Manufacturability and functionality assessment of different formats of T-cell engaging bispecific antibodies

References

• Ma J, Mo Y, Tang M, Shen J, Qi Y, Zhao W, Huang Y, Xu Y, Qian C. Bispecific antibodies: from research to clinical application. Front Immunol [Internet]. 2021; 12. [cited 2023 Feb 20]. doi: 10.3389/fimmu.2021.626616. Available from /pmc/articles/PMC8131538/.
   Web of Science ®Google Scholar
• Nie S, Wang Z, Moscoso-Castro M, D’Souza P, Lei C, Xu J, Gu J. Biology drives the discovery of bispecific antibodies as innovative therapeutics. Antib Ther. 2020;3(1):18–17. doi:10.1093/abt/tbaa003.
   PubMedGoogle Scholar
• Zugmaier G, Klinger M, Schmidt M, Subklewe M. Clinical overview of anti-CD19 BiTE® and ex vivo data from anti-CD33 BiTE® as examples for retargeting T cells in hematologic malignancies. Mol Immunol. 2015;67(2):58–66. doi:10.1016/j.molimm.2015.02.033.
   PubMed Web of Science ®Google Scholar
• Burt R, Warcel D, Fielding AK. Blinatumomab, a bispecific B-cell and T-cell engaging antibody, in the treatment of B-cell malignancies. Hum Vaccin Immunother [Internet]. 2019;15(3):594–602. Available from https://pubmed.ncbi.nlm.nih.gov/30380973.
   PubMed Web of Science ®Google Scholar
• Budde LE, Sehn LH, Matasar M, Schuster SJ, Assouline S, Giri P, Kuruvilla J, Canales M, Dietrich S, Fay K, et al. Safety and efficacy of mosunetuzumab, a bispecific antibody, in patients with relapsed or refractory follicular lymphoma: a single-arm, multicentre, phase 2 study. Lancet Oncol [Internet] Available from. 2022;23(8):1055–65. [cited 2023 Feb 20]. http://www.thelancet.com/article/S1470204522003357/fulltext.
   PubMed Web of Science ®Google Scholar
• Kang C. Teclistamab: first approval. Drugs Drugs [Internet] Available from /pmc/articles/PMC9646474/. 2022;82(16):1613. [[cited 2023 Feb 20]]. doi:10.1007/s40265-022-01793-1.
   PubMed Web of Science ®Google Scholar
• Wu Z, v CN. T cell engaging bispecific antibody (T-BsAb): from technology to therapeutics. Pharmacol Ther [Internet]. 2018;182:161–75. Available from https://pubmed.ncbi.nlm.nih.gov/28834699.
   PubMed Web of Science ®Google Scholar
• Husain B, Ellerman D. Expanding the boundaries of biotherapeutics with bispecific antibodies. BioDrugs [Internet]. 2018;32(5):441–64. Available from. doi:10.1007/s40259-018-0299-9.
   PubMed Web of Science ®Google Scholar
• Brinkmann U, Kontermann RE. The making of bispecific antibodies. MAbs [Internet]. 2017;9:182–212. doi:10.1080/19420862.2016.1268307. Available from.
   PubMed Web of Science ®Google Scholar
• Portell CA, Wenzell CM, Advani AS. Clinical and pharmacologic aspects of blinatumomab in the treatment of B-cell acute lymphoblastic leukemia. Clin Pharmacol. 2013;5:5–11. doi:10.2147/CPAA.S42689.
   PubMedGoogle Scholar
• Orcutt KD, Ackerman ME, Cieslewicz M, Quiroz E, Slusarczyk AL, v FJ, Wittrup KD. A modular IgG-scFv bispecific antibody topology. Protein Eng Des Sel. 2010;23(4):221–28. doi:10.1093/protein/gzp077.
   PubMed Web of Science ®Google Scholar
• Schoonjans R, Willems A, Schoonooghe S, Leœn J, Grooten J, Mertens N. A new model for intermediate molecular weight recombinant bispecific and trispecific antibodies by efficient heterodimerization of single chain variable domains through fusion to a Fab-chain. Biomol Eng. 2001;17(6):193–202. doi:10.1016/S1389-0344(01)00066-1.
   PubMedGoogle Scholar
• Jurchison S Aptevo therapeutics reports third quarter 2018 financial results. [Internet]. 2018 [cited 2022 Mar 1]; Available from: https://aptevotherapeutics.gcs-web.com/news-releases/news-release-details/aptevo-therapeutics-reports-third-quarter-2018-financial-results
   Google Scholar
• Fan G, Wang Z, Hao M, Li J. Bispecific antibodies and their applications. J Hematol Oncol. 2015;8(1):130. doi:10.1186/s13045-015-0227-0.
   PubMed Web of Science ®Google Scholar
• Ridgway JBB, Presta LG, Carter P. ‘Knobs-into-holes’ engineering of antibody CH3 domains for heavy chain heterodimerization. Protein Eng Des Sel. 1996;9(7):617–21. Available from. doi:10.1093/protein/9.7.617.
   Google Scholar
• Gunasekaran K, Pentony M, Shen M, Garrett L, Forte C, Woodward A, Bin NS, Born T, Retter M, Manchulenko K, et al. Enhancing antibody Fc heterodimer formation through electrostatic steering effects: applications to bispecific molecules and monovalent IgG. J Biol Chem. 2010;285(25):19637–46. doi:10.1074/jbc.M110.117382.
   PubMed Web of Science ®Google Scholar
• de Nardis C, Hendriks LJA, Poirier E, Arvinte T, Gros P, Bakker ABH, de Kruif J. A new approach for generating bispecific antibodies based on a common light chain format and the stable architecture of human immunoglobulin G1. J Biol Chem. 2017;292(35):14706–17. doi:10.1074/jbc.M117.793497.
   PubMed Web of Science ®Google Scholar
• Liu Z, Leng EC, Gunasekaran K, Pentony M, Shen M, Howard M, Stoops J, Manchulenko K, Razinkov V, Liu H, et al. A novel antibody engineering strategy for making monovalent bispecific heterodimeric IgG antibodies by electrostatic steering mechanism. J Biol Chem. 2015;290(12):7535–62. doi:10.1074/jbc.M114.620260.
   PubMed Web of Science ®Google Scholar
• Shiraiwa H, Narita A, Kamata-Sakurai M, Ishiguro T, Sano Y, Hironiwa N, Tsushima T, Segawa H, Tsunenari T, Ikeda Y, et al. Engineering a bispecific antibody with a common light chain: identification and optimization of an anti-CD3 epsilon and anti-GPC3 bispecific antibody, ERY974. Methods. 2019;154:10–20. doi:10.1016/j.ymeth.2018.10.005.
   PubMed Web of Science ®Google Scholar
• Lewis SM, Wu X, Pustilnik A, Sereno A, Huang F, Rick HL, Guntas G, Leaver-Fay A, Smith EM, Ho C, et al. Generation of bispecific IgG antibodies by structure-based design of an orthogonal Fab interface. Nat Biotechnol. 2014;32(2):191–98. doi:10.1038/nbt.2797.
   PubMed Web of Science ®Google Scholar
• Froning KJ, Leaver-Fay A, Wu X, Phan S, Gao L, Huang F, Pustilnik A, Bacica M, Houlihan K, Chai Q, et al. Computational design of a specific heavy chain/κ light chain interface for expressing fully IgG bispecific antibodies. Protein Sci. 2017;26(10):2021–38. doi:10.1002/pro.3240.
   PubMed Web of Science ®Google Scholar
• Schaefer W, Regula JT, Bähner M, Schanzer J, Croasdale R, Dürr H, Gassner C, Georges G, Kettenberger H, Imhof-Jung S, et al. Immunoglobulin domain crossover as a generic approach for the production of bispecific IgG antibodies. Proc Natl Acad Sci U S A. 2011;108(27):11187–92. doi:10.1073/pnas.1019002108.
   PubMed Web of Science ®Google Scholar
• Schanzer JM, Wartha K, Croasdale R, Moser S, Künkele KP, Ries C, Scheuer W, Duerr H, Pompiati S, Pollman J, et al. A novel glycoengineered bispecific antibody format for targeted inhibition of epidermal growth factor receptor (EGFR) and insulin-like growth factor receptor type i (IGF-1R) demonstrating unique molecular properties. J Biol Chem. 2014;289(27):18693–706. doi:10.1074/jbc.M113.528109.
   PubMed Web of Science ®Google Scholar
• Bardwell PD, Staron MM, Liu J, Tao Q, Scesney S, Bukofzer G, Rodriguez LE, Choi C-H, Wang J, Chang Q, et al. Potent and conditional redirected T cell killing of tumor cells using Half DVD-Ig. Protein Cell. 2018;9(1):121–29. doi:10.1007/s13238-017-0429-z.
   PubMed Web of Science ®Google Scholar
• Leong SR, Sukumaran S, Hristopoulos M, Totpal K, Stainton S, Lu E, Wong A, Tam L, Newman R, Vuillemenot BR, et al. An anti-CD3/anti–CLL-1 bispecific antibody for the treatment of acute myeloid leukemia. Blood. 2017;129(5):609–18. doi:10.1182/blood-2016-08-735365.
   PubMed Web of Science ®Google Scholar
• de Zafra CL Z, Fajardo F, Zhong W, Bernett MJ, Muchhal US, Moore GL, Stevens J, Case R, Pearson JT, Liu S, et al. Targeting multiple myeloma with AMG 424, a novel anti-CD38/CD3 bispecific T-cell–recruiting antibody optimized for cytotoxicity and cytokine release. Clin Cancer Res. 2019;25(13):3921–33. doi:10.1158/1078-0432.CCR-18-2752.
   PubMed Web of Science ®Google Scholar
• Trinklein ND, Pham D, Schellenberger U, Buelow B, Boudreau A, Choudhry P, Clarke SC, Dang K, Harris KE, Iyer S, et al. Efficient tumor killing and minimal cytokine release with novel T-cell agonist bispecific antibodies. MAbs [Internet]. Available from 2019 [[cited 2023 Feb 23]];11(4):639–52.
   PubMed Web of Science ®Google Scholar
• Ellerman D. Bispecific T-cell engagers: towards understanding variables influencing the in vitro potency and tumor selectivity and their modulation to enhance their efficacy and safety. Methods. 2019;154:102–17. doi:10.1016/j.ymeth.2018.10.026.
   PubMed Web of Science ®Google Scholar
• Slaga D, Ellerman D, Lombana TN, Vij R, Li J, Hristopoulos M, Clark R, Johnston J, Shelton A, Mai E, et al. Avidity-based binding to HER2 results in selective killing of HER2-overexpressing cells by anti-HER2/CD3. Sci Transl Med. 2018;10(463):10. doi:10.1126/scitranslmed.aat5775.
   Web of Science ®Google Scholar
• Bacac M, Fauti T, Sam J, Colombetti S, Weinzierl T, Ouaret D, Bodmer W, Lehmann S, Hofer T, Hosse RJ, et al. A novel carcinoembryonic antigen T-Cell bispecific antibody (CEA TCB) for the treatment of solid tumors. Clin Cancer Res. 2016;22(13):3286–97. doi:10.1158/1078-0432.CCR-15-1696.
   PubMed Web of Science ®Google Scholar
• Dickopf S, Georges GJ, Brinkmann U. Format and geometries matter: structure-based design defines the functionality of bispecific antibodies. Comput Struct Biotechnol J. 2020;18:1221–27. doi:10.1016/j.csbj.2020.05.006.
   PubMed Web of Science ®Google Scholar
• Wu Z, Cheung NV. T cell engaging bispecific antibody (T-BsAb): from technology to therapeutics. Pharmacology & Therapeutics. 2018;182:161–75. doi:10.1016/j.pharmthera.2017.08.005.
   PubMed Web of Science ®Google Scholar
• Ahmad ZA, Yeap SK, Ali AM, Ho WY, Alitheen NBM, Hamid M. ScFv antibody: principles and clinical application. Clin Dev Immunol. 2012;2012:1–15. doi:10.1155/2012/980250.
   Google Scholar
• Moore GL, Bernett MJ, Rashid R, Pong EW, Nguyen D-H, Jacinto J, Eivazi A, Nisthal A, Diaz JE, Chu SY, et al. A robust heterodimeric Fc platform engineered for efficient development of bispecific antibodies of multiple formats. Methods. 2019;154:38–50. doi:10.1016/j.ymeth.2018.10.006.
   PubMed Web of Science ®Google Scholar
• Qi J, Li X, Peng H, Cook EM, Dadashian EL, Wiestner A, Park H, Rader C Potent and selective antitumor activity of a T cell-engaging bispecific antibody targeting a membrane-proximal epitope of ROR1. Proceedings of the National Academy of Sciences [Internet] 2018; 115:E5467–E76. Available from: http://www.pnas.org/content/115/24/E5467.abstract
   Google Scholar
• Qi J, Chen S-S, Chiorazzi N, Rader C. An IgG1-like bispecific antibody targeting CD52 and CD20 for the treatment of B-cell malignancies. Methods. 2019;154:70–76. doi:10.1016/j.ymeth.2018.08.008.
   PubMed Web of Science ®Google Scholar
• Xu Y, Lee J, Tran C, Heibeck TH, Wang WD, Yang J, Stafford RL, Steiner AR, Sato AK, Hallam TJ, et al. Production of bispecific antibodies in “knobs-into-holes” using a cell-free expression system. MAbs [Internet]. 2015;7:231–42. doi:10.4161/19420862.2015.989013. Available from.
   PubMed Web of Science ®Google Scholar
• Tran B, Horvath L, Dorff TB, Greil R, Machiels J-P, Roncolato F, Autio KA, Rettig M, Fizazi K, Lolkema MP, et al. Phase I study of AMG 160, a half-life extended bispecific T-cell engager (HLE BiTE) immune therapy targeting prostate-specific membrane antigen (PSMA), in patients with metastatic castration-resistant prostate cancer (mCRPC). Journal Of Clinical Oncology [Internet]. 2020;38(6_suppl):TPS261–TPS261. doi:10.1200/JCO.2020.38.6_suppl.TPS261. Available from.
   Google Scholar
• Labrijn AF, Janmaat ML, Reichert JM, PWHI P. Bispecific antibodies: a mechanistic review of the pipeline. Nat Rev Drug Discov [Internet]. 2019;18(8):585–608. Available from. doi:10.1038/s41573-019-0028-1.
   PubMed Web of Science ®Google Scholar
• Dimasi N, Fleming R, Wu H, Gao C. Molecular engineering strategies and methods for the expression and purification of IgG1-based bispecific bivalent antibodies. Methods. 2019;154:77–86. doi:10.1016/j.ymeth.2018.08.004.
   PubMed Web of Science ®Google Scholar
• Lin TY, Park JA, Long A, Guo HF, v CN. Novel potent anti-STEAP1 bispecific antibody to redirect T cells for cancer immunotherapy. J Immunother Cancer [Internet]. 2021 [[cited 2023 Feb 23]];9(9):e003114. Available from https://jitc.bmj.com/content/9/9/e003114.
   PubMed Web of Science ®Google Scholar
• King CR, Kraus MH, Aaronson SA. Amplification of a novel v-erbB-related gene in a human mammary carcinoma. Science. 1985;229(4717):974–76. doi:10.1126/science.2992089.
   PubMed Web of Science ®Google Scholar
• Hummel HD, Kufer P, Grüllich C, Seggewiss-Bernhardt R, Deschler-Baier B, Chatterjee M, Goebeler ME, Miller K, de Santis M, Loidl W, et al. Pasotuxizumab, a BiTE®immune therapy for castration-resistant prostate cancer: phase I, dose-escalation study findings. Immunotherapy [Internet]. Available from 2021 [[cited 2023 Feb 19]];13(2):125–41.
   PubMed Web of Science ®Google Scholar
• Rosenberg AS. Effects of protein aggregates: an immunologic perspective. Aaps J. 2006;8(3):E501–7. doi:10.1208/aapsj080359.
   PubMed Web of Science ®Google Scholar
• Sauerborn M, Brinks V, Jiskoot W, Schellekens H. Immunological mechanism underlying the immune response to recombinant human protein therapeutics. Trends Pharmacol Sci. 2010;31(2):53–59. doi:10.1016/j.tips.2009.11.001.
   PubMed Web of Science ®Google Scholar
• Vermeer AW, Norde W. The thermal stability of immunoglobulin: unfolding and aggregation of a multi-domain protein. Biophys J. 2000;78(1):394–404. doi:10.1016/S0006-3495(00)76602-1.
   PubMed Web of Science ®Google Scholar
• Garber E, Demarest SJ. A broad range of Fab stabilities within a host of therapeutic IgGs. Biochem Biophys Res Commun. 2007;355(3):751–57. doi:10.1016/j.bbrc.2007.02.042.
   PubMed Web of Science ®Google Scholar
• Ionescu RM, Vlasak J, Price C, Kirchmeier M. Contribution of variable domains to the stability of humanized IgG1 monoclonal antibodies. J Pharm Sci [Internet]. 2008 [[cited 2023 Feb 19]];97(4):1414–26. Available from http://jpharmsci.org/article/S002235491632545X/fulltext.
   PubMed Web of Science ®Google Scholar
• Scheer JM, Sandoval W, Elliott JM, Shao L, Luis E, Lewin-Koh SC, Schaefer G, Vandlen R, Verma C. Reorienting the fab domains of trastuzumab results in potent HER2 activators. PLoS One [Internet] Available from. 2012;7(12):e51817. [[cited 2023 May 14]].
   PubMed Web of Science ®Google Scholar
• Kontermann RE, Brinkmann U. Bispecific antibodies. Drug Discov Today. 2015;20(7):838–47. doi:10.1016/j.drudis.2015.02.008.
   PubMed Web of Science ®Google Scholar
• Kimerer LK, Pabst TM, Hunter AK, Carta G. Chromatographic behavior of bivalent bispecific antibodies on cation exchange columns. II Biomol Perspect J Chromatogr A. 2019;1601:121–132.
   PubMed Web of Science ®Google Scholar
• Bird RE, Walker BW. Single chain antibody variable regions. Trends Biotechnol. 1991;9(1):132–37. doi:10.1016/0167-7799(91)90044-I.
   PubMedGoogle Scholar
• Krauss J, Arndt MAE, Zhu Z, Newton DL, Vu BK, Choudhry V, Darbha R, Ji X, Courtenay-Luck NS, Deonarain MP, et al. Impact of antibody framework residue VH-71 on the stability of a humanised anti-MUC1 scFv and derived immunoenzyme. Br J Cancer. 2004;90(9):1863–70. doi:10.1038/sj.bjc.6601759.
   PubMed Web of Science ®Google Scholar
• Roda-Navarro P, Álvarez-Vallina L. Understanding the spatial topology of artificial immunological synapses assembled in t cell-redirecting strategies: a major issue in cancer immunotherapy. Front Cell Dev Biol. 2020;7:370. doi:10.3389/fcell.2019.00370.
   PubMed Web of Science ®Google Scholar
• Li J, Stagg NJ, Johnston J, Harris MJ, Menzies SA, DiCara D, Clark V, Hristopoulos M, Cook R, Slaga D, et al. Membrane-proximal epitope facilitates efficient T cell synapse formation by anti-FcRH5/CD3 and is a requirement for myeloma cell killing. Cancer Cell. 2017;31(3):383–95. doi:10.1016/j.ccell.2017.02.001.
   PubMed Web of Science ®Google Scholar
• Bluemel C, Hausmann S, Fluhr P, Sriskandarajah M, Stallcup WB, Baeuerle PA, Kufer P. Epitope distance to the target cell membrane and antigen size determine the potency of T cell-mediated lysis by BiTE antibodies specific for a large melanoma surface antigen. Cancer Immunol Immun. 2010;59(8):1197–209. doi:10.1007/s00262-010-0844-y.
   PubMed Web of Science ®Google Scholar
• Cheng M, Santich B, Xu H, Ahmed M, Huse M, Cheung N-K. Successful engineering of a highly potent single-chain-variable-fragment (scFv) bispecific antibody to target disialoganglioside (GD2) positive tumors. Oncoimmunology. 2016;5(6):0. doi:10.1080/2162402X.2016.1168557.
   Web of Science ®Google Scholar
• Kipriyanov SM, Moldenhauer G, Braunagel M, Reusch U, Cochlovius B, le Gall F, Kouprianova OA, von der Lieth CW, Little M. Effect of domain order on the activity of bacterially produced bispecific single-chain Fv antibodies. J Mol Biol. 2003;330(1):99–111. doi:10.1016/S0022-2836(03)00526-6.
   PubMed Web of Science ®Google Scholar
• Onsum MD, Geretti E, Paragas V, Kudla AJ, Moulis SP, Luus L, Wickham TJ, McDonagh CF, Macbeath G, Hendriks BS. Single-cell quantitative HER2 measurement identifies heterogeneity and distinct subgroups within traditionally defined HER2-positive patients. Am J Pathol. 2013;183(5):1446–60. doi:10.1016/j.ajpath.2013.07.015.
   PubMed Web of Science ®Google Scholar
• Schlake T, Bode J. Use of mutated FLP recognition target (FRT) sites for the exchange of expression cassettes at defined chromosomal loci. Biochemistry. 1994;33(43):12746–51. doi:10.1021/bi00209a003.
   PubMed Web of Science ®Google Scholar
• Yeo JHM, SCL H, Mariati M, Koh E, Tay SJ, Woen S, Zhang P, Yang Y. Optimized selection marker and CHO host cell combinations for generating high monoclonal antibody producing cell lines. Biotechnol J. 2017;12(12):12. doi:10.1002/biot.201700175.
   Web of Science ®Google Scholar
• SCL H, Bardor M, Li B, Lee JJ, Song Z, Tong YW, Goh LT, Yang Y, Hendershot LM. Comparison of Internal Ribosome Entry Site (IRES) and Furin-2A (F2A) for monoclonal antibody expression level and quality in CHO Cells. PLoS One. 2013;8(5):e63247. doi:10.1371/journal.pone.0063247.
   PubMed Web of Science ®Google Scholar
• Ho SCL, Bardor M, Feng H, Mariati Tong YW, Song Z, Yap MGS, Yang Y IRES-mediated Tricistronic vectors for enhancing generation of high monoclonal antibody expressing CHO cell lines. J Biotechnol 2012; 157.
   Google Scholar
• SCL H, Koh EYC, Soo BPC, Chao SH, Yang Y, Yang Y. Evaluating the use of a CpG free promoter for long-term recombinant protein expression stability in Chinese hamster ovary cells. BMC Biotechnol. 2016;16(1). doi:10.1186/s12896-016-0300-y.
   Google Scholar
• Nguyen NTB, Lin J, Tay SJ, Mariati Yeo J, Nguyen-Khuong T, Yang Y, Yang Y. Multiplexed engineering glycosyltransferase genes in CHO cells via targeted integration for producing antibodies with diverse complex-type N-glycans. Sci Rep. 2021;11(1):11. doi:10.1038/s41598-021-92320-x.
   PubMed Web of Science ®Google Scholar
• Ong HK, Nguyen NTB, Bi J, Yang Y. Vector design for enhancing expression level and assembly of knob-into-hole based FabscFv-Fc bispecific antibodies in CHO cells. Antib Ther. 2022 [[cited 2023 Jun 18]];5(4):288–300. Available from https://pubmed.ncbi.nlm.nih.gov/36518226/.
   PubMedGoogle Scholar
• Huo J, Huang Y, Zheng Z, Tay XN, Bin MF, Zhang W, Lam KP, Yang Y, Xu S. Development of a T cell-redirecting bispecific antibody targeting B-cell maturation antigen for the suppression of multiple myeloma cell growth. Antib Ther. 2022 [[cited 2023 Feb 23]];5(2):138–49. Available from https://academic.oup.com/abt/article/5/2/138/6604657.
   PubMedGoogle Scholar