Nisonoff A, Wissler FC, Lipman LN. Properties of the major component of a peptic digest of rabbit antibody. Science. 1979;1960(132):1770–1.

Google Scholar 

Nisonoff A, Rivers MM. Recombination of a mixture of univalent antibody fragments of different specificity. Arch Biochem Biophys. 1961;93:460–2.

Article  CAS  PubMed  Google Scholar 

Wunderlich JR, Mezzanzanica D, Garrido MA, Neblock DS, Daddona PE, Andrew SM, et al. Bispecific antibodies and retargeted cellular cytotoxicity: novel approaches to cancer therapy. Int J Clin Lab Res. 1992;22:17–20.

Article  CAS  PubMed  Google Scholar 

Labrijn AF, Janmaat ML, Reichert JM, Parren PWHI. Bispecific antibodies: a mechanistic review of the pipeline. Nat Rev Drug Discov. 2019;18:585–608.

Article  CAS  PubMed  Google Scholar 

Ridgway JB, Presta LG, Carter P. “Knobs-into-holes” engineering of antibody CH3 domains for heavy chain heterodimerization. Protein Eng. 1996;9:617–21.

Article  CAS  PubMed  Google Scholar 

Merchant AM, Zhu Z, Yuan JQ, Goddard A, Adams CW, Presta LG, et al. An efficient route to human bispecific IgG. Nat Biotechnol. 1998;16:677–81.

Article  CAS  PubMed  Google Scholar 

Holliger P, Prospero T, Winter G. “Diabodies”: small bivalent and bispecific antibody fragments. Proc Natl Acad Sci USA. 1993;90:6444–8.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Coloma MJ, Morrison SL. Design and production of novel tetravalent bispecific antibodies. Nat Biotechnol. 1997;15:159–63.

Article  CAS  PubMed  Google Scholar 

Heiss MM, Murawa P, Koralewski P, Kutarska E, Kolesnik OO, Ivanchenko VV, et al. The trifunctional antibody catumaxomab for the treatment of malignant ascites due to epithelial cancer: results of a prospective randomized phase II/III trial. Int J Cancer. 2010;127:2209–21.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Seimetz D, Lindhofer H, Bokemeyer C. Development and approval of the trifunctional antibody catumaxomab (anti-EpCAM×anti-CD3) as a targeted cancer immunotherapy. Cancer Treat Rev. 2010;36:458–67.

Article  CAS  PubMed  Google Scholar 

Wimberger P, Heubner M, Kimmig R. Catumaxomab in the treatment of malignant ascites: the evidence of its therapeutic value. Clin Med Insights Ther. 2010;2:CMT.S4954.

Article  Google Scholar 

Husain B, Ellerman D. Expanding the boundaries of biotherapeutics with bispecific antibodies. BioDrugs. 2018;32:441–64.

Article  PubMed  PubMed Central  Google Scholar 

Baeuerle PA, Reinhardt C. Bispecific T-cell engaging antibodies for cancer therapy. Cancer Res. 2009;69:4941–4.

Article  CAS  PubMed  Google Scholar 

Bien-Ly N, Yu YJ, Bumbaca D, Elstrott J, Boswell CA, Zhang Y, et al. Transferrin receptor (TfR) trafficking determines brain uptake of TfR antibody affinity variants. J Exp Med. 2014;211:233–44. https://doi.org/10.1084/jem.20131660.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Yu YJ, Atwal JK, Zhang Y, Tong RK, Wildsmith KR, Tan C, et al. Therapeutic bispecific antibodies cross the blood–brain barrier in nonhuman primates. Sci Transl Med. 2014;6,261ra154–261ra154

Couch JA, Yu YJ, Zhang Y, Tarrant JM, Fuji RN, Meilandt WJ, et al. Addressing safety liabilities of TfR bispecific antibodies that cross the blood–brain barrier. Sci Transl Med. 2013;5(183):183ra57, 1–12

Poduslo JF, Curran GL, Berg CT. Macromolecular permeability across the blood-nerve and blood–brain barriers. Proc Natl Acad Sci. 1994;91:5705–9.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Jones AR, Shusta EV. Blood–brain barrier transport of therapeutics via receptor-mediation. Pharm Res. 2007;24:1759–71.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Baghirov H. Receptor-mediated transcytosis of macromolecules across the blood–brain barrier. Expert Opin Drug Deliv. 2023;20:1699–711.

Article  CAS  PubMed  Google Scholar 

Tashima T. Delivery of intravenously administered antibodies targeting Alzheimer’s disease-relevant tau species into the brain based on receptor-mediated transcytosis. Pharmaceutics. 2022;14:411.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Clarke E, Stocki P, Sinclair EH, Gauhar A, Fletcher EJR, Krawczun-Rygmaczewska A, et al. A single domain shark antibody targeting the transferrin receptor 1 delivers a TrkB agonist antibody to the brain and provides full neuroprotection in a mouse model of Parkinson’s disease. Pharmaceutics. 2022;14:1335.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Roshanbin S, Julku U, Xiong M, Eriksson J, Masliah E, Hultqvist G, et al. Reduction of αSYN pathology in a mouse model of PD using a brain-penetrating bispecific antibody. Pharmaceutics. 2022;14:1412.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Webster CI, Caram-Salas N, Haqqani AS, Thom G, Brown L, Rennie K, et al. Brain penetration, target engagement, and disposition of the blood–brain barrier-crossing bispecific antibody antagonist of metabotropic glutamate receptor type 1. FASEB J. 2016;30:1927–40.

Article  CAS  PubMed  Google Scholar 

Zhao P, Zhang N, An Z. Engineering antibody and protein therapeutics to cross the blood–brain barrier. Antib Ther. 2022;5:311–31.

CAS  PubMed  PubMed Central  Google Scholar 

Grimm HP, Schumacher V, Schäfer M, Imhof-Jung S, Freskgård P-O, Brady K, et al. Delivery of the BrainshuttleTM amyloid-beta antibody fusion trontinemab to non-human primate brain and projected efficacious dose regimens in humans. MAbs. 2023;15(1):2261509

Sonoda H, Takahashi K, Minami K, Hirato T, Yamamoto T, So S, et al. Treatment of neuronopathic mucopolysaccharidoses with blood–brain barrier-crossing enzymes: clinical application of receptor-mediated transcytosis. Pharmaceutics. 2022;14:1240.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Kariolis MS, Wells RC, Getz JA, Kwan W, Mahon CS, Tong R, et al. Brain delivery of therapeutic proteins using an Fc fragment blood–brain barrier transport vehicle in mice and monkeys. Sci Transl Med. 2020;12(545):eaay1359

Pornnoppadol G, Bond LG, Lucas MJ, Zupancic JM, Kuo Y-H, Zhang B, et al. Bispecific antibody shuttles targeting CD98hc mediate efficient and long-lived brain delivery of IgGs. Cell Chem Biol. 2024;31:361-372.e8.

Article  CAS  PubMed  Google Scholar 

Moores SL, Chiu ML, Bushey BS, Chevalier K, Luistro L, Dorn K, et al. A novel bispecific antibody targeting EGFR and cMet is effective against EGFR inhibitor-resistant lung tumors. Cancer Res. 2016;76:3942–53.

Article  CAS  PubMed  Google Scholar 

Papassotiriou I, Kapogiannatos A, Makatsoris C, Bakogeorgou S, Mantogiannakou I, Roussou E, et al. Efficacy and safety of amivantamab in advanced or metastatic EGFR-mutant non-small cell lung cancer: a systematic review. J Clin Med. 2024;13:5489.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Rabia E, Garambois V, Dhommée C, Larbouret C, Lajoie L, Buscail Y, et al. Design and selection of optimal ErbB-targeting bispecific antibodies in pancreatic cancer. Front Immunol. 2023;14:1168444.

Kreidieh FY, Tawbi HA, Alexaki A, Borghaei H, Kandalaft LE. Novel immunotherapeutics: perspectives on checkpoints, bispecifics, and vaccines in development. American Society of Clinical Oncology Educational Book; 2023. e391278

Cheng W, Kang K, Zhao A, Wu Y. Dual blockade immunotherapy targeting PD-1/PD-L1 and CTLA-4 in lung cancer. J Hematol Oncol. 2024;17:54.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Lim DW-T, Kao H-F, Suteja L, Li CH, Quah HS, Tan DS-W, et al. Clinical efficacy and biomarker analysis of dual PD-1/CTLA-4 blockade in recurrent/metastatic EBV-associated nasopharyngeal carcinoma. Nat Commun. 2023;14:2781.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Zhang T, Lin Y, Gao Q. Bispecific antibodies targeting immunomodulatory checkpoints for cancer therapy. Cancer Biol Med. 2023;20:181–95.

Article  CAS