Ehrlich, P. Collected Studies on Immunity 1st edn (J. Wiley & Sons, 1906).
Keller, M. A. & Stiehm, E. R. Passive immunity in prevention and treatment of infectious diseases. Clin. Microbiol. Rev. 13, 602–614 (2000).
Kohler, G. & Milstein, C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 256, 495 (1975).
This landmark publication outlines how to produce mAbs, as well as their therapeutic potential.
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).
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).
Vaickus, L. & Foon, K. A. Overview of monoclonal antibodies in the diagnosis and therapy of cancer. Cancer Invest. 9, 195–209 (1991).
Meeker, T. C. et al. A clinical trial of anti-idiotype therapy for B cell malignancy. Blood 65, 1349–1363 (1985).
This early clinical trial demonstrated the potential efficacy of mAb-based therapy and many of the challenges associated with it.
LoBuglio, A. F. et al. Mouse/human chimeric monoclonal antibody in man: kinetics and immune response. Proc. Natl Acad. Sci. USA 86, 4220–4224 (1989).
Maloney, D. G. et al. Idec-C2b8 (Rituximab) anti-CD20 monoclonal antibody therapy patients with relapsed low-grade non-Hodgkins lymphoma. Blood 90, 2188–2195 (1997).
This article details the first clinical trial to demonstrate the clear clinical efficacy of a chimeric human–murine mAb.
Scott, A. M., Wolchok, J. D. & Old, L. J. Antibody therapy of cancer. Nature Rev. Cancer 12, 278–287 (2012).
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).
Taylor, R. P. Of mice and mechanisms: identifying the role of complement in monoclonal antibody-based immunotherapy. Haematologica 91, 146a (2006).
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. USA 95, 652–656 (1998).
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. Blood 112, 4170–4177 (2008).
Shan, D., Ledbetter, J. A. & Press, O. W. Apoptosis of malignant human B cells by ligation of CD20 monoclonal antibodies. Blood 91, 1644–1652 (1998).
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. Blood 99, 1314–1319 (2002).
Weiner, G. J. Rituximab: mechanism of action. Semin. Hematol. 47, 115–123 (2010).
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).
Rimawi, M. F., Schiff, R. & Osborne, C. K. Targeting HER2 for the treatment of breast cancer. Annu. Rev. Med. 66, 111–128 (2015).
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).
Yarden, Y. & Sliwkowski, M. X. Untangling the ErbB signalling network. Nature Rev. Mol. Cell Biol. 2, 127–137 (2001).
Yarden, Y. & Pines, G. The ERBB network: at last, cancer therapy meets systems biology. Nature Rev. Cancer 12, 553–563 (2012).
Franklin, M. C. et al. Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex. Cancer Cell 5, 317–328 (2004).
Le, X. F. et al. Differential signaling by an anti-p185HER2 antibody and heregulin. Cancer Res. 60, 3522–3531 (2000).
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).
Flexner, S. & Noguchi, H. Snake venom in relation to haemolysis, bacteriolysis, and toxicity. J. Exp. Med. 6, 277–301 (1902).
Wang, S. Y. & Weiner, G. Complement and cellular cytotoxicity in antibody therapy of cancer. Expert Opin. Biol. Ther. 8, 759–768 (2008).
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).
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. Blood 117, 4519–4529 (2011).
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).
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. Blood 115, 4393–4402 (2010).
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).
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).
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 an in vivo model. Blood 114, 5322–5330 (2009).
Dall'Ozzo, S. et al. Rituximab-dependent cytotoxicity by natural killer cells: influence of FCGR3A polymorphism on the concentration–effect relationship. Cancer Res. 64, 4664–4669 (2004).
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).
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).
Beers, S. A. & Glennie, M. J. Neutrophils: “neu players” in antibody therapy? Blood 122, 3093–3094 (2013).
Clynes, R. A., Towers, T. L., Presta, L. G. & Ravetch, J. V. Inhibitory Fc receptors modulate in 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.
Bowles, J. A. & Weiner, G. J. CD16 polymorphisms and NK activation induced by monoclonal antibody-coated target cells. J. Immunol. Methods 304, 88–99 (2005).
Hoffmeyer, F., Witte, K. & Schmidt, R. E. The high-affinity FcγRI on PMN: regulation of expression and signal transduction. Immunology 92, 544–552 (1997).
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).
Rogers, L. M., Veeramani, S. & Weiner, G. J. Complement in monoclonal antibody therapy of cancer. Immunol. Res. 59, 203–210 (2014).
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. Blood 111, 1456–1463 (2008).
Harbers, S. O. et al. Antibody-enhanced cross-presentation of self antigen breaks T cell tolerance. J. Clin. Invest. 117, 1361–1369 (2007).
Vaughan, A. T. et al. Inhibitory FcγRIIb (CD32b) becomes activated by therapeutic mAb in both cis and trans and drives internalization according to antibody specificity. Blood 123, 669–677 (2014).
Feldman, A. M., Lorell, B. H. & Reis, S. E. Trastuzumab in the treatment of metastatic breast cancer: anticancer therapy versus cardiotoxicity. Circulation 102, 272–274 (2000).
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).
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. mAbs 6, 392–402 (2014).
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. Blood 108, 2648–2654. (2006).
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).
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. Blood 119, 5126–5132 (2012).
Cartron, G. et al. Obinutuzumab (GA101) in relapsed/refractory chronic lymphocytic leukemia: final data from the Phase 1/2 GAUGUIN study. Blood 124, 2196–2202 (2014).
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).
Dao, T., Liu, C. & Scheinberg, D. A. Approaching untargetable tumor-associated antigens with antibodies. Oncoimmunology 2, e24678 (2013).
Dubrovsky, L. et al. A TCR-mimic antibody to WT1 bypasses tyrosine kinase inhibitor resistance in human BCR–ABL+ leukemias. Blood 123, 3296–3304 (2014).
Sergeeva, A. et al. An anti-PR1/HLA-A2 T-cell receptor-like antibody mediates complement-dependent cytotoxicity against acute myeloid leukemia progenitor cells. Blood 117, 4262–4272 (2011).
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.
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).
Sennino, B. & McDonald, D. M. Controlling escape from angiogenesis inhibitors. Nature Rev. Cancer 12, 699–709 (2012).
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 ONE 6, e22681 (2011).
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).
Cristofanilli, M., Charnsangavej, C. & Hortobagyi, G. N. Angiogenesis modulation in cancer research: novel clinical approaches. Nature Rev. Drug Discov. 1, 415–426 (2002).
Pardoll, D. M. The blockade of immune checkpoints in cancer immunotherapy. Nature Rev. Cancer 12, 252–264 (2012).
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).
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).
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.
Robert, C. et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N. Engl. J. Med. 364, 2517–2526 (2011).
Sondak, V. K., Smalley, K. S., Kudchadkar, R., Grippon, S. & Kirkpatrick, P. Ipilimumab. Nature Rev. Drug Discov. 10, 411–412 (2011).
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).
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. Lancet 384, 1109–1117 (2014).
Wolchok, J. D. et al. Nivolumab plus ipilimumab in advanced melanoma. N. Engl. J. Med. 369, 122–133 (2013).
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).
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.
Order, S. E. The history and progress of serologic immunotherapy and radiodiagnosis. Radiology 118, 219–223 (1976).
Order, S. E. et al. Radiolabeled antibody in the treatment of primary and metastatic liver malignancies. Recent Results Cancer Res. 1986, 100307–100314 (1986).
Pouget, J. P. et al. Clinical radioimmunotherapy — the role of radiobiology. Nature Rev. Clin. Oncol. 8, 720–734 (2011).
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).
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).
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).
Kaminski, M. S. et al. Radioimmunotherapy of B-cell lymphoma with 131I anti-B1 (anti-CD20) antibody. N. Engl. J. Med. 329, 459–465 (1993).
This early clinical trial demonstrated the efficacy of radioimmunotherapy.
Kolstad, A. et al. Nordic MCL3 study: 90Y-ibritumomab-tiuxetan added to BEAM/C in non-CR patients before transplant in mantle cell lymphoma. Blood 123, 2953–2959 (2014).
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).
Allen, B. J. Can α-radioimmunotherapy increase efficacy for the systemic control of cancer? Immunotherapy 3, 455–458 (2011).
Zalutsky, M. R. & Pruszynski, M. Astatine-211: production and availability. Curr. Radiopharm. 4, 177–185 (2011).
Scheinberg, D. A. & McDevitt, M. R. Actinium-225 in targeted α-particle therapeutic applications. Curr. Radiopharm. 4, 306–320 (2011).
Ghetie, V. & Vitetta, E. Immunotoxins in the therapy of cancer: from bench to clinic. Pharmacol. Ther. 63, 209–234 (1994).
Zolot, R. S., Basu, S. & Million, R. P. Antibody–drug conjugates. Nature Rev. Drug Discov. 12, 259–260 (2013).
Mathur, R. & Weiner, G. J. Picking the optimal target for antibody–drug conjugates. American Society of Clinical Oncology [online], (2013).
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).
Pettit, G. R. et al. Antineoplastic agents 337. Synthesis of dolastatin 10 structural modifications. Anticancer Drug Des. 10, 529–544 (1995).
Kupchan, S. M. et al. Maytansine, a novel antileukemic ansa macrolide from Maytenus ovatus. J. Am. Chem. Soc. 94, 1354–1356 (1972).
Cooper, N. et al. Synthesis of novel C2-aryl pyrrolobenzodiazepines (PBDs) as potential antitumour agents. Chem. Commun. 21, 1764–1765 (2002).
Sievers, E. L. & Senter, P. D. Antibody–drug conjugates in cancer therapy. Annu. Rev. Med. 64, 15–29 (2013).
Shen, B. Q. et al. Conjugation site modulates the in vivo stability and therapeutic activity of antibody–drug conjugates. Nature Biotech. 30, 184–189 (2012).
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).
Gopal, A. K. et al. Durable remissions in a pivotal Phase 2 study of brentuximab vedotin in relapsed or refractory Hodgkin lymphoma. Blood 125, 1236–1243 (2015).
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.
Mullard, A. Maturing antibody–drug conjugate pipeline hits 30. Nature Rev. Drug Discov. 12, 329–332 (2013).
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).
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).
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).
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).
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).
Segal, D. M., Weiner, G. J. & Weiner, L. M. Bispecific antibodies in cancer therapy. Curr. Opin. Immunol. 11, 558–562 (1999).
Nagorsen, D. et al. Immunotherapy of lymphoma and leukemia with T-cell engaging BiTE antibody blinatumomab. Leukemia Lymphoma 50, 886–891 (2009).
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.
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).
June, C., Rosenberg, S. A., Sadelain, M. & Weber, J. S. T-cell therapy at the threshold. Nature Biotech. 30, 611–614 (2012).
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. Lancet 385, 517–528 (2014).
Maude, S. L. et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N. Engl. J. Med. 371, 1507–1517 (2014).
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.
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).
DeFrancesco, L. CAR-T cell therapy seeks strategies to harness cytokine storm. Nature Biotech. 32, 604 (2014).