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Annual Review of Chemical and Biomolecular Engineering

Volume 15, 2024

Mechanism-Driven Design of Multispecific Antibodies for Targeted Disease Treatment

Abstract

Antibody-based therapeutics constitute a rapidly growing class of pharmaceutical compounds. However, monoclonal antibodies, which specifically engage only one target, often lack the mechanistic intricacy to treat complex diseases. To expand the utility of antibody therapies, significant efforts have been invested in designing multispecific antibodies, which engage multiple targets using a single molecule. These efforts have culminated in remarkable translational progress, including nine US Food and Drug Administration–approved multispecific antibodies, with countless others in various stages of preclinical or clinical development. In this review, we discuss several categories of multispecific antibodies that have achieved clinical approval or shown promise in earlier stages of development. We focus on the molecular mechanisms used by multispecific antibodies and how these mechanisms inform their customized design and formulation. In particular, we discuss multispecific antibodies that target multiple disease markers, multiparatopic antibodies, and immune-interfacing antibodies. Overall, these innovative multispecific antibody designs are fueling exciting advances across the immunotherapeutic landscape.

Keyword(s): antibody, cancer, drug development, immunotherapy, protein engineering, T cell
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/content/journals/10.1146/annurev-chembioeng-100522-102155
2024-07-24
2024-10-11
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Literature Cited

  1. 1.
    Jin S, Sun Y, Liang X, Gu X, Ning J, et al. 2022.. Emerging new therapeutic antibody derivatives for cancer treatment. . Sig. Transduct. Target. Ther. 7::39
     [Crossref] [Google Scholar]
  2. 2.
    Köhler G, Milstein C. 1975.. Continuous cultures of fused cells secreting antibody of predefined specificity. . Nature 256:(5517):495–97
     [Crossref] [Google Scholar]
  3. 3.
    Cotton RGH, Milstein C. 1973.. Fusion of two immunoglobulin-producing myeloma cells. . Nature 244:(5410):42–43
     [Crossref] [Google Scholar]
  4. 4.
    Klinman NR. 1969.. Antibody with homogeneous antigen binding produced by splenic foci in organ culture. . Immunochemistry 6:(5):757–59
     [Crossref] [Google Scholar]
  5. 5.
    Cosimi AB, Burton RC, Colvin RB, Goldstein G, Delmonico FL, et al. 1981.. Treatment of acute renal allograft rejection with OKT3 monoclonal antibody. . Transplantation 32:(6):535–40
     [Crossref] [Google Scholar]
  6. 6.
    Chang TW, Kung PC, Gingras SP, Goldstein G. 1981.. Does OKT3 monoclonal antibody react with an antigen-recognition structure on human T cells?. PNAS 78:(3):1805–8
     [Crossref] [Google Scholar]
  7. 7.
    Thistlethwaite JR, Cosimi AB, Delmonico FL, Rubin RH, Talkoff-Rubin N, et al. 1984.. Evolving use of OKT3 monoclonal antibody for treatment of renal allograft rejection. . Transplantation 38:(6):695–700
     [Crossref] [Google Scholar]
  8. 8.
    Blasco LM, Parameshwar J, Vuylsteke A. 2009.. Anaesthesia for noncardiac surgery in the heart transplant recipient. . Curr. Opin. Anaesthesiol. 22:(1):109–13
     [Crossref] [Google Scholar]
  9. 9.
    Reichert JM. 2012.. Marketed therapeutic antibodies compendium. . mAbs 4:(3):413–15
     [Crossref] [Google Scholar]
  10. 10.
    Kaplon H, Crescioli S, Chenoweth A, Visweswaraiah J, Reichert JM. 2023.. Antibodies to watch in 2023. . mAbs 15:(1):2153410
     [Crossref] [Google Scholar]
  11. 11.
    Lyu X, Zhao Q, Hui J, Wang T, Lin M, et al. 2022.. The global landscape of approved antibody therapies. . Antibody Ther. 5:(4):233–57
     [Crossref] [Google Scholar]
  12. 12.
    Wang Z, Wang G, Lu H, Li H, Tang M, Tong A. 2022.. Development of therapeutic antibodies for the treatment of diseases. . Mol. Biomed. 3:(1):35
     [Crossref] [Google Scholar]
  13. 13.
    Zhong X, D'Antona AM. 2021.. Recent advances in the molecular design and applications of multispecific biotherapeutics. . Antibodies 10:(2):13
     [Crossref] [Google Scholar]
  14. 14.
    Carter PJ, Lazar GA. 2018.. Next generation antibody drugs: pursuit of the “high-hanging fruit. .” Nat. Rev. Drug Discov. 17:(3):197–223
     [Crossref] [Google Scholar]
  15. 15.
    Elshiaty M, Schindler H, Christopoulos P. 2021.. Principles and current clinical landscape of multispecific antibodies against cancer. . IJMS 22:(11):5632
     [Crossref] [Google Scholar]
  16. 16.
    Nisonoff A, Rivers MM. 1961.. Recombination of a mixture of univalent antibody fragments of different specificity. . Arch. Biochem. Biophys. 93:(2):460–62
     [Crossref] [Google Scholar]
  17. 17.
    Runcie K, Budman DR, John V, Seetharamu N. 2018.. Bi-specific and tri-specific antibodies—the next big thing in solid tumor therapeutics. . Mol. Med. 24::50
     [Crossref] [Google Scholar]
  18. 18.
    Sawant MS, Streu CN, Wu L, Tessier PM. 2020.. Toward drug-like multispecific antibodies by design. . IJMS 21:(20):7496
     [Crossref] [Google Scholar]
  19. 19.
    Deshaies RJ. 2020.. Multispecific drugs herald a new era of biopharmaceutical innovation. . Nature 580:(7803):329–38
     [Crossref] [Google Scholar]
  20. 20.
    Oostindie SC, Lazar GA, Schuurman J, Parren PWHI. 2022.. Avidity in antibody effector functions and biotherapeutic drug design. . Nat. Rev. Drug Discov. 21:(10):715–35
     [Crossref] [Google Scholar]
  21. 21.
    Labrijn AF, Janmaat ML, Reichert JM, Parren PWHI. 2019.. Bispecific antibodies: a mechanistic review of the pipeline. . Nat. Rev. Drug Discov. 18:(8):585–608
     [Crossref] [Google Scholar]
  22. 22.
    Li Z, Li S, Zhang G, Peng W, Chang Z, et al. 2022.. An engineered bispecific human monoclonal antibody against SARS-CoV-2. . Nat. Immunol. 23:(3):423–30
     [Crossref] [Google Scholar]
  23. 23.
    Sandeep, Shinde SH, Pande AH. 2023.. Polyspecificity—an emerging trend in the development of clinical antibodies. . Mol. Immunol. 155::175–83
     [Crossref] [Google Scholar]
  24. 24.
    van der Horst HJ, Nijhof IS, Mutis T, Chamuleau MED. 2020.. Fc-engineered antibodies with enhanced Fc-effector function for the treatment of B-cell malignancies. . Cancers 12:(10):3041
     [Crossref] [Google Scholar]
  25. 25.
    Burges A, Wimberger P, Kümper C, Gorbounova V, Sommer H, et al. 2007.. Effective relief of malignant ascites in patients with advanced ovarian cancer by a trifunctional anti-EpCAM × anti-CD3 antibody: a phase I/II study. . Clin. Cancer Res. 13:(13):3899–905
     [Crossref] [Google Scholar]
  26. 26.
    Heiss MM, Murawa P, Koralewski P, Kutarska E, Kolesnik OO, et al. 2010.. 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 127:(9):2209–21
     [Crossref] [Google Scholar]
  27. 27.
    Seimetz D, Lindhofer H, Bokemeyer C. 2010.. Development and approval of the trifunctional antibody catumaxomab (anti-EpCAM × anti-CD3) as a targeted cancer immunotherapy. . Cancer Treat. Rev. 36:(6):458–67
     [Crossref] [Google Scholar]
  28. 28.
    Linke R, Klein A, Seimetz D. 2010.. Catumaxomab: clinical development and future directions. . mAbs 2:(2):129–36
     [Crossref] [Google Scholar]
  29. 29.
    Lindhofer H, Mocikat R, Steipe B, Thierfelder S. 1995.. Preferential species-restricted heavy/light chain pairing in rat/mouse quadromas. Implications for a single-step purification of bispecific antibodies. . J. Immunol. 155:(1):219–25
     [Crossref] [Google Scholar]
  30. 30.
    Zeidler R, Reisbach G, Wollenberg B, Lang S, Chaubal S, et al. 1999.. Simultaneous activation of T cells and accessory cells by a new class of intact bispecific antibody results in efficient tumor cell killing. . J. Immunol. 163:(3):1246–52
     [Crossref] [Google Scholar]
  31. 31.
    Zeidler R, Mysliwietz J, Csánady M, Walz A, Ziegler I, et al. 2000.. The Fc-region of a new class of intact bispecific antibody mediates activation of accessory cells and NK cells and induces direct phagocytosis of tumour cells. . Br. J. Cancer 83:(2):261–66
     [Crossref] [Google Scholar]
  32. 32.
    Ma J, Mo Y, Tang M, Shen J, Qi Y, et al. 2021.. Bispecific antibodies: from research to clinical application. . Front. Immunol. 12::626616
     [Crossref] [Google Scholar]
  33. 33.
    Wang S, Chen K, Lei Q, Ma P, Yuan AQ, et al. 2021.. The state of the art of bispecific antibodies for treating human malignancies. . EMBO Mol. Med. 13:(9):e14291
     [Crossref] [Google Scholar]
  34. 34.
    Yuraszeck T, Kasichayanula S, Benjamin J. 2017.. Translation and clinical development of bispecific T-cell engaging antibodies for cancer treatment. . Clin. Pharmacol. Ther. 101:(5):634–45
     [Crossref] [Google Scholar]
  35. 35.
    Przepiorka D, Ko C-W, Deisseroth A, Yancey CL, Candau-Chacon R, et al. 2015.. FDA approval: blinatumomab. . Clin. Cancer Res. 21:(18):4035–39
     [Crossref] [Google Scholar]
  36. 36.
    Topp MS, Gökbuget N, Stein AS, Zugmaier G, O'Brien S, et al. 2015.. Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study. . Lancet Oncol. 16:(1):57–66
     [Crossref] [Google Scholar]
  37. 37.
    Gera N. 2022.. The evolution of bispecific antibodies. . Expert Opin. Biol. Ther. 22:(8):945–49
     [Crossref] [Google Scholar]
  38. 38.
    Wei J, Yang Y, Wang G, Liu M. 2022.. Current landscape and future directions of bispecific antibodies in cancer immunotherapy. . Front. Immunol. 13::1035276
     [Crossref] [Google Scholar]
  39. 39.
    Thieblemont C, Phillips T, Ghesquieres H, Cheah CY, Clausen MR, et al. 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:(12):2238–47
     [Crossref] [Google Scholar]
  40. 40.
    McBride WJ, Zanzonico P, Sharkey RM, Norén C, Karacay H, et al. 2006.. Bispecific antibody pretargeting PET (immunoPET) with an 124I-labeled hapten-peptide. . J. Nucl. Med. 47:(10):1678–88
     [Google Scholar]
  41. 41.
    Foubert F, Gouard S, Saï-Maurel C, Chérel M, Faivre-Chauvet A, et al. 2018.. Sensitivity of pretargeted immunoPET using 68Ga-peptide to detect colonic carcinoma liver metastases in a murine xenograft model: comparison with 18FDG PET-CT. . Oncotarget 9:(44):27502–13
     [Crossref] [Google Scholar]
  42. 42.
    Touchefeu Y, Bailly C, Frampas E, Eugène T, Rousseau C, et al. 2021.. Promising clinical performance of pretargeted immuno-PET with anti-CEA bispecific antibody and gallium-68-labelled IMP-288 peptide for imaging colorectal cancer metastases: a pilot study. . Eur. J. Nucl. Med. Mol. Imaging 48:(3):874–82
     [Crossref] [Google Scholar]
  43. 43.
    Li H, Er Saw P, Song E. 2020.. Challenges and strategies for next-generation bispecific antibody-based antitumor therapeutics. . Cell. Mol. Immunol. 17:(5):451–61
     [Crossref] [Google Scholar]
  44. 44.
    Milstein C, Cuello AC. 1983.. Hybrid hybridomas and their use in immunohistochemistry. . Nature 305:(5934):537–40
     [Crossref] [Google Scholar]
  45. 45.
    Krah S, Kolmar H, Becker S, Zielonka S. 2018.. Engineering IgG-like bispecific antibodies—an overview. . Antibodies 7:(3):28
     [Crossref] [Google Scholar]
  46. 46.
    Bönisch M, Sellmann C, Maresch D, Halbig C, Becker S, et al. 2017.. Novel CH1:CL interfaces that enhance correct light chain pairing in heterodimeric bispecific antibodies. . Protein Eng. Des. Select. 30:(9):685–96
     [Crossref] [Google Scholar]
  47. 47.
    Lewis SM, Wu X, Pustilnik A, Sereno A, Huang F, et al. 2014.. Generation of bispecific IgG antibodies by structure-based design of an orthogonal Fab interface. . Nat. Biotechnol. 32:(2):191–98
     [Crossref] [Google Scholar]
  48. 48.
    Schaefer W, Regula JT, Bähner M, Schanzer J, Croasdale R, et al. 2011.. Immunoglobulin domain crossover as a generic approach for the production of bispecific IgG antibodies. . PNAS 108:(27):11187–92
     [Crossref] [Google Scholar]
  49. 49.
    Dillon M, Yin Y, Zhou J, McCarty L, Ellerman D, et al. 2017.. Efficient production of bispecific IgG of different isotypes and species of origin in single mammalian cells. . mAbs 9:(2):213–30
     [Crossref] [Google Scholar]
  50. 50.
    Krah S, Schröter C, Eller C, Rhiel L, Rasche N, et al. 2017.. Generation of human bispecific common light chain antibodies by combining animal immunization and yeast display. . Protein Eng. Des. Sel. 30:(4):291–301
     [Google Scholar]
  51. 51.
    Mazor Y, Oganesyan V, Yang C, Hansen A, Wang J, et al. 2015.. Improving target cell specificity using a novel monovalent bispecific IgG design. . mAbs 7:(2):377–89
     [Crossref] [Google Scholar]
  52. 52.
    Froning KJ, Leaver-Fay A, Wu X, Phan S, Gao L, et al. 2017.. Computational design of a specific heavy chain/κ light chain interface for expressing fully IgG bispecific antibodies. . Protein Sci. 26:(10):2021–38
     [Crossref] [Google Scholar]
  53. 53.
    Wu X, Sereno AJ, Huang F, Zhang K, Batt M, et al. 2015.. Protein design of IgG/TCR chimeras for the co-expression of Fab-like moieties within bispecific antibodies. . mAbs 7:(2):364–76
     [Crossref] [Google Scholar]
  54. 54.
    Cooke HA, Arndt J, Quan C, Shapiro RI, Wen D, et al. 2018.. EFab domain substitution as a solution to the light-chain pairing problem of bispecific antibodies. . mAbs 10:(8):1248–59
     [Crossref] [Google Scholar]
  55. 55.
    Ridgway JBB, Presta LG, Carter P. 1996.. ‘Knobs-into-holes’ engineering of antibody CH3 domains for heavy chain heterodimerization. . Protein Eng. Des. Sel. 9:(7):617–21
     [Crossref] [Google Scholar]
  56. 56.
    Merchant AM, Zhu Z, Yuan JQ, Goddard A, Adams CW, et al. 1998.. An efficient route to human bispecific IgG. . Nat. Biotechnol. 16:(7):677–81
     [Crossref] [Google Scholar]
  57. 57.
    Davis JH, Aperlo C, Li Y, Kurosawa E, Lan Y, et al. 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:(4):195–202
     [Crossref] [Google Scholar]
  58. 58.
    Leaver-Fay A, Froning KJ, Atwell S, Aldaz H, Pustilnik A, et al. 2016.. Computationally designed bispecific antibodies using negative state repertoires. . Structure 24:(4):641–51
     [Crossref] [Google Scholar]
  59. 59.
    Van Der Neut Kolfschoten M, Schuurman J, Losen M, Bleeker WK, Martínez-Martínez P, et al. 2007.. Anti-inflammatory activity of human IgG4 antibodies by dynamic Fab arm exchange. . Science 317:(5844):1554–57
     [Crossref] [Google Scholar]
  60. 60.
    Labrijn AF, Meesters JI, de Goeij BECG, van den Bremer ETJ, Neijssen J, et al. 2013.. Efficient generation of stable bispecific IgG1 by controlled Fab-arm exchange. . PNAS 110:(13):5145–50
     [Crossref] [Google Scholar]
  61. 61.
    Labrijn AF, Rispens T, Meesters J, Rose RJ, Den Bleker TH, et al. 2011.. Species-specific determinants in the IgG CH3 domain enable Fab-arm exchange by affecting the noncovalent CH3–CH3 interaction strength. . J. Immunol. 187:(6):3238–46
     [Crossref] [Google Scholar]
  62. 62.
    Fischer N, Elson G, Magistrelli G, Dheilly E, Fouque N, et al. 2015.. Exploiting light chains for the scalable generation and platform purification of native human bispecific IgG. . Nat. Commun. 6::6113
     [Crossref] [Google Scholar]
  63. 63.
    Harms BD, Kearns JD, Iadevaia S, Lugovskoy AA. 2014.. Understanding the role of cross-arm binding efficiency in the activity of monoclonal and multispecific therapeutic antibodies. . Methods 65:(1):95–104
     [Crossref] [Google Scholar]
  64. 64.
    Kitazawa T, Shima M. 2020.. Emicizumab, a humanized bispecific antibody to coagulation factors IXa and X with a factor VIIIa-cofactor activity. . Int. J. Hematol. 111:(1):20–30
     [Crossref] [Google Scholar]
  65. 65.
    Sampei Z, Igawa T, Soeda T, Okuyama-Nishida Y, Moriyama C, et al. 2013.. Identification and multidimensional optimization of an asymmetric bispecific IgG antibody mimicking the function of factor VIII cofactor activity. . PLOS ONE 8:(2):e57479
     [Crossref] [Google Scholar]
  66. 66.
    Li JY, Perry SR, Muniz-Medina V, Wang X, Wetzel LK, et al. 2016.. A biparatopic HER2-targeting antibody-drug conjugate induces tumor regression in primary models refractory to or ineligible for HER2-targeted therapy. . Cancer Cell 29:(1):117–29
     [Crossref] [Google Scholar]
  67. 67.
    Bethune G, Bethune D, Ridgway N, Xu Z. 2010.. Epidermal growth factor receptor (EGFR) in lung cancer: an overview and update. . J. Thorac. Dis. 2:(1):48–51
     [Google Scholar]
  68. 68.
    Pérez-Soler R, Chachoua A, Hammond LA, Rowinsky EK, Huberman M, et al. 2004.. Determinants of tumor response and survival with erlotinib in patients with non–small-cell lung cancer. . J. Clin. Oncol. 22:(16):3238–47
     [Crossref] [Google Scholar]
  69. 69.
    Kobayashi S, Boggon TJ, Dayaram T, Jänne PA, Kocher O, et al. 2005.. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. . N. Engl. J. Med. 352:(8):786–92
     [Crossref] [Google Scholar]
  70. 70.
    Sequist LV, Waltman BA, Dias-Santagata D, Digumarthy S, Turke AB, et al. 2011.. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. . Sci. Transl. Med. 3:(75):75ra26
     [Crossref] [Google Scholar]
  71. 71.
    Yano S, Yamada T, Takeuchi S, Tachibana K, Minami Y, et al. 2011.. Hepatocyte growth factor expression in EGFR mutant lung cancer with intrinsic and acquired resistance to tyrosine kinase inhibitors in a Japanese cohort. . J. Thorac. Oncol. 6:(12):2011–17
     [Crossref] [Google Scholar]
  72. 72.
    Turke AB, Zejnullahu K, Wu Y-L, Song Y, Dias-Santagata D, et al. 2010.. Preexistence and clonal selection of MET amplification in EGFR mutant NSCLC. . Cancer Cell 17:(1):77–88
     [Crossref] [Google Scholar]
  73. 73.
    Moores SL, Chiu ML, Bushey BS, Chevalier K, Luistro L, et al. 2016.. A novel bispecific antibody targeting EGFR and cMet is effective against EGFR inhibitor-resistant lung tumors. . Cancer Res. 76:(13):3942–53
     [Crossref] [Google Scholar]
  74. 74.
    Satoh M, Iida S, Shitara K. 2006.. Non-fucosylated therapeutic antibodies as next-generation therapeutic antibodies. . Expert Opin. Biol. Ther. 6:(11):1161–73
     [Crossref] [Google Scholar]
  75. 75.
    Geuijen CAW, Nardis CD, Maussang D, Rovers E, Gallenne T, et al. 2018.. Unbiased combinatorial screening identifies a bispecific IgG1 that potently inhibits HER3 signaling via HER2-guided ligand blockade. . Cancer Cell 33:(5):922–36.e10
     [Crossref] [Google Scholar]
  76. 76.
    Schram AM, Drilon AE, Macarulla T, O'Reilly EM, Rodon J, et al. 2020.. A phase II basket study of MCLA-128, a bispecific antibody targeting the HER3 pathway, in NRG1 fusion-positive advanced solid tumors. . J. Clin. Oncol. 38:(15 Suppl.):TPS3654
     [Crossref] [Google Scholar]
  77. 77.
    Feng L, Qi Q, Wang P, Chen H, Chen Z, et al. 2018.. Serum levels of IL-6, IL-8, and IL-10 are indicators of prognosis in pancreatic cancer. . J. Int. Med. Res. 46:(12):5228–36
     [Crossref] [Google Scholar]
  78. 78.
    Kozłowski L, Zakrzewska I, Tokajuk P, Wojtukiewicz MZ. 2003.. Concentration of interleukin-6 (IL-6), interleukin-8 (IL-8) and interleukin-10 (IL-10) in blood serum of breast cancer patients. . Rocz. Akad. Med. Białymstoku 48::82–84
     [Google Scholar]
  79. 79.
    Ueda T, Shimada E, Urakawa T. 1994.. Serum levels of cytokines in patients with colorectal cancer: possible involvement of interleukin-6 and interleukin-8 in hematogenous metastasis. . J. Gastroenterol. 29:(4):423–29
     [Crossref] [Google Scholar]
  80. 80.
    Jayatilaka H, Tyle P, Chen JJ, Kwak M, Ju J, et al. 2017.. Synergistic IL-6 and IL-8 paracrine signalling pathway infers a strategy to inhibit tumour cell migration. . Nat. Commun. 8::15584
     [Crossref] [Google Scholar]
  81. 81.
    Yang H, Karl MN, Wang W, Starich B, Tan H, et al. 2022.. Engineered bispecific antibodies targeting the interleukin-6 and -8 receptors potently inhibit cancer cell migration and tumor metastasis. . Mol. Ther. 30:(11):3430–49
     [Crossref] [Google Scholar]
  82. 82.
    Chuntharapai A, Lee J, Hébert CA, Kim KJ. 1994.. Monoclonal antibodies detect different distribution patterns of IL-8 receptor A and IL-8 receptor B on human peripheral blood leukocytes. . J. Immunol. 153:(12):5682–88
     [Crossref] [Google Scholar]
  83. 83.
    Ashkenazi A, Dixit VM. 1998.. Death receptors: signaling and modulation. . Science 281:(5381):1305–8
     [Crossref] [Google Scholar]
  84. 84.
    Pan L, Fu T-M, Zhao W, Zhao L, Chen W, et al. 2019.. Higher-order clustering of the transmembrane anchor of DR5 drives signaling. . Cell 176:(6):1477–89.e14
     [Crossref] [Google Scholar]
  85. 85.
    Yang A, Wilson NS, Ashkenazi A. 2010.. Proapoptotic DR4 and DR5 signaling in cancer cells: toward clinical translation. . Curr. Opin. Cell Biol. 22:(6):837–44
     [Crossref] [Google Scholar]
  86. 86.
    Herbst RS, Kurzrock R, Hong DS, Valdivieso M, Hsu C-P, et al. 2010.. A first-in-human study of conatumumab in adult patients with advanced solid tumors. . Clin. Cancer Res. 16:(23):5883–91
     [Crossref] [Google Scholar]
  87. 87.
    Kindler HL, Richards DA, Garbo LE, Garon EB, Stephenson JJ, et al. 2012.. A randomized, placebo-controlled phase 2 study of ganitumab (AMG 479) or conatumumab (AMG 655) in combination with gemcitabine in patients with metastatic pancreatic cancer. . Ann. Oncol. 23:(11):2834–42
     [Crossref] [Google Scholar]
  88. 88.
    Wiezorek J, Holland P, Graves J. 2010.. Death receptor agonists as a targeted therapy for cancer. . Clin. Cancer Res. 16:(6):1701–8
     [Crossref] [Google Scholar]
  89. 89.
    Brennen WN, Isaacs JT, Denmeade SR. 2012.. Rationale behind targeting fibroblast activation protein-expressing carcinoma-associated fibroblasts as a novel chemotherapeutic strategy. . Mol. Cancer Ther. 11:(2):257–66
     [Crossref] [Google Scholar]
  90. 90.
    Garin-Chesa P, Old LJ, Rettig WJ. 1990.. Cell surface glycoprotein of reactive stromal fibroblasts as a potential antibody target in human epithelial cancers. . PNAS 87:(18):7235–39
     [Crossref] [Google Scholar]
  91. 91.
    Rettig WJ, Garin-Chesa P, Healey JH, Su SL, Ozer HL, et al. 1993.. Regulation and heteromeric structure of the fibroblast activation protein in normal and transformed cells of mesenchymal and neuroectodermal origin. . Cancer Res. 53:(14):3327–35
     [Google Scholar]
  92. 92.
    Brünker P, Wartha K, Friess T, Grau-Richards S, Waldhauer I, et al. 2016.. RG7386, a novel tetravalent FAP-DR5 antibody, effectively triggers FAP-dependent, avidity-driven DR5 hyperclustering and tumor cell apoptosis. . Mol. Cancer Ther. 15:(5):946–57
     [Crossref] [Google Scholar]
  93. 93.
    Akbari B, Farajnia S, Ahdi Khosroshahi S, Safari F, Yousefi M, et al. 2017.. Immunotoxins in cancer therapy: review and update. . Int. Rev. Immunol. 36:(4):207–19
     [Crossref] [Google Scholar]
  94. 94.
    Silver AB, Leonard EK, Gould JR, Spangler JB. 2021.. Engineered antibody fusion proteins for targeted disease therapy. . Trends Pharmacol. Sci. 42:(12):1064–81
     [Crossref] [Google Scholar]
  95. 95.
    Vallera DA, Todhunter DA, Kuroki DW, Shu Y, Sicheneder A, Chen H. 2005.. A bispecific recombinant immunotoxin, DT2219, targeting human CD19 and CD22 receptors in a mouse xenograft model of B-cell leukemia/lymphoma. . Clin. Cancer Res. 11:(10):3879–88
     [Crossref] [Google Scholar]
  96. 96.
    Bachanova V, Frankel AE, Cao Q, Lewis D, Grzywacz B, et al. 2015.. Phase I study of a bispecific ligand-directed toxin targeting CD22 and CD19 (DT2219) for refractory B-cell malignancies. . Clin. Cancer Res. 21:(6):1267–72
     [Crossref] [Google Scholar]
  97. 97.
    Masonic Cancer Cent., Univ. Minn. 2019.. HM2014–26 DT2219 immunotoxin for the treatment of relapsed or refractory CD19 (+) and/or CD 22 (+) B-lineage leukemia or lymphoma. Clin. Trial NCT02370160. https://classic.clinicaltrials.gov/ProvidedDocs/60/NCT02370160/Prot_SAP_000.pdf
    [Google Scholar]
  98. 98.
    Berntorp E, Fischer K, Hart DP, Mancuso ME, Stephensen D, et al. 2021.. Haemophilia. . Nat. Rev. Dis. Prim. 7::45
     [Crossref] [Google Scholar]
  99. 99.
    Kitazawa T, Igawa T, Sampei Z, Muto A, Kojima T, et al. 2012.. A bispecific antibody to factors IXa and X restores factor VIII hemostatic activity in a hemophilia A model. . Nat. Med. 18:(10):1570–74
     [Crossref] [Google Scholar]
  100. 100.
    Lippi G, Favaloro EJ. 2019.. Emicizumab (ACE910): clinical background and laboratory assessment of hemophilia A. . Adv. Clin. Chem. 88::151–67
     [Crossref] [Google Scholar]
  101. 101.
    US Food Drug Adm. (FDA). 2019.. FDA approves emicizumab-kxwh for hemophilia A with or without factor VIII inhibitors. Approv. , FDA, Washington, DC:
     [Google Scholar]
  102. 102.
    Rattner A, Williams J, Nathans J. 2019.. Roles of HIFs and VEGF in angiogenesis in the retina and brain. . J. Clin. Investig. 129:(9):3807–20
     [Crossref] [Google Scholar]
  103. 103.
    Schwarzer P, Ebneter A, Munk M, Wolf S, Zinkernagel MS. 2019.. One-year results of using a treat-and-extend regimen without a loading phase with anti-VEGF agents in patients with treatment-naive diabetic macular edema. . Ophthalmologica 241:(4):220–25
     [Crossref] [Google Scholar]
  104. 104.
    Nicolò M, Morlacchi A, Cappelli F, Ferro Desideri L, Colombo V, et al. 2020.. Real-life data in the treatment of neovascular age-related macular degeneration: results from the Imaculaweb registry evaluated in a single Italian medical retina center. . Ophthalmologica 243:(6):453–60
     [Crossref] [Google Scholar]
  105. 105.
    Battaglia Parodi M, Romano F, Arrigo A, Sacchi R, Scanzi G, et al. 2020.. Real-life anti-vascular endothelial growth factor treatment for age-related macular degeneration and diabetic macular edema in an Italian tertiary referral hospital. . Eur. J. Ophthalmol. 30:(6):1461–66
     [Crossref] [Google Scholar]
  106. 106.
    Saharinen P, Eklund L, Alitalo K. 2017.. Therapeutic targeting of the angiopoietin-TIE pathway. . Nat. Rev. Drug Discov. 16:(9):635–61
     [Crossref] [Google Scholar]
  107. 107.
    Thurston G, Daly C. 2012.. The complex role of angiopoietin-2 in the angiopoietin-tie signaling pathway. . Cold Spring Harb. Perspect. Med. 2:(9):a006550
     [Crossref] [Google Scholar]
  108. 108.
    Ferro Desideri L, Traverso CE, Nicolò M, Munk MR. 2023.. Faricimab for the treatment of diabetic macular edema and neovascular age-related macular degeneration. . Pharmaceutics 15:(5):1413
     [Crossref] [Google Scholar]
  109. 109.
    Scott AM, Wolchok JD, Old LJ. 2012.. Antibody therapy of cancer. . Nat. Rev. Cancer 12:(4):278–87
     [Crossref] [Google Scholar]
  110. 110.
    Pedersen MW, Jacobsen HJ, Koefoed K, Hey A, Pyke C, et al. 2010.. Sym004: a novel synergistic anti-epidermal growth factor receptor antibody mixture with superior anticancer efficacy. . Cancer Res. 70:(2):588–97
     [Crossref] [Google Scholar]
  111. 111.
    Friedman LM, Rinon A, Schechter B, Lyass L, Lavi S, et al. 2005.. Synergistic down-regulation of receptor tyrosine kinases by combinations of mAbs: implications for cancer immunotherapy. . PNAS 102:(6):1915–20
     [Crossref] [Google Scholar]
  112. 112.
    Perera RM, Narita Y, Furnari FB, Gan HK, Murone C, et al. 2005.. Treatment of human tumor xenografts with monoclonal antibody 806 in combination with a prototypical epidermal growth factor receptor-specific antibody generates enhanced antitumor activity. . Clin. Cancer Res. 11:(17):6390–99
     [Crossref] [Google Scholar]
  113. 113.
    Kamat V, Donaldson JM, Kari C, Quadros MRD, Lelkes PI, et al. 2008.. Enhanced EGFR inhibition and distinct epitope recognition by EGFR antagonistic mAbs C225 and 425. . Cancer Biol. Ther. 7:(5):726–33
     [Crossref] [Google Scholar]
  114. 114.
    Spangler JB, Neil JR, Abramovitch S, Yarden Y, White FM, et al. 2010.. Combination antibody treatment down-regulates epidermal growth factor receptor by inhibiting endosomal recycling. . PNAS 107:(30):13252–57
     [Crossref] [Google Scholar]
  115. 115.
    Spangler JB, Manzari MT, Rosalia EK, Chen TF, Wittrup KD. 2012.. Triepitopic antibody fusions inhibit cetuximab-resistant BRAF and KRAS mutant tumors via EGFR signal repression. . J. Mol. Biol. 422:(4):532–44
     [Crossref] [Google Scholar]
  116. 116.
    Gennari R, Menard S, Fagnoni F, Ponchio L, Scelsi M, et al. 2004.. Pilot study of the mechanism of action of preoperative trastuzumab in patients with primary operable breast tumors overexpressing HER2. . Clin. Cancer Res. 10:(17):5650–55
     [Crossref] [Google Scholar]
  117. 117.
    Austin CD, De Mazière AM, Pisacane PI, van Dijk SM, Eigenbrot C, et al. 2004.. Endocytosis and sorting of ErbB2 and the site of action of cancer therapeutics trastuzumab and geldanamycin. . Mol. Biol. Cell 15:(12):5268–82
     [Crossref] [Google Scholar]
  118. 118.
    Portera CC, Walshe JM, Rosing DR, Denduluri N, Berman AW, et al. 2008.. Cardiac toxicity and efficacy of trastuzumab combined with pertuzumab in patients with trastuzumab-insensitive human epidermal growth factor receptor 2-positive metastatic breast cancer. . Clin. Cancer Res. 14:(9):2710–16
     [Crossref] [Google Scholar]
  119. 119.
    Baselga J, Gelmon KA, Verma S, Wardley A, Conte P, et al. 2010.. Phase II trial of pertuzumab and trastuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer that progressed during prior trastuzumab therapy. . J. Clin. Oncol. 28:(7):1138–44
     [Crossref] [Google Scholar]
  120. 120.
    Hughes JB, Rødland MS, Hasmann M, Madshus IH, Stang E. 2012.. Pertuzumab increases 17-AAG-induced degradation of ErbB2, and this effect is further increased by combining pertuzumab with trastuzumab. . Pharmaceuticals 5:(7):674–89
     [Crossref] [Google Scholar]
  121. 121.
    Nahta R, Hung M-C, Esteva FJ. 2004.. The HER-2-targeting antibodies trastuzumab and pertuzumab synergistically inhibit the survival of breast cancer cells. . Cancer Res. 64:(7):2343–46
     [Crossref] [Google Scholar]
  122. 122.
    Bon G, Pizzuti L, Laquintana V, Loria R, Porru M, et al. 2020.. Loss of HER2 and decreased T-DM1 efficacy in HER2 positive advanced breast cancer treated with dual HER2 blockade: the SePHER Study. . J. Exp. Clin. Cancer Res. 39::279
     [Crossref] [Google Scholar]
  123. 123.
    Kelton C, Wesolowski JS, Soloviev M, Schweickhardt R, Fischer D, et al. 2012.. Anti-EGFR biparatopic-SEED antibody has enhanced combination-activity in a single molecule. . Arch. Biochem. Biophys. 526:(2):219–25
     [Crossref] [Google Scholar]
  124. 124.
    Weisser NE, Sanches M, Escobar-Cabrera E, O'Toole J, Whalen E, et al. 2023.. An anti-HER2 biparatopic antibody that induces unique HER2 clustering and complement-dependent cytotoxicity. . Nat. Commun. 14::1394
     [Crossref] [Google Scholar]
  125. 125.
    Meric-Bernstam F, Beeram M, Hamilton E, Oh D-Y, Hanna DL, et al. 2022.. 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. 23:(12):1558–70
     [Crossref] [Google Scholar]
  126. 126.
    Caffrey M. 2023.. Zanidatamab, with biparatopic binding to HER2, shows 84% OS in phase 2 study of gastroesophageal adenocarcinoma. . Evid.-Based Oncol. 29::SP104
     [Google Scholar]
  127. 127.
    Stüber JC, Richter CP, Bellón JS, Schwill M, König I, et al. 2021.. Apoptosis-inducing anti-HER2 agents operate through oligomerization-induced receptor immobilization. . Commun. Biol. 4::762
     [Crossref] [Google Scholar]
  128. 128.
    Fiedler U, Metz C, Zitt C, Bessey R, Béhé M, et al. 2017.. Abstract P4-21-18: pre-clinical antitumor activity, tumor localization, and pharmacokinetics of MP0274, an apoptosis inducing, biparatopic HER2-targeting DARPin®. . Cancer Res. 77:(4 Suppl.):P4–21-18
     [Google Scholar]
  129. 129.
    Baird R, Omlin A, Kiemle-Kallee J, Fiedler U, Zitt C, et al. 2018.. Abstract OT1-03-02: MP0274-CP101: a phase 1, first-in-human, single-arm, multi-center, open-label, dose escalation study to assess safety, tolerability, and pharmacokinetics of MP0274 in patients with advanced HER2-positive solid tumors. . Cancer Res. 78:(4 Suppl.):OT1–03-02
     [Google Scholar]
  130. 130.
    Robak T. 2013.. Emerging monoclonal antibodies and related agents for the treatment of chronic lymphocytic leukemia. . Future Oncol. 9:(1):69–91
     [Crossref] [Google Scholar]
  131. 131.
    Beckwith KA, Byrd JC, Muthusamy N. 2015.. Tetraspanins as therapeutic targets in hematological malignancy: a concise review. . Front. Physiol. 6::91
     [Crossref] [Google Scholar]
  132. 132.
    Witkowska M, Smolewski P, Robak T. 2018.. Investigational therapies targeting CD37 for the treatment of B-cell lymphoid malignancies. . Expert Opin. Investig. Drugs 27:(2):171–77
     [Crossref] [Google Scholar]
  133. 133.
    Payandeh Z, Noori E, Khalesi B, Mard-Soltani M, Abdolalizadeh J, Khalili S. 2018.. Anti-CD37 targeted immunotherapy of B-cell malignancies. . Biotechnol. Lett. 40:(11):1459–66
     [Crossref] [Google Scholar]
  134. 134.
    de Winde CM, Zuidscherwoude M, Vasaturo A, van der Schaaf A, Figdor CG, van Spriel AB. 2015.. Multispectral imaging reveals the tissue distribution of tetraspanins in human lymphoid organs. . Histochem. Cell Biol. 144:(2):133–46
     [Crossref] [Google Scholar]
  135. 135.
    Link MP, Bindl J, Meeker TC, Carswell C, Doss CA, et al. 1986.. A unique antigen on mature B cells defined by a monoclonal antibody. . J. Immunol. 137:(9):3013–18
     [Crossref] [Google Scholar]
  136. 136.
    Schwartz-Albiez R, Dörken B, Hofmann W, Moldenhauer G. 1988.. The B cell-associated CD37 antigen (gp40–52). Structure and subcellular expression of an extensively glycosylated glycoprotein. . J. Immunol. 140:(3):905–14
     [Crossref] [Google Scholar]
  137. 137.
    Oostindie SC, van der Horst HJ, Kil LP, Strumane K, Overdijk MB, et al. 2020.. DuoHexaBody-CD37®, a novel biparatopic CD37 antibody with enhanced Fc-mediated hexamerization as a potential therapy for B-cell malignancies. . Blood Cancer J. 10::30
     [Crossref] [Google Scholar]
  138. 138.
    Kast F, Schwill M, Stüber JC, Pfundstein S, Nagy-Davidescu G, et al. 2021.. Engineering an anti-HER2 biparatopic antibody with a multimodal mechanism of action. . Nat. Commun. 12::3790
     [Crossref] [Google Scholar]
  139. 139.
    Cheng J, Liang M, Carvalho MF, Tigue N, Faggioni R, et al. 2020.. Molecular mechanism of HER2 rapid internalization and redirected trafficking induced by anti-HER2 biparatopic antibody. . Antibodies 9:(3):49
     [Crossref] [Google Scholar]
  140. 140.
    DaSilva JO, Yang K, Perez Bay AE, Andreev J, Ngoi P, et al. 2020.. A biparatopic antibody that modulates MET trafficking exhibits enhanced efficacy compared with parental antibodies in MET-driven tumor models. . Clin. Cancer Res. 26:(6):1408–19
     [Crossref] [Google Scholar]
  141. 141.
    Geoghegan JC, Diedrich G, Lu X, Rosenthal K, Sachsenmeier KF, et al. 2016.. Inhibition of CD73 AMP hydrolysis by a therapeutic antibody with a dual, non-competitive mechanism of action. . mAbs 8:(3):454–67
     [Crossref] [Google Scholar]
  142. 142.
    Stefano JE, Lord DM, Zhou Y, Jaworski J, Hopke J, et al. 2020.. A highly potent CD73 biparatopic antibody blocks organization of the enzyme active site through dual mechanisms. . J. Biol. Chem. 295:(52):18379–89
     [Crossref] [Google Scholar]
  143. 143.
    Benedetti F, Stadlbauer K, Stadlmayr G, Rüker F, Wozniak-Knopp G. 2021.. A tetravalent biparatopic antibody causes strong HER2 internalization and inhibits cellular proliferation. . Life 11:(11):1157
     [Crossref] [Google Scholar]
  144. 144.
    Moody PR, Sayers EJ, Magnusson JP, Alexander C, Borri P, et al. 2015.. Receptor crosslinking: a general method to trigger internalization and lysosomal targeting of therapeutic receptor:ligand complexes. . Mol. Ther. 23:(12):1888–98
     [Crossref] [Google Scholar]
  145. 145.
    Mesa N. 2023.. Biopharma bets big on antibody-drug conjugates. . BioSpace, May 8. https://www.biospace.com/article/biopharma-bets-big-on-antibody-drug-conjugates/
    [Google Scholar]
  146. 146.
    Fu Z, Li S, Han S, Shi C, Zhang Y. 2022.. Antibody drug conjugate: the “biological missile” for targeted cancer therapy. . Signal Transduct. Target. Ther. 7:(1):93
     [Crossref] [Google Scholar]
  147. 147.
    Pegram MD, Hamilton EP, Tan AR, Storniolo AM, Balic K, et al. 2021.. 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. 20:(8):1442–53
     [Crossref] [Google Scholar]
  148. 148.
    Zhang X, Huang AC, Chen F, Chen H, Li L, et al. 2022.. Novel development strategies and challenges for anti-Her2 antibody-drug conjugates. . Antib. Ther. 5:(1):18–29
     [Google Scholar]
  149. 149.
    Hamblett K, Barnscher S, Davies R, Hammond P, Hernandez A, et al. 2019.. Abstract P6-17-13: ZW49, a HER2 targeted biparatopic antibody drug conjugate for the treatment of HER2 expressing cancers. . Cancer Res. 79:(4 Suppl.):P6–17-13
     [Google Scholar]
  150. 150.
    Escrivá-de-Romaní S, Saura C. 2023.. The change of paradigm in the treatment of HER2-positive breast cancer with the development of new generation antibody-drug conjugates. . Cancer Drug Resist. 6:(1):45–58
     [Crossref] [Google Scholar]
  151. 151.
    Bracken CJ, Lim SA, Solomon P, Rettko NJ, Nguyen DP, et al. 2021.. Bi-paratopic and multivalent VH domains block ACE2 binding and neutralize SARS-CoV-2. . Nat. Chem. Biol. 17:(1):113–21
     [Crossref] [Google Scholar]
  152. 152.
    Wagner TR, Schnepf D, Beer J, Ruetalo N, Klingel K, et al. 2022.. Biparatopic nanobodies protect mice from lethal challenge with SARS-CoV-2 variants of concern. . EMBO Rep. 23:(2):e53865
     [Crossref] [Google Scholar]
  153. 153.
    Jhajj HS, Lwo TS, Yao EL, Tessier PM. 2023.. Unlocking the potential of agonist antibodies for treating cancer using antibody engineering. . Trends Mol. Med. 29:(1):48–60
     [Crossref] [Google Scholar]
  154. 154.
    Watts TH. 2005.. TNF/TNFR family members in costimulation of T cell responses. . Annu. Rev. Immunol. 23::23–68
     [Crossref] [Google Scholar]
  155. 155.
    Schardt JS, Jhajj HS, O'Meara RL, Lwo TS, Smith MD, Tessier PM. 2022.. Agonist antibody discovery: experimental, computational, and rational engineering approaches. . Drug Discov. Today 27:(1):31–48
     [Crossref] [Google Scholar]
  156. 156.
    Yang Y, Yeh SH, Madireddi S, Matochko WL, Gu C, et al. 2019.. Tetravalent biepitopic targeting enables intrinsic antibody agonism of tumor necrosis factor receptor superfamily members. . mAbs 11:(6):996–1011
     [Crossref] [Google Scholar]
  157. 157.
    Overdijk MB, Strumane K, Beurskens FJ, Ortiz Buijsse A, Vermot-Desroches C, et al. 2020.. Dual epitope targeting and enhanced hexamerization by DR5 antibodies as a novel approach to induce potent antitumor activity through DR5 agonism. . Mol. Cancer Ther. 19:(10):2126–38
     [Crossref] [Google Scholar]
  158. 158.
    Seimetz D, Lindhofer H, Bokemeyer C. 2010.. Development and approval of the trifunctional antibody catumaxomab (anti-EpCAM × anti-CD3) as a targeted cancer immunotherapy. . Cancer Treat. Rev. 36:(6):458–67
     [Crossref] [Google Scholar]
  159. 159.
    Franquiz MJ, Short NJ. 2020.. Blinatumomab for the treatment of adult B-cell acute lymphoblastic leukemia: toward a new era of targeted immunotherapy. . Biologics 14::23–34
     [Google Scholar]
  160. 160.
    Kong Y, Yoshida S, Saito Y, Doi T, Nagatoshi Y, et al. 2008.. CD34+CD38+CD19+ as well as CD34+CD38-CD19+ cells are leukemia-initiating cells with self-renewal capacity in human B-precursor ALL. . Leukemia 22:(6):1207–13
     [Crossref] [Google Scholar]
  161. 161.
    US Food Drug Adm. (FDA). 2018.. FDA grants regular approval to blinatumomab and expands indication to include Philadelphia chromosome-positive B cell. Approv. , FDA, Washington, DC:
     [Google Scholar]
  162. 162.
    Nagorsen D, Kufer P, Baeuerle PA, Bargou R. 2012.. Blinatumomab: a historical perspective. . Pharmacol. Ther. 136:(3):334–42
     [Crossref] [Google Scholar]
  163. 163.
    Teachey DT, Rheingold SR, Maude SL, Zugmaier G, Barrett DM, et al. 2013.. Cytokine release syndrome after blinatumomab treatment related to abnormal macrophage activation and ameliorated with cytokine-directed therapy. . Blood 121:(26):5154–57
     [Crossref] [Google Scholar]
  164. 164.
    Stein AS, Schiller G, Benjamin R, Jia C, Zhang A, et al. 2019.. Neurologic adverse events in patients with relapsed/refractory acute lymphoblastic leukemia treated with blinatumomab: management and mitigating factors. . Ann. Hematol. 98:(1):159–67
     [Crossref] [Google Scholar]
  165. 165.
    Goebeler M-E, Knop S, Viardot A, Kufer P, Topp MS, et al. 2016.. Bispecific T-cell engager (BiTE) antibody construct blinatumomab for the treatment of patients with relapsed/refractory non-Hodgkin lymphoma: final results from a phase I study. . J. Clin. Oncol. 34:(10):1104–11
     [Crossref] [Google Scholar]
  166. 166.
    Hosseini I, Gadkar K, Stefanich E, Li C-C, Sun LL, et al. 2020.. Mitigating the risk of cytokine release syndrome in a Phase I trial of CD20/CD3 bispecific antibody mosunetuzumab in NHL: impact of translational system modeling. . NPJ Syst. Biol. Appl. 6::28
     [Crossref] [Google Scholar]
  167. 167.
    US Food Drug Adm. (FDA). 2023.. FDA D.I.S.C.O. Burst Edition: FDA approval of Lunsumio (mosunetuzumab-axgb) for adult patients with relapsed or refractory follicular lymphoma after two or more lines of systemic therapy. Approv. , FDA, Washington, DC:
     [Google Scholar]
  168. 168.
    Pillarisetti K, Powers G, Luistro L, Babich A, Baldwin E, et al. 2020.. Teclistamab is an active T cell-redirecting bispecific antibody against B-cell maturation antigen for multiple myeloma. . Blood Adv. 4:(18):4538–49
     [Crossref] [Google Scholar]
  169. 169.
    US Food Drug Adm. (FDA). 2022.. FDA approves teclistamab-cqyv for relapsed or refractory multiple myeloma. Approv., FDA, Washington, DC:
     [Google Scholar]
  170. 170.
    Oates J, Jakobsen BK. 2013.. ImmTACs: novel bi-specific agents for targeted cancer therapy. . Oncoimmunology 2:(2):e22891
     [Crossref] [Google Scholar]
  171. 171.
    Middleton MR, McAlpine C, Woodcock VK, Corrie P, Infante JR, et al. 2020.. Tebentafusp, a TCR/Anti-CD3 bispecific fusion protein targeting gp100, potently activated antitumor immune responses in patients with metastatic melanoma. . Clin. Cancer Res. 26:(22):5869–78
     [Crossref] [Google Scholar]
  172. 172.
    Allele Freq. Net Database. 2023.. HLA allele frequencies. https://www.allelefrequencies.net
    [Google Scholar]
  173. 173.
    Boudousquie C, Bossi G, Hurst JM, Rygiel KA, Jakobsen BK, Hassan NJ. 2017.. Polyfunctional response by ImmTAC (IMCgp100) redirected CD8+ and CD4+ T cells. . Immunology 152:(3):425–38
     [Crossref] [Google Scholar]
  174. 174.
    Liddy N, Bossi G, Adams KJ, Lissina A, Mahon TM, et al. 2012.. Monoclonal TCR-redirected tumor cell killing. . Nat. Med. 18:(6):980–87
     [Crossref] [Google Scholar]
  175. 175.
    Nathan P, Hassel JC, Rutkowski P, Baurain J-F, Butler MO, et al. 2021.. Overall survival benefit with tebentafusp in metastatic uveal melanoma. . N. Engl. J. Med. 385:(13):1196–206
     [Crossref] [Google Scholar]
  176. 176.
    Carvajal RD, Butler MO, Shoushtari AN, Hassel JC, Ikeguchi A, et al. 2022.. Clinical and molecular response to tebentafusp in previously treated patients with metastatic uveal melanoma: a phase 2 trial. . Nat. Med. 28:(11):2364–73
     [Crossref] [Google Scholar]
  177. 177.
    US Food Drug Adm. (FDA). 2022.. FDA approves tebentafusp-tebn for unresectable or metastatic uveal melanoma. Approv. , FDA, Washington, DC:
     [Google Scholar]
  178. 178.
    Nordstrom JL, Ferrari G, Margolis DM. 2022.. Bispecific antibody-derived molecules to target persistent HIV infection. . J. Virus Erad. 8:(3):100083
     [Crossref] [Google Scholar]
  179. 179.
    MacroGenics. 2023.. A study of MGD020 alone or combined with MGD014 in persons with HIV-1 on antiretroviral therapy. NCT05261191 . https://clinicaltrials.gov/study/NCT05261191
    [Google Scholar]
  180. 180.
    Linsley PS, Greene JL, Brady W, Bajorath J, Ledbetter JA, Peach R. 1994.. Human B7–1 (CD80) and B7–2 (CD86) bind with similar avidities but distinct kinetics to CD28 and CTLA-4 receptors. . Immunity 1:(9):793–801
     [Crossref] [Google Scholar]
  181. 181.
    Riley JL, Mao M, Kobayashi S, Biery M, Burchard J, et al. 2002.. Modulation of TCR-induced transcriptional profiles by ligation of CD28, ICOS, and CTLA-4 receptors. . PNAS 99:(18):11790–95
     [Crossref] [Google Scholar]
  182. 182.
    Schneider H, Downey J, Smith A, Zinselmeyer BH, Rush C, et al. 2006.. Reversal of the TCR stop signal by CTLA-4. . Science 313:(5795):1972–75
     [Crossref] [Google Scholar]
  183. 183.
    Qureshi OS, Zheng Y, Nakamura K, Attridge K, Manzotti C, et al. 2011.. Trans-endocytosis of CD80 and CD86: a molecular basis for the cell-extrinsic function of CTLA-4. . Science 332:(6029):600–3
     [Crossref] [Google Scholar]
  184. 184.
    Korman AJ, Peggs KS, Allison JP. 2006.. Checkpoint blockade in cancer immunotherapy. . Adv. Immunol. 90::297–339
     [Crossref] [Google Scholar]
  185. 185.
    De Sousa Linhares A, Leitner J, Grabmeier-Pfistershammer K, Steinberger P. 2018.. Not all immune checkpoints are created equal. . Front. Immunol. 9::1909
     [Crossref] [Google Scholar]
  186. 186.
    Ishida Y, Agata Y, Shibahara K, Honjo T. 1992.. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. . EMBO J. 11:(11):3887–95
     [Crossref] [Google Scholar]
  187. 187.
    Freeman GJ, Long AJ, Iwai Y, Bourque K, Chernova T, et al. 2000.. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. . J. Exp. Med. 192:(7):1027–34
     [Crossref] [Google Scholar]
  188. 188.
    Keir ME, Liang SC, Guleria I, Latchman YE, Qipo A, et al. 2006.. Tissue expression of PD-L1 mediates peripheral T cell tolerance. . J. Exp. Med. 203:(4):883–95
     [Crossref] [Google Scholar]
  189. 189.
    Keir ME, Butte MJ, Freeman GJ, Sharpe AH. 2008.. PD-1 and its ligands in tolerance and immunity. . Annu. Rev. Immunol. 26::677–704
     [Crossref] [Google Scholar]
  190. 190.
    Topalian SL, Drake CG, Pardoll DM. 2015.. Immune checkpoint blockade: a common denominator approach to cancer therapy. . Cancer Cell 27:(4):450–61
     [Crossref] [Google Scholar]
  191. 191.
    Seidel JA, Otsuka A, Kabashima K. 2018.. Anti-PD-1 and anti-CTLA-4 therapies in cancer: mechanisms of action, efficacy, and limitations. . Front. Oncol. 8::86
     [Crossref] [Google Scholar]
  192. 192.
    Vaddepally RK, Kharel P, Pandey R, Garje R, Chandra AB. 2020.. Review of indications of FDA-approved immune checkpoint inhibitors per NCCN guidelines with the level of evidence. . Cancers 12:(3):738
     [Crossref] [Google Scholar]
  193. 193.
    Chester C, Sanmamed MF, Wang J, Melero I. 2018.. Immunotherapy targeting 4-1BB: mechanistic rationale, clinical results, and future strategies. . Blood 131:(1):49–57
     [Crossref] [Google Scholar]
  194. 194.
    Fisher TS, Kamperschroer C, Oliphant T, Love VA, Lira PD, et al. 2012.. Targeting of 4–1BB by monoclonal antibody PF-05082566 enhances T-cell function and promotes anti-tumor activity. . Cancer Immunol. Immunother. 61:(10):1721–33
     [Crossref] [Google Scholar]
  195. 195.
    Rotte A. 2019.. Combination of CTLA-4 and PD-1 blockers for treatment of cancer. . J. Exp. Clin. Cancer Res. 38:(1):255
     [Crossref] [Google Scholar]
  196. 196.
    Hodi FS, Chesney J, Pavlick AC, Robert C, Grossmann KF, et al. 2016.. Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. . Lancet Oncol. 17:(11):1558–68
     [Crossref] [Google Scholar]
  197. 197.
    Jiang C, Tian Q, Xu X, Li P, He S, et al. 2023.. Enhanced antitumor immune responses via a new agent [131I]-labeled dual-target immunosuppressant. . Eur. J. Nucl. Med. Mol. Imaging 50:(2):275–86
     [Crossref] [Google Scholar]
  198. 198.
    Zhou C, Xiong A, Li W, Ma Z, Li X, et al. 2021.. P77.03 a phase II study of KN046 (bispecific anti-PD-L1/CTLA-4) in patients (pts) with metastatic non-small cell lung cancer (NSCLC). . J. Thorac. Oncol. 16:(3):S636
     [Crossref] [Google Scholar]
  199. 199.
    Xiong A, Li W, Li X, Fan Y, Ma Z, et al. 2023.. Efficacy and safety of KN046, a novel bispecific antibody against PD-L1 and CTLA-4, in patients with non-small cell lung cancer who failed platinum-based chemotherapy: a phase II study. . Eur. J. Cancer 190::112936
     [Crossref] [Google Scholar]
  200. 200.
    Kozłowski M, Borzyszkowska D, Cymbaluk-Płoska A. 2022.. The role of TIM-3 and LAG-3 in the microenvironment and immunotherapy of ovarian cancer. . Biomedicines 10:(11):2826
     [Crossref] [Google Scholar]
  201. 201.
    Long L, Zhang X, Chen F, Pan Q, Phiphatwatchara P, et al. 2018.. The promising immune checkpoint LAG-3: from tumor microenvironment to cancer immunotherapy. . Genes Cancer 9:(5–6):176–89
     [Crossref] [Google Scholar]
  202. 202.
    Graydon CG, Mohideen S, Fowke KR. 2021.. LAG3’s enigmatic mechanism of action. . Front. Immunol. 11::615317
     [Crossref] [Google Scholar]
  203. 203.
    Freeman GJ, Casasnovas JM, Umetsu DT, DeKruyff RH. 2010.. TIM genes: a family of cell surface phosphatidylserine receptors that regulate innate and adaptive immunity. . Immunol. Rev. 235:(1):172–89
     [Crossref] [Google Scholar]
  204. 204.
    Zhu C, Anderson AC, Schubart A, Xiong H, Imitola J, et al. 2005.. The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. . Nat. Immunol. 6:(12):1245–52
     [Crossref] [Google Scholar]
  205. 205.
    Huang Y-H, Zhu C, Kondo Y, Anderson AC, Gandhi A, et al. 2016.. Corrigendum: CEACAM1 regulates TIM-3-mediated tolerance and exhaustion. . Nature 536:(7616):359
     [Crossref] [Google Scholar]
  206. 206.
    Nakayama M, Akiba H, Takeda K, Kojima Y, Hashiguchi M, et al. 2009.. Tim-3 mediates phagocytosis of apoptotic cells and cross-presentation. . Blood 113:(16):3821–30
     [Crossref] [Google Scholar]
  207. 207.
    Chiba S, Baghdadi M, Akiba H, Yoshiyama H, Kinoshita I, et al. 2012.. Tumor-infiltrating DCs suppress nucleic acid-mediated innate immune responses through interactions between the receptor TIM-3 and the alarmin HMGB1. . Nat. Immunol. 13:(9):832–42
     [Crossref] [Google Scholar]
  208. 208.
    Acharya N, Sabatos-Peyton C, Anderson AC. 2020.. Tim-3 finds its place in the cancer immunotherapy landscape. . J. Immunother. Cancer 8:(1):e000911
     [Crossref] [Google Scholar]
  209. 209.
    Liu J. 2023.. Phase 1 study of LB1410, a bivalent TIM-3/PD-1 bispecific antibody, in patients with advanced solid tumors or lymphoma. . J. Cancer Oncol. 41:(16 Suppl.):TPS2663
     [Google Scholar]
  210. 210.
    Huang Z, Pang X, Zhong T, Jin C, Chen N, et al. 2022.. Abstract 5520: AK129, an anti-PD1/LAG-3 bi-specific antibody for cancer therapy. . Cancer Res. 82:(12 Suppl.):5520
     [Crossref] [Google Scholar]
  211. 211.
    Cappell KM, Kochenderfer JN. 2021.. A comparison of chimeric antigen receptors containing CD28 versus 4–1BB costimulatory domains. . Nat. Rev. Clin. Oncol. 18:(11):715–27
     [Crossref] [Google Scholar]
  212. 212.
    Tacke M, Hanke G, Hanke T, Hünig T. 1997.. CD28-mediated induction of proliferation in resting T cells in vitro and in vivo without engagement of the T cell receptor: evidence for functionally distinct forms of CD28. . Eur. J. Immunol. 27:(1):239–47
     [Crossref] [Google Scholar]
  213. 213.
    Hünig T. 2016.. The rise and fall of the CD28 superagonist TGN1412 and its return as TAB08: a personal account. . FEBS J. 283:(18):3325–34
     [Crossref] [Google Scholar]
  214. 214.
    Choi Y, Shi Y, Haymaker CL, Naing A, Ciliberto G, Hajjar J. 2020.. T-cell agonists in cancer immunotherapy. . J. Immunother. Cancer 8:(2):e000966
     [Crossref] [Google Scholar]
  215. 215.
    Brennan FR, Morton LD, Spindeldreher S, Kiessling A, Allenspach R, et al. 2010.. Safety and immunotoxicity assessment of immunomodulatory monoclonal antibodies. . mAbs 2:(3):233–55
     [Crossref] [Google Scholar]
  216. 216.
    Attarwala H. 2010.. TGN1412: from discovery to disaster. . J. Young Pharm. 2:(3):332–36
     [Crossref] [Google Scholar]
  217. 217.
    Suntharalingam G, Perry MR, Ward S, Brett SJ, Castello-Cortes A, et al. 2006.. Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. . N. Engl. J. Med. 355:(10):1018–28
     [Crossref] [Google Scholar]
  218. 218.
    Tyrsin D, Chuvpilo S, Matskevich A, Nemenov D, Römer PS, et al. 2016.. From TGN1412 to TAB08: the return of CD28 superagonist therapy to clinical development for the treatment of rheumatoid arthritis. . Clin. Exp. Rheumatol. 34:(4 Suppl. 98):45–48
     [Google Scholar]
  219. 219.
    Zeng V, Moore G, Diaz J, Bonzon C, Avery K, et al. 2021.. 698 PD-L1 targeted CD28 costimulatory bispecific antibodies enhance T cell activation in solid tumors. . J. Immunother. Cancer 9:(Suppl. 2):A726
     [Google Scholar]
  220. 220.
    Brandl M, Große-Hovest L, Holler E, Kolb H-J, Jung G. 1999.. Bispecific antibody fragments with CD20 × CD28 specificity allow effective autologous and allogeneic T-cell activation against malignant cells in peripheral blood and bone marrow cultures from patients with B-cell lineage leukemia and lymphoma. . Exp. Hematol. 27:(8):1264–70
     [Crossref] [Google Scholar]
  221. 221.
    Goodwin RG, Din WS, Davis-Smith T, Anderson DM, Gimpel SD, et al. 1993.. Molecular cloning of a ligand for the inducible T cell gene 4-1BB: a member of an emerging family of cytokines with homology to tumor necrosis factor. . Eur. J. Immunol. 23:(10):2631–41
     [Crossref] [Google Scholar]
  222. 222.
    Wang Y-T, Ji W-D, Jiao H-M, Lu A, Chen K-F, Liu Q-B. 2022.. Targeting 4-1BB for tumor immunotherapy from bench to bedside. . Front. Immunol. 13::975926
     [Crossref] [Google Scholar]
  223. 223.
    Gauttier V, Judor J-P, Le Guen V, Cany J, Ferry N, Conchon S. 2014.. Agonistic anti-CD137 antibody treatment leads to antitumor response in mice with liver cancer. . Int. J. Cancer 135:(12):2857–67
     [Crossref] [Google Scholar]
  224. 224.
    Li B, Lin J, Vanroey M, Jure-Kunkel M, Jooss K. 2007.. Established B16 tumors are rejected following treatment with GM-CSF-secreting tumor cell immunotherapy in combination with anti-4-1BB mAb. . Clin. Immunol. 125:(1):76–87
     [Crossref] [Google Scholar]
  225. 225.
    Segal NH, Gopal AK, Bhatia S, Kohrt HE, Levy R, et al. 2014.. A phase 1 study of PF-05082566 (anti-4–1BB) in patients with advanced cancer. . J. Cancer Oncol. 32:(15 Suppl.):3007
     [Google Scholar]
  226. 226.
    Segal NH, Logan TF, Hodi FS, McDermott D, Melero I, et al. 2017.. Results from an integrated safety analysis of urelumab, an agonist anti-CD137 monoclonal antibody. . Clin. Cancer Res. 23:(8):1929–36
     [Crossref] [Google Scholar]
  227. 227.
    Segal NH, He AR, Doi T, Levy R, Bhatia S, et al. 2018.. Phase I study of single-agent utomilumab (PF-05082566), a 4-1BB/CD137 agonist, in patients with advanced cancer. . Clin. Cancer Res. 24:(8):1816–23
     [Crossref] [Google Scholar]
  228. 228.
    Cohen EEW, Pishvaian MJ, Shepard DR, Wang D, Weiss J, et al. 2019.. A phase Ib study of utomilumab (PF-05082566) in combination with mogamulizumab in patients with advanced solid tumors. . J. ImmunoTher. Cancer 7::342
     [Crossref] [Google Scholar]
  229. 229.
    Mayes PA, Hance KW, Hoos A. 2018.. The promise and challenges of immune agonist antibody development in cancer. . Nat. Rev. Drug Discov. 17:(7):509–27
     [Crossref] [Google Scholar]
  230. 230.
    Goebeler M-E, Bargou RC. 2020.. T cell-engaging therapies—BiTEs and beyond. . Nat. Rev. Clin. Oncol. 17:(7):418–34
     [Crossref] [Google Scholar]
  231. 231.
    Hashimoto K. 2021.. CD137 as an attractive T cell co-stimulatory target in the TNFRSF for immuno-oncology drug development. . Cancers 13:(10):2288
     [Crossref] [Google Scholar]
  232. 232.
    Park DE, Cheng J, McGrath JP, Lim MY, Cushman C, et al. 2020.. Merkel cell polyomavirus activates LSD1-mediated blockade of non-canonical BAF to regulate transformation and tumorigenesis. . Nat. Cell Biol. 22:(5):603–15
     [Crossref] [Google Scholar]
  233. 233.
    Simão DC, Zarrabi KK, Mendes JL, Luz R, Garcia JA, et al. 2023.. Bispecific T-cell engagers therapies in solid tumors: focusing on prostate cancer. . Cancers 15:(5):1412
     [Crossref] [Google Scholar]
  234. 234.
    Tian Z, Liu M, Zhang Y, Wang X. 2021.. Bispecific T cell engagers: an emerging therapy for management of hematologic malignancies. . J. Hematol. Oncol. 14:(1):75
     [Crossref] [Google Scholar]
  235. 235.
    Laskowski TJ, Biederstädt A, Rezvani K. 2022.. Natural killer cells in antitumour adoptive cell immunotherapy. . Nat. Rev. Cancer 22:(10):557–75
     [Crossref] [Google Scholar]
  236. 236.
    Du N, Guo F, Wang Y, Cui J. 2021.. NK cell therapy: a rising star in cancer treatment. . Cancers 13:(16):4129
     [Crossref] [Google Scholar]
  237. 237.
    Shimasaki N, Jain A, Campana D. 2020.. NK cells for cancer immunotherapy. . Nat. Rev. Drug Discov. 19:(3):200–18
     [Crossref] [Google Scholar]
  238. 238.
    Fucà G, Spagnoletti A, Ambrosini M, De Braud F, Di Nicola M. 2021.. Immune cell engagers in solid tumors: promises and challenges of the next generation immunotherapy. . ESMO Open 6:(1):100046
     [Crossref] [Google Scholar]
  239. 239.
    Paul S, Lal G. 2017.. The molecular mechanism of natural killer cells function and its importance in cancer immunotherapy. . Front. Immunol. 8::1124
     [Crossref] [Google Scholar]
  240. 240.
    Pinto S, Pahl J, Schottelius A, Carter PJ, Koch J. 2022.. Reimagining antibody-dependent cellular cytotoxicity in cancer: the potential of natural killer cell engagers. . Trends Immunol. 43:(11):932–46
     [Crossref] [Google Scholar]
  241. 241.
    Reusch U, Burkhardt C, Fucek I, Le Gall F, Le Gall M, et al. 2014.. A novel tetravalent bispecific TandAb (CD30/CD16A) efficiently recruits NK cells for the lysis of CD30+ tumor cells. . mAbs 6:(3):727–38
     [Crossref] [Google Scholar]
  242. 242.
    Rothe A, Sasse S, Topp MS, Eichenauer DA, Hummel H, et al. 2015.. A phase 1 study of the bispecific anti-CD30/CD16A antibody construct AFM13 in patients with relapsed or refractory Hodgkin lymphoma. . Blood 125:(26):4024–31
     [Crossref] [Google Scholar]
  243. 243.
    Sawas A, Elgedawe H, Vlad G, Lipschitz M, Chen P-H, et al. 2018.. Clinical and biological evaluation of the novel CD30/CD16A tetravalent bispecific antibody (AFM13) in relapsed or refractory CD30-positive lymphoma with cutaneous presentation: a biomarker phase Ib/IIa study (NCT03192202). . Blood 132:(Suppl. 1):2908
     [Crossref] [Google Scholar]
  244. 244.
    Sasse S, Bröckelmann PJ, Momotow J, Plütschow A, Hüttmann A, et al. 2022.. AFM13 in patients with relapsed or refractory classical Hodgkin lymphoma: final results of an open-label, randomized, multicenter phase II trial. . Leuk. Lymphoma 63:(8):1871–78
     [Crossref] [Google Scholar]
  245. 245.
    Kerbauy LN, Marin ND, Kaplan M, Banerjee PP, Berrien-Elliott MM, et al. 2021.. Combining AFM13, a bispecific CD30/CD16 antibody, with cytokine-activated blood and cord blood-derived NK cells facilitates CAR-like responses against CD30+ malignancies. . Clin. Cancer Res. 27:(13):3744–56
     [Crossref] [Google Scholar]
  246. 246.
    Nieto Y, Banerjee PP, Kaur I, Griffin L, Ganesh C, et al. 2022.. Innate cell engager AFM13 combined with preactivated and expanded cord blood-derived NK cells for patients with double refractory CD30+ lymphoma. . Blood 140:(Suppl. 1):415–16
     [Crossref] [Google Scholar]
  247. 247.
    Bartlett NL, Herrera AF, Domingo-Domenech E, Mehta A, Forero-Torres A, et al. 2020.. A phase 1b study of AFM13 in combination with pembrolizumab in patients with relapsed or refractory Hodgkin lymphoma. . Blood 136:(21):2401–9
     [Crossref] [Google Scholar]
  248. 248.
    Felices M, Warlick E, Juckett M, Weisdorf D, Vallera D, et al. 2021.. 444 GTB-3550 tri-specific killer engager TriKE™ drives NK cells expansion and cytotoxicity in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) patients. . J. Immunother. Cancer 9:(Suppl. 2):A473
     [Google Scholar]
  249. 249.
    Mantovani A, Allavena P, Marchesi F, Garlanda C. 2022.. Macrophages as tools and targets in cancer therapy. . Nat. Rev. Drug Discov. 21:(11):799–820
     [Crossref] [Google Scholar]
  250. 250.
    Bart VMT, Pickering RJ, Taylor PR, Ipseiz N. 2021.. Macrophage reprogramming for therapy. . Immunology 163:(2):128–44
     [Crossref] [Google Scholar]
  251. 251.
    Khan SU, Khan MU, Azhar Ud Din M, Khan IM, Khan MI, et al. 2023.. Reprogramming tumor-associated macrophages as a unique approach to target tumor immunotherapy. . Front. Immunol. 14::1166487
     [Crossref] [Google Scholar]
  252. 252.
    Feng M, Jiang W, Kim BYS, Zhang CC, Fu Y-X, Weissman IL. 2019.. Phagocytosis checkpoints as new targets for cancer immunotherapy. . Nat. Rev. Cancer 19:(10):568–86
     [Crossref] [Google Scholar]
  253. 253.
    Logtenberg MEW, Scheeren FA, Schumacher TN. 2020.. The CD47-SIRPα immune checkpoint. . Immunity 52:(5):742–52
     [Crossref] [Google Scholar]
  254. 254.
    Dheilly E, Moine V, Broyer L, Salgado-Pires S, Johnson Z, et al. 2017.. Selective blockade of the ubiquitous checkpoint receptor CD47 is enabled by dual-targeting bispecific antibodies. . Mol. Ther. 25:(2):523–33
     [Crossref] [Google Scholar]
  255. 255.
    Hawkes E, Lewis KL, Wong Doo N, Patil SS, Miskin HP, et al. 2022.. First-in-human (FIH) study of the fully-human kappa-lambda CD19/CD47 bispecific antibody TG-1801 in patients (pts) with B-cell lymphoma. . Blood 140:(Suppl. 1):6599–601
     [Crossref] [Google Scholar]
  256. 256.
    Yu J, Li S, Chen D, Liu D, Guo H, et al. 2023.. IMM0306, a fusion protein of CD20 mAb with the CD47 binding domain of SIRPα, exerts excellent cancer killing efficacy by activating both macrophages and NK cells via blockade of CD47-SIRPα interaction and FcɣR engagement by simultaneously binding to CD47 and CD20 of B cells. . Leukemia 37:(3):695–98
     [Crossref] [Google Scholar]
  257. 257.
    Ke H, Zhang F, Wang J, Xiong L, An X, et al. 2023.. HX009, a novel BsAb dual targeting PD1 × CD47, demonstrates potent anti-lymphoma activity in preclinical models. . Sci. Rep. 13:(1):5419
     [Crossref] [Google Scholar]
  258. 258.
    Wang J, Sun Y, Chu Q, Duan J, Wan R, et al. 2022.. Abstract CT513: phase I study of IBI322 (anti-CD47/PD-L1 bispecific antibody) monotherapy therapy in patients with advanced solid tumors in China. . Cancer Res. 82:(12 Suppl.):CT513
     [Crossref] [Google Scholar]
  259. 259.
    Wang Y, Ni H, Zhou S, He K, Gao Y, et al. 2021.. Tumor-selective blockade of CD47 signaling with a CD47/PD-L1 bispecific antibody for enhanced anti-tumor activity and limited toxicity. . Cancer Immunol. Immunother. 70:(2):365–76
     [Crossref] [Google Scholar]
  260. 260.
    Liew PX, Kubes P. 2019.. The neutrophil's role during health and disease. . Physiol. Rev. 99:(2):1223–48
     [Crossref] [Google Scholar]
  261. 261.
    Xiong S, Dong L, Cheng L. 2021.. Neutrophils in cancer carcinogenesis and metastasis. . J. Hematol. Oncol. 14::173
     [Crossref] [Google Scholar]
  262. 262.
    Chiang C-C, Korinek M, Cheng W-J, Hwang T-L. 2020.. Targeting neutrophils to treat acute respiratory distress syndrome in coronavirus disease. . Front. Pharmacol. 11::572009
     [Crossref] [Google Scholar]
  263. 263.
    Sewnath CAN, Behrens LM, Van Egmond M. 2022.. Targeting myeloid cells with bispecific antibodies as novel immunotherapies of cancer. . Expert Opin. Biol. Ther. 22:(8):983–95
     [Crossref] [Google Scholar]
  264. 264.
    Valone FH, Kaufman PA, Guyre PM, Lewis LD, Memoli V, et al. 1995.. Phase Ia/Ib trial of bispecific antibody MDX-210 in patients with advanced breast or ovarian cancer that overexpresses the proto-oncogene HER-2/neu. . J. Cancer Oncol. 13:(9):2281–92
     [Google Scholar]
  265. 265.
    Curnow RT. 1997.. Clinical experience with CD64-directed immunotherapy. An overview. . Cancer Immunol. Immunother. 45:(3–4):210–15
     [Crossref] [Google Scholar]
  266. 266.
    Behrens LM, Van Egmond M, Van Den Berg TK. 2023.. Neutrophils as immune effector cells in antibody therapy in cancer. . Immunol. Rev. 314:(1):280–301
     [Crossref] [Google Scholar]
  267. 267.
    Heemskerk N, Gruijs M, Temming AR, Heineke MH, Gout DY, et al. 2021.. Augmented antibody-based anticancer therapeutics boost neutrophil cytotoxicity. . J. Clin. Investig. 131:(6):e134680
     [Crossref] [Google Scholar]
  268. 268.
    Ali SO, Yu XQ, Robbie GJ, Wu Y, Shoemaker K, et al. 2019.. Phase 1 study of MEDI3902, an investigational anti-Pseudomonas aeruginosa PcrV and Psl bispecific human monoclonal antibody, in healthy adults. . Clin. Microbiol. Infect. 25:(5):629.e1–e6
     [Crossref] [Google Scholar]
  269. 269.
    Le HN, Tran VG, Vu TTT, Gras E, Le VTM, et al. 2019.. Treatment efficacy of MEDI3902 in Pseudomonas aeruginosa bloodstream infection and acute pneumonia rabbit models. . Antimicrob. Agents Chemother. 63:(8):e00710-19
     [Crossref] [Google Scholar]
  270. 270.
    Chastre J, François B, Bourgeois M, Komnos A, Ferrer R, et al. 2022.. Safety, efficacy, and pharmacokinetics of gremubamab (MEDI3902), an anti-Pseudomonas aeruginosa bispecific human monoclonal antibody, in P. aeruginosa-colonised, mechanically ventilated intensive care unit patients: a randomised controlled trial. . Crit. Care 26:(1):355
     [Crossref] [Google Scholar]
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Mechanism-Driven Design of Multispecific Antibodies for Targeted Disease Treatment
Annual Review of Chemical and Biomolecular Engineering 15, 105 (2024); https://doi.org/10.1146/annurev-chembioeng-100522-102155
/content/journals/10.1146/annurev-chembioeng-100522-102155
/content/journals/10.1146/annurev-chembioeng-100522-102155
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