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Antibody-based cancer therapy

Abstract

Over the past 25 years, antibody therapeutics have emerged as clinically and commercially successful pharmaceuticals, rapidly approaching 100 Food and Drug Administration approvals with combined annual global sales exceeding $100 billion. Nearly half of the marketed antibody therapeutics are used in oncology. These antibody-based cancer therapies can be broken down into three categories based on their different mechanisms of action, i.e., (i) natural properties, (ii) engagement of cytotoxic T cells, and (iii) delivery of cytotoxic payloads. Both natural and engineered properties of the antibody molecule are founded on its highly stable and modular architecture. In this review we provide an overview and outlook of the rapidly evolving landscape of antibody-based cancer therapy.

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Fig. 1: Structural and functional modularity of the antibody molecule.
Fig. 2: Structural and functional diversity of FDA-approved T-cell engaging antibodies.
Fig. 3: Composition of FDA-approved ADCs.

References

  1. 1.

    Kaplon H, Reichert JM. Antibodies to watch in 2021. MAbs. 2021;13:1860476.

    PubMed  PubMed Central  Google Scholar 

  2. 2.

    Wang LX, Tong X, Li C, Giddens JP, Li T. Glycoengineering of antibodies for modulating functions. Annu Rev Biochem. 2019;88:433–59.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Rajewsky K. Clonal selection and learning in the antibody system. Nature. 1996;381:751–8.

    CAS  PubMed  Google Scholar 

  4. 4.

    Briney B, Inderbitzin A, Joyce C, Burton DR. Commonality despite exceptional diversity in the baseline human antibody repertoire. Nature. 2019;566:393–7.

    PubMed  PubMed Central  Google Scholar 

  5. 5.

    Beerli RR, Rader C. Mining human antibody repertoires. MAbs. 2010;2:365–78.

    PubMed  Google Scholar 

  6. 6.

    Alfaleh MA, Alsaab HO, Mahmoud AB, Alkayyal AA, Jones ML, Mahler SM, et al. Phage display derived monoclonal antibodies: from bench to bedside. Front Immunol. 2020;11:1986.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Zheng S, Moores S, Jarantow S, Pardinas J, Chiu M, Zhou H, et al. Cross-arm binding efficiency of an EGFR x c-Met bispecific antibody. MAbs. 2016;8:551–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Scott DE, Bayly AR, Abell C, Skidmore J. Small molecules, big targets: drug discovery faces the protein-protein interaction challenge. Nat Rev Drug Discov. 2016;15:533–50.

    CAS  PubMed  Google Scholar 

  9. 9.

    Brezski RJ, Georgiou G. Immunoglobulin isotype knowledge and application to Fc engineering. Curr Opin Immunol. 2016;40:62–9.

    CAS  PubMed  Google Scholar 

  10. 10.

    Liu R, Oldham RJ, Teal E, Beers SA, Cragg MS. Fc-engineering for modulated effector functions-improving antibodies for cancer treatment. Antibodies. 2020;9:64

    PubMed Central  Google Scholar 

  11. 11.

    Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science. 2011;331:1565–70.

    CAS  Google Scholar 

  12. 12.

    Dougan M, Pietropaolo M. Time to dissect the autoimmune etiology of cancer antibody immunotherapy. J Clin Invest. 2020;130:51–61.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Wolchok JD, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N. Engl J Med. 2017;377:1345–56.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Rutkowski P, Lao CD, et al. Five-year survival with combined nivolumab and ipilimumab in advanced melanoma. N. Engl J Med. 2019;381:1535–46.

    CAS  PubMed  Google Scholar 

  15. 15.

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

    CAS  Google Scholar 

  16. 16.

    Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12:252–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Mayes PA, Hance KW, Hoos A. The promise and challenges of immune agonist antibody development in cancer. Nat Rev Drug Discov. 2018;17:509–27.

    CAS  PubMed  Google Scholar 

  18. 18.

    Lemery S, Keegan P, Pazdur R, First FDA. Approval agnostic of cancer site—when a biomarker defines the indication. N. Engl J Med. 2017;377:1409–12.

    PubMed  Google Scholar 

  19. 19.

    Galluzzi L, Buque A, Kepp O, Zitvogel L, Kroemer G. Immunogenic cell death in cancer and infectious disease. Nat Rev Immunol. 2017;17:97–111.

    CAS  PubMed  Google Scholar 

  20. 20.

    Kroemer G, Galluzzi L, Kepp O, Zitvogel L. Immunogenic cell death in cancer therapy. Annu Rev Immunol. 2013;31:51–72.

    CAS  PubMed  Google Scholar 

  21. 21.

    Müller P, Kreuzaler M, Khan T, Thommen DS, Martin K, Glatz K, et al. Trastuzumab emtansine (T-DM1) renders HER2+ breast cancer highly susceptible to CTLA-4/PD-1 blockade. Sci Transl Med. 2015;7:315ra188

    PubMed  Google Scholar 

  22. 22.

    Beck A, Goetsch L, Dumontet C, Corvaia N. Strategies and challenges for the next generation of antibody-drug conjugates. Nat Rev Drug Discov. 2017;16:315–37.

    CAS  PubMed  Google Scholar 

  23. 23.

    Feng M, Jiang W, Kim BYS, Zhang CC, Fu YX, Weissman IL. Phagocytosis checkpoints as new targets for cancer immunotherapy. Nat Rev Cancer. 2019;19:568–86.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Clynes RA, Desjarlais JR. Redirected T cell cytotoxicity in cancer therapy. Annu Rev Med. 2019;70:437–50.

    CAS  Google Scholar 

  25. 25.

    Rader C. Bispecific antibodies in cancer immunotherapy. Curr Opin Biotechnol. 2020;65:9–16.

    CAS  PubMed  Google Scholar 

  26. 26.

    Wu X, Demarest SJ. Building blocks for bispecific and trispecific antibodies. Methods. 2019;154:3–9.

    CAS  PubMed  Google Scholar 

  27. 27.

    Brinkmann U, Kontermann RE. The making of bispecific antibodies. MAbs. 2017;9:182–212.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Ellerman D. Bispecific T-cell engagers: towards understanding variables influencing the in vitro potency and tumor selectivity and their modulation to enhance their efficacy and safety. Methods. 2019;154:102–17.

    CAS  PubMed  Google Scholar 

  29. 29.

    Gross G, Waks T, Eshhar Z. Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity. Proc Natl Acad Sci U.S.A. 1989;86:10024–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    June CH, O’Connor RS, Kawalekar OU, Ghassemi S, Milone MC. CAR T cell immunotherapy for human cancer. Science. 2018;359:1361–5.

    CAS  Google Scholar 

  31. 31.

    Sadelain M, Riviere I, Riddell S. Therapeutic T cell engineering. Nature. 2017;545:423–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Hong M, Clubb JD, Chen YY. Engineering CAR-T cells for next-generation cancer therapy. Cancer Cell. 2020;38:473–88.

    CAS  PubMed  Google Scholar 

  33. 33.

    Stadtmauer EA, Fraietta JA, Davis MM, Cohen AD, Weber KL, Lancaster E, et al. CRISPR-engineered T cells in patients with refractory cancer. Science. 2020;367:eaba7365

    CAS  Google Scholar 

  34. 34.

    Srivastava S, Furlan SN, Jaeger-Ruckstuhl CA, Sarvothama M, Berger C, Smythe KS, et al. Immunogenic chemotherapy enhances recruitment of CAR-T cells to lung tumors and improves antitumor efficacy when combined with checkpoint blockade. Cancer Cell. 2021;39:193–208.

    CAS  PubMed  Google Scholar 

  35. 35.

    Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N. Engl J Med. 2018;378:439–48.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Daher M, Rezvani K. Outlook for new CAR-based therapies with a focus on CAR NK cells: what lies beyond CAR-engineered T cells in the race against cancer. Cancer Discov. 2021;11:45–58.

    CAS  PubMed  Google Scholar 

  37. 37.

    Hodgins JJ, Khan ST, Park MM, Auer RC, Ardolino M. Killers 2.0: NK cell therapies at the forefront of cancer control. J Clin Invest. 2019;129:3499–510.

    PubMed  PubMed Central  Google Scholar 

  38. 38.

    Neri D, Sondel PM. Immunocytokines for cancer treatment: past, present and future. Curr Opin Immunol. 2016;40:96–102.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Rosenberg SA. IL-2: the first effective immunotherapy for human cancer. J Immunol. 2014;192:5451–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Walsh SJ, Bargh JD, Dannheim FM, Hanby AR, Seki H, Counsell AJ, et al. Site-selective modification strategies in antibody-drug conjugates. Chem Soc Rev. 2021;50:1305–53.

    CAS  PubMed  Google Scholar 

  41. 41.

    Kreitman RJ, Pastan I. Antibody fusion proteins: anti-CD22 recombinant immunotoxin moxetumomab pasudotox. Clin Cancer Res. 2011;17:6398–405.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Mazor R, Pastan I. Immunogenicity of immunotoxins containing pseudomonas exotoxin A: causes, consequences, and mitigation. Front Immunol. 2020;11:1261.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Green DJ, Press OW. Whither radioimmunotherapy: to be or not to be? Cancer Res. 2017;77:2191–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Kraeber-Bodere F, Faivre-Chauvet A, Ferrer L, Vuillez JP, Brard PY, Rousseau C, et al. Pharmacokinetics and dosimetry studies for optimization of anti-carcinoembryonic antigen x anti-hapten bispecific antibody-mediated pretargeting of Iodine-131-labeled hapten in a phase I radioimmunotherapy trial. Clin Cancer Res. 2003;9:3973S–81S.

    CAS  PubMed  Google Scholar 

  45. 45.

    Kobayashi H, Choyke PL. Near-infrared photoimmunotherapy of cancer. Acc Chem Res. 2019;52:2332–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Mitsunaga M, Ogawa M, Kosaka N, Rosenblum LT, Choyke PL, Kobayashi H. Cancer cell-selective in vivo near infrared photoimmunotherapy targeting specific membrane molecules. Nat Med. 2011;17:1685–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Desnoyers LR, Vasiljeva O, Richardson JH, Yang A, Menendez EE, Liang TW, et al. Tumor-specific activation of an EGFR-targeting probody enhances therapeutic index. Sci Transl Med. 2013;5:207ra144.

    PubMed  Google Scholar 

  48. 48.

    Johnston RJ, Su LJ, Pinckney J, Critton D, Boyer E, Krishnakumar A, et al. VISTA is an acidic pH-selective ligand for PSGL-1. Nature. 2019;574:565–70.

    CAS  PubMed  Google Scholar 

  49. 49.

    Kamata-Sakurai M, Narita Y, Hori Y, Nemoto T, Uchikawa R, Honda M, et al. Antibody to CD137 activated by extracellular adenosine triphosphate is tumor selective and broadly effective in vivo without systemic immune activation. Cancer Discov. 2021;11:158–75.

    CAS  PubMed  Google Scholar 

  50. 50.

    Denkberg G, Cohen CJ, Lev A, Chames P, Hoogenboom HR, Reiter Y. Direct visualization of distinct T cell epitopes derived from a melanoma tumor-associated antigen by using human recombinant antibodies with MHC-restricted T cell receptor-like specificity. Proc Natl Acad Sci U.S.A. 2002;99:9421–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Hsiue EH-C, Wright KM, Douglass J, Hwang MS, Mog BJ, Pearlman AH, et al. Targeting a neoantigen derived from a common TP53 mutation. Science. 2021;371:eabc8697

    CAS  PubMed  Google Scholar 

  52. 52.

    Cotton AD, Nguyen DP, Gramespacher JA, Seiple IB, Wells JA. Development of antibody-based PROTACs for the degradation of the cell-surface immune checkpoint protein PD-L1. J Am Chem Soc. 2021;143:593–8.

    CAS  PubMed  Google Scholar 

  53. 53.

    Goydel RS, Weber J, Peng H, Qi J, Soden J, Freeth J, et al. Affinity maturation, humanization, and co-crystallization of a rabbit anti-human ROR2 monoclonal antibody for therapeutic applications. J Biol Chem. 2020;295:5995–6006.

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We acknowledge support by predoctoral stipends from the Klorfine Foundation and the Frenchman’s Creek Women for Cancer Research (to R.S.G.) and National Institutes of Health Grants R01 CA174844, R01 CA181258, R01 CA204484, and R21 CA229961 (to C.R.). We thank Dr. HaJeung Park from the X-Ray Crystallography Core of The Scripps Research Institute (Jupiter, FL) for contributing Fig. 1C.

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Correspondence to Christoph Rader.

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Goydel, R.S., Rader, C. Antibody-based cancer therapy. Oncogene 40, 3655–3664 (2021). https://doi.org/10.1038/s41388-021-01811-8

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