Biomolecules & Therapeutics

  • 제32권6호
  • /
  • Pages.708-722
  • /
  • 2024
  • /
  • 1976-9148(pISSN)
  • /
  • 2005-4483(eISSN)
한국응용약물학회 (The Korean Society of Applied Pharmacology)
권호 표지
DOI QR코드

DOI QR Code

Mechanism of Action and Pharmacokinetics of Approved Bispecific Antibodies

  • Seong Min Choi (Department of Biohealth Regulatory Science, Graduate School of Ajou University) ;
  • Ju-Hee Lee (College of Korean Medicine, Dongguk University) ;
  • Soyeon Ko (Department of Biomedical Sciences, College of Medicine & Program in Biomedicals Science & Engineering, Inha University) ;
  • Soon-Sun Hong (Department of Biomedical Sciences, College of Medicine & Program in Biomedicals Science & Engineering, Inha University) ;
  • Hyo-Eon Jin (Department of Biohealth Regulatory Science, Graduate School of Ajou University)
  • 투고 : 2024.08.21
  • 심사 : 2024.09.20
  • 발행 : 2024.11.01
PDF 다운로드
⟨ 이전 논문 다음 논문 ⟩

초록

Bispecific antibodies represent a significant advancement in therapeutic antibody engineering, offering the ability to simultaneously target two distinct antigens. This dual-targeting capability enhances therapeutic efficacy, especially in complex diseases, such as cancer and autoimmune disorders, where drug resistance and incomplete target coverage are prevalent challenges. Bispecific antibodies facilitate immune cell engagement and disrupt multiple signaling pathways, providing a more comprehensive treatment approach than traditional monoclonal antibodies. However, the intricate structure of bispecific antibodies introduces unique pharmacokinetic challenges, including issues related to their absorption, distribution, metabolism, and excretion, which can significantly affect their efficacy and safety. This review provides an in-depth analysis of the structural design, mechanisms of action, and pharmacokinetics of the currently approved bispecific antibodies. It also highlights the engineering innovations that have been implemented to overcome these challenges, such as Fc modifications and advanced dimerization techniques, which enhance the stability and half-life of bispecific antibodies. Significant progress has been made in bispecific antibody technology; however, further research is necessary to broaden their clinical applications, enhance their safety profiles, and optimize their incorporation into combination therapies. Continuous advancements in this field are expected to enable bispecific antibodies to provide more precise and effective therapeutic strategies for a range of complex diseases, ultimately improving patient outcomes and advancing precision medicine.

키워드

과제정보

This work was supported by the National Research Foundation of Korea (NRF) grants funded by the Korean government (MSIT) (Nos. 2022R1A2C1004714, 2021R1A5A2031612, and 2024M3A9J4006509). S. M. Choi was supported by a grant (21153MFDS602) from the Ministry of Food and Drug Safety.

참고문헌

  1. Ahmad, Z. A., Yeap, S. K., Ali, A. M., Ho, W. Y., Alitheen, N. B. and Hamid, M. (2012) scFv antibody: principles and clinical application. Clin. Dev. Immunol. 2012, 980250.
  2. Ahmed, H., Mahmud, A. R., Siddiquee, M. F., Shahriar, A., Biswas, P., Shimul, M. E. K., Ahmed, S. Z., Ema, T. I., Rahman, N., Khan, M. A., Mizan, M. F. R. and Emran, T. B. (2023) Role of T cells in cancer immunotherapy: opportunities and challenges. Cancer Pathog. Ther. 1, 116-126.
  3. Al-Taie, A. and Sheta, N. (2024) Clinically approved monoclonal antibodies-based immunotherapy: association with glycemic control and impact role of clinical pharmacist for cancer patient care. Clin. Ther. 46, e29-e44.
  4. Aldeghaither, D. S., Zahavi, D. J., Murray, J. C., Fertig, E. J., Graham, G. T., Zhang, Y. W., O'Connell, A., Ma, J., Jablonski, S. A. and Weiner, L. M. (2019) A mechanism of resistance to antibody-targeted immune attack. Cancer Immunol. Res. 7, 230-243.
  5. Baeuerle, P. A. and Wesche, H. (2022) T-cell-engaging antibodies for the treatment of solid tumors: challenges and opportunities. Curr. Opin. Oncol. 34, 552-558.
  6. Baker, M. P., Reynolds, H. M., Lumicisi, B. and Bryson, C. J. (2010) Immunogenicity of protein therapeutics: the key causes, consequences and challenges. Self Nonself 1, 314-322.
  7. Barrueto, L., Caminero, F., Cash, L., Makris, C., Lamichhane, P. and Deshmukh, R. R. (2020) Resistance to checkpoint inhibition in cancer immunotherapy. Transl. Oncol. 13, 100738.
  8. Baxter, L. T., Zhu, H., Mackensen, D. G. and Jain, R. K. (1994) Physiologically based pharmacokinetic model for specific and nonspecific monoclonal antibodies and fragments in normal tissues and human tumor xenografts in nude mice. Cancer Res. 54, 1517-1528.
  9. Blair, H. A. (2019) Emicizumab: a review in haemophilia A. Drugs 79, 1697-1707.
  10. Brinkmann, U. and Kontermann, R. E. (2017) The making of bispecific antibodies. MAbs 9, 182-212.
  11. Buchbinder, E. I. and Desai, A. (2016) CTLA-4 and PD-1 pathways: similarities, differences, and implications of their inhibition. Am. J. Clin. Oncol. 39, 98-106.
  12. Burkholder, B., Huang, R. Y., Burgess, R., Luo, S., Jones, V. S., Zhang, W., Lv, Z. Q., Gao, C. Y., Wang, B. L., Zhang, Y. M. and Huang, R. P. (2014) Tumor-induced perturbations of cytokines and immune cell networks. Biochim. Biophys. Acta 1845, 182-201.
  13. Carrasco-Padilla, C., Hernaiz-Esteban, A., Alvarez-Vallina, L., Aguilar-Sopena, O. and Roda-Navarro, P. (2022) Bispecific antibody format and the organization of immunological synapses in T cell-redirecting strategies for cancer immunotherapy. Pharmaceutics 15, 132.
  14. Carter, P. J. and Lazar, G. A. (2018) Next generation antibody drugs: pursuit of the 'high-hanging fruit'. Nat. Rev. Drug Discov. 17, 197-223.
  15. Cattaruzza, F., Nazeer, A., To, M., Hammond, M., Koski, C., Liu, L. Y., Pete Yeung, V., Rennerfeldt, D. A., Henkensiefken, A., Fox, M., Lam, S., Morrissey, K. M., Lange, Z., Podust, V. N., Derynck, M. K., Irving, B. A. and Schellenberger, V. (2023) Precision-activated T-cell engagers targeting HER2 or EGFR and CD3 mitigate ontarget, off-tumor toxicity for immunotherapy in solid tumors. Nat. Cancer 4, 485-501.
  16. Chelius, D., Ruf, P., Gruber, P., Ploscher, M., Liedtke, R., Gansberger, E., Hess, J., Wasiliu, M. and Lindhofer, H. (2010) Structural and functional characterization of the trifunctional antibody catumaxomab. MAbs 2, 309-319.
  17. Chen, S. H., Dominik, P. K., Stanfield, J., Ding, S., Yang, W., Kurd, N., Llewellyn, R., Heyen, J., Wang, C., Melton, Z., Van Blarcom, T., Lindquist, K. C., Chaparro-Riggers, J. and Salek-Ardakani, S. (2021) Dual checkpoint blockade of CD47 and PD-L1 using an affinity-tuned bispecific antibody maximizes antitumor immunity. J. Immunother. Cancer 9, e003464.
  18. Chen, Y. and Xu, Y. (2017) Pharmacokinetics of bispecific antibody. Curr. Pharmacol. Rep. 3, 126-137.
  19. Chirmule, N., Jawa, V. and Meibohm, B. (2012) Immunogenicity to therapeutic proteins: impact on PK/PD and efficacy. AAPS J. 14, 296-302.
  20. Chiu, M. L., Goulet, D. R., Teplyakov, A. and Gilliland, G. L. (2019) Antibody structure and function: the basis for engineering therapeutics. Antibodies (Basel) 8, 55.
  21. Cho, B. C., Simi, A., Sabari, J., Vijayaraghavan, S., Moores, S. and Spira, A. (2023) Amivantamab, an epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition factor (MET) bispecific antibody, designed to enable multiple mechanisms of action and broad clinical applications. Clin. Lung Cancer 24, 89-97.
  22. Cooke, H. A., Arndt, J., Quan, C., Shapiro, R. I., Wen, D., Foley, S., Vecchi, M. M. and Preyer, M. (2018) EFab domain substitution as a solution to the light-chain pairing problem of bispecific antibodies. MAbs 10, 1248-1259.
  23. Cumber, A. J., Ward, E. S., Winter, G., Parnell, G. D. and Wawrzynczak, E. J. (1992) Comparative stabilities in vitro and in vivo of a recombinant mouse antibody FvCys fragment and a bisFvCys conjugate. J. Immunol. 149, 120-126.
  24. Datta-Mannan, A., Croy, J. E., Schirtzinger, L., Torgerson, S., Breyer, M. and Wroblewski, V. J. (2016) Aberrant bispecific antibody pharmacokinetics linked to liver sinusoidal endothelium clearance mechanism in cynomolgus monkeys. MAbs 8, 969-982.
  25. Dickinson, M. J., Carlo-Stella, C., Morschhauser, F., Bachy, E., Corradini, P., Iacoboni, G., Khan, C., Wrobel, T., Offner, F., Trneny, M., Wu, S. J., Cartron, G., Hertzberg, M., Sureda, A., Perez-Callejo, D., Lundberg, L., Relf, J., Dixon, M., Clark, E., Humphrey, K. and Hutchings, M. (2022) Glofitamab for relapsed or refractory diffuse large B-cell lymphoma. N. Engl. J. Med. 387, 2220-2231.
  26. Dustin, M. L. (2014) The immunological synapse. Cancer Immunol. Res. 2, 1023-1033.
  27. Ebrahimi, S. B. and Samanta, D. (2023) Engineering protein-based therapeutics through structural and chemical design. Nat. Commun. 14, 2411.
  28. Einsele, H., Moreau, P., Bahlis, N., Bhutani, M., Vincent, L., Karlin, L., Perrot, A., Goldschmidt, H., van de Donk, N. W. C. J., Ocio, E. M., Martinez-Lopez, J., Rodriguez-Otero, P., Dytfeld, D., Diels, J., Strulev, V., Haddad, I., Renaud, T., Ammann, E., Cabrieto, J., Perualila, N., Gan, R., Zhang, Y., Parekh, T., Albrecht, C., Weisel, K. and Mateos, M.-V. (2024) Comparative efficacy of talquetamab vs. current treatments in the LocoMMotion and MoMMent studies in patients with triple-class-exposed relapsed/refractory multiple myeloma. Adv. Ther. 41, 1576-1593.
  29. Fan, G., Wang, Z., Hao, M. and Li, J. (2015) Bispecific antibodies and their applications. J. Hematol. Oncol. 8, 130.
  30. Farhangnia, P., Ghomi, S. M., Akbarpour, M. and Delbandi, A. A. (2023) Bispecific antibodies targeting CTLA-4: game-changer troopers in cancer immunotherapy. Front. Immunol. 14, 1155778.
  31. Ferro Desideri, L., Traverso, C. E., Nicolo, M. and Munk, M. R. (2023) Faricimab for the treatment of diabetic macular edema and neovascular age-related macular degeneration. Pharmaceutics 15, 1413.
  32. Food and Drug Administration (2023) Elrexfio (Elranatamab) Prescribing Information (2023). U.S. Food and Drug Administration.
  33. Food and Drug Administration (2024a) Vabysmo (Faricimab) Prescribing Information (2024). U.S. Food and Drug Administration.
  34. Food and Drug Administration (2024b) Amivantamab (Rybrevant) Prescribing Information (2024). U.S. Food and Drug Administration.
  35. Food and Drug Administration (2024c) Blinatumomab (Blincyto) Prescribing Information (2024). U.S. Food and Drug Administration.
  36. Food and Drug Administration (2024d) Columvi (Glofitamab) Prescribing Information (2024). U.S. Food and Drug Administration.
  37. Food and Drug Administration (2024e) Emicizumab (Hemlibra) Prescribing Information (2024). U.S. Food and Drug Administration.
  38. Food and Drug Administration (2024f) Epkinly (Epcoritamab) Prescribing Information (2024). U.S. Food and Drug Administration.
  39. Food and Drug Administration (2024g) Lunsumio (Mosunetuzumab) Prescribing Information (2024). U.S. Food and Drug Administration.
  40. Food and Drug Administration (2024h) Talquetamab (Talvey) Prescribing Information (2023). U.S. Food and Drug Administration.
  41. Food and Drug Administration (2024i) Tebentafusp (Kimmtrak) Prescribing Information (2024). U.S. Food and Drug Administration.
  42. Food and Drug Administration (2024j) Tecvayli (Teclistamab) Prescribing Information (2024). U.S. Food and Drug Administration.
  43. Gibbs, J. P., Yuraszeck, T., Biesdorf, C., Xu, Y. and Kasichayanula, S. (2020) Informing development of bispecific antibodies using physiologically based pharmacokinetic-pharmacodynamic models: current capabilities and future opportunities. J. Clin. Pharmacol. 60, S132-S146.
  44. Gil, D., Schamel, W. W., Montoya, M., Sanchez-Madrid, F. and Alarcon, B. (2002) Recruitment of Nck by CD3 epsilon reveals a ligandinduced conformational change essential for T cell receptor signaling and synapse formation. Cell 109, 901-912.
  45. Gillette, J. R. (1973) The importance of tissue distribution in pharmacokinetics. J. Pharmacokinet. Biopharm. 1, 497-520.
  46. Goebeler, M. E. and Bargou, R. (2016) Blinatumomab: a CD19/CD3 bispecific T cell engager (BiTE) with unique anti-tumor efficacy. Leuk. Lymphoma 57, 1021-1032.
  47. Haas, C., Krinner, E., Brischwein, K., Hoffmann, P., Lutterbuse, R., Schlereth, B., Kufer, P. and Baeuerle, P. A. (2009) Mode of cytotoxic action of T cell-engaging BiTE antibody MT110. Immunobiology 214, 441-453.
  48. Han, Y., Liu, D. and Li, L. (2020) PD-1/PD-L1 pathway: current researches in cancer. Am. J. Cancer Res. 10, 727-742.
  49. Haraya, K., Tachibana, T. and Nezu, J. (2017) Quantitative prediction of therapeutic antibody pharmacokinetics after intravenous and subcutaneous injection in human. Drug Metab. Pharmacokinet. 32, 208-217.
  50. Hermeling, S., Crommelin, D. J., Schellekens, H. and Jiskoot, W. (2004) Structure-immunogenicity relationships of therapeutic proteins. Pharm. Res. 21, 897-903.
  51. Holliger, P., Prospero, T. and Winter, G. (1993) "Diabodies": small bivalent and bispecific antibody fragments. Proc. Natl. Acad. Sci. U. S. A. 90, 6444-6448.
  52. Hosseini, S. S., Khalili, S., Baradaran, B., Bidar, N., Shahbazi, M. A., Mosafer, J., Hashemzaei, M., Mokhtarzadeh, A. and Hamblin, M. R. (2021) Bispecific monoclonal antibodies for targeted immunotherapy of solid tumors: recent advances and clinical trials. Int. J. Biol. Macromol. 167, 1030-1047.
  53. Howlett, S., Carter, T. J., Shaw, H. M. and Nathan, P. D. (2023) Tebentafusp: a first-in-class treatment for metastatic uveal melanoma. Ther. Adv. Med. Oncol. 15, 17588359231160140.
  54. Hua, G., Carlson, D. and Starr, J. R. (2022) Tebentafusp-tebn: a novel bispecific T-cell engager for metastatic uveal melanoma. J. Adv. Pract. Oncol. 13, 717-723.
  55. Huang, S., van Duijnhoven, S. M. J., Sijts, A. and van Elsas, A. (2020) Bispecific antibodies targeting dual tumor-associated antigens in cancer therapy. J. Cancer Res. Clin. Oncol. 146, 3111-3122.
  56. Huehls, A. M., Coupet, T. A. and Sentman, C. L. (2015) Bispecific T-cell engagers for cancer immunotherapy. Immunol. Cell Biol. 93, 290-296.
  57. Johnson, M. L., Braiteh, F., Grilley-Olson, J. E., Chou, J., Davda, J., Forgie, A., Li, R., Jacobs, I., Kazazi, F. and Hu-Lieskovan, S. (2019) Assessment of subcutaneous vs intravenous administration of anti-PD-1 antibody PF-06801591 in patients with advanced solid tumors: a phase 1 dose-escalation trial. JAMA Oncol. 5, 999-1007.
  58. Johnson, S., Burke, S., Huang, L., Gorlatov, S., Li, H., Wang, W., Zhang, W., Tuaillon, N., Rainey, J., Barat, B., Yang, Y., Jin, L., Ciccarone, V., Moore, P. A., Koenig, S. and Bonvini, E. (2010) Effector cell recruitment with novel Fv-based dual-affinity re-targeting protein leads to potent tumor cytolysis and in vivo B-cell depletion. J. Mol. Biol. 399, 436-449.
  59. Jonaitis, L., Markovic, S., Farkas, K., Gheorghe, L., Krznaric, Z., Salupere, R., Mokricka, V., Spassova, Z., Gatev, D., Grosu, I., Lijovic, A., Mitrovic, O., Saje, M., Schafer, E., Ursic, V., Roblek, T. and Drobne, D. (2021) Intravenous versus subcutaneous delivery of biotherapeutics in IBD: an expert's and patient's perspective. BMC Proc. 15, 25.
  60. Jorgovanovic, D., Song, M., Wang, L. and Zhang, Y. (2020) Roles of IFN-gamma in tumor progression and regression: a review. Biomark Res. 8, 49.
  61. Joussen, A. M., Ricci, F., Paris, L. P., Korn, C., Quezada-Ruiz, C. and Zarbin, M. (2021) Angiopoietin/Tie2 signalling and its role in retinal and choroidal vascular diseases: a review of preclinical data. Eye (Lond.) 35, 1305-1316.
  62. Kang, C. (2022a) Mosunetuzumab: first approval. Drugs 82, 1229-1234.
  63. Kang, C. (2022b) Teclistamab: first approval. Drugs 82, 1613-1619.
  64. Kang, J., Sun, T. and Zhang, Y. (2022) Immunotherapeutic progress and application of bispecific antibody in cancer. Front. Immunol. 13, 1020003.
  65. Kantae, V., Krekels, E. H. J., Esdonk, M. J. V., Lindenburg, P., Harms, A. C., Knibbe, C. A. J., Van der Graaf, P. H. and Hankemeier, T. (2017) Integration of pharmacometabolomics with pharmacokinetics and pharmacodynamics: towards personalized drug therapy. Metabolomics 13, 9.
  66. Keam, S. J. (2022) Cadonilimab: first approval. Drugs 82, 1333-1339.
  67. Keam, S. J. (2023) Talquetamab: first approval. Drugs 83, 1439-1445.
  68. Keir, M. E., Butte, M. J., Freeman, G. J. and Sharpe, A. H. (2008) PD-1 and its ligands in tolerance and immunity. Annu. Rev. Immunol. 26, 677-704.
  69. Keir, M. E., Liang, S. C., Guleria, I., Latchman, Y. E., Qipo, A., Albacker, L. A., Koulmanda, M., Freeman, G. J., Sayegh, M. H. and Sharpe, A. H. (2006) Tissue expression of PD-L1 mediates peripheral T cell tolerance. J. Exp. Med. 203, 883-895.
  70. Kim, J., Hayton, W. L., Robinson, J. M. and Anderson, C. L. (2007) Kinetics of FcRn-mediated recycling of IgG and albumin in human: pathophysiology and therapeutic implications using a simplified mechanism-based model. Clin. Immunol. 122, 146-155.
  71. Kipriyanov, S. M., Moldenhauer, G., Schuhmacher, J., Cochlovius, B., Von der Lieth, C. W., Matys, E. R. and Little, M. (1999) Bispecific tandem diabody for tumor therapy with improved antigen binding and pharmacokinetics. J. Mol. Biol. 293, 41-56.
  72. Kitazawa, T., Igawa, T., Sampei, Z., Muto, A., Kojima, T., Soeda, T., Yoshihashi, K., Okuyama-Nishida, Y., Saito, H., Tsunoda, H., Suzuki, T., Adachi, H., Miyazaki, T., Ishii, S., Kamata-Sakurai, M., Iida, T., Harada, A., Esaki, K., Funaki, M., Moriyama, C., Tanaka, E., Kikuchi, Y., Wakabayashi, T., Wada, M., Goto, M., Toyoda, T., Ueyama, A., Suzuki, S., Haraya, K., Tachibana, T., Kawabe, Y., Shima, M., Yoshioka, A. and Hattori, K. (2012) A bispecific antibody to factors IXa and X restores factor VIII hemostatic activity in a hemophilia A model. Nat. Med. 18, 1570-1574.
  73. Kitazawa, T. and Shima, M. (2020) Emicizumab, a humanized bispecific antibody to coagulation factors IXa and X with a factor VIIIacofactor activity. Int. J. Hematol. 111, 20-30.
  74. Klein, C., Brinkmann, U., Reichert, J. M. and Kontermann, R. E. (2024) The present and future of bispecific antibodies for cancer therapy. Nat. Rev. Drug Discov. 23, 301-319.
  75. Klein, C., Schaefer, W., Regula, J. T., Dumontet, C., Brinkmann, U., Bacac, M. and Umana, P. (2019) Engineering therapeutic bispecific antibodies using CrossMab technology. Methods 154, 21-31.
  76. Kohler, G. and Milstein, C. (1975) Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 256, 495-497.
  77. Kontermann, R. E. (2012) Dual targeting strategies with bispecific antibodies. MAbs 4, 182-197.
  78. Krishnamurthy, A. and Jimeno, A. (2018) Bispecific antibodies for cancer therapy: a review. Pharmacol. Ther. 185, 122-134.
  79. Labrijn, A. F., Meesters, J. I., Priem, P., de Jong, R. N., van den Bremer, E. T., van Kampen, M. D., Gerritsen, A. F., Schuurman, J. and Parren, P. W. (2014) Controlled Fab-arm exchange for the generation of stable bispecific IgG1. Nat. Protoc. 9, 2450-2463.
  80. Lejeune, M., Kose, M. C., Duray, E., Einsele, H., Beguin, Y. and Caers, J. (2020) Bispecific, T-cell-recruiting antibodies in B-cell malignancies. Front. Immunol. 11, 762.
  81. Lesokhin, A. M., Tomasson, M. H., Arnulf, B., Bahlis, N. J., Miles Prince, H., Niesvizky, R., Rodrίguez-Otero, P., Martinez-Lopez, J., Koehne, G., Touzeau, C., Jethava, Y., Quach, H., Depaus, J., Yokoyama, H., Gabayan, A. E., Stevens, D. A., Nooka, A. K., Manier, S., Raje, N., Iida, S., Raab, M.-S., Searle, E., Leip, E., Sullivan, S. T., Conte, U., Elmeliegy, M., Czibere, A., Viqueira, A. and Mohty, M. (2023) Elranatamab in relapsed or refractory multiple myeloma: phase 2 MagnetisMM-3 trial results. Nat. Med. 29, 2259-2267.
  82. 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., Kuhlman, B. and Demarest, S. J. (2014) Generation of bispecific IgG antibodies by structure-based design of an orthogonal Fab interface. Nat. Biotechnol. 32, 191-198.
  83. Li, H., Er Saw, P. and Song, E. (2020) Challenges and strategies for next-generation bispecific antibody-based antitumor therapeutics. Cell. Mol. Immunol. 17, 451-461.
  84. Li, T., Niu, M., Zhou, J., Wu, K. and Yi, M. (2024) The enhanced antitumor activity of bispecific antibody targeting PD-1/PD-L1 signaling. Cell Commun. Signal. 22, 179.
  85. Liu, L. (2018) Pharmacokinetics of monoclonal antibodies and Fc-fusion proteins. Protein Cell 9, 15-32.
  86. Liu, X., Testa, B. and Fahr, A. (2011) Lipophilicity and its relationship with passive drug permeation. Pharm. Res. 28, 962-977.
  87. Ma, J., Mo, Y., Tang, M., Shen, J., Qi, Y., Zhao, W., Huang, Y., Xu, Y. and Qian, C. (2021) Bispecific antibodies: from research to clinical application. Front. Immunol. 12, 626616.
  88. Mahlangu, J., Oldenburg, J., Paz-Priel, I., Negrier, C., Niggli, M., Mancuso, M. E., Schmitt, C., Jimenez-Yuste, V., Kempton, C., Dhalluin, C., Callaghan, M. U., Bujan, W., Shima, M., Adamkewicz, J. I., Asikanius, E., Levy, G. G. and Kruse-Jarres, R. (2018) Emicizumab prophylaxis in patients who have hemophilia a without inhibitors. N. Engl. J. Med. 379, 811-822.
  89. Mandrup, O. A., Ong, S. C., Lykkemark, S., Dinesen, A., Rudnik-Jansen, I., Dagnaes-Hansen, N. F., Andersen, J. T., Alvarez-Vallina, L. and Howard, K. A. (2021) Programmable half-life and anti-tumour effects of bispecific T-cell engager-albumin fusions with tuned FcRn affinity. Commun. Biol. 4, 310.
  90. Meibohm, B. and Derendorf, H. (2002) Pharmacokinetic/pharmacodynamic studies in drug product development. J. Pharm. Sci. 91, 18-31.
  91. Milstein, C. and Cuello, A. C. (1983) Hybrid hybridomas and their use in immunohistochemistry. Nature 305, 537-540.
  92. Monnier, P. P., Vigouroux, R. J. and Tassew, N. G. (2013) In vivo applications of single chain Fv (variable domain) (scFv) fragments. Antibodies 2, 193-208.
  93. Nathan, P., Hassel, J. C., Rutkowski, P., Baurain, J. F., Butler, M. O., Schlaak, M., Sullivan, R. J., Ochsenreither, S., Dummer, R., Kirkwood, J. M., Joshua, A. M., Sacco, J. J., Shoushtari, A. N., Orloff, M., Piulats, J. M., Milhem, M., Salama, A. K. S., Curti, B., Demidov, L., Gastaud, L., Mauch, C., Yushak, M., Carvajal, R. D., Hamid, O., Abdullah, S. E., Holland, C., Goodall, H. and Piperno-Neumann, S.; IMCgp100-202 Investigators (2021) Overall survival benefit with tebentafusp in metastatic uveal melanoma. N. Engl. J. Med. 385, 1196-1206.
  94. Nguyen, H. H., Kim, T., Song, S. Y., Park, S., Cho, H. H., Jung, S.-H., Ahn, J.-S., Kim, H.-J., Lee, J.-J. and Kim, H.-O. (2016) Naive CD8+ T cell derived tumor-specific cytotoxic effectors as a potential remedy for overcoming TGF-β immunosuppression in the tumor microenvironment. Sci. Rep. 6, 28208.
  95. Nicolo, M., Ferro Desideri, L., Vagge, A. and Traverso, C. E. (2021) Faricimab: an investigational agent targeting the Tie-2/angiopoietin pathway and VEGF-A for the treatment of retinal diseases. Expert Opin. Investig. Drugs 30, 193-200.
  96. Nilvebrant, J., Alm, T., Hober, S. and Lofblom, J. (2011) Engineering bispecificity into a single albumin-binding domain. PLoS One 6, e25791.
  97. Nisonoff, A. and Mandy, W. J. (1962) Quantitative estimation of the hybridization of rabbit antibodies. Nature 194, 355-359.
  98. Oie, S. (1986) Drug distribution and binding. J. Clin. Pharmacol. 26, 583-586.
  99. Panos, G. D., Lakshmanan, A., Dadoukis, P., Ripa, M., Motta, L. and Amoaku, W. M. (2023) Faricimab: transforming the future of macular diseases treatment - a comprehensive review of clinical studies. Drug Des. Devel. Ther. 17, 2861-2873.
  100. Pardoll, D. M. (2012) The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12, 252-264.
  101. Patel, S. S., Sahni, J., Sadikhov, S., Pauly-Evers, M., Szczesny, P. and Weikert, R. (2018) Anti-VEGF/anti-angiopoietin-2 bispecific antibody RG7716 in diabetic macular edema: complete 36-week results from the phase 2, multicenter, randomized, active treatment-controlled BOULEVARD clinical trial. Investig. Ophthalmol. Vis. Sci. 59, 1959.
  102. Pineda, C., Castaneda Hernandez, G., Jacobs, I. A., Alvarez, D. F. and Carini, C. (2016) Assessing the immunogenicity of biopharmaceuticals. BioDrugs 30, 195-206.
  103. Qi, T., Liao, X. and Cao, Y. (2023) Development of bispecific T cell engagers: harnessing quantitative systems pharmacology. Trends Pharmacol. Sci. 44, 880-890.
  104. Ratanji, K. D., Derrick, J. P., Dearman, R. J. and Kimber, I. (2014) Immunogenicity of therapeutic proteins: influence of aggregation. J. Immunotoxicol. 11, 99-109.
  105. Rathi, C. and Meibohm, B. (2015) Clinical pharmacology of bispecific antibody constructs. J. Clin. Pharmacol. 55, S21-S28.
  106. Regula, J. T., Lundh von Leithner, P., Foxton, R., Barathi, V. A., Cheung, C. M., Bo Tun, S. B., Wey, Y. S., Iwata, D., Dostalek, M., Moelleken, J., Stubenrauch, K. G., Nogoceke, E., Widmer, G., Strassburger, P., Koss, M. J., Klein, C., Shima, D. T. and Hartmann, G. (2016) Targeting key angiogenic pathways with a bispecific CrossMAb optimized for neovascular eye diseases. EMBO Mol. Med. 8, 1265-1288.
  107. Reichel, A. and Lienau, P. (2016) Pharmacokinetics in drug discovery: an exposure-centred approach to optimising and predicting drug efficacy and safety. Handb. Exp. Pharmacol. 232, 235-260.
  108. 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.
  109. Roberts, J. A., Pea, F. and Lipman, J. (2013) The clinical relevance of plasma protein binding changes. Clin. Pharmacokinet. 52, 1-8.
  110. Roopenian, D. C. and Akilesh, S. (2007) FcRn: the neonatal Fc receptor comes of age. Nat. Rev. Immunol. 7, 715-725.
  111. Ruf, P., Kluge, M., Jager, M., Burges, A., Volovat, C., Heiss, M. M., Hess, J., Wimberger, P., Brandt, B. and Lindhofer, H. (2010a) Pharmacokinetics, immunogenicity and bioactivity of the therapeutic antibody catumaxomab intraperitoneally administered to cancer patients. Br. J. Clin. Pharmacol. 69, 617-625.
  112. Ruf, P., Kluge, M., Jager, M., Burges, A., Volovat, C., Heiss, M. M., Hess, J., Wimberger, P., Brandt, B. and Lindhofer, H. (2010b) Pharmacokinetics, immunogenicity and bioactivity of the therapeutic antibody catumaxomab intraperitoneally administered to cancer patients. Br. J. Clin. Pharmacol. 69, 617-625.
  113. Salvaris, R., Ong, J. and Gregory, G. P. (2021) Bispecific antibodies: a review of development, clinical efficacy and toxicity in B-cell lymphomas. J. Pers. Med. 11, 355.
  114. Samuel, A. S. and Naz, R. K. (2008) Isolation of human single chain variable fragment antibodies against specific sperm antigens for immunocontraceptive development. Hum. Reprod. 23, 1324-1337.
  115. Sanz, L., Cuesta, A. M., Compte, M. and Alvarez-Vallina, L. (2005) Antibody engineering: facing new challenges in cancer therapy. Acta Pharmacol. Sin. 26, 641-648.
  116. Schaefer, W., Regula, J. T., Bahner, M., Schanzer, J., Croasdale, R., Durr, 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.
  117. Schmitt, C., Adamkewicz, J. I., Xu, J., Petry, C., Catalani, O., Young, G., Negrier, C., Callaghan, M. U. and Levy, G. G. (2021) Pharmacokinetics and pharmacodynamics of emicizumab in persons with hemophilia A with factor VIII inhibitors: HAVEN 1 study. Thromb. Haemost. 121, 351-360.
  118. Scott, L. J. and Kim, E. S. (2018) Emicizumab-kxwh: first global approval. Drugs 78, 269-274.
  119. Sela-Culang, I., Kunik, V. and Ofran, Y. (2013) The structural basis of antibody-antigen recognition. Front. Immunol. 4, 302.
  120. Seshacharyulu, P., Ponnusamy, M. P., Haridas, D., Jain, M., Ganti, A. K. and Batra, S. K. (2012) Targeting the EGFR signaling pathway in cancer therapy. Expert Opin. Ther. Targets 16, 15-31.
  121. Shirley, M. (2022) Faricimab: first approval. Drugs 82, 825-830.
  122. Smith-Garvin, J. E., Koretzky, G. A. and Jordan, M. S. (2009) T cell activation. Annu. Rev. Immunol. 27, 591-619.
  123. Stoner, K. L., Harder, H., Fallowfield, L. J. and Jenkins, V. A. (2014) Intravenous versus subcutaneous drug administration. Which do patients prefer? A systematic review. Patient 8, 145-153.
  124. Strohl, W. R. (2015) Fusion proteins for half-life extension of biologics as a strategy to make biobetters. BioDrugs 29, 215-239.
  125. Strohl, W. R. and Naso, M. (2019) Bispecific T-cell redirection versus chimeric antigen receptor (CAR)-T cells as approaches to kill cancer cells. Antibodies (Basel) 8, 41.
  126. Sun, Y., Estevez, A., Schlothauer, T. and Wecksler, A. T. (2020) Antigen physiochemical properties allosterically effect the IgG Fcregion and Fc neonatal receptor affinity. MAbs 12, 1802135.
  127. Sun, Y., Yu, X., Wang, X., Yuan, K., Wang, G., Hu, L., Zhang, G., Pei, W., Wang, L., Sun, C. and Yang, P. (2023) Bispecific antibodies in cancer therapy: target selection and regulatory requirements. Acta Pharm. Sin. B 13, 3583-3597.
  128. Surowka, M. and Klein, C. (2024) A pivotal decade for bispecific antibodies? MAbs 16, 2321635.
  129. Syed, Y. Y. (2021) Amivantamab: first approval. Drugs 81, 1349-1353.
  130. Taefehshokr, N., Baradaran, B., Baghbanzadeh, A. and Taefehshokr, S. (2020) Promising approaches in cancer immunotherapy. Immunobiology 225, 151875.
  131. Tailor, P., Tsai, S., Shameli, A., Serra, P., Wang, J., Robbins, S., Nagata, M., Szymczak-Workman, A. L., Vignali, D. A. and Santamaria, P. (2008) The proline-rich sequence of CD3epsilon as an amplifier of low-avidity TCR signaling. J. Immunol. 181, 243-255.
  132. Thieblemont, C., Phillips, T., Ghesquieres, H., Cheah, C. Y., Clausen, M. R., Cunningham, D., Do, Y. R., Feldman, T., Gasiorowski, R., Jurczak, W., Kim, T. M., Lewis, D. J., van der Poel, M., Poon, M. L., Cota Stirner, M., Kilavuz, N., Chiu, C., Chen, M., Sacchi, M., Elliott, B., Ahmadi, T., Hutchings, M. and Lugtenburg, P. J. (2023) Epcoritamab, a novel, subcutaneous CD3xCD20 bispecific T-cell-engaging antibody, in relapsed or refractory large B-cell lymphoma: dose expansion in a phase I/II trial. J. Clin. Oncol. 41, 2238-2247.
  133. Tian, Z., Liu, M., Zhang, Y. and Wang, X. (2021) Bispecific T cell engagers: an emerging therapy for management of hematologic malignancies. J. Hematol. Oncol. 14, 75.
  134. Tiller, K. E. and Tessier, P. M. (2015) Advances in antibody design. Annu. Rev. Biomed. Eng. 17, 191-216.
  135. Tojjari, A., Saeed, A., Sadeghipour, A., Kurzrock, R. and Cavalcante, L. (2023) Overcoming immune checkpoint therapy resistance with SHP2 inhibition in cancer and immune cells: a review of the literature and novel combinatorial approaches. Cancers (Basel) 15, 5384.
  136. Tomasson, M., Iida, S., Niesvizky, R., Mohty, M., Bahlis, N. J., Martinez-Lopez, J., Koehne, G., Rodriguez Otero, P., Prince, H. M., Viqueira, A., Leip, E., Conte, U., Sullivan, S. T. and Lesokhin, A. (2023) Long-term efficacy and safety of elranatamab monotherapy in the phase 2 Magnetismm-3 trial in relapsed or refractory multiple myeloma (RRMM). Blood 142, 3385-3385.
  137. Torka, P., Barth, M., Ferdman, R. and Hernandez-Ilizaliturri, F. J. (2019) Mechanisms of resistance to monoclonal antibodies (mAbs) in lymphoid malignancies. Curr. Hematol. Malig. Rep. 14, 426-438.
  138. Toutain, P. L. and Bousquet-Melou, A. (2004) Volumes of distribution. J. Vet. Pharmacol. Ther. 27, 441-453.
  139. van de Donk, N., O'Neill, C., de Ruijter, M. E. M., Verkleij, C. P. M. and Zweegman, S. (2023) T-cell redirecting bispecific and trispecific antibodies in multiple myeloma beyond BCMA. Curr. Opin. Oncol. 35, 601-611.
  140. van de Donk, N. and Zweegman, S. (2023) T-cell-engaging bispecific antibodies in cancer. Lancet 402, 142-158.
  141. van Gils, M. J. and Sanders, R. W. (2017) Opposites attract in bispecific antibody engineering. J. Biol. Chem. 292, 14718-14719.
  142. von Behring, E. (2024) Emil von Behring - Nobel Lecture. NobelPrize. org. Nobel Prize Outreach AB 2024. Nobel Prize Outreach AB. Available from: http://www.nobelprize.org/prizes/medicine/1901/behring/lecture/ [accessed 2024 Jul 30].
  143. Vugmeyster, Y., Xu, X., Theil, F. P., Khawli, L. A. and Leach, M. W. (2012) Pharmacokinetics and toxicology of therapeutic proteins: advances and challenges. World J. Biol. Chem. 3, 73-92.
  144. Wu, J., Fu, J., Zhang, M. and Liu, D. (2015) Blinatumomab: a bispecific T cell engager (BiTE) antibody against CD19/CD3 for refractory acute lymphoid leukemia. J. Hematol. Oncol. 8, 104.
  145. Xu, X. and Vugmeyster, Y. (2012) Challenges and opportunities in absorption, distribution, metabolism, and excretion studies of therapeutic biologics. AAPS J. 14, 781-791.
  146. Xu, Y., Lee, J., Tran, C., Heibeck, T. H., Wang, W. D., Yang, J., Stafford, R. L., Steiner, A. R., Sato, A. K., Hallam, T. J. and Yin, G. (2015) Production of bispecific antibodies in "knobs-into-holes" using a cell-free expression system. MAbs 7, 231-242.
  147. Yarden, Y. and Shilo, B.-Z. (2007) SnapShot: EGFR signaling pathway. Cell 131, 1018.e1-1018.e2.
  148. Zhu, Y., Choi, S. H. and Shah, K. (2015) Multifunctional receptor-targeting antibodies for cancer therapy. Lancet Oncol. 16, e543-e554.