Biparatopic antibodies: therapeutic applications and prospects

References

• U.S. Food & Drug Administration Center for Drug Evaluation and Research. Advancing health through innovation: new drug therapy approvals 2022. Silver Spring, Maryland. 2023. Accessed 2023 Jul 24. https://www.fda.gov/media/164429/download?attachment.
   Google Scholar
• Kaplon H, Crescioli S, Chenoweth A, Visweswaraiah J, Reichert JM. Antibodies to watch in 2023. MAbs. 2023;15(1):15. doi:10.1080/19420862.2022.2153410.
   Web of Science ®Google Scholar
• Cheong HS, Chang JS, Park JM, Byun SM. Affinity enhancement of bispecific antibody against two different epitopes in the same antigen. Biochem Bioph Res Co. 1990;173(3):795–13. doi:10.1016/S0006-291X(05)80857-5.
   PubMed Web of Science ®Google Scholar
• Yanakieva D, Pekar L, Evers A, Fleischer M, Keller S, Mueller-Pompalla D, Toleikis L, Kolmar H, Zielonka S, Krah S. Beyond bispecificity: controlled fab arm exchange for the generation of antibodies with multiple specificities. MAbs. 2022;14(1):14. doi:10.1080/19420862.2021.2018960.
   Web of Science ®Google Scholar
• Gera N. The evolution of bispecific antibodies. Expert Opin Biol Ther. 2022;22(8):945–49. doi:10.1080/14712598.2022.2040987.
   PubMed Web of Science ®Google Scholar
• Underwood DJ, Bettencourt J, Jawad Z. The manufacturing considerations of bispecific antibodies. Expert Opin Biol Ther. 2022;22(8):1043–65. doi:10.1080/14712598.2022.2095900.
   PubMed Web of Science ®Google Scholar
• Jähnichen S, Blanchetot C, Maussang D, Gonzalez-Pajuelo M, Chow KY, Bosch L, De Vrieze S, Serruys B, Ulrichts H, Vandevelde W. et al. CXCR4 nanobodies (VHH-based single variable domains) potently inhibit chemotaxis and HIV-1 replication and mobilize stem cells. Proc Natl Acad Sci U S A. 2010;107(47):20565–70. doi:10.1073/pnas.1012865107.
   PubMed Web of Science ®Google Scholar
• Steeland S, Vandenbroucke RE, Libert C. Nanobodies as therapeutics: big opportunities for small antibodies. Drug Discov Today. 2016;21(7):1076–113. doi:10.1016/j.drudis.2016.04.003.
   PubMed Web of Science ®Google Scholar
• Fan X, Zhuang Q, Yang L, Hao J, Zhao D, Zhao Y, Wang P, Geng D. Preclinical assessment of LCAR-B38M, a novel BCMA-targeting chimeric antigen receptor (CAR)-T cell therapy in relapsed/refractory multiple myeloma. Clin Lymphoma Myeloma Leuk. 2019;19(10):e160. doi:10.1016/j.clml.2019.09.267.
   Web of Science ®Google Scholar
• Zhou J, Shi Z, Shi F, Chen S, Huang C, Li H, Zhang Y, Yi R, Wang H, Li X-Y. et al. Optimization of GPRC5D-targeted CAR T cells (OriCAR-017) for multiple myeloma. J Immunother Cancer BMJ. 2023;11:A370–2. doi:10.1136/jitc-2023-SITC2023.0326
   Google Scholar
• Li JY, Perry SR, Muniz-Medina V, Wang X, Wetzel LK, Rebelatto MC, Hinrichs MJM, Bezabeh BZ, Fleming RL, Dimasi N. et al. A biparatopic HER2-targeting antibody-drug conjugate induces tumor regression in primary models refractory to or ineligible for HER2-targeted therapy. Cancer Cell. 2016;29(1):117–29. doi:10.1016/j.ccell.2015.12.008.
   PubMed Web of Science ®Google Scholar
• Zhang H, Huang H, Li R, Zhang L, Wang Z, Liang S, Li J, Chen J, Su H, Zheng D. et al. Broadly potent neutralizing bi-specific antibody against SARS CoV 2. Virol Curr Res. 2022;574:1–8. doi:10.1016/j.virol.2022.07.003.
   Google Scholar
• Xu T, Yin Q, Yan R, Li Q, Wang Y. Method for preventing and/or treating thromboembolic diseases. 2023. WIPO WO2023098637A1.
   Google Scholar
• Chiu M. Multi-specific cMet x EGFR x VEGF antibody for difficult to treat cancers. Cancer Res. 2023;83(7_Supplement):4494. doi:10.1158/1538-7445.AM2023-4494.
   Google Scholar
• DaSilva JO, Yang K, Perez Bay AE, Andreev J, Ngoi P, Pyles E, Franklin MC, Dudgeon D, Rafique A, Dore A. et al. A biparatopic antibody that modulates MET trafficking exhibits enhanced efficacy compared with parental antibodies in MET-driven tumor models. Clin Cancer Res. 2020;26(6):1408–19. doi:10.1158/1078-0432.CCR-19-2428.
   PubMed Web of Science ®Google Scholar
• Smith EJ, Olson K, Haber LJ, Varghese B, Duramad P, Tustian AD, Oyejide A, Kirshner JR, Canova L, Menon J. et al. A novel, native-format bispecific antibody triggering T-cell killing of B-cells is robustly active in mouse tumor models and cynomolgus monkeys. Sci Rep. 2015;5(1):5. doi:10.1038/srep17943.
   Google Scholar
• Oostindie SC, van der Horst HJ, Kil LP, Strumane K, Overdijk MB, van den Brink EN, van den Brakel JHN, Rademaker HJ, van Kessel B, van den Noort J. et al. DuoHexaBody-CD37®, a novel biparatopic CD37 antibody with enhanced Fc-mediated hexamerization as a potential therapy for B-cell malignancies. Blood Cancer J. 2020;10(3):10. doi:10.1038/s41408-020-0292-7.
   PubMed Web of Science ®Google Scholar
• Murphy AJ, Macdonald LE, Stevens S, Karow M, Dore AT, Pobursky K, Huang TT, Poueymirou WT, Esau L, Meola M. et al. Mice with megabase humanization of their immunoglobulin genes generate antibodies as efficiently as normal mice. Proc Natl Acad Sci U S A. 2014;111(14):5153–58. doi:10.1073/pnas.1324022111.
   PubMed Web of Science ®Google Scholar
• Wei H, Cai H, Jin Y, Wang P, Zhang Q, Lin Y, Wang W, Cheng J, Zeng N, Xu T. et al. Structural basis of a novel heterodimeric Fc for bispecific antibody production. Oncotarget. 2017;8(31):51037–49. doi:10.18632/oncotarget.17558.
   PubMedGoogle Scholar
• Liu Z, Liu Y, Hao X, Zhang X, Guo J. Anti-human-TSLP antibody and use thereof . 2021. WIPO WO2021155634A1.
   Google Scholar
• Sammicheli S, Grandclement C, Labanca V, De Angelis S, Estoppey C, Chimen M, Pouleau B, Suere P, Nallet E, Srivastava A. et al. Preclinical evaluation of ISB 1442, a first-in-class CD38 and CD47 bispecific antibody innate cell modulator for the treatment of AML and T-ALL. Blood. 2022;140 (Supplement 1):6237-6238. doi: 10.1182/blood-2022-162201.
   Google Scholar
• Xu L, Pegu A, Rao E, Doria-Rose N, Beninga J, McKee K, Lord DM, Wei RR, Deng G, Louder M. et al. Trispecific broadly neutralizing HIV antibodies mediate potent SHIV protection in macaques. Science 2017;358(6359):85–90. doi:10.1126/science.aan8630.
   PubMed Web of Science ®Google Scholar
• Weisser NE, Sanches M, Escobar-Cabrera E, O’Toole J, Whalen E, Chan PWY, Wickman G, Abraham L, Choi K, Harbourne B. et al. An anti-HER2 biparatopic antibody that induces unique HER2 clustering and complement-dependent cytotoxicity. Nat Commun. 2023;14:1394. doi:10.1038/s41467-023-37029-3.
   PubMed Web of Science ®Google Scholar
• Ugamraj HS, Dang K, Ouisse LH, Buelow B, Chini EN, Castello G, Allison J, Clarke SC, Davison LM, Buelow R. et al. TNB-738, a biparatopic antibody, boosts intracellular NAD+ by inhibiting CD38 ecto-enzyme activity. MAbs. 2022;14(1):e2095949. doi:10.1080/19420862.2022.2095949.
   PubMed Web of Science ®Google Scholar
• Fischer S, Gӧtze TO, Omlin A, Baird RD, Dawson KM, Zitt C, Arany Z, Tresch G, Fiedler U, Jeger S. et al. A case of sustained tumor regression with MP0274, a novel DARPin therapeutic targeting human epidermal growth factor receptor 2 signaling, in metastatic human epidermal growth factor receptor 2–positive breast cancer after prior trastuzumab and Pertuzumab. JCO Precis Oncol. 2022;6(6):e2200006. doi:10.1200/PO.22.00006.
   PubMed Web of Science ®Google Scholar
• Labrijn AF, Janmaat ML, Reichert JM, Parren PWHI. Bispecific antibodies: a mechanistic review of the pipeline. Nat Rev Drug Discov. 2019;18(8):585–608. doi:10.1038/s41573-019-0028-1.
   PubMed Web of Science ®Google Scholar
• Harms BD, Kearns JD, Iadevaia S, Lugovskoy AA. Understanding the role of cross-arm binding efficiency in the activity of monoclonal and multispecific therapeutic antibodies. Methods. 2014;65(1):95–104. doi:10.1016/j.ymeth.2013.07.017.
   PubMed Web of Science ®Google Scholar
• Neri D, Momo M, Prospero T, Winter G. High-affinity Antigen Binding by Chelating Recombinant Antibodies (CRAbs). J Mol Biol. 1995;246(3):367–73. doi:10.1006/jmbi.1994.0091.
   PubMed Web of Science ®Google Scholar
• Robert B, Dorvillius M, Buchegger F, Garambois V, Mani JC, Pugnières M, Mach JP, Pèlegrin A. Tumor targeting with newly designed biparatopic antibodies directed against two different epitopes of the Carcinoembryonic Antigen (CEA). Int J Cancer. 1999;81(2):285–91. doi:10.1002/(SICI)1097-0215(19990412)81:2<285:AID-IJC19>3.0.CO;2-T.
   PubMed Web of Science ®Google Scholar
• Kim JC, Roh SA, Koo KH, Ryu JH, Hong HK, Oh SJ, Ryu JS, Kim HJ, Bodmer WF. Enhancement of colorectal tumor targeting using a novel biparatopic monoclonal antibody against carcinoembryonic antigen in experimental radioimmunoguided surgery. Int J Cancer. 2002;97(4):542–47. doi:10.1002/ijc.1630.
   PubMed Web of Science ®Google Scholar
• Henry KA, Nguyen TD, Baral TN, Hussack G, Raphael S, Arbabi-Ghahroudi M, Robert A, Durocher Y, Wu C, Jaramillo ML. et al. Biparatopic single-domain antibodies against Axl achieve ultra-high affinity through intramolecular engagement. Biochem Biophys Res Commun. 2021;562:154–61. doi:10.1016/j.bbrc.2021.05.030.
   PubMed Web of Science ®Google Scholar
• Roovers RC, Vosjan MJWD, Laeremans T, El Khoulati R, De Bruin RCG, Ferguson KM, Verkleij AJ, Van Dongen GAMS, Van Bergen En Henegouwen PMP. A biparatopic anti-EGFR nanobody efficiently inhibits solid tumour growth. Int J Cancer. 2011;129:2013–24. doi:10.1002/ijc.26145.
   PubMed Web of Science ®Google Scholar
• Fleetwood F, Klint S, Hanze M, Gunneriusson E, Frejd FY, Ståhl S, Löfblom J. Simultaneous targeting of two ligand-binding sites on VEGFR2 using biparatopic affibody molecules results in dramatically improved affinity. Sci Rep. 2014;4:7518. doi:10.1038/srep07518.
   PubMed Web of Science ®Google Scholar
• Bradley ME, Dombrecht B, Manini J, Willis J, Vlerick D, De Taeye S, Van Den Heede K, Roobrouck A, Grot E, Kent TC. et al. Potent and efficacious inhibition of CXCR2 signaling by biparatopic nanobodies combining two distinct modes of action. Mol Pharmacol. 2015;87(2):251–62. doi:10.1124/mol.114.094821.
   PubMed Web of Science ®Google Scholar
• Akiba H, Fujita J, Ise T, Nishiyama K, Miyata T, Kato T, Namba K, Ohno H, Kamada H, Nagata S. et al. Development of a 1: 1-binding biparatopic anti-TNFR2 antagonist by epitope selection. Commun Biol. 2023;6:987. doi:10.1038/s42003-023-05326-8.
   Web of Science ®Google Scholar
• Kast F, Schwill M, Stüber JC, Pfundstein S, Nagy-Davidescu G, Rodríguez JMM, Seehusen F, Richter CP, Honegger A, Hartmann KP. et al. Engineering an anti-HER2 biparatopic antibody with a multimodal mechanism of action. Nat Commun. 2021;12:3790. doi:10.1038/s41467-021-23948-6.
   PubMed Web of Science ®Google Scholar
• Spangler JB, Manzari MT, Rosalia EK, Chen TF, Wittrup KD. Triepitopic antibody fusions inhibit cetuximab-resistant BRAF and KRAS mutant tumors via EGFR signal repression. J Mol Biol. 2012;422(4):532–44. doi:10.1016/j.jmb.2012.06.014.
   PubMed Web of Science ®Google Scholar
• Wright MJ, Deonarain MP. Phage display of chelating recombinant antibody libraries. Mol Immunol. 2007;44(11):2860–69. doi:10.1016/j.molimm.2007.01.026.
   PubMed Web of Science ®Google Scholar
• Liu J, Wu X, Lin L, Pan H, Wang Y, Li Y, Zhao Y, Wang Z. Bp-Bs, a novel T-cell engaging bispecific antibody with biparatopic Her2 binding, has potent anti-tumor activities. Mol Ther Oncolytics. 2019;14:66–73. doi:10.1016/j.omto.2019.03.009.
   PubMed Web of Science ®Google Scholar
• Rennert PD, Dufort FJ, Su L, Sanford T, Birt A, Wu L, Lobb RR, Ambrose C. Anti-CD19 CAR T cells that secrete a biparatopic anti-CLEC12A bridging protein have potent activity against highly aggressive acute myeloid leukemia in vitro and in vivo. Mol Cancer Ther. 2021;20(10):2071–81. doi:10.1158/1535-7163.MCT-20-1030.
   PubMed Web of Science ®Google Scholar
• Dai Z, Mu W, Zhao Y, Jia X, Liu J, Wei Q, Tan T, Zhou J. The rational development of CD5-targeting biepitopic CARs with fully human heavy-chain-only antigen recognition domains. Mol Ther. 2021;29(9):2707–22. doi:10.1016/j.ymthe.2021.07.001.
   PubMed Web of Science ®Google Scholar
• Ettenberg SA, Charlat O, Daley MP, Liu S, Vincent KJ, Stuart DD, Schuller AG, Yuan J, Ospina B, Green J. et al. Inhibition of tumorigenesis driven by different wnt proteins requires blockade of distinct ligand-binding regions by LRP6 antibodies. Proc Natl Acad Sci U S A. 2010;107(35):15473–78. doi:10.1073/pnas.1007428107.
   PubMed Web of Science ®Google Scholar
• Jost C, Schilling J, Tamaskovic R, Schwill M, Honegger A, Plückthun A. Structural basis for eliciting a cytotoxic effect in HER2-overexpressing cancer cells via binding to the extracellular domain of HER2. Structure. 2013;21(11):1979–91. doi:10.1016/j.str.2013.08.020.
   PubMed Web of Science ®Google Scholar
• Stefano JE, Lord DM, Zhou Y, Jaworski J, Hopke J, Travaline T, Zhang N, Wong K, Lennon A, He T. et al. A highly potent CD73 biparatopic antibody blocks organization of the enzyme active site through dual mechanisms. J Biol Chem. 2020;295(52):18379–89. doi:10.1074/jbc.RA120.012395.
   PubMed Web of Science ®Google Scholar
• Gammelgaard OL, Terp MG, Renn C, Labrijn AF, Hamaker O, Nielsen AY, Vever H, Hansen SWK, Gjerstorff MF, Müller CE. et al. Targeting two distinct epitopes on human CD73 with a bispecific antibody improves anticancer activity. J Immunother Cancer. 2022;10(9):e004554. doi:10.1136/jitc-2022-004554.
   PubMed Web of Science ®Google Scholar
• Yang Y, Yeh SH, Madireddi S, Matochko WL, Gu C, Pacheco Sanchez P, Ultsch M, De Leon Boenig G, Harris SF, Leonard B. et al. Tetravalent biepitopic targeting enables intrinsic antibody agonism of tumor necrosis factor receptor superfamily members. MAbs. 2019;11(6):996–1011. doi:10.1080/19420862.2019.1625662.
   PubMed Web of Science ®Google Scholar
• Shi SY, Lu YW, Liu Z, Stevens J, Murawsky CM, Wilson V, Hu Z, Richards WG, Michaels ML, Zhang J. et al. A biparatopic agonistic antibody that mimics fibroblast growth factor 21 ligand activity. J Biol Chem. 2018;293(16):5909–19. doi:10.1074/jbc.RA118.001752.
   PubMed Web of Science ®Google Scholar
• Rougé L, Chiang N, Steffek M, Kugel C, Croll TI, Tam C, Estevez A, Arthur CP, Koth CM, Ciferri C. et al. Structure of CD20 in complex with the therapeutic monoclonal antibody rituximab. Science. 2020;367(6483):1224–30. doi:10.1126/science.aaz9356.
   PubMed Web of Science ®Google Scholar
• Bogen JP, Carrara SC, Fiebig D, Grzeschik J, Hock B, Kolmar H. Expeditious generation of biparatopic common light chain antibodies via chicken immunization and yeast display screening. Front Immunol. 2020;11:606878. doi:10.3389/fimmu.2020.606878.
   Web of Science ®Google Scholar
• Kasturirangan S, Rainey GJ, Xu L, Wang X, Portnoff A, Chen T, Fazenbaker C, Zhong H, Bee J, Zeng Z. et al. Targeted Fcγ receptor (FcγR)-mediated clearance by a biparatopic bispecific antibody. J Biol Chem. 2017;292(10):4361–70. doi:10.1074/jbc.M116.770628.
   PubMed Web of Science ®Google Scholar
• Cano-Garrido O, Álamo P, Sánchez-García L, Falgàs A, Sánchez-Chardi A, Serna N, Parladé E, Unzueta U, Roldán M, Voltà-Durán E. et al. Biparatopic protein nanoparticles for the precision therapy of CXCR4+ cancers. Cancers. 2021;13(12):2929. doi:10.3390/cancers13122929.
   PubMed Web of Science ®Google Scholar
• Emmerson CD, van der Vlist Els J, Braam MR, Vanlandschoot P, Merchiers P, de Haard Hans JW, Verrips CT, van Bergen En Henegouwen MP, Dolk E, Bansal GP. Enhancement of polymeric immunoglobulin receptor transcytosis by biparatopic VHH. PLOS ONE. 2011;6(10):e26299. doi:10.1371/journal.pone.0026299.
   Web of Science ®Google Scholar
• Cheng J, Liang M, Carvalho MF, Tigue N, Faggioni R, Roskos LK, Vainshtein I. Molecular mechanism of HER2 rapid internalization and redirected trafficking induced by anti-HER2 biparatopic antibody. Antibodies. 2020;9(3):1–21. doi:10.3390/antib9030049.
   Web of Science ®Google Scholar
• Benedetti F, Stadlbauer K, Stadlmayr G, Rüker F, Wozniak-Knopp G. A tetravalent biparatopic antibody causes strong HER2 internalization and inhibits cellular proliferation. Life. 2021;11(11):1157. doi:10.3390/life11111157.
   Google Scholar
• Oganesyan V, Peng L, Bee JS, Li J, Perry SR, Comer F, Xu L, Cook K, Senthil K, Clarke L. et al. Structural insights into the mechanism of action of a biparatopic anti-HER2 antibody. J Biol Chem. 2018;293(22):8439–48. doi:10.1074/jbc.M117.818013.
   PubMed Web of Science ®Google Scholar
• DaSilva JO, Yang K, Surriga O, Nittoli T, Kunz A, Franklin MC, Delfino FJ, Mao S, Zhao F, Giurleo JT. et al. A biparatopic antibody–drug conjugate to treat MET-expressing cancers, including those that are unresponsive to MET pathway blockade. Mol Cancer Ther. 2021;20(10):1966–76. doi:10.1158/1535-7163.MCT-21-0009.
   PubMed Web of Science ®Google Scholar
• Barnscher SD, Rojas AH, Hamblett KJ, Escalante N. Zanidatamab zovodotin. (ZW49) induces hallmarks of immunogenic cell death and is active in patient-derived xenograft models of gastric cancer. Cancer Res. 2023;83(7_Supplement):2633. doi:10.1158/1538-7445.AM2023-2633.
   Google Scholar
• Ab O, Bartle LM, Lanieri L, Ponte JF, Qiu Q, Sikka S, Costoplus JA, Deats W, Yoder NC, Widdison WC. et al. IMGN151 - a next generation folate receptor alpha targeting antibody drug conjugate active against tumors with low, medium and high receptor expression. Cancer Res. 2020;80(16_Supplement):2890. doi: 10.1158/1538-7445.AM2020-2890.
   Google Scholar
• Caskey M, Klein F, Nussenzweig MC. Broadly neutralizing anti-HIV-1 monoclonal antibodies in the clinic. Nat Med. 2019;25(4):547–53. doi:10.1038/s41591-019-0412-8.
   PubMed Web of Science ®Google Scholar
• Cho H, Kay Gonzales-Wartz K, Huang D, Yuan M, Peterson M, Liang J, Beutler N, Torres JL, Cong Y, Postnikova E. et al. Bispecific antibodies targeting distinct regions of the spike protein potently neutralize SARS-CoV-2 variants of concern. Sci Transl Med. 2021;13(616):1–19. doi:10.1126/scitranslmed.abj5413.
   Web of Science ®Google Scholar
• Ahn S, Li J, Sun C, Gao K, Hirabayashi K, Li H, Savoldo B, Liu R, Dotti G. Cancer immunotherapy with T cells carrying bispecific receptors that mimic antibodies. Cancer Immunol Res. 2019;7(5):773–83. doi:10.1158/2326-6066.CIR-18-0636.
   PubMed Web of Science ®Google Scholar
• Martin T, Usmani SZ, Berdeja JG, Agha M, Cohen AD, Hari P, Avigan D, Deol A, Htut M. Ciltacabtagene autoleucel, an anti– B-cell maturation antigen chimeric antigen receptor T-cell therapy, for relapsed/refractory multiple myeloma: CARTITUDE-1 2-year follow-up. J Clin Oncol. 2022;41(6):1265–74. doi:10.1200/JCO.22.00842.
   PubMed Web of Science ®Google Scholar
• Zhang M, Wei G, Zhou L, Zhou J, Chen S, Zhang W, Wang D, Luo X, Cui J, Huang S. et al. GPRC5D CAR T cells (OriCAR-017) in patients with relapsed or refractory multiple myeloma (POLARIS): a first-in-human, single-centre, single-arm, phase 1 trial. Lancet Haematol. 2023;10(2):e107–16. doi:10.1016/S2352-3026(22)00372-6.
   PubMed Web of Science ®Google Scholar
• Sia H, Tan PT, Richter J, Ho PJ, Cochrane T, Quach H, Dhakal B, Proscurshim I, Jiang T, Mancino E. et al. A phase 1/2, first-in-human, multicenter, open-label, dose escalation and dose-expansion study of single-agent ISB 1442 in patients with relapsed/refractory multiple myeloma. Blood. 2022;140 (Supplement 1):10182-10184. doi: 10.1182/blood-2022-157585.
   Google Scholar
• Fiedler U, Metz C, Zitt C, Bessey R, Béhé M, Blanc A, Schibli R, Dolado I, Herbst J, Dawson K. et al. Pre-clinical antitumor activity, tumor localization, and pharmacokinetics of MP0274, an apoptosis inducing, biparatopic HER2-targeting DARPin®. Cancer Res. 2017;77(4_Supplement):P4-21-18. doi: 10.1158/1538-7445.SABCS16-P4-21-18
   Google Scholar
• Wang P, Guo K, Peng J, Sun J, Xu T. JSKN003, A novel biparatopic anti-HER2 antibody-drug conjugate, exhibits potent antitumor efficacy. Antib Ther. 2023;6(Supplement_1):tbad014.009. doi: 10.1093/abt/tbad014.009.
   Google Scholar
• De Santis R. Anti-ErbB2 immunotherapeutics: struggling to make better antibodies for cancer therapy. MAbs. 2020;12:1725346. doi:10.1080/19420862.2020.1725346.
   PubMed Web of Science ®Google Scholar
• Prokofyev AV, Kharatian NG, Krendeleva EA, Shitikova VO, Shchemeleva MA, Anikina AV, Nazarenko OV, Evstrateva AV, Sozonova AA, Cherkasov AV. et al. Bispecific antibody that specifically binds to subdomains IV and II of the extracellular domain of human her2. 2019. WIPO WO2019190359A1.
   Google Scholar
• Zhang X, Chen T, Feng W, Zhang B, Tang X, Xu T, Wang X, Sheng H, Zhang Z, Wang H. et al. Antibody drug conjugate. 2022. WIPO WO2022033578A1.
   Google Scholar
• Zhu X, Ye J, Wang J, He W. Bispecific antibody-drug conjugate. 2022. WIPO WO2022228422A1.
   Google Scholar
• Howlader N, Altekruse SF, Li CI, Chen VW, Clarke CA, Ries LAG, Cronin KA. US incidence of breast cancer subtypes defined by joint hormone receptor and HER2 status. J Natl Cancer Inst. 2014;106(5):dju055. doi:10.1093/jnci/dju055.
   PubMedGoogle Scholar
• Cronin KA, Harlan LC, Dodd KW, Abrams JS, Ballard-Barbash R. Population-based estimate of the prevalence of HER-2 positive breast cancer tumors for early stage patients in the US. Cancer Invest. 2010;28(9):963–68. doi:10.3109/07357907.2010.496759.
   PubMed Web of Science ®Google Scholar
• Jagosky M, Tan AR. Combination of pertuzumab and trastuzumab in the treatment of HER2-positive early breast cancer: a review of the emerging clinical data. Breast Cancer Targets Ther. 2021;13:393–407. doi:10.2147/BCTT.S176514.
   PubMed Web of Science ®Google Scholar
• Tabernero J, Hoff PM, Shen L, Ohtsu A, Shah MA, Cheng K, Song C, Wu H, Eng-Wong J, Kim K. et al. Pertuzumab plus trastuzumab and chemotherapy for HER2-positive metastatic gastric or gastro-oesophageal junction cancer (JACOB): final analysis of a double-blind, randomised, placebo-controlled phase 3 study. Lancet Oncol. 2018;19(10):1372–84. doi:10.1016/S1470-2045(18)30481-9.
   PubMed Web of Science ®Google Scholar
• Wang Y, Yan A, Song D, Dong C, Rao M, Gao Y, Qi R, Ma X, Wang Q, Xu H. et al. Biparatopic antibody BA7208/7125 effectively neutralizes SARS-CoV-2 variants including Omicron BA.1-BA.5. Cell Discov. 2023;9:3. doi:10.1038/s41421-022-00509-9.
   Web of Science ®Google Scholar
• De Boever S, Jacobs S, Serruys B, Snoeck V, Cromie K, Baumeister J. Safety of nanobody ALX-0651 targeting the G protein coupledr eceptor CXCR4. Toxicol Lett. 2012;211:S43. doi:10.1016/j.toxlet.2012.03.178.
   Web of Science ®Google Scholar
• Pegram MD, Hamilton EP, Tan AR, Storniolo AM, Balic K, Rosenbaum AI, Liang M, He P, Marshall S, Scheuber A. et al. First-in-human, phase 1 dose-escalation study of biparatopic anti-HER2 antibody–drug conjugate MEDI4276 in patients with HER2-positive advanced breast or gastric cancer. Mol Cancer Ther. 2021;20(8):1442–53. doi:10.1158/1535-7163.MCT-20-0014.
   PubMed Web of Science ®Google Scholar
• Xu J, Chen LJ, Yang SS, Sun Y, Wu W, Liu YF, Xu J, Zhuang Y, Zhang W, Weng XQ. et al. Exploratory trial of a biepitopic CAR T-targeting B cell maturation antigen in relapsed/refractory multiple myeloma. Proc Natl Acad Sci U S A. 2019;116(19):9543–51. doi:10.1073/pnas.1819745116.
   PubMed Web of Science ®Google Scholar
• Zhao WH, Wang BY, Chen LJ, Fu WJ, Xu J, Liu J, Jin SW, Chen YX, Cao XM, Yang Y. et al. Four-year follow-up of LCAR-B38M in relapsed or refractory multiple myeloma: a phase 1, single-arm, open-label, multicenter study in China (LEGEND-2). J Hematol Oncol. 2022;15:86. doi:10.1186/s13045-022-01301-8.
   Web of Science ®Google Scholar
• Meric-Bernstam F, Beeram M, Hamilton E, Oh DY, Hanna DL, Kang YK, Elimova E, Chaves J, Goodwin R, Lee J. et al. Zanidatamab, a novel bispecific antibody, for the treatment of locally advanced or metastatic HER2-expressing or HER2-amplified cancers: a phase 1, dose-escalation and expansion study. Lancet Oncol. 2022;23(12):1558–70. doi:10.1016/S1470-2045(22)00621-0.
   PubMed Web of Science ®Google Scholar
• Molecular Partners. Molecular partners annual report 2020. 2021. Accessed 2023 Sep 21. https://investors.molecularpartners.com/static-files/9d71a3de-34be-454b-bbc4-18090eb2304f.
   Google Scholar
• Zhang J, Ji D, Cai L, Yao H, Yan M, Wang X, Shen W, Du Y, Pang H, Lai X. et al. First-in-human HER2-targeted bispecific antibody KN026 for the treatment of patients with HER2-positive metastatic breast cancer: results from a phase I study. Clin Cancer Res. 2022;28(4):618–28. doi:10.1158/1078-0432.CCR-21-2827.
   PubMedGoogle Scholar
• Xu J, Ying J, Liu R, Wu J, Ye F, Xu N, Zhang Y, Zhao R, Xiang X, Wang J. et al. KN026 (anti-HER2 bispecific antibody) in patients with previously treated, advanced HER2-expressing gastric or gastroesophageal junction cancer. Eur J Cancer. 2023;178:1–12. doi:10.1016/j.ejca.2022.10.004.
   PubMed Web of Science ®Google Scholar
• Huang S, Li F, Liu H, Ye P, Fan X, Yuan X, Wu Z, Chen J, Jin C, Shen B. et al. Structural and functional characterization of MBS301, an afucosylated bispecific anti-HER2 antibody. MAbs. 2018;10(6):864–75. doi:10.1080/19420862.2018.1486946.
   PubMed Web of Science ®Google Scholar
• Dufloo J, Planchais C, Frémont S, Lorin V, Guivel-Benhassine F, Stefic K, Casartelli N, Echard A, Roingeard P, Mouquet H. et al. Broadly neutralizing anti-HIV-1 antibodies tether viral particles at the surface of infected cells. Nat Commun. 2022;13:630. doi:10.1038/s41467-022-28307-7.
   Google Scholar
• Pegu A, Xu L, DeMouth ME, Fabozzi G, March K, Almasri CG, Cully MD, Wang K, Yang ES, Dias J. et al. Potent anti-viral activity of a trispecific HIV neutralizing antibody in SHIV-infected monkeys. Cell Rep. 2022;39(1):110199. doi:10.1016/j.celrep.2021.110199.
   PubMed Web of Science ®Google Scholar
• Perez Bay AE, Faulkner D, DaSilva JO, Young TM, Yang K, Giurleo JT, Ma D, Delfino FJ, Olson WC, Thurston G. et al. A bispecific METxMET antibody–drug conjugate with cleavable linker is processed in recycling and late endosomes. Mol Cancer Ther. 2023;22(3):357–70. doi:10.1158/1535-7163.MCT-22-0414.
   PubMed Web of Science ®Google Scholar
• Wagner TR, Schnepf D, Beer J, Ruetalo N, Klingel K, Kaiser PD, Junker D, Sauter M, Traenkle B, Frecot DI. et al. Biparatopic nanobodies protect mice from lethal challenge with SARS‐CoV‐2 variants of concern. EMBO Rep. 2022;23:e53865. doi:10.15252/embr.202153865.
   PubMed Web of Science ®Google Scholar
• Pymm P, Redmond SJ, Dolezal O, Mordant F, Lopez E, Cooney JP, Davidson KC, Haycroft ER, Tan CW, Seneviratna R. et al. Biparatopic nanobodies targeting the receptor binding domain efficiently neutralize SARS-CoV-2. iScience. 2022;25(11):105259. doi:10.1016/j.isci.2022.105259.
   PubMed Web of Science ®Google Scholar
• Chi X, Zhang X, Pan S, Yu Y, Shi Y, Lin T, Duan H, Liu X, Chen W, Yang X. et al. An ultrapotent RBD-targeted biparatopic nanobody neutralizes broad SARS-CoV-2 variants. Sig Transduct Target Ther. 2022;7:44. doi:10.1038/s41392-022-00912-4.
   Web of Science ®Google Scholar
• Koenig PA, Das H, Liu H, Kümmerer BM, Gohr FN, Jenster LM, Schiffelers LDJ, Tesfamariam YM, Uchima M, Wuerth JD. et al. Structure-guided multivalent nanobodies block SARS-CoV-2 infection and suppress mutational escape. Science 2021;371(6530):eabe6230. doi:10.1126/science.abe6230.
   Web of Science ®Google Scholar
• Walter JD, Scherer M, Hutter CAJ, Garaeva AA, Zimmermann I, Wyss M, Rheinberger J, Ruedin Y, Earp JC, Egloff P. et al. Biparatopic sybodies neutralize SARS‐CoV‐2 variants of concern and mitigate drug resistance. EMBO Rep. 2022;23:e54199. doi:10.15252/embr.202154199.
   PubMed Web of Science ®Google Scholar
• Li C, Zhan W, Yang Z, Tu C, Hu G, Zhang X, Song W, Du S, Zhu Y, Huang K. et al. Broad neutralization of SARS-CoV-2 variants by an inhalable bispecific single-domain antibody. Cell. 2022;185(8):1389–1401.e18. doi:10.1016/j.cell.2022.03.009.
   PubMed Web of Science ®Google Scholar