Movatterモバイル変換

[0]ホーム
URL:

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.

Advertisement

Nature Reviews Cancer
  • Review Article
  • Published:

Building better monoclonal antibody-based therapeutics

Nature Reviews Cancervolume 15, pages361–370 (2015)Cite this article

Subjects

Key Points

  • Monoclonal antibody (mAb)-based therapeutics are now standard in the treatment of cancer, and the numbers and varieties of clinically applicable mAb-based approaches continue to grow.

  • Effective mAb-based treatments of cancer include directly targeting the cancer, altering the host response to the cancer, delivering cytotoxic moieties to the cancer and retargeting T cells towards the cancer.

  • mAb-based treatments that directly target the cancer mediate their effects through direct signalling, antibody-dependent cellular cytotoxicity and complement-mediated lysis. Differentiating which of these mechanisms is most important for a given mAb can be difficult but is important when working to identify better mAb-based treatments.

  • mAb-based treatments that alter the host response can alter tumour angiogenesis or the T cell response through T cell checkpoint blockade. Checkpoint-blockade mAbs are showing particular promise.

  • mAb-based treatments that deliver cytotoxic agents to the cancer include radioimmunotherapy and antibody–drug conjugates (ADCs). ADCs are complex because of the need to match the target cancer to the right mAb, linker and drug, but early results are promising and many new ADCs are in development.

  • mAb-based treatments that retarget T cells towards cancer include bispecific antibodies and chimeric antigen receptor T cells. Both approaches are logistically challenging but have demonstrated exciting early results, particularly in B cell malignancies.

  • Each of these approaches has advantages and disadvantages that need to be considered in their development and evaluation.

  • Rapid progress is taking place in the development of new agents and the testing of new approaches, both alone and in combination, in each of these areas.

Abstract

For 20 years, monoclonal antibodies (mAbs) have been a standard component of cancer therapy, but there is still much room for improvement. Efforts continue to build better cancer therapeutics based on mAbs. Anticancer mAbs function through various mechanisms, including directly targeting the malignant cells, modifying the host response, delivering cytotoxic moieties and retargeting cellular immunity towards the malignant cells. Characteristics of mAbs that affect their efficacy include antigen specificity, overall structure, affinity for the target antigen and how a mAb component is incorporated into a construct that can trigger target cell death. This Review discusses the various approaches to using mAb-based therapeutics to treat cancer and the strategies used to take advantage of the unique potential of each approach, and provides examples of current mAb-based treatments.

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

Access options

Access through your institution

Subscription info for Japanese customers

We have a dedicated website for our Japanese customers. Please go tonatureasia.com to subscribe to this journal.

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF

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

Figure 1: Monoclonal antibody-based cancer therapeutic strategies.
Figure 2: Mechanisms of action of monoclonal antibodies that target cancer cells.
Figure 3: Modifying monoclonal antibody structure.

Similar content being viewed by others

References

  1. Ehrlich, P.Collected Studies on Immunity 1st edn (J. Wiley & Sons, 1906).

    Google Scholar 

  2. Keller, M. A. & Stiehm, E. R. Passive immunity in prevention and treatment of infectious diseases.Clin. Microbiol. Rev.13, 602–614 (2000).

    Article CAS PubMed PubMed Central  Google Scholar 

  3. Kohler, G. & Milstein, C. Continuous cultures of fused cells secreting antibody of predefined specificity.Nature256, 495 (1975).This landmark publication outlines how to produce mAbs, as well as their therapeutic potential.

    Article CAS PubMed  Google Scholar 

  4. Milstein, C. From the structure of antibodies to the diversification of the immune response. Nobel lecture, 8 December 1984.Biosci. Rep.5, 275–297 (1985).

    Article CAS PubMed  Google Scholar 

  5. Bernard, A. & Boumsell, L. The clusters of differentiation (CD) defined by the First International Workshop on Human Leucocyte Differentiation Antigens.Hum. Immunol.11, 1–10 (1984).

    Article CAS PubMed  Google Scholar 

  6. Vaickus, L. & Foon, K. A. Overview of monoclonal antibodies in the diagnosis and therapy of cancer.Cancer Invest.9, 195–209 (1991).

    Article CAS PubMed  Google Scholar 

  7. Meeker, T. C. et al. A clinical trial of anti-idiotype therapy for B cell malignancy.Blood65, 1349–1363 (1985).This early clinical trial demonstrated the potential efficacy of mAb-based therapy and many of the challenges associated with it.

    Article CAS PubMed  Google Scholar 

  8. LoBuglio, A. F. et al. Mouse/human chimeric monoclonal antibody in man: kinetics and immune response.Proc. Natl Acad. Sci. USA86, 4220–4224 (1989).

    Article CAS PubMed PubMed Central  Google Scholar 

  9. Maloney, D. G. et al. Idec-C2b8 (Rituximab) anti-CD20 monoclonal antibody therapy patients with relapsed low-grade non-Hodgkins lymphoma.Blood90, 2188–2195 (1997).This article details the first clinical trial to demonstrate the clear clinical efficacy of a chimeric human–murine mAb.

    Article CAS PubMed  Google Scholar 

  10. Scott, A. M., Wolchok, J. D. & Old, L. J. Antibody therapy of cancer.Nature Rev. Cancer12, 278–287 (2012).

    Article CAS  Google Scholar 

  11. Tutt, A. L. et al. Monoclonal antibody therapy of B cell lymphoma: signaling activity on tumor cells appears more important than recruitment of effectors.J. Immunol.161, 3176–3185 (1998).

    CAS PubMed  Google Scholar 

  12. Taylor, R. P. Of mice and mechanisms: identifying the role of complement in monoclonal antibody-based immunotherapy.Haematologica91, 146a (2006).

    PubMed  Google Scholar 

  13. Clynes, R., Takechi, Y., Moroi, Y., Houghton, A. & Ravetch, J. V. Fc receptors are required in passive and active immunity to melanoma.Proc. Natl Acad. Sci. USA95, 652–656 (1998).

    Article CAS PubMed PubMed Central  Google Scholar 

  14. Beers, S. A. et al. Type II (tositumomab) anti-CD20 monoclonal antibody out performs type I (rituximab-like) reagents in B-cell depletion regardless of complement activation.Blood112, 4170–4177 (2008).

    Article CAS PubMed  Google Scholar 

  15. Shan, D., Ledbetter, J. A. & Press, O. W. Apoptosis of malignant human B cells by ligation of CD20 monoclonal antibodies.Blood91, 1644–1652 (1998).

    Article CAS PubMed  Google Scholar 

  16. Pedersen, I. M., Buhl, A. M., Klausen, P., Geisler, C. H. & Jurlander, J. The chimeric anti-CD20 antibody rituximab induces apoptosis in B-cell chronic lymphocytic leukemia cells through a p38 mitogen activated protein-kinase-dependent mechanism.Blood99, 1314–1319 (2002).

    Article CAS PubMed  Google Scholar 

  17. Weiner, G. J. Rituximab: mechanism of action.Semin. Hematol.47, 115–123 (2010).

    Article CAS PubMed PubMed Central  Google Scholar 

  18. Shan, D., Ledbetter, J. A. & Press, O. W. Signaling events involved in anti-CD20-induced apoptosis of malignant human B cells.Cancer Immunol. Immunother.48, 673–683 (2000).

    Article CAS PubMed  Google Scholar 

  19. Rimawi, M. F., Schiff, R. & Osborne, C. K. Targeting HER2 for the treatment of breast cancer.Annu. Rev. Med.66, 111–128 (2015).

    Article CAS PubMed  Google Scholar 

  20. Lavaud, P. & Andre, F. Strategies to overcome trastuzumab resistance in HER2-overexpressing breast cancers: focus on new data from clinical trials.BMC Med.12, 132 (2014).

    Article PubMed PubMed Central CAS  Google Scholar 

  21. Yarden, Y. & Sliwkowski, M. X. Untangling the ErbB signalling network.Nature Rev. Mol. Cell Biol.2, 127–137 (2001).

    Article CAS  Google Scholar 

  22. Yarden, Y. & Pines, G. The ERBB network: at last, cancer therapy meets systems biology.Nature Rev. Cancer12, 553–563 (2012).

    Article CAS  Google Scholar 

  23. Franklin, M. C. et al. Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex.Cancer Cell5, 317–328 (2004).

    Article CAS PubMed  Google Scholar 

  24. Le, X. F. et al. Differential signaling by an anti-p185HER2 antibody and heregulin.Cancer Res.60, 3522–3531 (2000).

    CAS PubMed  Google Scholar 

  25. Swain, S. M. et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, Phase 3 study.Lancet Oncol.14, 461–471 (2013).

    Article CAS PubMed PubMed Central  Google Scholar 

  26. Flexner, S. & Noguchi, H. Snake venom in relation to haemolysis, bacteriolysis, and toxicity.J. Exp. Med.6, 277–301 (1902).

    Article CAS PubMed PubMed Central  Google Scholar 

  27. Wang, S. Y. & Weiner, G. Complement and cellular cytotoxicity in antibody therapy of cancer.Expert Opin. Biol. Ther.8, 759–768 (2008).

    Article CAS PubMed  Google Scholar 

  28. Teeling, J. L. et al. The biological activity of human CD20 monoclonal antibodies is linked to unique epitopes on CD20.J. Immunol.177, 362–371 (2006).

    Article CAS PubMed  Google Scholar 

  29. Alduaij, W. et al. Novel type II anti-CD20 monoclonal antibody (GA101) evokes homotypic adhesion and actin-dependent, lysosome-mediated cell death in B-cell malignancies.Blood117, 4519–4529 (2011).

    Article CAS PubMed PubMed Central  Google Scholar 

  30. Natsume, A., Shimizu-Yokoyama, Y., Satoh, M., Shitara, K. & Niwa, R. Engineered anti-CD20 antibodies with enhanced complement-activating capacity mediate potent anti-lymphoma activity.Cancer Sci.100, 2411–2418 (2009).

    Article CAS PubMed  Google Scholar 

  31. Mossner, E. et al. Increasing the efficacy of CD20 antibody therapy through the engineering of a new type II anti-CD20 antibody with enhanced direct and immune effector cell-mediated B-cell cytotoxicity.Blood115, 4393–4402 (2010).

    Article CAS PubMed PubMed Central  Google Scholar 

  32. Pawluczkowycz, A. W. et al. Binding of submaximal C1q promotes complement-dependent cytotoxicity (CDC) of B cells opsonized with anti-CD20 mAbs ofatumumab (OFA) or rituximab (RTX): considerably higher levels of CDC are induced by OFA than by RTX.J. Immunol.183, 749–758 (2009).

    Article CAS PubMed  Google Scholar 

  33. Beum, P. V. et al. Loss of CD20 and bound CD20 antibody from opsonized B cells occurs more rapidly because of trogocytosis mediated by Fc receptor-expressing effector cells than direct internalization by the B cells.J. Immunol.187, 3438–3447 (2011).

    Article CAS PubMed  Google Scholar 

  34. Wang, S. Y. et al. Depletion of the C3 component of complement enhances the ability of rituximab-coated target cells to activate human NK cells and improves the efficacy of monoclonal antibody therapy in anin vivo model.Blood114, 5322–5330 (2009).

    Article CAS PubMed PubMed Central  Google Scholar 

  35. Dall'Ozzo, S. et al. Rituximab-dependent cytotoxicity by natural killer cells: influence ofFCGR3A polymorphism on the concentration–effect relationship.Cancer Res.64, 4664–4669 (2004).

    Article CAS PubMed  Google Scholar 

  36. Lefebvre, M. L., Krause, S. W., Salcedo, M. & Nardin, A.Ex vivo-activated human macrophages kill chronic lymphocytic leukemia cells in the presence of rituximab: mechanism of antibody-dependent cellular cytotoxicity and impact of human serum.J. Immunother.29, 388–397 (2006).

    Article CAS PubMed  Google Scholar 

  37. Hernandez-Ilizaliturri, F. J. et al. Neutrophils contribute to the biological antitumor activity of rituximab in a non-Hodgkin's lymphoma severe combined immunodeficiency mouse model.Clin. Cancer Res.9, 5866–5873 (2003).

    CAS PubMed  Google Scholar 

  38. Beers, S. A. & Glennie, M. J. Neutrophils: “neu players” in antibody therapy?Blood122, 3093–3094 (2013).

    Article CAS PubMed  Google Scholar 

  39. Clynes, R. A., Towers, T. L., Presta, L. G. & Ravetch, J. V. Inhibitory Fc receptors modulatein vivo cytotoxicity against tumor targets.Nature Med.6, 443–446 (2000).This important publication illustrates the importance of both activating and inhibitory FcRs in mediating the antitumour effects of mAbs.

    Article CAS PubMed  Google Scholar 

  40. Bowles, J. A. & Weiner, G. J.CD16 polymorphisms and NK activation induced by monoclonal antibody-coated target cells.J. Immunol. Methods304, 88–99 (2005).

    Article CAS PubMed  Google Scholar 

  41. Hoffmeyer, F., Witte, K. & Schmidt, R. E. The high-affinity FcγRI on PMN: regulation of expression and signal transduction.Immunology92, 544–552 (1997).

    Article CAS PubMed PubMed Central  Google Scholar 

  42. Glennie, M. J., French, R. R., Cragg, M. S. & Taylor, R. P. Mechanisms of killing by anti-CD20 monoclonal antibodies.Mol. Immunol.44, 3823–3837 (2007).

    Article CAS PubMed  Google Scholar 

  43. Rogers, L. M., Veeramani, S. & Weiner, G. J. Complement in monoclonal antibody therapy of cancer.Immunol. Res.59, 203–210 (2014).

    Article CAS PubMed PubMed Central  Google Scholar 

  44. Wang, S. Y., Racila, E., Taylor, R. P. & Weiner, G. J. NK-cell activation and antibody-dependent cellular cytotoxicity induced by rituximab-coated target cells is inhibited by the C3b component of complement.Blood111, 1456–1463 (2008).

    Article CAS PubMed PubMed Central  Google Scholar 

  45. Harbers, S. O. et al. Antibody-enhanced cross-presentation of self antigen breaks T cell tolerance.J. Clin. Invest.117, 1361–1369 (2007).

    Article CAS PubMed PubMed Central  Google Scholar 

  46. Vaughan, A. T. et al. Inhibitory FcγRIIb (CD32b) becomes activated by therapeutic mAb in bothcis andtrans and drives internalization according to antibody specificity.Blood123, 669–677 (2014).

    Article CAS PubMed  Google Scholar 

  47. Feldman, A. M., Lorell, B. H. & Reis, S. E. Trastuzumab in the treatment of metastatic breast cancer: anticancer therapy versus cardiotoxicity.Circulation102, 272–274 (2000).

    Article CAS PubMed  Google Scholar 

  48. Nadler, L. M. et al. Serotherapy of a patient with a monoclonal antibody directed against a human lymphoma-associated antigen.Cancer Res.40, 3147–3154 (1980).

    CAS PubMed  Google Scholar 

  49. de Goeij, B. E. et al. HER2 monoclonal antibodies that do not interfere with receptor heterodimerization-mediated signaling induce effective internalization and represent valuable components for rational antibody–drug conjugate design.mAbs6, 392–402 (2014).

    Article PubMed PubMed Central  Google Scholar 

  50. Bowles, J. A. et al. Anti-CD20 monoclonal antibody with enhanced affinity for CD16 activates NK cells at lower concentrations and more effectively than rituximab.Blood108, 2648–2654. (2006).

    Article CAS PubMed PubMed Central  Google Scholar 

  51. Dalle, S. et al. Preclinical studies on the mechanism of action and the anti-lymphoma activity of the novel anti-CD20 antibody GA101.Mol. Cancer Ther.10, 178–185 (2011).

    Article CAS PubMed  Google Scholar 

  52. Salles, G. et al. Phase 1 study results of the type II glycoengineered humanized anti-CD20 monoclonal antibody obinutuzumab (GA101) in B-cell lymphoma patients.Blood119, 5126–5132 (2012).

    Article CAS PubMed  Google Scholar 

  53. Cartron, G. et al. Obinutuzumab (GA101) in relapsed/refractory chronic lymphocytic leukemia: final data from the Phase 1/2 GAUGUIN study.Blood124, 2196–2202 (2014).

    Article CAS PubMed  Google Scholar 

  54. Lohse, S. et al. Recombinant dimeric IgA antibodies against the epidermal growth factor receptor mediate effective tumor cell killing.J. Immunol.186, 3770–3778 (2011).

    Article CAS PubMed  Google Scholar 

  55. Dao, T., Liu, C. & Scheinberg, D. A. Approaching untargetable tumor-associated antigens with antibodies.Oncoimmunology2, e24678 (2013).

    Article PubMed PubMed Central  Google Scholar 

  56. Dubrovsky, L. et al. A TCR-mimic antibody to WT1 bypasses tyrosine kinase inhibitor resistance in human BCR–ABL+ leukemias.Blood123, 3296–3304 (2014).

    Article CAS PubMed PubMed Central  Google Scholar 

  57. Sergeeva, A. et al. An anti-PR1/HLA-A2 T-cell receptor-like antibody mediates complement-dependent cytotoxicity against acute myeloid leukemia progenitor cells.Blood117, 4262–4272 (2011).

    Article CAS PubMed PubMed Central  Google Scholar 

  58. Folkman, J. Tumor angiogenesis: therapeutic implications.N. Engl. J. Med.285, 1182–1186 (1971).This article is a description of the potential therapeutic impact of altering angiogenesis.

    Article CAS PubMed  Google Scholar 

  59. Ferrara, N., Hillan, K. J., Gerber, H. P. & Novotny, W. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer.Nature Rev. Drug Discov.3, 391–400 (2004).

    Article CAS  Google Scholar 

  60. Sennino, B. & McDonald, D. M. Controlling escape from angiogenesis inhibitors.Nature Rev. Cancer12, 699–709 (2012).

    Article CAS  Google Scholar 

  61. Lima, A. B., Macedo, L. T. & Sasse, A. D. Addition of bevacizumab to chemotherapy in advanced non-small cell lung cancer: a systematic review and meta-analysis.PLoS ONE6, e22681 (2011).

    Article CAS PubMed PubMed Central  Google Scholar 

  62. Wen, P. Y. et al. Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group.J. Clin. Oncol.28, 1963–1972 (2010).

    Article PubMed  Google Scholar 

  63. Cristofanilli, M., Charnsangavej, C. & Hortobagyi, G. N. Angiogenesis modulation in cancer research: novel clinical approaches.Nature Rev. Drug Discov.1, 415–426 (2002).

    Article CAS  Google Scholar 

  64. Pardoll, D. M. The blockade of immune checkpoints in cancer immunotherapy.Nature Rev. Cancer12, 252–264 (2012).

    Article CAS  Google Scholar 

  65. Page, D. B., Postow, M. A., Callahan, M. K., Allison, J. P. & Wolchok, J. D. Immune modulation in cancer with antibodies.Annu. Rev. Med.65, 185–202 (2014).

    Article CAS PubMed  Google Scholar 

  66. Peggs, K. S., Quezada, S. A., Korman, A. J. & Allison, J. P. Principles and use of anti-CTLA4 antibody in human cancer immunotherapy.Curr. Opin. Immunol.18, 206–213 (2006).

    Article CAS PubMed  Google Scholar 

  67. Hodi, F. S. et al. Improved survival with ipilimumab in patients with metastatic melanoma.N. Engl. J. Med.363, 711–723 (2010).This article documents a successful clinical trial of checkpoint blockade in cancer.

    Article CAS PubMed PubMed Central  Google Scholar 

  68. Robert, C. et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma.N. Engl. J. Med.364, 2517–2526 (2011).

    Article CAS PubMed  Google Scholar 

  69. Sondak, V. K., Smalley, K. S., Kudchadkar, R., Grippon, S. & Kirkpatrick, P. Ipilimumab.Nature Rev. Drug Discov.10, 411–412 (2011).

    Article CAS  Google Scholar 

  70. Brahmer, J. R. et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer.N. Engl. J. Med.366, 2455–2465 (2012).

    Article CAS PubMed PubMed Central  Google Scholar 

  71. Robert, C. et al. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a Phase 1 trial.Lancet384, 1109–1117 (2014).

    Article CAS PubMed  Google Scholar 

  72. Wolchok, J. D. et al. Nivolumab plus ipilimumab in advanced melanoma.N. Engl. J. Med.369, 122–133 (2013).

    Article CAS PubMed PubMed Central  Google Scholar 

  73. Topalian, S. L. et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.N. Engl. J. Med.366, 2443–2454 (2012).

    Article CAS PubMed PubMed Central  Google Scholar 

  74. Ansell, S. M. et al. PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma.N. Engl. J. Med.372, 311–319 (2015).This article describes an early phase clinical trial that demonstrates how an enhanced understanding of the immune response can lead to the development of a new therapeutic approach.

    Article PubMed CAS  Google Scholar 

  75. Order, S. E. The history and progress of serologic immunotherapy and radiodiagnosis.Radiology118, 219–223 (1976).

    Article CAS PubMed  Google Scholar 

  76. Order, S. E. et al. Radiolabeled antibody in the treatment of primary and metastatic liver malignancies.Recent Results Cancer Res.1986, 100307–100314 (1986).

    Google Scholar 

  77. Pouget, J. P. et al. Clinical radioimmunotherapy — the role of radiobiology.Nature Rev. Clin. Oncol.8, 720–734 (2011).

    Article CAS  Google Scholar 

  78. Jain, M., Venkatraman, G. & Batra, S. K. Optimization of radioimmunotherapy of solid tumors: biological impediments and their modulation.Clin. Cancer Res.13, 1374–1382 (2007).

    Article CAS PubMed  Google Scholar 

  79. Chen, S. et al. Pivotal study of iodine-131-labeled chimeric tumor necrosis treatment radioimmunotherapy in patients with advanced lung cancer.J. Clin. Oncol.23, 1538–1547 (2005).

    Article PubMed  Google Scholar 

  80. Witzig, T. E. et al. Randomized controlled trial of yttrium-90-labeled ibritumomab tiuxetan radioimmunotherapy versus rituximab immunotherapy for patients with relapsed or refractory low-grade, follicular, or transformed B-cell non-Hodgkin's lymphoma.J. Clin. Oncol.20, 2453–2463 (2002).

    Article CAS PubMed  Google Scholar 

  81. Kaminski, M. S. et al. Radioimmunotherapy of B-cell lymphoma with131I anti-B1 (anti-CD20) antibody.N. Engl. J. Med.329, 459–465 (1993).This early clinical trial demonstrated the efficacy of radioimmunotherapy.

    Article CAS PubMed  Google Scholar 

  82. Kolstad, A. et al. Nordic MCL3 study: 90Y-ibritumomab-tiuxetan added to BEAM/C in non-CR patients before transplant in mantle cell lymphoma.Blood123, 2953–2959 (2014).

    Article CAS PubMed PubMed Central  Google Scholar 

  83. Witzig, T. E. et al. A Phase I trial of immunostimulatory CpG 7909 oligodeoxynucleotide and yttrium ibritumomab tiuxetan radioimmunotherapy for relapsed B-cell non-Hodgkin lymphoma.Am. J. Hematol.53, 211–217 (2012).

    Google Scholar 

  84. Allen, B. J. Can α-radioimmunotherapy increase efficacy for the systemic control of cancer?Immunotherapy3, 455–458 (2011).

    Article PubMed  Google Scholar 

  85. Zalutsky, M. R. & Pruszynski, M. Astatine-211: production and availability.Curr. Radiopharm.4, 177–185 (2011).

    Article CAS PubMed PubMed Central  Google Scholar 

  86. Scheinberg, D. A. & McDevitt, M. R. Actinium-225 in targeted α-particle therapeutic applications.Curr. Radiopharm.4, 306–320 (2011).

    Article CAS PubMed PubMed Central  Google Scholar 

  87. Ghetie, V. & Vitetta, E. Immunotoxins in the therapy of cancer: from bench to clinic.Pharmacol. Ther.63, 209–234 (1994).

    Article CAS PubMed  Google Scholar 

  88. Zolot, R. S., Basu, S. & Million, R. P. Antibody–drug conjugates.Nature Rev. Drug Discov.12, 259–260 (2013).

    Article CAS  Google Scholar 

  89. Mathur, R. & Weiner, G. J. Picking the optimal target for antibody–drug conjugates.American Society of Clinical Oncology[online], (2013).

    Google Scholar 

  90. Hinman, L. M. et al. Preparation and characterization of monoclonal antibody conjugates of the calicheamicins: a novel and potent family of antitumor antibiotics.Cancer Res.53, 3336–3342 (1993).

    CAS PubMed  Google Scholar 

  91. Pettit, G. R. et al. Antineoplastic agents 337. Synthesis of dolastatin 10 structural modifications.Anticancer Drug Des.10, 529–544 (1995).

    CAS PubMed  Google Scholar 

  92. Kupchan, S. M. et al. Maytansine, a novel antileukemic ansa macrolide fromMaytenus ovatus.J. Am. Chem. Soc.94, 1354–1356 (1972).

    Article CAS PubMed  Google Scholar 

  93. Cooper, N. et al. Synthesis of novel C2-aryl pyrrolobenzodiazepines (PBDs) as potential antitumour agents.Chem. Commun.21, 1764–1765 (2002).

    Article CAS  Google Scholar 

  94. Sievers, E. L. & Senter, P. D. Antibody–drug conjugates in cancer therapy.Annu. Rev. Med.64, 15–29 (2013).

    Article CAS PubMed  Google Scholar 

  95. Shen, B. Q. et al. Conjugation site modulates thein vivo stability and therapeutic activity of antibody–drug conjugates.Nature Biotech.30, 184–189 (2012).

    Article CAS  Google Scholar 

  96. Younes, A. et al. Results of a pivotal Phase II study of brentuximab vedotin for patients with relapsed or refractory Hodgkin's lymphoma.J. Clin. Oncol.30, 2183–2189 (2012).

    Article CAS PubMed PubMed Central  Google Scholar 

  97. Gopal, A. K. et al. Durable remissions in a pivotal Phase 2 study of brentuximab vedotin in relapsed or refractory Hodgkin lymphoma.Blood125, 1236–1243 (2015).

    Article CAS PubMed PubMed Central  Google Scholar 

  98. Verma, S. et al. Trastuzumab emtansine for HER2-positive advanced breast cancer.N. Engl. J. Med.367, 1783–1791 (2012).This clinical trial demonstrated the potential efficacy of an ADC in a solid tumour.

    Article CAS PubMed PubMed Central  Google Scholar 

  99. Mullard, A. Maturing antibody–drug conjugate pipeline hits 30.Nature Rev. Drug Discov.12, 329–332 (2013).

    Article CAS  Google Scholar 

  100. Bendell, J. et al. Phase I/II study of the antibody–drug conjugate glembatumumab vedotin in patients with locally advanced or metastatic breast cancer.J. Clin. Oncol.32, 3619–3625 (2014).

    Article CAS PubMed  Google Scholar 

  101. Ott, P. A. et al. Phase I/II study of the antibody–drug conjugate glembatumumab vedotin in patients with advanced melanoma.J. Clin. Oncol.32, 3659–3666 (2014).

    Article CAS PubMed PubMed Central  Google Scholar 

  102. Yu, A. L. et al. Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma.N. Engl. J. Med.363, 1324–1334 (2010).

    Article CAS PubMed PubMed Central  Google Scholar 

  103. Shusterman, S. et al. Antitumor activity of hu14.18-IL2 in patients with relapsed/refractory neuroblastoma: a Children's Oncology Group (COG) Phase II study.J. Clin. Oncol.28, 4969–4975 (2010).

    Article CAS PubMed PubMed Central  Google Scholar 

  104. Navid, F. et al. Phase I trial of a novel anti-GD2 monoclonal antibody, Hu14.18K322A, designed to decrease toxicity in children with refractory or recurrent neuroblastoma.J. Clin. Oncol.32, 1445–1452 (2014).

    Article CAS PubMed PubMed Central  Google Scholar 

  105. Segal, D. M., Weiner, G. J. & Weiner, L. M. Bispecific antibodies in cancer therapy.Curr. Opin. Immunol.11, 558–562 (1999).

    Article CAS PubMed  Google Scholar 

  106. Nagorsen, D. et al. Immunotherapy of lymphoma and leukemia with T-cell engaging BiTE antibody blinatumomab.Leukemia Lymphoma50, 886–891 (2009).

    Article CAS PubMed  Google Scholar 

  107. Topp, M. S. et al. Targeted therapy with the T-cell-engaging antibody blinatumomab of chemotherapy-refractory minimal residual disease in B-lineage acute lymphoblastic leukemia patients results in high response rate and prolonged leukemia-free survival.J. Clin. Oncol.29, 2493–2498 (2011).This clinical trial demonstrated the potential efficacy of bispecific antibody therapy.

    Article CAS PubMed  Google Scholar 

  108. Barrett, D. M., Singh, N., Porter, D. L., Grupp, S. A. & June, C. H. Chimeric antigen receptor therapy for cancer.Annu. Rev. Med.65, 333–347 (2014).

    Article CAS PubMed  Google Scholar 

  109. June, C., Rosenberg, S. A., Sadelain, M. & Weber, J. S. T-cell therapy at the threshold.Nature Biotech.30, 611–614 (2012).

    Article CAS  Google Scholar 

  110. Lee, D. W. et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a Phase 1 dose-escalation trial.Lancet385, 517–528 (2014).

    Article PubMed PubMed Central CAS  Google Scholar 

  111. Maude, S. L. et al. Chimeric antigen receptor T cells for sustained remissions in leukemia.N. Engl. J. Med.371, 1507–1517 (2014).

    Article PubMed PubMed Central CAS  Google Scholar 

  112. Kalos, M. et al. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia.Sci. Transl Med.3, 95ra73 (2011).This early demonstration of the potential of CAR T cells included the potential to develop CAR T memory cells.

    Article CAS PubMed PubMed Central  Google Scholar 

  113. Maude, S. L., Barrett, D., Teachey, D. T. & Grupp, S. A. Managing cytokine release syndrome associated with novel T cell-engaging therapies.Cancer J.20, 119–122 (2014).

    Article CAS PubMed PubMed Central  Google Scholar 

  114. DeFrancesco, L. CAR-T cell therapy seeks strategies to harness cytokine storm.Nature Biotech.32, 604 (2014).

    Article  Google Scholar 

Download references

Acknowledgements

The author would like to acknowledge support from the US National Institutes of Health grants P30 CA86862 and P50 CA97274.

Author information

Authors and Affiliations

  1. Holden Comprehensive Cancer Center, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, 5970Z-JPP, Iowa City, 52242, Iowa, USA

    George J. Weiner

Authors
  1. George J. Weiner

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence toGeorge J. Weiner.

Ethics declarations

Competing interests

The author declares no competing financial interests.

Glossary

Cluster of differentiation numbers

Numbers assigned to cell surface molecules on the basis of immunophenotyping. They are often used to identify different monoclonal antibodies that bind to the same antigen.

Transmembrane signalling

The process by which an extracellular signal, mediated by a natural ligand or an alternative agent such as a monoclonal antibody, binds to a membrane receptor and generates an intracellular signal that can affect a broad range of cellular functions, including cell growth, cell differentiation and cell death.

Complement-mediated cytotoxicity

(CMC). Also known as complement-dependent cytotoxicity. Cell death resulting from the activation of the complement cascade by a monoclonal antibody that leads to the formation of a membrane attack complex on the surface of the cell.

Antibody-dependent cellular cytotoxicity

(ADCC). Lysis of a target cell by an immune effector cell (such as a natural killer cell, monocyte, macrophage or granulocyte) induced by the recognition of an antibody bound to the surface of the target cell.

Fc receptors

(FcRs). A family of protein receptors specific for an epitope on the constant region of an antibody. When FcRs on immune effector cells come into contact with an antibody-coated target cell, this can result in immune effector cell activation (FcRs with immunoreceptor tyrosine-based activation motifs (ITAMs)) or inhibition (FcRs with immunoreceptor tyrosine-based inhibitory motifs (ITIMs)).

Complement fixation

Initiation of the complement cascade by an antibody bound to an antigen. It can lead to complement-mediated cytotoxicity of the target cell, as well as other complex effects mediated by the activation of various complement components.

mAb isotype

The subtype of a monoclonal antibody (mAb) based on the amino acid sequence of the constant region. Isotypes (IgG1, IgG2, IgG3 and IgG4) vary in their ability to mediate antibody-dependent cellular cytotoxicity and complement-mediated cytotoxicity.

Glycosylation

The post-translational attachment of a carbohydrate moiety to a protein. The Fc region of immunoglobulin G includes carbohydrate moieties. Altering the enzymes responsible for glycosylation in a cell line that produces a monoclonal antibody (mAb) can alter the glycosylation of the mAb, thereby altering its ability to activate immune effector cells.

Opsonization

The process by which a target is marked for phagocytosis or for destruction by phagocytes. This term is often used to describe phagocytosis of microbial pathogens. In the case of monoclonal antibody therapy of cancer, the target is a cancer cell.

Checkpoint blockade

Inhibitory pathways limit T cell activation in order to maintain self-tolerance and prevent autoimmunity. Checkpoint blockade involves blocking these inhibitory pathways, and thereby allowing for to a more robust T cell response.

Breakthrough therapy designation

US Food and Drug Administration (FDA) designation if a new drug is intended to treat a serious or life-threatening disease and preliminary clinical evidence suggests that it provides a substantial improvement over existing therapies.

Bispecific antibody

(Also known as bifunctional antibody). An engineered monoclonal antibody (mAb) that is composed of fragments of two different mAbs that bind to two different antigens. In cancer therapy, it typically binds to an activating antigen on an immune effector cell with one arm and to a tumour-associated antigen on a cancer cell with the other arm, thereby retargeting the immune effector cell towards the target cancer cell.

Chimeric antigen receptor

(CAR). An engineered receptor that grafts an alternative specificity onto an immune effector cell, most often a T cell. Most of the current constructs for engineered receptors include a single-chain monoclonal antibody variable region that recognizes the target cell and is linked to activating transmembrane domains that activate the T cell when it comes into contact with a target cell.

Rights and permissions

This article is cited by

Access through your institution
Buy or subscribe

Associated content

Collection

Nobel Prize in Chemistry 2018

Advertisement

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for theNature 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
[8]ページ先頭
©2009-2025 Movatter.jp