clark, Rutilio ^a,c   Foltz, Ian N ^a,d   Yan, Wei ^a,c  

^a Department of Therapeutic Discovery ^*  (United States)

^b Therapeutic Innovation Unit   (United States)

^c AMGEN INC   (United States)

^d AMGEN INC   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CHAINS; CYTOTOXICITY; ELECTROSTATICS; MAMMALS; MOBILE SECURITY; TUMORS;

ANTIBODY ENGINEERING; ANTIBODY LIGHT CHAIN; ANTIBODY-DEPENDENT CELLULAR CYTOTOXICITIES; BIOLOGICAL ASSAYS; CLINICAL TESTING; INTERFACE RESIDUES; STEERING MECHANISMS; THERAPEUTIC ANTIBODIES;

ANTIBODIES;

ADCC ENHANCED HUMAN EPIDERMAL GROWTH FACTOR RECEPTOR 2 EPIDERMAL GROWTH FACTOR RECEPTOR HETERO IMMUNOGLOBULIN G1 ANTIBODY; ANTINEOPLASTIC AGENT; BISPECIFIC ANTIBODY; BISPECIFIC HUMAN EPIDERMAL GROWTH FACTOR RECEPTOR 2 EPIDERMAL GROWTH FACTOR RECEPTOR HETERO IMMUNOGLOBULIN G1 ANTIBODY; DNA; DNA FRAGMENT; EPIDERMAL GROWTH FACTOR RECEPTOR E7.6.3 IMMUNOGLOBULIN G1 ANTIBODY; HUMAN EPIDERMAL GROWTH FACTOR RECEPTOR 2 EPIDERMAL GROWTH FACTOR RECEPTOR HETERO IMMUNOGLOBULIN G1 ANTIBODY; HUMAN EPIDERMAL GROWTH FACTOR RECEPTOR 2 HUMAN AB4D5 8 IMMUNOGLOBULIN G1 ANTIBODY; HUMAN IMMUNOGLOBULIN G1 ISOTYPE; IMMUNOGLOBULIN ANTIBODY; IMMUNOGLOBULIN G ANTIBODY; PANITUMUMAB; PERTUZUMAB; TRASTUZUMAB; UNCLASSIFIED DRUG; AMINO ACID; IMMUNOGLOBULIN G;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANTIBODY DEPENDENT CELLULAR CYTOTOXICITY; ANTIBODY ENGINEERING; ANTIBODY STRUCTURE; ANTINEOPLASTIC ACTIVITY; ARTICLE; BASE PAIRING; BINDING AFFINITY; CANCER INHIBITION; COMPUTER MODEL; CONTROLLED STUDY; DEGLYCOSYLATION; DRUG BINDING; EC50; ELECTROSTATIC STEERING MECHANISM; ENZYME INHIBITION; ENZYME PHOSPHORYLATION; FEMALE; HEAVY CHAIN; HUMAN; HUMAN CELL; IC50; IMMUNOGENICITY; LIGHT CHAIN; MOUSE; MUTAGENESIS; NONHUMAN; PANCREAS ADENOCARCINOMA; PRIORITY JOURNAL; THERMOSTABILITY; TUMOR XENOGRAFT; ANIMAL; CELL LINE; CHEMISTRY; CHO CELL LINE; CRICETULUS; DIMERIZATION; ENZYME LINKED IMMUNOSORBENT ASSAY; IMMUNOLOGY; PROTEIN ENGINEERING; STATIC ELECTRICITY; SURFACE PLASMON RESONANCE;

MAMMALIA;

AMINO ACIDS; ANIMALS; ANTIBODY-DEPENDENT CELL CYTOTOXICITY; CELL LINE; CHO CELLS; CRICETULUS; DIMERIZATION; ENZYME-LINKED IMMUNOSORBENT ASSAY; HUMANS; IMMUNOGLOBULIN G; MICE; PROTEIN ENGINEERING; STATIC ELECTRICITY; SURFACE PLASMON RESONANCE;

EID: 84925321830     PISSN: 00219258     EISSN: 1083351X     Source Type: Journal    
DOI: 10.1074/jbc.M114.620260     Document Type: Article

References (48)

1. Jemal, A., Siegel, R., Xu, J., and Ward, E. (2010) Cancer statistics, 2010. CA Cancer J. Clin. 60, 277-300
2. Yamanaka, Y., Friess, H., Kobrin, M. S., Buchler, M., Beger, H. G., and Korc, M. (1993) Coexpression of epidermal growth factor receptor and ligands in human pancreatic cancer is associated with enhanced tumor aggressiveness. Anticancer Res. 13, 565-569
3. Jones, J. T., Akita, R. W., and Sliwkowski, M. X. (1999) Binding specificities and affinities of EGF domains for ErbB receptors. FEBS Lett. 447, 227-231
4. Olayioye, M. A., Graus-Porta, D., Beerli, R. R., Rohrer, J., Gay, B., and Hynes, N. E. (1998) ErbB-1 and ErbB-2 acquire distinct signaling properties dependent upon their dimerization partner. Mol. Cell. Biol. 18, 5042-5051
5. Vlacich, G., and Coffey, R. J. (2011) Resistance to EGFR-targeted therapy: a family affair. Cancer Cell 20, 423-425
6. Yonesaka K., Zejnullahu K., Okamoto I., Satoh T., Cappuzzo F., Souglakos J., Ercan D., Rogers A., Roncalli M., Takeda M., Fujisaka Y., Philips J., Shimizu T., Maenishi O., Cho Y., Sun J., et al. (2011) Activation of ERBB2 signaling causes resistance to the EGFR-directed therapeutic antibody cetuximab. Sci. Transl. Med. 3, 99ra86
7. Maron, R., Schechter, B., Mancini, M., Mahlknecht, G., Yarden, Y., and Sela, M. (2013) Inhibition of pancreatic carcinoma by homo- and heterocombinations of antibodies against EGF-receptor and its kin HER2/ErbB-2. Proc. Natl. Acad. Sci. U.S.A. 110, 15389-15394
8. Larbouret, C., Robert, B., Navarro-Teulon, I., Thèzenas, S., Ladjemi, M. Z., Morisseau, S., Campigna, E., Bibeau, F., Mach, J. P., and Pèlegrin, A. (2007) In vivo therapeutic synergism of anti-epidermal growth factor receptor and anti-HER2 monoclonal antibodies against pancreatic carcinomas. Clin. Cancer Res. 13, 3356-3362
9. Kufer, P., Lutterbüse, R., and Baeuerle, P. A. (2004) A revival of bispecific antibodies. Trends Biotechnol. 22, 238-244
10. Chames, P., and Baty, D. (2009) Bispecific antibodies for cancer therapy: the light at the end of the tunnel? mAbs 1, 539-547
11. Wu, C., Ying, H., Grinnell, C., Bryant, S., Miller, R., Clabbers, A., Bose, S., McCarthy, D., Zhu, R. R., Santora, L., Davis-Taber, R., Kunes, Y., Fung, E., Schwartz, A., Sakorafas, P., et al. (2007) Simultaneous targeting of multiple disease mediators by a dual-variable-domain immunoglobulin. Nat. Biotechnol. 25, 1290-1297
12. Schaefer, W., Regula, J. T., Bähner, M., Schanzer, J., Croasdale, R., Dürr, H., Gassner, C., Georges, G., Kettenberger, H., Imhof-Jung, S., Schwaiger, M., Stubenrauch, K. G., Sustmann, C., Thomas, M., Scheuer, W., and Klein, C. (2011) Immunoglobulin domain crossover as a generic approach for the production of bispecific IgG antibodies. Proc. Natl. Acad. Sci. U.S.A. 108, 11187-11192
13. Bostrom, J., Yu, S. F., Kan, D., Appleton, B. A., Lee, C. V., Billeci, K., Man, W., Peale, F., Ross, S., Wiesmann, C., and Fuh, G. (2009) Variants of the antibody herceptin that interact with HER2 and VEGF at the antigen binding site. Science 323, 1610-1614
14. Mack, M., Riethmüller, G., and Kufer, P. (1995) A small bispecific antibody construct expressed as a functional single-chain molecule with high tumor cell cytotoxicity. Proc. Natl. Acad. Sci. U.S.A. 92, 7021-7025
15. Kontermann, R. E. (2012) Dual targeting strategies with bispecific antibodies. mAbs 4, 182-197
16. Klein, C., Sustmann, C., Thomas, M., Stubenrauch, K., Croasdale, R., Schanzer, J., Brinkmann, U., Kettenberger, H., Regula, J. T., and Schaefer, W. (2012) Progress in overcoming the chain association issue in bispecific heterodimeric IgG antibodies. mAbs 4, 653-663
17. Carter, P. (2001) Bispecific human IgG by design. J. Immunol. Methods 248, 7-15
18. Ridgway, J. B., Presta, L. G., and Carter, P. (1996) 'Knobs-into-holes' engineering of antibody CH3 domains for heavy chain heterodimerization. Protein Eng. 9, 617-621
19. Davis, J. H., Aperlo, C., Li, Y., Kurosawa, E., Lan, Y., Lo, K. M., and Huston, J. S. (2010) SEEDbodies: fusion proteins based on strand-exchange engineered domain (SEED) CH3 heterodimers in an Fc analogue platform for asymmetric binders or immunofusions and bispecific antibodies. Protein Eng. Des. Sel. 23, 195-202
20. Gunasekaran, K., Pentony, M., Shen, M., Garrett, L., Forte, C., Woodward, A., Ng, S. B., Born, T., Retter, M., Manchulenko, K., Sweet, H., Foltz, I. N., Wittekind, M., and Yan, W. (2010) Enhancing antibody Fc heterodimer formation through electrostatic steering effects: applications to bispecific molecules and monovalent IgG. J. Biol. Chem. 285, 19637-19646
21. Merchant, A. M., Zhu, Z., Yuan, J. Q., Goddard, A., Adams, C. W., Presta, L. G., and Carter, P. (1998) An efficient route to human bispecific IgG. Nat. Biotechnol. 16, 677-681
22. Milstein, C., and Cuello, A. C. (1983) Hybrid hybridomas and their use in immunohistochemistry. Nature 305, 537-540
23. Seimetz, D., Lindhofer, H., and Bokemeyer, C. (2010) Development and approval of the trifunctional antibody catumaxomab (anti-EpCAM X anti-CD3) as a targeted cancer immunotherapy. Cancer Treat. Rev. 36, 458-467
24. Strop, P., Ho, W. H., Boustany, L. M., Abdiche, Y. N., Lindquist, K. C., Farias, S. E., Rickert, M., Appah, C. T., Pascua, E., Radcliffe, T., Sutton, J., Chaparro-Riggers, J., Chen, W., Casas, M. G., Chin, S. M., et al. (2012) Generating bispecific human IgG1 and IgG2 antibodies from any antibody pair. J. Mol. Biol. 420, 204-219
25. Labrijn, A. F., Meesters, J. I., de Goeij, B. E., van den Bremer, E. T., Neijssen, J., van Kampen, M. D., Strumane, K., Verploegen, S., Kundu, A., Gramer, M. J., van Berkel, P. H., van de Winkel, J. G., Schuurman, J., and Parren, P. W. (2013) Efficient generation of stable bispecific IgG1 by controlled Fab-arm exchange. Proc. Natl. Acad. Sci. U.S.A. 110, 5145-5150
26. Spiess, C., Merchant, M., Huang, A., Zheng, Z., Yang, N.Y., Peng, J., Ellerman, D., Shatz, W., Reilly, D., Yansura, D. G., and Scheer, J. M. (2013) Bispecific antibodies with natural architecture produced by co-culture of bacteria expressing 2 distinct half-antibodies. Nat. Biotechnol. 31, 753-758
27. Knarr, G., Gething, M. J., Modrow, S., and Buchner, J. (1995) BiP binding sequences in antibodies. J. Biol. Chem. 270, 27589-27594
28. Feige, M. J., Groscurth, S., Marcinowski, M., Shimizu, Y., Kessler, H., Hendershot, L. M., and Buchner, J. (2009) An unfolded CH1 domain controls the assembly and secretion of IgG antibodies. Mol. Cell 34, 569-579
29. Reiter, Y., Brinkmann, U., Lee, B., and Pastan, I. (1996) Engineering antibody Fv fragments for cancer detection and therapy: disulfide-stabilized Fv fragments. Nat. Biotechnol. 14, 1239-1245
30. Potapov, V., Sobolev, V., Edelman, M., Kister, A., and Gelfand, I. (2004) Protein-protein recognition: juxtaposition of domain and interface cores in immunoglobulins and other sandwich-like proteins. J. Mol. Biol. 342, 665-679
31. Röthlisberger, D., Honegger, A., and Plückthun, A. (2005) Domain interactions in the Fab fragment: a comparative evaluation of the single-chain Fv and Fab format engineered with variable domains of different stability. J. Mol. Biol. 347, 773-789
32. Sturniolo, T., Bono, E., Ding, J., Raddrizzani, L., Tuereci, O., Sahin, U., Braxenthaler, M., Gallazzi, F., Protti, M. P., Sinigaglia, F., and Hammer, J. (1999) Generation of tissue-specific and promiscuous HLA ligand databases using DNA microarrays and virtual HLA class II matrices. Nat. Biotechnol. 17, 555-561
33. Carter, P., Presta, L., Gorman, C. M., Ridgway, J. B., Henner, D., Wong, W. L., Rowland, A. M., Kotts, C., Carver, M. E., and Shepard, H. M. (1992) Humanization of an anti-p185HER2 antibody for human cancer therapy. Proc. Natl. Acad. Sci. U.S.A. 15, 4285-4289
34. Adams, C. W., Allison, D. E., Flagella, K., Presta, L., Clarke, J., Dybdal, N., McKeever, K., and Sliwkowski, M. X. (2006) Humanization of a recombinant monoclonal antibody to produce a therapeutic HER dimerization inhibitor, pertuzumab. Cancer Immunol. Immunother. 55, 717-727
35. Yang, X. D., Jia, X. C., Corvalan, J. R., Wang, P., Davis, C. G., and Jakobovits, A. (1999) Eradication of established tumors by a fully human monoclonal antibody to the epidermal growth factor receptor without concomitant chemotherapy. Cancer Res. 59, 1236-1243
36. Zhang, J., Liu, X., Bell, A., To, R., Baral, T. N., Azizi, A., Li, J., Cass, B., and Durocher, Y. (2009) Transient expression and purification of chimeric heavy chain antibodies. Protein Expr. Purif. 65, 77-82
37. Szymczak, A. L., Workman, C. J., Wang, Y., Vignali, K. M., Dilioglou, S., Vanin, E. F., and Vignali, D. A. (2004) Correction of multi-gene deficiency in vivo using a single 'self-cleaving' 2A peptide-based retroviral vector. Nat. Biotechnol. 22, 589-594
38. Fang, J., Qian, J. J., Yi, S., Harding, T. C., Tu, G. H., VanRoey, M., and Jooss, K. (2005) Stable antibody expression at therapeutic levels using the 2A peptide. Nat. Biotechnol. 23, 584-590
39. Igawa, T., Tsunoda, H., Kikuchi, Y., Yoshida, M., Tanaka, M., Koga, A., Sekimori, Y., Orita, T., Aso, Y., Hattori, K., and Tsuchiya, M. (2010) VH/VL interface engineering to promote selective expression and inhibit conformational isomerization of thrombopoietin receptor agonist single-chain diabody. Protein Eng. Des. Sel. 23, 667-677
40. Liu, Z., Gunasekaran, K., Wang, W., Razinkov, V., Sekirov, L., Leng, E., Sweet, H., Foltz, I., Howard, M., Rousseau, A. M., Kozlosky, C., Fanslow, W., and Yan, W. (2014) Asymmetrical Fc engineering greatly enhances antibody-dependent cellular cytotoxicity (ADCC) effector function and stability of the modified antibodies. J. Biol. Chem. 289, 3571-3590
41. Gijsen, M., King, P., Perera, T., Parker, P. J., Harris, A. L., Larijani, B., and Kong, A. (2010) HER2 phosphorylation is maintained by a PKB negative feedback loop in response to anti-HER2 herceptin in breast cancer. PLoS Biol. 8, e1000563
42. Scheuer, W., Friess, T., Burtscher, H., Bossenmaier, B., Endl, J., and Hasmann, M. (2009) Strongly enhanced antitumor activity of trastuzumab and pertuzumab combination treatment on HER2-positive human xenograft tumor models. Cancer Res. 69, 9330-9336
43. Yamashita-Kashima, Y., Iijima, S., Yorozu, K., Furugaki, K, Kurasawa, M., Ohta, M., and Fujimoto-Ouchi, K. (2011) Pertuzumab in combination with trastuzumab shows significantly enhanced antitumor activity in HER2-positive human gastric cancer xenograft models. Clin. Cancer Res. 17, 5060-5070
44. Tanner, M., Kapanen, A. I., Junttila, T., Raheem, O., Grenman, S., Elo, J., Elenius, K., and Isola, J. (2004) Characterization of a novel cell line established from a patient with Herceptin-resistant breast cancer. Mol. Cancer Ther. 3, 1585-1592
45. Rusnak, D. W., Alligood, K. J., Mullin, R. J., Spehar, G. M., Arenas-Elliott, C., Martin, A. M., Degenhardt, Y., Rudolph, S. K., Haws, T. F., Jr., Hudson-Curtis, B. L., and Gilmer, T. M. (2007) Assessment of epidermal growth factor receptor (EGFR, ErbB1) and HER2 (ErbB2) protein expression levels and response to lapatinib (Tykerb, GW572016) in an expanded panel of human normal and tumour cell lines. Cell Prolif. 40, 580-594
46. Schlaeth, M., Berger, S., Derer, S., Klausz, K., Lohse, S., Dechant, M., Lazar, G. A., Schneider-Merck, T., Peipp, M., and Valerius, T. (2010) Fc-engineered EGF-R antibodies mediate improved antibody-dependent cellular cytotoxicity (ADCC) against KRAS-mutated tumor cells. Cancer Sci. 101, 1080-1088
47. Lewis, S. M., Wu, X., Pustilnik, A., Sereno, A., Huang, F., Rick, H. L., Guntas, G., Leaver-Fay, A., Smith, E. M., Ho, C., Hansen-Estruch, C., Chamberlain, A. K., Truhlar, S. M., Conner, E. M., Atwell, S., et al. (2014) Generation of bispecific IgG antibodies by structure-based design of an orthogonal Fab interface. Nat. Biotechnol. 32, 191-198
48. van Schouwenburg, P. A., Kruithof, S., Votsmeier, C., van Schie, K., Hart, M. H., de Jong, R. N., van Buren, E. E., van Ham, M., Aarden, L., Wolbink, G., Wouters, D., and Rispens, T. (2014) Functional analysis of the anti-adalimumab response using patient-derived monoclonal antibodies. J. Biol. Chem. 289, 34482-34488