Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Molecular imaging supports the development of multispecific cancer antibodies

Nature Reviews Clinical Oncology volume 21, pages 852–866 (2024)Cite this article

Subjects

Abstract

Multispecific antibodies are engineered antibody derivatives that can bind to two or more distinct epitopes or antigens. Unlike mixtures of monospecific antibodies, the binding properties of multispecific antibodies enable two specific molecules to be physically linked, a characteristic with important applications in cancer therapy. The field of multispecific antibodies is highly dynamic and expanding rapidly; to date, 15 multispecific antibodies have been approved for clinical use, of which 11 were approved for oncological indications, and more than 100 new antibodies are currently in clinical development. Nevertheless, substantial challenges limit the applications of multispecific antibodies in cancer therapy, particularly inefficient targeting of solid tumours and substantial adverse effects. Both PET and single photon emission CT imaging can reveal the biodistribution and complex pharmacology of radiolabelled multispecific antibodies. This Review summarizes the insights obtained from preclinical and clinical molecular imaging studies of multispecific antibodies, focusing on their structural properties, such as molecular weight, shape, target specificity, affinity and avidity. The opportunities associated with use of molecular imaging studies to support the clinical development of multispecific antibody therapies are also highlighted.

Key points

  • The use of multispecific antibodies in cancer treatment is expanding rapidly: 11 agents have been approved to date and many others are undergoing clinical development.

  • The design of multispecific antibodies with optimal pharmacological properties has resulted in a wide variety of molecule formats.

  • PET and single photon emission CT imaging are powerful non-invasive tools for studying the biodistribution of radiolabelled antibodies, including their uptake in tumour and healthy tissues, pharmacokinetics and target expression.

  • Preclinical and clinical molecular imaging studies of multispecific antibodies underscore key structural properties that affect their biodistribution, including target affinity and avidity, molecular weight and structure.

  • Biological factors that also influence the biodistribution of multispecific antibodies include target expression in tumour tissues, off-tumour and immune target engagement, antibody internalization, tracer dose and target saturation.

  • Molecular imaging can aid the development of multispecific antibodies by facilitating their selection and design for clinical applications and by identifying biomarkers for the stratification of patient groups.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Timeline of multispecific antibody approvals.
Fig. 2: Formats of multispecific antibodies in clinical development.
Fig. 3: Drug development stages and opportunities for using molecular imaging to support this process.

Similar content being viewed by others

References

  1. Johnson, D. B., Nebhan, C. A., Moslehi, J. J. & Balko, J. M. Immune-checkpoint inhibitors: long-term implications of toxicity. Nat. Rev. Clin. Oncol. 19, 254–267 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  2. Marin-Acevedo, J. A. et al. Next generation of immune checkpoint therapy in cancer: new developments and challenges. J. Hematol. Oncol. 11, 39 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Jin, S. et al. Emerging new therapeutic antibody derivatives for cancer treatment. Signal. Transduct. Target. Ther. 7, 39 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Labrijn, A. F., Janmaat, M. L., Reichert, J. M. & Parren, P. W. H. I. Bispecific antibodies: a mechanistic review of the pipeline. Nat. Rev. Drug. Discov. 18, 585–608 (2019).

    Article  CAS  PubMed  Google Scholar 

  5. van de Donk, N. W. C. J. & Zweegman, S. T-cell-engaging bispecific antibodies in cancer. Lancet 402, 142–158 (2023).

    Article  PubMed  Google Scholar 

  6. Klein, C., Brinkmann, U., Reichert, J. M. & Kontermann, R. E. The present and future of bispecific antibodies for cancer therapy. Nat. Rev. Drug. Discov. 23, 301–319 (2024).

    Article  CAS  PubMed  Google Scholar 

  7. Goebeler, M. E., Stuhler, G. & Bargou, R. Bispecific and multispecific antibodies in oncology: opportunities and challenges. Nat. Rev. Clin. Oncol. 21, 539–560 (2024).

    Article  PubMed  Google Scholar 

  8. Przepiorka, D. et al. FDA approval: blinatumomab. Clin. Cancer Res. 21, 4035–4039 (2015).

    Article  CAS  PubMed  Google Scholar 

  9. Deshaies, R. J. Multispecific drugs herald a new era of biopharmaceutical innovation. Nature 580, 329–338 (2020).

    Article  CAS  PubMed  Google Scholar 

  10. Saez-Ibanez, A. R., Upadhaya, S. & Campbell, J. Immuno-oncology clinical trials take a turn beyond PD1/PDL1 inhibitors. Nat. Rev. Drug. Discov. 22, 442–443 (2023).

    Article  CAS  PubMed  Google Scholar 

  11. Saez-Ibañez, A. R., Sommers, E., Upadhaya, S. & Campbell, J. PD1/PDL1 clinical trials adapt to a growing landscape of patients resistant to PDx. Nat. Rev. Drug. Discov. 22, 944–945 (2023).

    Article  PubMed  Google Scholar 

  12. Kantarjian, H. et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N. Engl. J. Med. 376, 836–847 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Stein, A. S. et al. Neurologic adverse events in patients with relapsed/refractory acute lymphoblastic leukemia treated with blinatumomab: management and mitigating factors. Ann. Hematol. 98, 159–167 (2019).

    Article  CAS  PubMed  Google Scholar 

  14. Frey, N. V. & Porter, D. L. Cytokine release syndrome with novel therapeutics for acute lymphoblastic leukemia. Am. Soc. Hematol. Educ. Program. 2016, 567–572 (2016).

    Article  Google Scholar 

  15. Li, H., Er Saw, P. & Song, E. Challenges and strategies for next-generation bispecific antibody-based antitumor therapeutics. Cell Mol. Immunol. 17, 451–461 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Sun, D., Gao, W., Hu, H. & Zhou, S. Why 90% of clinical drug development fails and how to improve it? Acta Pharm. Sin. B. 12, 3049–3062 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Irani, V. et al. Molecular properties of human IgG subclasses and their implications for designing therapeutic monoclonal antibodies against infectious diseases. Mol. Immunol. 67, 171–182 (2015).

    Article  CAS  PubMed  Google Scholar 

  18. Saunders, K. O. Conceptual approaches to modulating antibody effector functions and circulation half-life. Front. Immunol. 10, 1296 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Zinn, S. et al. Advances in antibody-based therapy in oncology. Nat. Cancer 4, 165–180 (2023).

    Article  PubMed  Google Scholar 

  20. Edwards, C. J. et al. The multi-specific VH-based Humabody CB213 co-targets PD1 and LAG3 on T cells to promote anti-tumour activity. Br. J. Cancer 126, 1168–1177 (2022).

    Article  CAS  PubMed  Google Scholar 

  21. Archer, S. et al. CB307: a dual targeting costimulatory Humabody VH therapeutic for treating PSMA-positive tumors. Clin. Cancer Res. 30, 1595–1606 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Power, C. A. & Bates, A. David vs. Goliath: the structure, function, and clinical prospects of antibody fragments. Antibodies 8, 28 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Suurs, F. V., Lub-de Hooge, M. N., de Vries, E. G. E. & de Groot, D. J. A. A review of bispecific antibodies and antibody constructs in oncology and clinical challenges. Pharmacol. Ther. 201, 103–119 (2019).

    Article  CAS  PubMed  Google Scholar 

  24. Al Ojaimi, Y. et al. Therapeutic antibodies – natural and pathological barriers and strategies to overcome them. Pharmacol. Ther. 233, 108022 (2022).

    Article  CAS  PubMed  Google Scholar 

  25. Bensch, F. et al. Comparative biodistribution analysis across four different 89Zr-monoclonal antibody tracers – the first step towards an imaging warehouse. Theranostics 8, 4295–4304 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Lu, G. et al. Predicting therapeutic antibody delivery into human head and neck cancers. Clin. Cancer Res. 26, 2582–2594 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Dennis, M. S. et al. Imaging tumors with an albumin-binding Fab, a novel tumor-targeting agent. Cancer Res. 67, 254–261 (2007).

    Article  CAS  PubMed  Google Scholar 

  28. Mir, O. et al. Pharmacokinetics/pharmacodynamic (PK/PD) relationship of therapeutic monoclonal antibodies used in oncology: what’s new? Eur. J. Cancer 128, 103–106 (2020).

    Article  CAS  PubMed  Google Scholar 

  29. Ryman, J. T. & Meibohm, B. Pharmacokinetics of monoclonal antibodies. Clin. Pharmacokinet. 6, 493–507 (2017).

    Google Scholar 

  30. Keizer, R. J., Huitema, A. D. R., Schellens, J. H. M. & Beijnen, J. H. Clinical pharmacokinetics of therapeutic monoclonal antibodies. Clin. Pharmacokinet. 49, 493–507 (2010).

    Article  CAS  PubMed  Google Scholar 

  31. Roopenian, D. C. & Akilesh, S. FcRn: the neonatal Fc receptor comes of age. Nat. Rev. Immunol. 7, 715–725 (2007).

    Article  CAS  PubMed  Google Scholar 

  32. Sharma, S. K. et al. Fc-mediated anomalous biodistribution of therapeutic antibodies in immunodeficient mouse models. Cancer Res. 78, 1820–1832 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Wei, W. et al. Development and characterization of CD54-targeted immunoPET imaging in solid tumors. Eur. J. Nucl. Med. Mol. Imaging 47, 2765–2775 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Zhu, M. et al. Blinatumomab, a bispecific T-cell engager (BiTE®) for CD-19 targeted cancer immunotherapy: clinical pharmacology and its implications. Clin. Pharmacokinet. 55, 1271–1288 (2016).

    Article  CAS  PubMed  Google Scholar 

  35. Moek, K. L. et al. 89Zr-labeled bispecific T-cell engager AMG 211 PET shows AMG 211 accumulation in CD3-rich tissues and clear, heterogeneous tumor uptake. Clin. Cancer Res. 25, 3517–3527 (2019).

    Article  CAS  PubMed  Google Scholar 

  36. Park, K. et al. Amivantamab in EGFR exon 20 insertion-mutated non-small-cell lung cancer progressing on platinum chemotherapy: initial results from the CHRYSALIS phase I study. J. Clin. Oncol. 39, 3391–3402 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. European Medicines Agency. Rybrevant: product information. EMA www.ema.europa.eu/en/documents/product-information/rybrevant-epar-product-information_en.pdf (2024).

  38. Dewulf, J., Adhikari, K., Vangestel, C., van den Wyngaert, T. & Elvas, F. Development of antibody immuno-PET/SPECT radiopharmaceuticals for imaging of oncological disorders – an update. Cancers 12, 1868 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Sneddon, D. & Cornelissen, B. Emerging chelators for nuclear imaging. Curr. Opin. Chem. Biol. 63, 152–162 (2021).

    Article  CAS  PubMed  Google Scholar 

  40. Wei, W. et al. ImmunoPET: concept, design, and applications. Chem. Rev. 120, 3787–3851 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Dammes, N. & Peer, D. Monoclonal antibody-based molecular imaging strategies and theranostic opportunities. Theranostics 10, 938–955 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Volpe, A., Adusumilli, P. S., Schöder, H. & Ponomarev, V. Imaging cellular immunotherapies and immune cell biomarkers: from preclinical studies to patients. J. Immunother. Cancer 10, e004902 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  43. Rowe, S. P. & Pomper, M. G. Molecular imaging in oncology: current impact and future directions. CA Cancer J. Clin. 72, 333–352 (2022).

    Article  PubMed  Google Scholar 

  44. Korpanty, G., Carbon, J. G., Grayburn, P. A., Fleming, J. B. & Brekken, R. A. Monitoring response to anticancer therapy by targeting microbubbles to tumor vasculature. Clin. Cancer Res. 13, 323–330 (2007).

    Article  CAS  PubMed  Google Scholar 

  45. Cheng, Y. A. et al. Humanized bispecific antibody (mPEG × HER2) rapidly confers PEGylated nanoparticles tumor specificity for multimodality imaging in breast cancer. J. Nanobiotechnol. 18, 118–130 (2020).

    Article  CAS  Google Scholar 

  46. Lehmann, S. et al. In vivo fluorescence imaging of the activity of CEA TCB, a novel T-cell bispecific antibody, reveals highly specific tumor targeting and fast induction of T-cell-mediated tumor killing. Clin. Cancer Res. 22, 4417–4427 (2016).

    Article  CAS  PubMed  Google Scholar 

  47. Luo, H. et al. ImmunoPET and near-infrared fluorescence imaging of pancreatic cancer with a dual-labeled bispecific antibody fragment. Mol. Pharm. 14, 1646–1655 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Gabriëls, R. Y. et al. Fluorescently labelled vedolizumab to visualise drug distribution and mucosal target cells in inflammatory bowel disease. Gut 73, 1454–1463 (2024).

    Article  PubMed  Google Scholar 

  49. Warram, J. M. et al. Fluorescence imaging to localize head and neck squamous cell carcinoma for enhanced pathological assessment. J. Pathol. Clin. Res. 2, 104–112 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Nessler, I. et al. Increased tumor penetration of single-domain antibody-drug conjugates improves in vivo efficacy in prostate cancer models. Cancer Res. 80, 1268–1278 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Oliveira, S. et al. Rapid visualization of human tumor xenografts through optical imaging with a near-infrared fluorescent anti-epidermal growth factor receptor nanobody. Mol. Imaging 11, 33–46 (2012).

    Article  CAS  PubMed  Google Scholar 

  52. Grevys, A. et al. A human endothelial cell-based recycling assay for screening of FcRn targeted molecules. Nat. Commun. 9, 621 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Stork, R., Campigna, E., Robert, B., Müller, D. & Kontermann, R. E. Biodistribution of a bispecific single-chain diabody and its half-life extended derivatives. J. Biol. Chem. 284, 25612–25619 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Tijink, B. M. et al. Improved tumor targeting of anti-epidermal growth factor receptor nanobodies through albumin binding: taking advantage of modular nanobody technology. Mol. Cancer Ther. 7, 2288–2297 (2008).

    Article  CAS  PubMed  Google Scholar 

  55. Suurs, F. V. et al. Mesothelin/CD3 half-life – extended bispecific T-cell engager molecule shows specific tumor uptake and distributes to mesothelin and CD3-expressing tissues. J. Nucl. Med. 62, 1797–1804 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Waaijer, S. J. H. et al. Molecular imaging of radiolabeled bispecific T-cell engager 89Zr-AMG211 targeting CEA-positive tumors. Clin. Cancer Res. 24, 4988–4996 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Warnders, F. J. et al. Biodistribution and PET imaging of labeled bispecific T cell-engaging antibody targeting EpCAM. J. Nucl. Med. 57, 812–817 (2016).

    Article  CAS  PubMed  Google Scholar 

  58. Suurs, F. V. et al. The biodistribution of a CD3 and EpCAM bispecific T-cell engager is driven by the CD3 arm. J. Nucl. Med. 61, 1594–1601 (2020).

    Article  CAS  PubMed  Google Scholar 

  59. Hu, G. et al. Development and comparison of three 89Zr-labeled anti-CLDN18.2 antibodies to noninvasively evaluate CLDN18.2 expression in gastric cancer: a preclinical study. Eur. J. Nucl. Med. Mol. Imaging 49, 2634–2644 (2022).

    Article  CAS  PubMed  Google Scholar 

  60. Burvenich, I. J. G. et al. Radiolabelling and preclinical characterization of 89Zr-Df-radiolabelled bispecific anti-PD-L1/TGF-βRII fusion protein bintrafusp alfa. Eur. J. Nucl. Med. Mol. Imaging 48, 3075–3088 (2021).

    Article  CAS  PubMed  Google Scholar 

  61. Yu, X. et al. Reducing affinity as a strategy to boost immunomodulatory antibody agonism. Nature 614, 539–547 (2023).

    Article  CAS  PubMed  Google Scholar 

  62. Mandikian, D. et al. Relative target affinities of T-cell-dependent bispecific antibodies determine biodistribution in a solid tumor mouse model. Mol. Cancer Ther. 17, 776–785 (2018).

    Article  CAS  PubMed  Google Scholar 

  63. Haber, L. et al. Generation of T-cell-redirecting bispecific antibodies with differentiated profiles of cytokine release and biodistribution by CD3 affinity tuning. Sci. Rep. 11, 14397 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. van Lith, S. A. M. et al. Novel VHH-based tracers with variable plasma half-lives for imaging of CAIX-expressing hypoxic tumor cells. Mol. Pharm. 19, 3511–3520 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  65. Waaijer, S. J. H. et al. Preclinical PET imaging of bispecific antibody ERY974 targeting CD3 and glypican 3 reveals that tumor uptake correlates to T cell infiltrate. J. Immunother. Cancer 8, e000548 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  66. Kwon, L. Y., Scollard, D. A. & Reilly, R. M. 64Cu-labeled trastuzumab Fab-PEG24-EGF radioimmunoconjugates bispecific for HER2 and EGFR: pharmacokinetics, biodistribution, and tumor imaging by PET in comparison to monospecific agents. Mol. Pharm. 14, 492–501 (2017).

    Article  CAS  PubMed  Google Scholar 

  67. Razumienko, E. J., Chen, J. C., Cai, Z., Chan, C. & Reilly, R. M. Dual-receptor-targeted radioimmunotherapy of human breast cancer xenografts in athymic mice coexpressing HER2 and EGFR using 177Lu-or 111In-labeled bispecific radioimmunoconjugates. J. Nucl. Med. 57, 444–452 (2016).

    Article  CAS  PubMed  Google Scholar 

  68. Razumienko, E. J., Scollard, D. A. & Reilly, R. M. Small-animal SPECT/CT of HER2 and HER3 expression in tumor xenografts in athymic mice using trastuzumab Fab-heregulin bispecific radioimmunoconjugates. J. Nucl. Med. 53, 1943–1950 (2012).

    Article  CAS  PubMed  Google Scholar 

  69. Razumienko, E., Dryden, L., Scollard, D. & Reilly, R. M. MicroSPECT/CT imaging of co-expressed HER2 and EGFR on subcutaneous human tumor xenografts in athymic mice using 111In-labeled bispecific radioimmunoconjugates. Breast Cancer Res. Treat. 138, 709–718 (2013).

    Article  CAS  PubMed  Google Scholar 

  70. Puranik, A. D. et al. Target heterogeneity in oncology: the best predictor for differential response to radioligand therapy in neuroendocrine tumors and prostate cancer. Cancers 13, 3607 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Mileva, M. et al. Molecular imaging predicts lack of T-DM1 response in advanced HER2-positive breast cancer (final results of ZEPHIR trial). NPJ Breast Cancer 10, 4 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Sandker, G. G. W. et al. Longitudinal evaluation of the biodistribution and cellular internalization of the bispecific CD3xTRP1 antibody in syngeneic mouse tumor models. J. Immunother. Cancer 11, e007596 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  73. Cavaliere, A. et al. Development of [89Zr]ZrDFO-amivantamab bispecific to EGFR and c-MET for PET imaging of triple-negative breast cancer. Eur. J. Nucl. Med. Mol. Imaging 48, 383–394 (2022).

    Article  Google Scholar 

  74. Fenis, A., Demaria, O., Gauthier, L., Vivier, E. & Narni-Mancinelli, E. New immune cell engagers for cancer immunotherapy. Nat. Rev. Clin. Oncol. 24, 471–486 (2024).

    CAS  Google Scholar 

  75. Crawford, A. et al. A mucin 16 bispecific T cell-engaging antibody for the treatment of ovarian cancer. Sci. Transl. Med. 11, eaau7534 (2019).

    Article  PubMed  Google Scholar 

  76. Warnders, F. J. et al. Human epidermal growth factor receptor 3-specific tumor uptake and biodistribution of 89Zr-MSB0010853 visualized by real-time and noninvasive PET imaging. J. Nucl. Med. 58, 1210–1215 (2017).

    Article  CAS  PubMed  Google Scholar 

  77. Chiu, D. et al. A PSMA-targeting CD3 bispecific antibody induces antitumor responses that are enhanced by 4-1BB costimulation. Cancer Immunol. Res. 8, 596–608 (2020).

    Article  CAS  PubMed  Google Scholar 

  78. Heynickx, N., Segers, C., Coolkens, A., Baatout, S. & Vermeulen, K. Characterization of non-specific uptake and retention mechanisms of [177Lu]Lu-PSMA-617 in the salivary glands. Pharmaceuticals 16, 692 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Abusalem, M., Martiniova, L., Soebianto, S., DePalatis, L. & Ravizzini, G. Current status of radiolabeled monoclonal antibodies targeting PSMA for imaging and therapy. Cancers 15, 4537 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Crawford, A. & Chiu, D. Targeting solid tumors using CD3 bispecific antibodies. Mol. Cancer Ther. 20, 1350–1358 (2021).

    Article  CAS  PubMed  Google Scholar 

  81. Klein, C. et al. Cergutuzumab amunaleukin (CEA-IL2v), a CEA-targeted IL-2 variant-based immunocytokine for combination cancer immunotherapy: overcoming limitations of aldesleukin and conventional IL-2-based immunocytokines. Oncoimmunology 6, e1277306 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  82. Banushi, B., Joseph, S. R., Lum, B., Lee, J. J. & Simpson, F. Endocytosis in cancer and cancer therapy. Nat. Rev. Cancer 23, 450–473 (2023).

    Article  CAS  PubMed  Google Scholar 

  83. Chitneni, S. K., Koumarianou, E., Vaidyanathan, G. & Zalutsky, M. R. Observations on the effects of residualization and dehalogenation on the utility of N-succinimidyl ester acylation agents for radioiodination of the internalizing antibody trastuzumab. Molecules 24, 3907 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Shih, L. et al. The processing and fate of antibodies and their radiolabels bound to the surface of tumor cells in vitro: a comparison of nine radiolabels. J. Nucl. Med. 35, 899–908 (1994).

    CAS  PubMed  Google Scholar 

  85. Martinez-Forero, I. et al. T cell costimulation with anti-CD137 monoclonal antibodies is mediated by K63–polyubiquitin-dependent signals from endosomes. J. Immunol. 190, 6694–6706 (2013).

    Article  CAS  PubMed  Google Scholar 

  86. Lee, J. M. et al. Novel strategy for a bispecific antibody: induction of dual target internalization and degradation. Oncogene 35, 4437–4446 (2016).

    Article  CAS  PubMed  Google Scholar 

  87. Geuijen, C. et al. A human CD137 × PD-L1 bispecific antibody promotes anti-tumor immunity via context-dependent T cell costimulation and checkpoint blockade. Nat. Commun. 12, 4445 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Dijkers, E. C. et al. Biodistribution of 89Zr-trastuzumab and PET imaging of HER2-positive lesions in patients with metastatic breast cancer. Clin. Pharmacol. Ther. 87, 586–592 (2010).

    Article  CAS  PubMed  Google Scholar 

  89. Bensch, F. et al. 89Zr-lumretuzumab PET imaging before and during HER3 antibody lumretuzumab treatment in patients with solid tumors. Clin. Cancer Res. 23, 6128–6137 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Ntzifa, A. et al. Gene expression in circulating tumor cells reveals a dynamic role of EMT and PD-L1 during osimertinib treatment in NSCLC patients. Sci. Rep. 11, 2313 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Wang, Y. et al. Dose escalation PET imaging for safety and effective therapy dose optimization of a bispecific antibody. MAbs 12, 1748322 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  92. Wijngaarden, J. E. et al. Optimal imaging time points considering accuracy and precision of Patlak linearization for 89Zr-immuno-PET: a simulation study. EJNMMI Res. 12, 54 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Menke-van der Houven van Oordt, C. W. et al. Immuno-PET imaging to assess target engagement: experience from 89Zr-anti-HER3 mAb (GSK2849330) in patients with solid tumors. J. Nucl. Med. 60, 902–909 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. van de Donk, P. P. et al. Molecular imaging to support cancer immunotherapy. J. Immunother. Cancer 10, e004949 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  95. van Brummelen, E. M. J. et al. 89Zr-labeled CEA-targeted IL-2 variant immunocytokine in patients with solid tumors: CEA-mediated tumor accumulation and role of IL-2 receptor-binding. Oncotarget 9, 24737–24749 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  96. Sharpless, N. E. & DePinho, R. A. The mighty mouse: genetically engineered mouse models in cancer drug development. Nat. Rev. Drug. Discov. 5, 741–754 (2006).

    Article  CAS  PubMed  Google Scholar 

  97. Bensch, F. et al. 89Zr-atezolizumab imaging as a non-invasive approach to assess clinical response to PD-L1 blockade in cancer. Nat. Med. 24, 1852–1858 (2018).

    Article  CAS  PubMed  Google Scholar 

  98. Kist de Ruijter, L. et al. First-in-human study of the biodistribution and pharmacokinetics of 89Zr-CX-072, a novel immunoPET tracer based on an anti-PD-L1 probody. Clin. Cancer Res. 27, 5325–5333 (2021).

    Article  PubMed  Google Scholar 

  99. van Dongen, G. A. M. S. et al. The role of 89Zr-immuno-PET in navigating and derisking the development of biopharmaceuticals. J. Nucl. Med. 62, 438–445 (2021).

    Article  PubMed  Google Scholar 

  100. Kist de Ruijter, L. et al. Whole-body CD8+ T cell visualization before and during cancer immunotherapy: a phase 1/2 trial. Nat. Med. 28, 2601–2610 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Morgan, P. et al. Can the flow of medicines be improved? Fundamental pharmacokinetic and pharmacological principles toward improving phase II survival. Drug. Discov. Today 17, 419–424 (2012).

    Article  CAS  PubMed  Google Scholar 

  102. Farid, S. S., Baron, M., Stamatis, C., Nie, W. & Coffman, J. Benchmarking biopharmaceutical process development and manufacturing cost contributions to R&D. MAbs 12, 1754999 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  103. Hemmerle, T. et al. The antibody-based targeted delivery of TNF in combination with doxorubicin eradicates sarcomas in mice and confers protective immunity. Br. J. Cancer 109, 1206–1213 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Mårlind, J. et al. Antibody-mediated delivery of interleukin-2 to the stroma of breast cancer strongly enhances the potency of chemotherapy. Clin. Cancer Res. 14, 6515–6524 (2008).

    Article  PubMed  Google Scholar 

  105. Dakhel, S. et al. Targeted enhancement of the therapeutic window of L19-TNF by transient and selective inhibition of RIPK1-signaling cascade. Oncotarget 10, 6678–6690 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  106. Schwager, K. et al. Preclinical characterization of DEKAVIL (F8-IL10), a novel clinical-stage immunocytokine which inhibits the progression of collagen-induced arthritis. Arthritis Res. Ther. 11, R142 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  107. Hess, C. & Neri, D. Tumor-targeting properties of novel immunocytokines based on murine IL1β and IL6. Protein Eng. Des. Sel. 27, 207–213 (2014).

    Article  CAS  PubMed  Google Scholar 

  108. Corbellari, R. et al. A novel antibody-IL15 fusion protein selectively localizes to tumors, synergizes with TNF-based immunocytokine, and inhibits metastasis. Mol. Cancer Ther. 20, 859–871 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Pasche, N., Wulhfard, S., Pretto, F., Carugati, E. & Neri, D. The antibody-based delivery of interleukin-12 to the tumor neovasculature eradicates murine models of cancer in combination with paclitaxel. Clin. Cancer Res. 18, 4092–4103 (2012).

    Article  CAS  PubMed  Google Scholar 

  110. Luo, H. et al. Dual targeting of tissue factor and CD105 for preclinical PET imaging of pancreatic cancer. Clin. Cancer Res. 22, 3821–3830 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Luo, H. et al. Noninvasive brain cancer imaging with a bispecific antibody fragment, generated via click chemistry. Proc. Natl Acad. Sci. USA 112, 12806–12811 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. List, T. & Neri, D. Biodistribution studies with tumor-targeting bispecific antibodies reveal selective accumulation at the tumor site. MAbs 4, 775–783 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  113. Johnson, E. E. et al. Intratumoral immunocytokine treatment results in enhanced antitumor effects. Cancer Immunol. Immunother. 57, 1891–1902 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Jiang, C. et al. Enhanced antitumor immune responses via a new agent [131I]-labeled dual-target immunosuppressant. Eur. J. Nucl. Med. Mol. Imaging 50, 275–286 (2023).

    Article  CAS  PubMed  Google Scholar 

  115. Koopmans, I. et al. A novel bispecific antibody for EGFR-directed blockade of the PD-1/PD-L1 immune checkpoint. Oncoimmunology 7, e1466016 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  116. Williams, L. et al. Comparison of IL-2-antibody to IL-2-Fc with or without stereotactic radiation therapy in CEA immunocompetent mice with CEA positive tumors. Cancer Med. 13, e6909 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Gellert, J. et al. GT-00AxIL15, a novel tumor-targeted IL-15-based immunocytokine for the treatment of TA-MUC1-positive solid tumors: preclinical in vitro and in vivo pharmacodynamics and biodistribution studies. Int. J. Mol. Sci. 25, 1406 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Schilbach, K. et al. Cancer-targeted IL-12 controls human rhabdomyosarcoma by senescence induction and myogenic differentiation. Oncoimmunology 4, e1014760 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  119. Eckert, F. et al. Enhanced binding of necrosis-targeting immunocytokine NHS-IL12 after local tumour irradiation in murine xenograft models. Cancer Immunol. Immunother. 65, 1003–1013 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. The Antibody Society. Antibody therapeutics approved or in regulatory review in the EU or US. Antibody Society www.antibodysociety.org/resources/approved-antibodies/ (2024).

Download references

Author information

Author notes

  1. These authors contributed equally: Claudia A. J. van Winkel, Frank R. Pierik.

Authors and Affiliations

  1. Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands

    Claudia A. J. van Winkel, Derk Jan A. de Groot & Elisabeth G. E. de Vries

  2. Department of Clinical Pharmacy and Pharmacology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands

    Frank R. Pierik & Marjolijn N. Lub-de Hooge

  3. Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, Groningen, Netherlands

    Adrienne H. Brouwers & Marjolijn N. Lub-de Hooge

Authors
  1. Claudia A. J. van Winkel
    View author publications

    Search author on:PubMed Google Scholar

  2. Frank R. Pierik
    View author publications

    Search author on:PubMed Google Scholar

  3. Adrienne H. Brouwers
    View author publications

    Search author on:PubMed Google Scholar

  4. Derk Jan A. de Groot
    View author publications

    Search author on:PubMed Google Scholar

  5. Elisabeth G. E. de Vries
    View author publications

    Search author on:PubMed Google Scholar

  6. Marjolijn N. Lub-de Hooge
    View author publications

    Search author on:PubMed Google Scholar

Contributions

C.A.J.v.W and F.R.P. researched data for the article, wrote the manuscript and contributed substantially to discussions of its content and to review or editing of the article before submission. M.N.L.-d.H., D.J.A.d.G and E.G.E.d.V. also contributed substantially to discussions of the manuscript content and to review or editing of the manuscript before submission. A.H.B. contributed to review and/or editing of the manuscript before submission.

Corresponding author

Correspondence to Marjolijn N. Lub-de Hooge.

Ethics declarations

Competing interests

D.J.A.d.G. declares that he received institutional financial support for clinical trials or contracted research from Amgen, Bayer, GE Healthcare, Hoffmann La Roche and Siemens. E.G.E.d.V. declares that she received institutional financial support for acting as a member of advisory boards or consultancy services from Crescendo Biologics, Daiichi Sankyo and NSABP, as well as institutional financial support for clinical trials or contracted research grants from Amgen, Bayer, Crescendo Biologics, Genentech, Regeneron, Roche and Servier. M.N.L.-d.H. declares that she received institutional financial support for acting as a member of advisory boards or consultancy services from Merck and institutional financial support for conducting clinical and preclinical studies from Amgen, Bayer and Servier. The other authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Clinical Oncology thanks Weijun Wei and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Review criteria

Primary research articles published in English from 1 January 2014 to 18 March 2024 were identified using PubMed. Search terms included the names of known multispecific antibody constructs, solid tumours and PET or SPECT radioligands. In addition, the ClinicalTrials.gov database was searched for trials of multispecific antibodies up to September 2023 and abstracts from the American Association for Cancer Research and the American Society of Clinical Oncology annual meetings from 2023 were also reviewed to identify further relevant articles. Full details of the literature search strategy are provided in the Supplementary information.

Related links

ClinicalTrials.gov: https://clinicaltrials.gov/

PubMed: https://pubmed.ncbi.nlm.nih.gov/

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

van Winkel, C.A.J., Pierik, F.R., Brouwers, A.H. et al. Molecular imaging supports the development of multispecific cancer antibodies. Nat Rev Clin Oncol 21, 852–866 (2024). https://doi.org/10.1038/s41571-024-00946-3

Download citation

  • Accepted:

  • Published:

  • Version of record:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41571-024-00946-3

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer