Nature Reviews Cancer 12, 278-287 (April 2012) | doi:10.1038/nrc3236

Focus on: Tumour immunology & immunotherapy

Antibody therapy of cancer

Andrew M. Scott1, Jedd D. Wolchok2,3,4,5 & Lloyd J. Old3,4,5  About the authors


The use of monoclonal antibodies (mAbs) for cancer therapy has achieved considerable success in recent years. Antibody–drug conjugates are powerful new treatment options for lymphomas and solid tumours, and immunomodulatory antibodies have also recently achieved remarkable clinical success. The development of therapeutic antibodies requires a deep understanding of cancer serology, protein-engineering techniques, mechanisms of action and resistance, and the interplay between the immune system and cancer cells. This Review outlines the fundamental strategies that are required to develop antibody therapies for cancer patients through iterative approaches to target and antibody selection, extending from preclinical studies to human trials.

Antibody-based therapy for cancer has become established over the past 15 years and is now one of the most successful and important strategies for treating patients with haematological malignancies and solid tumours. The fundamental basis of antibody-based therapy of tumours dates back to the original observations of antigen expression by tumour cells through serological techniques in the 1960s1. The definition of cell surface antigens that are expressed by human cancers has revealed a broad array of targets that are overexpressed, mutated or selectively expressed compared with normal tissues2. A key challenge has been to identify antigens that are suitable for antibody-based therapeutics. Such therapeutics can function through mediating alterations in antigen or receptor function (such as agonist or antagonist functions), modulating the immune system (for example, changing Fc function and T cell activation) or delivering a specific drug that is conjugated to an antibody that targets a specific antigen2, 3, 4, 5. Molecular techniques that can alter antibody pharmacokinetics, effector function, size and immunogenicity have emerged as key elements in the development of new antibody-based therapies. Evidence from clinical trials of antibodies in cancer patients has revealed the importance of iterative approaches for the selection of antigen targets and optimal antibodies, including the affinity and avidity of antibodies, the choice of antibody construct, the therapeutic approach (such as signalling abrogation or immune effector function) and the need to critically examine the pharmacokinetic and pharmacodynamic properties of antibodies in early clinical trials. This Review summarizes the steps that are necessary to transform monoclonal antibodies (mAbs) into reagents for human use, the success of antibodies in the treatment of cancer patients, the challenges in target and construct selection, and the crucial role of the immune system in antibody therapy.

Cancer serology

The idea that antibodies could serve as 'magic bullets' in the diagnosis and therapy of cancer has a long history, which started soon after their discovery in the late nineteenth century. A considerable effort over the ensuing decades involved the immunization of various animal species with human cancer in the hope of generating antisera with some degree of cancer specificity1. Despite repeated claims of success and much controversy, this approach yielded little of enduring value, with the notable exception of the discovery of carcinoembryonic antigen (CEA), which is a marker for colon cancer and other cancers, and α-fetoprotein, which is a marker for hepatocellular cancer1, 2. The development of inbred mice initiated a new era of serological investigation of cancer, with the emergence of the cytotoxic test as a powerful tool to analyse the cell surface reactivity of alloantibodies. This led to the recognition that the cell surface is a highly differentiated structure. The identification of cell surface differentiation antigens, which were initially used to distinguish lymphocyte subsets, set the stage for a revolution in biological and biomedical sciences. This revolution was fuelled by the development of hybridoma technology and analytical tools such as fluorescence-activated cell sorting (FACS). In view of these remarkable advances, cancer immunologists renewed their search for human cancer-specific antigens and initiated a massive effort to dissect the surface structure of human cancer cells with mAbs2. More recent studies have shown that, in addition to changes in the surface antigenic structure of cancer cells, tumour stromal and tumour vascular cells express novel antigens that distinguish them from their normal counterparts6, 7, 8, 9, 10, 11. As a consequence, a detailed picture of the surface antigens of human cancers is emerging, and with bioinformatic tools steps are being taken towards the ultimate aim of constructing the complete cancer 'surface-ome'. What has become evident is that the long sought-after cancer-specific antigen group has not been found. Rather, antibodies that predominantly bind antigens in cancer cells compared with normal tissues have been found3. Despite this lack of absolute specificity for cancer cells, these antibodies with preferential cancer reactivity have among the highest tumour specificity of any targeted therapeutic approach that has yet been defined4, 5.

Mechanisms of tumour cell killing

The mechanisms of tumour cell killing by antibodies are outlined in Fig. 1. This cell killing can be summarized as being due to several mechanisms: direct action of the antibody (through receptor blockade or agonist activity, induction of apoptosis, or delivery of a drug or cytotoxic agent); immune-mediated cell killing mechanisms (including, complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC) and regulation of T cell function); and specific effects of an antibody on tumour vasculature and stroma. The Fc function of antibodies is particularly important for mediating tumour cell killing through CDC and ADCC. All of these approaches have been successfully applied in the clinic. The abrogation of tumour cell signalling (for example, by cetuximab and trastuzumab)12, 13, the induction of effector function primarily through ADCC (for example, by rituximab)14 and the immune modulation of T cell function (for example, by ipilimumab)15 are the approaches that have been most successful and that have led to the approval of antibodies using these mechanisms (discussed below).

Figure 1 | Mechanisms of tumour cell killing by antibodies.
Figure 1 : Mechanisms of tumour cell killing by antibodies. Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, or to obtain a text description, please contact npg@nature.coma | Direct tumour cell killing can be elicited by receptor agonist activity, such as an antibody binding to a tumour cell surface receptor and activating it, leading to apoptosis (represented by the mitochondrion). It can also be mediated by receptor antagonist activity, such as an antibody binding to a cell surface receptor and blocking dimerization, kinase activation and downstream signalling, leading to reduced proliferation and apoptosis. An antibody binding to an enzyme can lead to neutralization, signalling abrogation and cell death, and conjugated antibodies can be used to deliver a payload (such as a drug, toxin, small interfering RNA or radioisotope) to a tumour cell. b | Immune-mediated tumour cell killing can be carried out by the induction of phagocytosis; complement activation; antibody-dependent cellular cytotoxicity (ADCC); genetically modified T cells being targeted to the tumour by single-chain variable fragment (scFv); T cells being activated by antibody-mediated cross-presentation of antigen to dendritic cells; and inhibition of T cell inhibitory receptors, such as cytotoxic T lymphocyte-associated antigen 4 (CTLA4). c | Vascular and stromal cell ablation can be induced by vasculature receptor antagonism or ligand trapping (not shown); stromal cell inhibition; delivery of a toxin to stromal cells; and delivery of a toxin to the vasculature. MAC, membrane attack complex; MHC, major histocompatibility complex; NK, natural killer.

Although most of the antibodies that have been successful in the clinic are intact immunoglobulin G (IgG) molecules, multiple approaches for antibody construction and for the delivery of conjugated cytotoxic drugs have been used (Table 1). The broad range of antibody engineering approaches that have been used in the clinic has recently been reviewed5, 6, 16.

Tumour antigens as antibody targets

The safety and efficacy of therapeutic mAbs in oncology vary depending on the nature of the target antigen. Ideally, the target antigen should be abundant and accessible and should be expressed homogeneously, consistently and exclusively on the surface of cancer cells. Antigen secretion should be minimal, as secreted antigens can bind the antibody in the circulation and could prevent sufficient antibody from binding to the tumour. If the desired mechanism of action is ADCC or CDC, then it is desirable that the antigen–mAb complex should not be rapidly internalized so as to maximize the availability of the Fc region to immune effector cells and complement proteins, respectively. By contrast, good internalization is desirable for antibodies or proteins that deliver toxins into the cancer cell and for antibodies the action of which is primarily based on the downregulation of cell surface receptors2.

Tumour-associated antigens recognized by therapeutic mAbs fall into several different categories (Table 2). Haematopoietic differentiation antigens are glycoproteins that are usually associated with cluster of differentiation (CD) groupings and include CD20, CD30, CD33 and CD52 (Refs 2,5,16,17). Cell surface differentiation antigens are a diverse group of glycoproteins and carbohydrates that are found on the surface of both normal and tumour cells. Antigens that are involved in growth and differentiation signalling are often growth factors and growth factor receptors. Growth factors that are targets for antibodies in cancer patients include CEA2, epidermal growth factor receptor (EGFR; also known as ERBB1)12, ERBB2 (also known as HER2)13, ERBB3 (Ref. 18), MET (also known as HGFR)19, insulin-like growth factor 1 receptor (IGF1R)20, ephrin receptor A3 (EPHA3)21, tumour necrosis factor (TNF)-related apoptosis-inducing ligand receptor 1 (TRAILR1; also known as TNFRSF10A), TRAILR2 (also known as TNFRSF10B) and receptor activator of nuclear factor-κB ligand (RANKL; also known as TNFSF11)22. Antigens involved in angiogenesis are usually proteins or growth factors that support the formation of new microvasculature, including vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR), integrin αVβ3 and integrin α5β1 (Ref. 10). Tumour stroma and the extracellular matrix are indispensable support structures for a tumour. Stromal and extracellular matrix antigens that are therapeutic targets include fibroblast activation protein (FAP) and tenascin7, 11, 23.

Considerable effort has recently been invested in identifying new antigen targets that are suitable for antibody-based therapies in cancer. Serological, genomic, proteomic and bioinformatic databases have been used to identify antigens and receptors that are overexpressed in tumour cell populations or that are linked to gene mutations identified as driving cancer cell proliferation2, 5. Examples of antigens that have been identified as suitable targets for antibody therapy with these approaches include EGFRvIII, MET, cytotoxic T lymphocyte-associated antigen 4 (CTLA4) and FAP15, 19, 23, 24.

Development of antibodies for the clinic

The successful development of candidate antibodies for the clinic involves a complex process of scientific and preclinical evaluations, informed by deep understanding of cancer biology and the properties of antibodies in vivo. Essential preclinical characterization includes identification of the physical and chemical properties of the antibody; detailed specificity analysis of antigen expression using panels of normal and malignant tissues; study of the immune effector functions and signalling pathway effects of the antibody; analysis of in vivo antibody localization and distribution in transplanted or syngeneic tumour systems; antibody chimerization and humanization (or the use of phage display and xenomice to produce fully human antibodies); and observation of the in vivo therapeutic activity of the antibody either alone or conjugated with radioactive isotopes or other toxic agents3, 5, 7, 9, 17, 25, 26.

With regard to the clinical phase of antibody analysis, a major objective has been determining the toxicity and therapeutic efficacy of the antibody either alone or as a delivery system for radioisotopes or other toxic agents. However, one of the most essential steps in the clinical evaluation of a potential therapeutic antibody is in vivo specificity — determining the biodistribution of an antibody (often radiolabelled) in patients to assess the ratio of antibody uptake in the tumour versus normal tissues3, 11, 26 (Fig. 2). This information is essential for the rational design of antibody therapy, for which knowledge about the targeting of normal tissues is crucial for predicting toxicity17, 26. In addition, the presence of normal tissue uptake of antibodies can assist with defining dose requirements for achieving optimal tumour and plasma concentration of antibodies, as well as in establishing the possible effects of antigen–receptor saturation at high protein-loading doses. At the Ludwig Institute for Cancer Research, we developed a model of a clinical trial that incorporates biodistribution, pharmacokinetics and pharmacodynamics analyses with toxicity assessment3. This trial design has been successfully applied to first-in-human clinical trials of more than 15 antibodies in cancer patients3, 11, 23, 26, 27, 28, 29. This approach can identify properties of antibodies, including subtle physico-chemical changes26, that affect biodistribution, which can significantly affect efficacy. Normal tissue distribution can be quantitated, thus allowing the relationship of the loading dose to tumour concentration to be accurately assessed, rather than relying on plasma concentration and clearance rates to establish an optimal dose. Examples of the successful use of this approach include the early biodistribution studies of mouse EGFR-specific antibodies 528 and 225 (which were preludes to cetuximab), which identified the liver antigen sink (due to the expression of wild-type EGFR) for systemic antibody and its effect on the concentration of antibody that reached the tumour; and the more recent studies of trastuzumab (which targets ERBB2) biodistribution and in vivo assessment of ERBB2 expression by tumours30, 31. In non-Hodgkin's lymphomas (NHLs), the biodistribution of a radioconjugate in the tumour and an assessment of whole-body dosimetry were essential in initial trials exploring patient suitability for treatment and treatment dose for the US Food and Drug Administration (FDA)-approved CD20-specific radioimmunoconjugates tositumomab and ibritumomab tiuxetan17, 32. In conjunction with other pharmacodynamic studies, including computerized tomography with magnetic resonance imaging, positron emission tomography, plasma-based protein, cell and genomic analyses, and tumour biopsies, the effect of antibody abrogation of a signalling pathway function can also be determined32.

Figure 2 | Biodistribution and pharmacodynamics of an antibody in vivo.
Figure 2 : Biodistribution and pharmacodynamics of an antibody in vivo. Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, or to obtain a text description, please contact npg@nature.coma | Whole-body coronal positron emission tomography–computed tomography (PET–CT) images of 124I-labelled cG250 (carbonic anhydrase IX (CAIX)-specific) monoclonal antibody, obtained 5 days after antibody infusion. The specific uptake of the antibody can be seen in the left renal tumour (arrow), which is expressing CAIX antigen. A quantitative concentration of an antibody in a tumour can be measured using this imaging methodology. Some normal blood pool activity can also be seen, owing to the antibody circulating in blood, but no other tissues show antibody localization. b | Transaxial PET–CT images through the left kidney mass, showing antibody localization in the tumour in detail (arrow). The right-hand panel shows combined (fused) PET–CT images. c | A quantitative tumour blood flow assessment using H215O PET–CT. Tumour perfusion is readily apparent (arrow) in the left kidney mass. Pharmacodynamic changes in the tumour following treatment can be assessed non-invasively using imaging techniques.

Because antibodies by themselves may have limited therapeutic activity, more emphasis is being placed on increasing the biological effector function of antibodies, such as ADCC (through optimized Fcγ receptor (FcγR) binding) and cytotoxicity, and on using antibodies as delivery vehicles for toxic agents4, 9, 17, 25, 26.

Clinical efficacy of antibodies in cancer patients

Despite the great promise of antibody-based therapies, we are only beginning to see and explore the full potential of antibodies in the control and therapy of cancer. Since 1997, 12 antibodies have received approval from the FDA for the treatment of various solid tumours and haematological malignancies (Table 3), and a large number of additional therapeutic antibodies are currently being tested in early stage and late-stage clinical trials (; see Further information). Most antibodies that have been approved have different and often milder toxicities compared with conventional chemotherapeutic agents33, 34. Approval for the therapeutic use of these antibodies by regulatory bodies such as the FDA usually requires the demonstration of an overall survival benefit with their use compared with standard therapy use in large Phase III trials (Table 3). However, in some instances, approval has been granted based on surrogate markers. For example, tumour response rate was used for the approval of bevacizumab in glioblastoma and for gemtuzumab ozogamicin in relapsed acute myeloid leukaemia (AML), and progression-free survival was used for the approval of panitumumab in colorectal cancer4, 35, 36. Occasionally, regulatory approval can be based on Phase II data when this is considered sufficiently promising in a disease with few therapeutic options, as occurred for bevacizumab therapy in patients with glioblastoma35.

The use of therapeutic mAbs in patients with solid tumours has been most successful with classes of antibodies targeting the ERBB family (which includes EGFR) and VEGF. Recent evidence showing that patients with colorectal cancer treated with EGFR-specific antibodies who have improved responses12, 36, disease control36 and survival37, 38 have wild-type KRAS has resulted in the approved use of these agents being restricted to patients with colorectal cancer in which KRAS is not mutated. The use of trastuzumab has also been restricted to patients with high levels of ERBB2 expression, as studies have shown that this is the group that derives maximum benefit from trastuzumab treatment5, 39. These are examples of predictive biomarkers that are pivotal in optimal patient selection and in regulatory and funding approval. As a result of the clinical success of these antibodies, and preclinical data demonstrating the improved tumour response (and reversal of resistance to a single agent) of combined signalling blockade with antibodies to different receptors or to different epitopes on the same receptor (for example, trastuzumab and pertuzumab), numerous clinical trials of antibodies as combination therapies are currently underway5.

A number of antibodies have also been approved for the treatment of haematological malignancies, both as unconjugated antibodies and for the delivery of isotopes and drugs or toxins to cancer cells (Table 3).). I Rituximab has enjoyed considerable success in patients with CD20-positive NHL and chronic lymphocytic leukaemia. Radioimmunotherapy with 131I-labelled and 90Y-labelled CD20 conjugates has also shown improved response rates and progression-free survival in patients with NHL (Table 3).Interestingly, antibody–drug or antibody–toxin conjugates have been shown to have high potency in haematological malignancies, and there have been two approved by the FDA: gemtuzumab ozogamicin in elderly patients with CD33-positive AML (although this drug was withdrawn in June 2010 following a post-marketing Phase III trial, which showed no survival improvement in patients with AML treated with gemtuzumab ozogamicin and chemotherapy versus chemotherapy alone); and, more recently, brentuximab vedotin in patients with CD30-positive Hodgkin's lymphoma4, 40. These antibody conjugates have provided the first proof-in-principle for antibodies selectively delivering drug payloads to cancer cells, and a similar approach in patients with advanced ERBB2-positive breast cancer with the antibody–drug conjugate trastuzumab–emtansine (also known as T-DM1)41 is currently being explored in Phase III trials (NCT00829166 and NCT01120184).

It should also be noted that outside the United States there are other antibodies that are approved for cancer indications. Catumaxomab, a mouse bispecific antibody against CD3 and epithelial cell adhesion molecule (EPCAM), is approved in the European Union for use in patients with malignant ascites generated by an EPCAM-positive tumour42. Nimotuzumab, a humanized IgG antibody against EGFR, is approved for use in some countries in Asia, South American and Africa for the treatment of head and neck cancer, glioma and nasopharyngeal cancer43. Finally, the antibody Vivatuxin (Shanghai MediPharm Biotech), which is an 131I-radiolabelled IgG1κ chimeric mAb against intracellular DNA-associated antigens, is approved by the Chinese drug regulator for the treatment of malignant lung cancer44.

Immune regulation by antibodies

Aside from targeting antigens that are involved in cancer cell proliferation and survival, antibodies can also function to either activate or antagonize immunological pathways that are important in cancer immune surveillance. It is now clear that an antigen-specific immune response is the result of a complex dynamic interplay between antigen-presenting cells, T lymphocytes and target cells. The recognition of specific antigenic peptides bound to major histocompatibility complex by the T cell receptor is insufficient for T cell activation and must be accompanied by ligation of CD28, a T cell activator, to a member of the B7 family of co-stimulatory molecules (CD80 or CD86). This triggers a series of signalling pathways, resulting in autocrine interleukin-2 (IL-2) production and T cell activation. At the same time, CTLA4, a molecule that is normally found in intracellular stores, is transported to the immunological synapse, where it serves to downregulate the activated T cell by binding with high avidity to the B7 molecules and stopping the activation signals mediated by CD28. The potential of blocking CTLA4 with an antibody to potentiate T cell activation and responses to targets on tumour cells was first reported in 1996 (Ref. 39) and provided the scientific foundation for the development of two fully human mAbs that block CTLA4 (ipilimumab and tremelimumab). A pivotal Phase III trial demonstrated that ipilimumab prolonged overall survival of patients with metastatic melanoma and resulted in the approval of ipilimumab for the treatment of this disease by the FDA, the European Medicines Agency (EMA) and regulatory agencies from a number of countries15. Indeed, ipilimumab was the first treatment to be shown to increase survival in this challenging patient population. CTLA4 blockade does present challenges in terms of toxicity. Given the nonspecific nature of the disinhibition of T cells, a series of tissue-specific inflammatory responses, termed immune-related adverse events (irAEs), have been observed. These are largely confined to the skin and gastrointestinal tract but can, more rarely, affect the liver and endocrine glands. With early recognition, these events are generally manageable with corticosteroids, which seem not to interfere with the antitumour effect of ipilimumab15.

The success of immunological checkpoint blockade with ipilimumab has opened the door to other immune-modulating antibodies. The next most advanced product is MDX-1106, a fully human antibody that blocks programmed cell death protein 1 (PD1), which is a marker of activated or exhausted T cells that can trigger apoptosis when bound by its ligand, PD1 ligand 1 (PDL1; also known as B7H1)45. Interestingly, this ligand is found not only on antigen-presenting cells but also on many tumour cells. PD1 blockade has been shown in early clinical trials to result in durable responses in patients with melanoma, renal cell carcinoma, non-small-cell lung cancer and colorectal cancer45. Other antibodies that target PD1 are also in development46, 47.

Agonistic antibodies are also being explored as immunomodulatory cancer therapies. These include two fully human antibodies to CD137 (also known as 4-1BB), an activator of T cells, from Pfizer and Bristol-Myers Squibb (BMS). The BMS antibody has been in Phase I trials, demonstrating antitumour efficacy at a wide range of doses, but also severe hepatic toxicity at high doses5. Studies are now reopening using low doses of antibody only. This highlights an important aspect of antibody therapeutics. Although higher doses of a blocking antibody may yield improved efficacy, low doses of agonistic antibodies may provide a better risk–benefit profile compared with higher doses. Other pathways of interest for agonistic antibodies include those of CD40, for which favourable preclinical and clinical results have been noted, particularly in pancreatic cancer46, and the glucocorticoid-induced TNF receptor (GITR)46.

Antibody therapeutics might also have a role in the generation of de novo immune responses to the antigen targeted by the antibody through promoting antigen presentation to Fc receptor-bearing cells48. Such responses may allow for the effects of therapeutic antibodies to persist after the dosing is completed.

Tumour escape mechanisms

There are multiple mechanisms by which antibody treatment of patients with malignant tumours may not achieve a therapeutic effect (Table 4). These include the heterogeneity of target antigen expression in the tumour (which can be present initially or which can develop during therapy)2, physical properties and pharmacokinetics of antibodies that have an impact on uniform penetrance into a tumour49 and intratumoural microenvironment (including, vascularity and interstitial pressure)49. Antibody dose and concentration in the tumour and possible receptor saturation kinetics can also affect theraputic impact49, 50, as can signalling pathway promiscuity (which can lead to poor response to therapy and subsequent development of resistance51), as well as immune escape through ineffective FcγR binding and immune suppression5, 9, 49.

Although the physical properties of antibodies are highly relevant to their efficient penetration of the tumour and concentration achieved in vivo, detailed information on intratumoural concentration achievable in the clinic is lacking for most clinically approved antibodies49. In addition, although it is known that tumour expression of the target antigen or receptor is also crucial for antibody efficacy, heterogeneity in expression between primary and metastatic lesions, and between individual metastatic lesions, is common2. Intriguingly, although high receptor expression is known to be associated with response to trastuzumab, it is not necessarily predictive of response, and it can be downregulated as part of the development of resistance. Moreover, expression of EGFR in archived samples of colorectal cancer has not been shown to be predictive of response to cetuximab or panitumumab, indicating that target receptor expression is only one part of the complex interplay between binding of the antibody to the tumour and the therapeutic response49, 50.

ADCC has been demonstrated to have a major role in antibody efficacy, and there is evidence that FcγRIIa-131H polymorphisms have a favourable effect on response rates for cetuximab in colorectal cancer, trastuzumab in breast cancer and rituximab in follicular lymphoma52, 53, 54. As a result, strategies to improve ADCC activity, such as fucosylation modification, have become commonly used for new antibodies that are being introduced into the clinic. However, FcγR genotypes are not completely predictive of response, indicating that other factors are also highly relevant to tumour response to antibody therapy. In addition, tumour cell expression of natural killer cell inhibitory proteins, such as human leukocyte antigen E (HLA-E) and HLA-G, might also have an impact on the ADCC function of antibodies55. Furthermore, the ability of antibodies to generate T cell responses to tumour antigens may be affected by a broad range of factors, including cross-presentation of antigen by dendritic cells, the efficiency of antigen processing and immune escape through regulatory T cells55.

The abrogation of signalling pathways is known to be a principle mechanism for antibody-based tumour killing, and the development of resistance to therapy may be due to multiple inherent and acquired mechanisms. Primary resistance may be attributable to gene mutations (such as KRAS in colorectal cancer)36, 37, 38 or to promiscuous signalling because of interactions between cell surface receptors (such as EGFR and MET)51. Signalling attenuation, which may occur as a result of alterations in receptor internalization and degradation, might also have an impact on the effectiveness of signalling blockade with antibodies. The development of resistance to antibody therapy, through overactivation of alternative signalling pathways (such as MET, IGF1R and SRC activity), may also play a major part in the lack of tumour response to treatment49. An understanding of the complexity of signalling pathways in different tumours may assist in selecting patients who are suited to a specific antibody treatment and might also provide insight into combinations of therapies that may have efficacy in selected patients5, 49, 50.


The use of mAbs for the therapy of cancer is one of the great success stories of the past decade. This success builds on a long history of scientific investigation that aimed to understand the complexities of antibody serology, target selection, antibody–receptor function and immune regulation of tumour growth. The future promise of antibody therapeutics in cancer is dependent on having a better understanding of the lessons learned from laboratory studies and clinical trials, on applying innovative approaches to target and antibody selection and on early phase clinical trials that will guide appropriate development strategies, leading to clinical benefit in cancer patients.



A.M.S. is supported by the Ludwig Institute for Cancer Research (LICR), National Health and Medical Research Council, Australia, grants 487922 and 1030469, and Operational Infrastructure Support funding from the Victorian government, Australia. J.D.W. is supported by LICR and the Cancer Research Institute (CRI), New York, USA. L.J.O. was supported by LICR and CRI.

Competing interests statement

The authors declare no competing financial interests.



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Author affiliations

  1. Ludwig Institute for Cancer Research; University of Melbourne; and Centre for PET, Austin Hospital, Melbourne, Victoria 3084, Australia.
  2. Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10065-6306, USA.
  3. Ludwig Institute for Cancer Research, Memorial Sloan-Kettering Cancer Center, New York, New York 10065-6306, USA.
  4. Ludwig Center for Cancer Immunotherapy, Memorial Sloan-Kettering Cancer Center, New York, New York 10065-6306, USA.
  5. Weill Cornell Medical College, New York, New York 10065-4896, USA.

Correspondence to: Andrew M. Scott1 Email:

Published online 22 March 2012