Expert Review of Molecular Diagnostics
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The application of monoclonal antibodies in cancer diagnosis Xuemei Zhang, Gamini Soori, Thomas J Dobleman & Gary G Xiao To cite this article: Xuemei Zhang, Gamini Soori, Thomas J Dobleman & Gary G Xiao (2014) The application of monoclonal antibodies in cancer diagnosis, Expert Review of Molecular Diagnostics, 14:1, 97-106, DOI: 10.1586/14737159.2014.866039 To link to this article: https://doi.org/10.1586/14737159.2014.866039
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Review
The application of monoclonal antibodies in cancer diagnosis Expert Rev. Mol. Diagn. 14(1), 97–106 (2014)
Xuemei Zhang1, Gamini Soori2, Thomas J Dobleman2 and Gary G Xiao*2 1 The Medical College of Dalian University, Dalian Economic & Technical Development Zone, Dalian 116622, People’s Republic of China, China 2 Departments of Medicine and Medical Microbiology & Immunology, Creighton University, 601 N 30th ST, Omaha, NE 68131, USA *Author for correspondence: Fax: +1 402 280 4284 [email protected]
Cancer becomes the second leading cause of death in the world. An effective strategy for early diagnosis of the disease is key to reduce the mortality and morbidity. Development of effective monoclonal antibody (mAb)-based assays or diagnostic imaging techniques for detection of antigens and small molecules that are released from cancerous cells will enhance modern diagnostic medicine of cancer significantly. Although mAb technology is still under development, recent advances in preparation of recombinant antigen and antibody engineering techniques have dramatically enhanced the applications of this technology in cancer diagnosis. Compared with other methods, mAb-based assays may provide spatial, temporal, accurate and quantitative measurement for diagnosis of the disease. This review summarizes the progress of the mAb-based assays in the field of molecular diagnosis of cancer. KEYWORDS: biomarker • cancer • molecular diagnosis • monoclonal antibody fragment • phage display
Challenges in cancer diagnosis
Cancer is a complicated disease driven by multistep accumulation that caused genetic and epigenetic alterations of genes. It is about 16 million people who are diagnosed with cancer every year. This number tends to increase year-by-year while the death rates remains high with an estimated 9 million people dying from cancer by 2015 and 11.4 million dying by 2030 [1,2]. This is caused by inappropriate diagnosis since the examination methods widely used in clinic, such as radiography, ultrasonography, computed tomography, low-dose spiral computed tomography, fluorescence endoscopy and MRI, are lack of sensitivity and specificity and unable to provide sufficient evident for prediction of the tumors’ behavior [3]. Although MRI can provide a powerful imaging detection with high spatial resolution (£100 m) and tomographic capabilities, the major challenge of this method is the low sensitivity for early detection of the disease. The histopathologic examination by microscopy of biopsy as the gold standard has been used for diagnosis, prognosis and administration of cancer for many decades [4]. However, this ‘gold standard’ method faces challenge to
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10.1586/14737159.2014.866039
modern molecular diagnosis since it provides very limited information about cell physiology, which may be misled in molecular diagnosis of cancer. Moreover, the microscopic detection of many cancers may not provide enough information for early diagnosis of the disease, thus, the diagnosis based on histopathological features requires additional validation process by using tools from molecular pathology as described in FIGURE 1. Biomarkers for early detection of cancer
Early diagnosis of cancer is an ideal strategy to reduce the incidence of the disease and improve its survival rate significantly. Biomarkers are important molecular signatures of the cell phenotype, which can be used for early detection of cancer [5]. Biomarker discovery for early detection of cancer is a crucial unmet need to improve patient outcomes. Development of cancer biomarker gains beneficial from newly developed technologies in metabolomics, genomics and proteomics. Differential metabolic profile between cancerous cells and normal cells was observed in many types of cancer cells, resulting in discovery of metabolic biomarkers specific to cancerous cells as well as to different cancer types. These metabolic
2014 Informa UK Ltd
ISSN 1473-7159
97
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Zhang, Soori, Dobleman & Xiao
Sensitivity Enzyme immunoassays Chemical pathology
Fluorescence labled immunoassay
Tissue pathology Pathology Diagnosis
Low
Radioimmunoassays High
Microscopic examination of tumor cells using immunohistology and immunohistochemistry Visualized by Enzymatic method Fluorescence
arrays [30], has been made, including biomarkers used for early diagnosis of the disease [31], development of new drug for cancer, and cancer etiology [32]. modified SILAC has now extensively used for biomarker study in vitro, ex vivo, and in vivo due to its high sensitivity for detection of protein turnover [33,34]. Antibody-based diagnosis of cancer
Diagnosis of disease depends frequently on quantitative identification or localization of particular molecules in cells, tisClear morphology sues or body fluids. Owning to the exquisite specificity, antibodies are widely Development of cancer biomarkers used Molecular used reagents in the clinical diagnostic for early diagnosis of cancer by metabolic, pathology laboratory. Use of monoclonal antibody genomic and proteomic approaches (mAb) for molecular diagnosis of cancer comes true is superior to polyclonal antibody since it Figure 1. Cancer diagnosis. provides high accuracy, sensitivity, reproducibility and specificity [35]. As a specific biomarkers include spermine and citrate, which were used for proteomic approach for biomarker discovery, antibody microarassessing prostate cancer aggressiveness [6], metabolic biomarkers rays has been applying for protein profiling indifferent clinical leptin, resistin, hypersensitive C-reactive protein, TNF-a, and specimens, including serum, saliva, sputum, urine, tumor interangiotensin II, were successfully utilized in clinic for early diag- stitial fluid and tissues [36]. Use of antibody microarray for nosis of breast cancer [7], metabolic biomarker phosphor- monitoring the activity of the tumor cells in peripheral blood Aktser473 was recently used for evaluating treatment efficacy of offers several advantages: less invasive approach for diagnosis of both MK-2206 and BEZ235 on basal-like breast cancer [8]. cancer and high specificity. Therefore, antibody microarray can Because mRNA level may not be correlated with gene expression provide multiplexed, qualitative assays at a time for panels of in a cell, then information obtained by other methods, such as tumor markers that requires samples with a minimum volgene microarray, may not precisely indicate the status of the dis- ume [37,38]. Quantum dot technology coupled with antibody ease. Development of protein biomarker may provide better arrays, as an example, offers remarkable photostability, brightstrategy for monitoring development of cancer and guiding ther- ness and low photobleaching, and can increase the limit of proapy of the disease [9,10]. Use of this strategy led to identification tein detection in specimens (serum, plasma, body fluids) of numerous biomarkers, some of which may have been used for significantly [39]. Proteins at low abundance in a cell or body early diagnosis of breast cancer, such as C3a des-arginine ana- fluids are usually active signal molecules, indicating changes of phylatoxin (molecular weight: 8938 Da) and fragments of cell physiology, and can be developed as biomarkers. Identificainter-alpha trypsin inhibitor heavy chain H4 [11], circulating tion of this group of proteins in cells has been a major chalMACC1 transcripts for diagnosis of colorectal cancer [12], lenge in the field of proteomics. A number of technologies MCM2 used for diagnosis of gastric cardiac cancer [13]. have been developed aiming to increase the sensitivity to idenAntibody-based strategy, such as the enzyme-linked immu- tify proteins at low abundance in a cell and body fluids. These nosorbent spot and phage display library screening, has been technologies include antibody ultramicroarrays (UM) and surproven good for discovery of protein biomarkers used for early face plasmon resonance imaging (SPRI). UM was initially detection of human diseases [14–20], biomarkers discovered by developed as a PCR-like high-throughput bioassay method enzyme-linked immunosorbent spot include tumor-specific car- used for detection of low abundant protein molecules in speciboxy-terminal frameshift peptides, which have been used for mens. The sizes of the spots on the array are in the range of diagnosis of colorectal cancer [21]. Biomarkers discovered by 1–20 mm in diameter, taking a tiny fraction of the surface area phage display technology include serum autoantibodies [22–24], of a conventional (100 mm diameter) microarray spot. This that have been used for early diagnosis of breast cancer. technique is now gaining attention to the field of biomarker Recently, enormous progression in development of biomarker discovery by directly performing protein profiles from using proteomics technology, such as SILAC and modified extremely limited sample volumes. It is also compatible with a SILAC [9], radioimmunoassay, multidimensional protein identifi- standard high-throughput readout system available in the curcation technology, surface-enhanced laser desorption/ionization rent market [40]. UM has been successfully applied for detection time-of-flight analysis [25], multiple reaction monitoring mass of IL-6 and prostate-specific antigen in prostate cancer cells spectrometry [26–28], positron emission tomography [29] antibody with limitation of detection in the attomolar range [40]. Counterstaining
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The application of monoclonal antibodies in cancer diagnosis
SPRI microarrays have been also used for measurement of low abundant proteins in serum with limitation of detection in the picomolar range [41]. The SPRI signal is generated by the formation of a surface aptamer–protein–antibody complex. This technique has been used for measuring the VEGF in a cell. This technique has now been used in clinic by measuring the circulated VEGF level in serum in order to provide effective strategy for anti-angiogenic therapies of breast, lung and colorectal cancer [41]. Two-color rolling circle amplification method was developed lately and has been successfully used for the detection of the low abundant proteins with good reproducibility and accuracy in serum specimens [42]. Biomarkers discovered by two-color rolling circle amplification method include thrombospondin-1, which have been used for early diagnosis of prostate cancer [43]. Additionally, Sandwich assays, such as resonance light scattering [42], enhanced chemiluminescence [44] and the tyramide signal amplification method [37], have been also shown promising for measuring low abundant proteins in body fluids. In summary, combinational utility of these detection strategies for measuring proteins at low abundance in specimens could provide powerful approaches for discovery of cancer-specific biomarker. Biomarker in a certain signaling pathway can be used for monitoring drug efficacy and therapy of cancer [31,45,46]. Development of a cancer biomarker, showing highly expressed in tumor cells instead of normal cells may be effective strategy for early diagnosis of cancer [38]. Biomarkers amenable for early detection of cancer may promote the imaging diagnosis of the disease significantly. Effective antibodies with high affinity and specificity are the key reagents available for molecular imaging diagnosis. Development of the mAb with high affinity to its target/biomarker as an imaging probe provides an effective visualized approach for precise and accurate diagnosis of the disease at its early stages [47]. Development of mAb arrays may provide an important revenue for identification of novel biomarker from tissues and/or body fluids specimens used for early detection of the disease. Thus, mAb arrays in this instance are also referred to as a targeted proteomics [30]. This technology has been applied for identification and validation of unique biomarker from various specimens of cancer [32,38]. These include folate receptor-a, CCL2 and p95HER2, which were used for diagnosis of gynecologic malignancies [48], cancer metastasis [49] and non-small cell lung cancer [50]. Thus, successful use of mAb arrays in clinic may provide not only an evident for early diagnosis and stratification of cancer, but also additional information for understanding of the biological mechanisms underlying tumorigenesis and disease progression [45]. Although a mAb-based immunohistochemistry has remarkably improved the sensitivity and the specificity of cancer detection as compared with the H&E staining procedure alone, it still faces challenges for effective detection of disease, such as low specificity. Antibodies against tumor markers of interest must be more specific and sensitive to the tumor cells than to the adjacent non-tumor cells [30,38,51–53]. www.expert-reviews.com
Review
Intriguingly, a recent study showed that antibody array can be used specifically for multiplexed profiling of glycosylated proteins [54]. Protein carbohydrate post-translational modifications play an important role in tumorigenesis and metastasis. A study showed that glycan variation on proteins in multiple serum samples from pancreatic cancer patients is associated with the pancreas tumorigenesis using parallel sandwich and glycan-detection assays [55]. Therefore, antibody array-based detection of glycan variation on biomarkers may be developed as a strategy for early diagnosis of cancer. Although application of antibody arrays still faces challenge due to a limited antibody available, this technology coupled with gene microarray can be developed as a promising platform used for detection of cancer. Antibody array provides supportive data for gene microarray analysis to confirm the developmental status of the disease [10]. Compared with biomarkers developed by other technical methods, such as proteomics, genomics and genetics, antibody-based microarray assay shows unprecedented advantages for high-throughput and multiplexed detection of cancer-related analytes in minute volume of blood samples. Antibody against some surface molecules can be used as probes to study cellular function. Cell activation and differentiation are often accompanied by the changes in expression of cell surface or cytoplasmic molecules, antibodies can be used to track down these molecules and to monitor cellular activity dynamically, and to help understand molecular mechanisms underlying cell response to exogenous stimuli. Use of mAb provides an effective application for a specific cell sorting in flow cytometry (FCM). Antibodies conjugated with different fluorochromes can help track down multiple signals in a cell, which enables multiplexed applications for study of molecular mechanisms, and for prediction of clinical outcome [56]. Bead/suspension arrays have been also used for discovery of protein biomarkers. Antibody-based beads arrays are a multiplex flow cytometric-based system that utilizes up to a few hundreds of color-coded polystyrene bead sets. Each bead set is internally dyed with different ratios of two spectrally distinct fluorophores. Each of the bead sets can be conjugated with a unique antibody. The conjugated beads are pooled together in the wells of a microplate with the sample to be tested (i.e., sera), followed by the addition of a detection antibody, forming a capture immunoassay that is then read by the Bio-Plex suspension array reader. Each separate reaction is identified and quantitated based on the bead color (FIGURE 2). This allows a single sample to be tested simultaneously for reaction to a number of different antigens [57–60]. This technology has been applied for identification of novel biomarkers used for prediction of progression, and diagnosis of cancer [57,61,62]. In a recent study, the Luminex multiplex bead arrays was used to analyze serum samples from patients who had breast cancer and from healthy subjects, and found that serum levels of epidermal growth factor, soluble CD40-ligand and proapolipoprotein A1 were significantly higher in breast cancer subjects than in healthy subjects, resulting in identification of diagnosis 99
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Each bead conjugated with a unique antibody. 1
The conjugated beads are pooled together in
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the wells of a microplate. 2
4 3
Microplate Step 1: Preparation of microplate and sample Samples: sera, plasma, body fluids, saliva, sputum, urine, tumor interstitial fluid
3
Step 3: Beads washing and incubation with biotinylated detection antibody
5
1
Step 4: Beads washing and incubation with streptavidin-PE Step 2: Incubation of antibody-coupled beads with sample
1
3
5
Step 5: Readout on the Bio-Plex suspension array system according to the bead color
Figure 2. Illustration of bead/suspension arrays.
biomarkers [62]. Antibody beads arrays covering 24 angiogenesisrelated molecules were utilized to analyze the differential expression of the angiogenesis signals in serum samples from colorectal cancer patients before and after surgical treatments, and found that serum levels of both VCAM-1 and plasminogen activator inhibitor-1 were significantly higher in the after surgical treatment than in the before surgical treatment, leading to identification of biomarkers used for prediction of the surgical treatments [63]. Cancer diagnosis & monovalent antibody
mAb used as a probe can enhance the signal of the target significantly in an imaging diagnosis. It can be produced by use of a hybridoma technology. Antibody avidity is referred to as antibody functional affinity, antibody interactions in which multiple antigen-binding sites simultaneously interact with the target antigenic epitopes [47]. In general, the higher antibody avidity is, the higher sensitivity and specificity could be achieved. Utilization of the whole antibody, however, faces 100
great challenge for an effective imaging diagnosis due to the relatively large size of the antibody and low avidity resulting in too long half-life time and too strong contrast and poor sensitivity. The mAb molecule has two identical Fab, which consists of two variable regions H and L loops (also referred to as complementarity determining regions). The base of the Y-shaped protein mAb, also called Fc (fragment, crystallizable), plays a role in modulating immune responses through its interaction with Fc receptors [64,65]. Because of the unwanted effects generated by Fc, poor results from the imaging diagnosis are often observed by use of the whole antibody. For example, a long half-life in serum results in poor contrast in imaging applications. False-positive signals in FCM applications are often observed due to an inappropriate activation of Fc receptor leading to induction of cross-reactivity. Deletion of the antigenic sites in the Fc region might reduce the interferences with heterogeneous antibodies in the application of FCM. Compared with the whole antibody, Fab fragment antibody has higher avidity and more sensitivity of detection. For Expert Rev. Mol. Diagn. 14(1), (2014)
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example, the engineered Fab fragment senSamples sitively recognizes the membraneassociated Hsp70 protein localized in the plasma membrane of human tumors but Tumor not in normal tissues. This Fab has been markers successfully used for detection of tumor Antibody microarrays cells in vitro and in vivo [66]. F(ab)2 microarrays The molecular size of the mAb can affect its pharmacokinetics and biodistribution significantly. The full-sized antibody usually penetrates solid tumors slowly and non-uniformed distribution. By contrast, small antibody fragments, such as Fab, are cleared rapidly and have poor tumor retention. Because of the poor tissue penetration rate, the full-sized antibody limits its medical applications in parallel sandwich immunoassays and antibody Detection primary Abs microarrays. Thus, the size of the ideal tumor-targeting reagents would be an intermediate-sized molecule with molecular weight of 55 kDa in order to provide a rapid tissue penetration, high target retention and rapid blood clearance. Recently, as development of the innovative recombinant DNA technologies, recombinant FITC-labeled secondary Ab Signal amplification mAbs can have been dissected into small binding fragments, resembled into multivalent high-avidity reagents, which can be used in the applications of the imaging and the biosensors [3,30]. Smaller recombinant antibody fragments (monovalent antibody: Fab, scFv) and engineered variants (diabodies, triabodies, minibodies and single-domain antibodies) without Fc domain than the full-sized antibody possess superior propImaging Imaging erties of tissue penetration and potentially target cryptic epitopes in addition to a similar binding specificity to the full-sized antibody. Notably, among these smaller Accuracy False positive signal antibody fragments, single-domain antibodies can significantly expand the reperFigure 3. Comparison of the full-sized antibody arrays and F(ab)2 toire of antibody-based reagents against antibody arrays. numbers of novel cancer biomarkers disIntriguingly, antibody fragments F(ab)2-based microarray covered through proteomics, and provide an ideal approach in obtaining an optimal image than the intact antibody [30]. Com- was newly developed for molecular diagnosis. Compared with pared with the intact antibody, these small fragments possess other assay methods for diagnostics of cancer, such as immumore compact size, shorter clearance time and better tumor noradiometric assays using the full-sized mAb, F(ab)2 microarpenetration. These small molecules, thus, may be applied for rays showed an improvement in not only the sensitivity, but monitoring therapy of cancer in addition to the application of also the specificity, of the detection [71]. Innovation in the immobilization surfaces and detection the imaging diagnosis [67]. With the improved tumor penetration, rapid blood clearance and high affinity of cryptic epito- strategies leads to development of microrray, such as planar pes, use of antibody Fab and scFv fragments can enhance the arrays and bead-based antibody arrays. Planar arrays are antibody arrays in which all of the elements (i.e., antibody quality of the diagnostic imaging [68–70]. www.expert-reviews.com
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Table 1. The application of monoclonal antibodies to the existing biomarkers in cancer diagnosis during the last 5 years. Antibody
Biomarker
Detect method
Cancer early diagnosis
Ref.
Angiotensin II
ELISA
Early breast cancer
[7]
Antibody toward pAktser473
pAktser473
Dual near-infrared immunofluorescent imaging method
Basal-like breast cancer
[8]
Mouse anti-human monoclonal (CRCT5.1)
MCM2
Immunohistochemistry
Gastric cardiac cancer
[13]
FRA-specific monoclonal antibody (mAb 26B3)
FRA
Immunohistochemistry
Gynecologic tumors
[48]
NSE
Multiplex suspension bead array
Lung cancer
[57]
CYFRA21-1
Multiplex suspension bead array
Lung cancer
[57]
AFP
Multiplex suspension bead array
Liver cancer
[57]
CA242
Multiplex suspension bead array
Pancreatic, gastric, rectum cancer, cholangiocarcinoma
[57]
Free b-hCG
Multiplex suspension bead array
Ovarian cancer
[57]
Free-PSA, total-PSA
Multiplex suspension bead array
Prostate cancer
[57]
PSA
Rapid bead-based immunoassay
Prostate carcinoma
[60]
VCAM-1/PAI-1
Antibody suspension bead arrays
Post-operative recurrence in patients with colorectal cancer
[63]
MCP-1
Sandwich ELISA
Hepatocellular carcinoma
[71]
HE4
Sandwich ELISA
Ovarian and endometrial cancer
[76]
CA-125
Sandwich ELISA
Ovarian cancer
[76]
Four biomarkers panel (CA125, HE4, CEA and VCAM1)
Multiplex xMAP beadbased immunoassays
Early-stage ovarian cancer
[77]
R21, a mouse mAb against sAC
Human sAC protein
Immunohistochemistry
Lentigo maligna
[78]
Antibodies against MAPKAPK3 and ACVR2B
MAPKAPK3/ ACVR2B
ELISA
Colorectal cancer
[79]
Full-sized antibody
Mouse monoclonal anti-PSA antibodies (5G6 and 8A6) for coating; mouse monoclonal anti-PSA antibody (5A6) for detection
FRA: Folate receptor-a; hCE1: Human carboxylesterase 1; mAb: Monoclonal antibody; NSCLC: Non-small cell lung cancer; PSA: Prostate-specific antigen.
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Table 1. The application of monoclonal antibodies to the existing biomarkers in cancer diagnosis during the last 5 years (cont.). Antibody
Biomarker
Detect method
Cancer early diagnosis
Ref.
hCE1 mAb and biotinylated polyclonal anti-hCE1 antibody
hCE1
Sandwich ELISA
Hepatocellular carcinoma
[80]
Rabbit anti-ERG antibody (clone ID: EPR3864)
ERG protein
Immunohistochemistry
Prostate carcinoma
[81]
CA-S27-mAb
CA-S27
Sandwich ELISA
Cholangiocarcinoma
[82]
B6 scFv for IgM
Lung cancerassociated IgM autoantibodies
Electrochemiluminescent assay
NSCLC
[83]
Alexa-conjugated scFv
HER2 receptor
Flow cytometer
Human breast adenocarcinoma
[84]
Full-sized antibody (cont.)
Minimized antibody
FRA: Folate receptor-a; hCE1: Human carboxylesterase 1; mAb: Monoclonal antibody; NSCLC: Non-small cell lung cancer; PSA: Prostate-specific antigen.
fragments) are in one plane. Planar antibody array has been extensively used in clinical research for discovery of drug targets and biomarkers. The planar arrays comprise single label-based antibody array and ‘sandwich’-type assay [52]. The former requires a direct target labeling with fluorophores, which often leads to poor quality of the image due to potential perturbation of antibody–antigen interactions. ‘Sandwich’ assays can provide better results than the single labeled array due to a significant improvement in the specificity and the sensitivity of the detection. Recently, serum monocyte chemoattractant protein-1 and prolactin developed by using ‘sandwich’ array were used for diagnosis of hepatocellular carcinoma [72]. Adapted from planar antibody arrays, bead-based antibody array offers a fast, flexible and multiplexed procedure to screen larger numbers of samples without extensive sample preparation by utilizing microparticles [73]. Breast cancer serum markers were identified by bead-based immunoassay successfully. Several proteins were found to be increased significantly, including epidermal growth factor, soluble CD40-ligand and proapolipoprotein A1. These proteins were demonstrated to be able to distinguish primary breast cancer patients from healthy controls with higher accuracy [62]. Because of the advantages of the F(ab)2, the sensitivity of F(ab)2-based microarray assays is higher than that of ELISA. The use of F(ab)2 fragments as capturing probes is an important feature of this antibody microarray platform. Removal of species-specific Fc fragments minimizes the cross-reaction and provides a rationale for development of antibody-based diagnosis of cancer (FIGURE 3). Currently, there are many of these products in clinical and preclinical studies. Several recombinant Fabs and scFvs have been approved by the US FDA for molecular diagnosis of cancer [65].
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Biosensors are designed for detection of cancer biomarkers and for determination of drug efficacy at different target sites. It provides fast and accurate detection, reliable imaging of cancer cells and monitoring of angiogenesis and cancer metastasis [45,74]. Fab antibody fragments would be ideal reagents since they are small, stable, high specificity and can be developed as novel biosensing devices used for molecular diagnosis of cancer. This technology has been successfully applied to diagnosis of cancer [71,75,76]. In addition, the exquisite selectivity and easy manipulation of the Fab fragments facilitate more exotic applications including targeting quantum dots and therapeutic delivery vehicles. Recombinant mAb Fab fragments are now extensively used in design of multiplexed arrays for gene expression analysis and discovery of novel biomarkers. As new biomarkers have been generating by an integrated omics technologies, novel small mAb Fab reagents with high affinity can be developed as effective diagnostic tools used for early diagnosis and therapy of cancer [69]. The antibody-based cancer diagnoses to the existing biomarkers developed in the last 5 years are summarized in TABLE 1. Expert commentary
Molecular oncologic pathology has become an alternative approach for early diagnosis of cancer and for prediction of the biological behavior of a tumor and for better understanding of tumor therapy. As an important dimension in molecular diagnosis of cancer, a mAb Fab-based microarray platform due to its high sensitivity and the specificity for detection of antigens will provide an effective approach for development of novel biomarkers used for early diagnosis of cancer. In addition, it may also provide unique approach for development of the mAb Fab-based biosensor used for determination of novel drug effectiveness, monitoring disease progression and intervention. 103
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Five-year view
Financial & competing interests disclosure
The mAb fragments, because of their chemical properties, such as small, stable, high affinity against the tumor-associated antigen, provide valuable alternative approach for development of new biosensor devices with high sensitivity and specificity [62]. Such antibody bioassays will have an important impact on early diagnosis and therapeutic administration of cancer [47,68]. Thus, development of these new bioassay reagents (mAb Fabs) are anticipated to be new trend for early diagnose of cancer over next 5 years. It may be developed as a breakthrough approach for early diagnosis of cancer with improvement of sensitivity and specificity that cannot be achieved by other methods in the coming years.
This research was supported by a grant of Chinese National Technology R&D Program for the 11th five-year plan (2009BAK61B04) and the Dobleman Head and Neck Cancer Foundation in the USA. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties. No writing assistance was utilized in the production of this manuscript.
Key issues • Quantitative proteomics and biomarker discovery in human cancer. • The promise of biomarkers in cancer screening and detection. • Novel antibody vectors for imaging. • Monoclonal antibodies: diagnostic uses. • Protein-based tumor imaging probes. • Monoclonal antibody arrays as an emerging tool for discovery of cancer biomarkers. • Antibody arrays: technical considerations and clinical applications in cancer. • A monoclonal antibody Fabs microarray platform and its clinical applications.
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Expert Rev. Mol. Diagn. 14(1), (2014)
ISSN: 1473-7159 (Print) 1744-8352 (Online) Journal homepage: https://www.tandfonline.com/loi/iero20
The application of monoclonal antibodies in cancer diagnosis Xuemei Zhang, Gamini Soori, Thomas J Dobleman & Gary G Xiao To cite this article: Xuemei Zhang, Gamini Soori, Thomas J Dobleman & Gary G Xiao (2014) The application of monoclonal antibodies in cancer diagnosis, Expert Review of Molecular Diagnostics, 14:1, 97-106, DOI: 10.1586/14737159.2014.866039 To link to this article: https://doi.org/10.1586/14737159.2014.866039
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The application of monoclonal antibodies in cancer diagnosis Expert Rev. Mol. Diagn. 14(1), 97–106 (2014)
Xuemei Zhang1, Gamini Soori2, Thomas J Dobleman2 and Gary G Xiao*2 1 The Medical College of Dalian University, Dalian Economic & Technical Development Zone, Dalian 116622, People’s Republic of China, China 2 Departments of Medicine and Medical Microbiology & Immunology, Creighton University, 601 N 30th ST, Omaha, NE 68131, USA *Author for correspondence: Fax: +1 402 280 4284 [email protected]
Cancer becomes the second leading cause of death in the world. An effective strategy for early diagnosis of the disease is key to reduce the mortality and morbidity. Development of effective monoclonal antibody (mAb)-based assays or diagnostic imaging techniques for detection of antigens and small molecules that are released from cancerous cells will enhance modern diagnostic medicine of cancer significantly. Although mAb technology is still under development, recent advances in preparation of recombinant antigen and antibody engineering techniques have dramatically enhanced the applications of this technology in cancer diagnosis. Compared with other methods, mAb-based assays may provide spatial, temporal, accurate and quantitative measurement for diagnosis of the disease. This review summarizes the progress of the mAb-based assays in the field of molecular diagnosis of cancer. KEYWORDS: biomarker • cancer • molecular diagnosis • monoclonal antibody fragment • phage display
Challenges in cancer diagnosis
Cancer is a complicated disease driven by multistep accumulation that caused genetic and epigenetic alterations of genes. It is about 16 million people who are diagnosed with cancer every year. This number tends to increase year-by-year while the death rates remains high with an estimated 9 million people dying from cancer by 2015 and 11.4 million dying by 2030 [1,2]. This is caused by inappropriate diagnosis since the examination methods widely used in clinic, such as radiography, ultrasonography, computed tomography, low-dose spiral computed tomography, fluorescence endoscopy and MRI, are lack of sensitivity and specificity and unable to provide sufficient evident for prediction of the tumors’ behavior [3]. Although MRI can provide a powerful imaging detection with high spatial resolution (£100 m) and tomographic capabilities, the major challenge of this method is the low sensitivity for early detection of the disease. The histopathologic examination by microscopy of biopsy as the gold standard has been used for diagnosis, prognosis and administration of cancer for many decades [4]. However, this ‘gold standard’ method faces challenge to
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10.1586/14737159.2014.866039
modern molecular diagnosis since it provides very limited information about cell physiology, which may be misled in molecular diagnosis of cancer. Moreover, the microscopic detection of many cancers may not provide enough information for early diagnosis of the disease, thus, the diagnosis based on histopathological features requires additional validation process by using tools from molecular pathology as described in FIGURE 1. Biomarkers for early detection of cancer
Early diagnosis of cancer is an ideal strategy to reduce the incidence of the disease and improve its survival rate significantly. Biomarkers are important molecular signatures of the cell phenotype, which can be used for early detection of cancer [5]. Biomarker discovery for early detection of cancer is a crucial unmet need to improve patient outcomes. Development of cancer biomarker gains beneficial from newly developed technologies in metabolomics, genomics and proteomics. Differential metabolic profile between cancerous cells and normal cells was observed in many types of cancer cells, resulting in discovery of metabolic biomarkers specific to cancerous cells as well as to different cancer types. These metabolic
2014 Informa UK Ltd
ISSN 1473-7159
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Zhang, Soori, Dobleman & Xiao
Sensitivity Enzyme immunoassays Chemical pathology
Fluorescence labled immunoassay
Tissue pathology Pathology Diagnosis
Low
Radioimmunoassays High
Microscopic examination of tumor cells using immunohistology and immunohistochemistry Visualized by Enzymatic method Fluorescence
arrays [30], has been made, including biomarkers used for early diagnosis of the disease [31], development of new drug for cancer, and cancer etiology [32]. modified SILAC has now extensively used for biomarker study in vitro, ex vivo, and in vivo due to its high sensitivity for detection of protein turnover [33,34]. Antibody-based diagnosis of cancer
Diagnosis of disease depends frequently on quantitative identification or localization of particular molecules in cells, tisClear morphology sues or body fluids. Owning to the exquisite specificity, antibodies are widely Development of cancer biomarkers used Molecular used reagents in the clinical diagnostic for early diagnosis of cancer by metabolic, pathology laboratory. Use of monoclonal antibody genomic and proteomic approaches (mAb) for molecular diagnosis of cancer comes true is superior to polyclonal antibody since it Figure 1. Cancer diagnosis. provides high accuracy, sensitivity, reproducibility and specificity [35]. As a specific biomarkers include spermine and citrate, which were used for proteomic approach for biomarker discovery, antibody microarassessing prostate cancer aggressiveness [6], metabolic biomarkers rays has been applying for protein profiling indifferent clinical leptin, resistin, hypersensitive C-reactive protein, TNF-a, and specimens, including serum, saliva, sputum, urine, tumor interangiotensin II, were successfully utilized in clinic for early diag- stitial fluid and tissues [36]. Use of antibody microarray for nosis of breast cancer [7], metabolic biomarker phosphor- monitoring the activity of the tumor cells in peripheral blood Aktser473 was recently used for evaluating treatment efficacy of offers several advantages: less invasive approach for diagnosis of both MK-2206 and BEZ235 on basal-like breast cancer [8]. cancer and high specificity. Therefore, antibody microarray can Because mRNA level may not be correlated with gene expression provide multiplexed, qualitative assays at a time for panels of in a cell, then information obtained by other methods, such as tumor markers that requires samples with a minimum volgene microarray, may not precisely indicate the status of the dis- ume [37,38]. Quantum dot technology coupled with antibody ease. Development of protein biomarker may provide better arrays, as an example, offers remarkable photostability, brightstrategy for monitoring development of cancer and guiding ther- ness and low photobleaching, and can increase the limit of proapy of the disease [9,10]. Use of this strategy led to identification tein detection in specimens (serum, plasma, body fluids) of numerous biomarkers, some of which may have been used for significantly [39]. Proteins at low abundance in a cell or body early diagnosis of breast cancer, such as C3a des-arginine ana- fluids are usually active signal molecules, indicating changes of phylatoxin (molecular weight: 8938 Da) and fragments of cell physiology, and can be developed as biomarkers. Identificainter-alpha trypsin inhibitor heavy chain H4 [11], circulating tion of this group of proteins in cells has been a major chalMACC1 transcripts for diagnosis of colorectal cancer [12], lenge in the field of proteomics. A number of technologies MCM2 used for diagnosis of gastric cardiac cancer [13]. have been developed aiming to increase the sensitivity to idenAntibody-based strategy, such as the enzyme-linked immu- tify proteins at low abundance in a cell and body fluids. These nosorbent spot and phage display library screening, has been technologies include antibody ultramicroarrays (UM) and surproven good for discovery of protein biomarkers used for early face plasmon resonance imaging (SPRI). UM was initially detection of human diseases [14–20], biomarkers discovered by developed as a PCR-like high-throughput bioassay method enzyme-linked immunosorbent spot include tumor-specific car- used for detection of low abundant protein molecules in speciboxy-terminal frameshift peptides, which have been used for mens. The sizes of the spots on the array are in the range of diagnosis of colorectal cancer [21]. Biomarkers discovered by 1–20 mm in diameter, taking a tiny fraction of the surface area phage display technology include serum autoantibodies [22–24], of a conventional (100 mm diameter) microarray spot. This that have been used for early diagnosis of breast cancer. technique is now gaining attention to the field of biomarker Recently, enormous progression in development of biomarker discovery by directly performing protein profiles from using proteomics technology, such as SILAC and modified extremely limited sample volumes. It is also compatible with a SILAC [9], radioimmunoassay, multidimensional protein identifi- standard high-throughput readout system available in the curcation technology, surface-enhanced laser desorption/ionization rent market [40]. UM has been successfully applied for detection time-of-flight analysis [25], multiple reaction monitoring mass of IL-6 and prostate-specific antigen in prostate cancer cells spectrometry [26–28], positron emission tomography [29] antibody with limitation of detection in the attomolar range [40]. Counterstaining
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The application of monoclonal antibodies in cancer diagnosis
SPRI microarrays have been also used for measurement of low abundant proteins in serum with limitation of detection in the picomolar range [41]. The SPRI signal is generated by the formation of a surface aptamer–protein–antibody complex. This technique has been used for measuring the VEGF in a cell. This technique has now been used in clinic by measuring the circulated VEGF level in serum in order to provide effective strategy for anti-angiogenic therapies of breast, lung and colorectal cancer [41]. Two-color rolling circle amplification method was developed lately and has been successfully used for the detection of the low abundant proteins with good reproducibility and accuracy in serum specimens [42]. Biomarkers discovered by two-color rolling circle amplification method include thrombospondin-1, which have been used for early diagnosis of prostate cancer [43]. Additionally, Sandwich assays, such as resonance light scattering [42], enhanced chemiluminescence [44] and the tyramide signal amplification method [37], have been also shown promising for measuring low abundant proteins in body fluids. In summary, combinational utility of these detection strategies for measuring proteins at low abundance in specimens could provide powerful approaches for discovery of cancer-specific biomarker. Biomarker in a certain signaling pathway can be used for monitoring drug efficacy and therapy of cancer [31,45,46]. Development of a cancer biomarker, showing highly expressed in tumor cells instead of normal cells may be effective strategy for early diagnosis of cancer [38]. Biomarkers amenable for early detection of cancer may promote the imaging diagnosis of the disease significantly. Effective antibodies with high affinity and specificity are the key reagents available for molecular imaging diagnosis. Development of the mAb with high affinity to its target/biomarker as an imaging probe provides an effective visualized approach for precise and accurate diagnosis of the disease at its early stages [47]. Development of mAb arrays may provide an important revenue for identification of novel biomarker from tissues and/or body fluids specimens used for early detection of the disease. Thus, mAb arrays in this instance are also referred to as a targeted proteomics [30]. This technology has been applied for identification and validation of unique biomarker from various specimens of cancer [32,38]. These include folate receptor-a, CCL2 and p95HER2, which were used for diagnosis of gynecologic malignancies [48], cancer metastasis [49] and non-small cell lung cancer [50]. Thus, successful use of mAb arrays in clinic may provide not only an evident for early diagnosis and stratification of cancer, but also additional information for understanding of the biological mechanisms underlying tumorigenesis and disease progression [45]. Although a mAb-based immunohistochemistry has remarkably improved the sensitivity and the specificity of cancer detection as compared with the H&E staining procedure alone, it still faces challenges for effective detection of disease, such as low specificity. Antibodies against tumor markers of interest must be more specific and sensitive to the tumor cells than to the adjacent non-tumor cells [30,38,51–53]. www.expert-reviews.com
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Intriguingly, a recent study showed that antibody array can be used specifically for multiplexed profiling of glycosylated proteins [54]. Protein carbohydrate post-translational modifications play an important role in tumorigenesis and metastasis. A study showed that glycan variation on proteins in multiple serum samples from pancreatic cancer patients is associated with the pancreas tumorigenesis using parallel sandwich and glycan-detection assays [55]. Therefore, antibody array-based detection of glycan variation on biomarkers may be developed as a strategy for early diagnosis of cancer. Although application of antibody arrays still faces challenge due to a limited antibody available, this technology coupled with gene microarray can be developed as a promising platform used for detection of cancer. Antibody array provides supportive data for gene microarray analysis to confirm the developmental status of the disease [10]. Compared with biomarkers developed by other technical methods, such as proteomics, genomics and genetics, antibody-based microarray assay shows unprecedented advantages for high-throughput and multiplexed detection of cancer-related analytes in minute volume of blood samples. Antibody against some surface molecules can be used as probes to study cellular function. Cell activation and differentiation are often accompanied by the changes in expression of cell surface or cytoplasmic molecules, antibodies can be used to track down these molecules and to monitor cellular activity dynamically, and to help understand molecular mechanisms underlying cell response to exogenous stimuli. Use of mAb provides an effective application for a specific cell sorting in flow cytometry (FCM). Antibodies conjugated with different fluorochromes can help track down multiple signals in a cell, which enables multiplexed applications for study of molecular mechanisms, and for prediction of clinical outcome [56]. Bead/suspension arrays have been also used for discovery of protein biomarkers. Antibody-based beads arrays are a multiplex flow cytometric-based system that utilizes up to a few hundreds of color-coded polystyrene bead sets. Each bead set is internally dyed with different ratios of two spectrally distinct fluorophores. Each of the bead sets can be conjugated with a unique antibody. The conjugated beads are pooled together in the wells of a microplate with the sample to be tested (i.e., sera), followed by the addition of a detection antibody, forming a capture immunoassay that is then read by the Bio-Plex suspension array reader. Each separate reaction is identified and quantitated based on the bead color (FIGURE 2). This allows a single sample to be tested simultaneously for reaction to a number of different antigens [57–60]. This technology has been applied for identification of novel biomarkers used for prediction of progression, and diagnosis of cancer [57,61,62]. In a recent study, the Luminex multiplex bead arrays was used to analyze serum samples from patients who had breast cancer and from healthy subjects, and found that serum levels of epidermal growth factor, soluble CD40-ligand and proapolipoprotein A1 were significantly higher in breast cancer subjects than in healthy subjects, resulting in identification of diagnosis 99
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Each bead conjugated with a unique antibody. 1
The conjugated beads are pooled together in
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the wells of a microplate. 2
4 3
Microplate Step 1: Preparation of microplate and sample Samples: sera, plasma, body fluids, saliva, sputum, urine, tumor interstitial fluid
3
Step 3: Beads washing and incubation with biotinylated detection antibody
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1
Step 4: Beads washing and incubation with streptavidin-PE Step 2: Incubation of antibody-coupled beads with sample
1
3
5
Step 5: Readout on the Bio-Plex suspension array system according to the bead color
Figure 2. Illustration of bead/suspension arrays.
biomarkers [62]. Antibody beads arrays covering 24 angiogenesisrelated molecules were utilized to analyze the differential expression of the angiogenesis signals in serum samples from colorectal cancer patients before and after surgical treatments, and found that serum levels of both VCAM-1 and plasminogen activator inhibitor-1 were significantly higher in the after surgical treatment than in the before surgical treatment, leading to identification of biomarkers used for prediction of the surgical treatments [63]. Cancer diagnosis & monovalent antibody
mAb used as a probe can enhance the signal of the target significantly in an imaging diagnosis. It can be produced by use of a hybridoma technology. Antibody avidity is referred to as antibody functional affinity, antibody interactions in which multiple antigen-binding sites simultaneously interact with the target antigenic epitopes [47]. In general, the higher antibody avidity is, the higher sensitivity and specificity could be achieved. Utilization of the whole antibody, however, faces 100
great challenge for an effective imaging diagnosis due to the relatively large size of the antibody and low avidity resulting in too long half-life time and too strong contrast and poor sensitivity. The mAb molecule has two identical Fab, which consists of two variable regions H and L loops (also referred to as complementarity determining regions). The base of the Y-shaped protein mAb, also called Fc (fragment, crystallizable), plays a role in modulating immune responses through its interaction with Fc receptors [64,65]. Because of the unwanted effects generated by Fc, poor results from the imaging diagnosis are often observed by use of the whole antibody. For example, a long half-life in serum results in poor contrast in imaging applications. False-positive signals in FCM applications are often observed due to an inappropriate activation of Fc receptor leading to induction of cross-reactivity. Deletion of the antigenic sites in the Fc region might reduce the interferences with heterogeneous antibodies in the application of FCM. Compared with the whole antibody, Fab fragment antibody has higher avidity and more sensitivity of detection. For Expert Rev. Mol. Diagn. 14(1), (2014)
The application of monoclonal antibodies in cancer diagnosis
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example, the engineered Fab fragment senSamples sitively recognizes the membraneassociated Hsp70 protein localized in the plasma membrane of human tumors but Tumor not in normal tissues. This Fab has been markers successfully used for detection of tumor Antibody microarrays cells in vitro and in vivo [66]. F(ab)2 microarrays The molecular size of the mAb can affect its pharmacokinetics and biodistribution significantly. The full-sized antibody usually penetrates solid tumors slowly and non-uniformed distribution. By contrast, small antibody fragments, such as Fab, are cleared rapidly and have poor tumor retention. Because of the poor tissue penetration rate, the full-sized antibody limits its medical applications in parallel sandwich immunoassays and antibody Detection primary Abs microarrays. Thus, the size of the ideal tumor-targeting reagents would be an intermediate-sized molecule with molecular weight of 55 kDa in order to provide a rapid tissue penetration, high target retention and rapid blood clearance. Recently, as development of the innovative recombinant DNA technologies, recombinant FITC-labeled secondary Ab Signal amplification mAbs can have been dissected into small binding fragments, resembled into multivalent high-avidity reagents, which can be used in the applications of the imaging and the biosensors [3,30]. Smaller recombinant antibody fragments (monovalent antibody: Fab, scFv) and engineered variants (diabodies, triabodies, minibodies and single-domain antibodies) without Fc domain than the full-sized antibody possess superior propImaging Imaging erties of tissue penetration and potentially target cryptic epitopes in addition to a similar binding specificity to the full-sized antibody. Notably, among these smaller Accuracy False positive signal antibody fragments, single-domain antibodies can significantly expand the reperFigure 3. Comparison of the full-sized antibody arrays and F(ab)2 toire of antibody-based reagents against antibody arrays. numbers of novel cancer biomarkers disIntriguingly, antibody fragments F(ab)2-based microarray covered through proteomics, and provide an ideal approach in obtaining an optimal image than the intact antibody [30]. Com- was newly developed for molecular diagnosis. Compared with pared with the intact antibody, these small fragments possess other assay methods for diagnostics of cancer, such as immumore compact size, shorter clearance time and better tumor noradiometric assays using the full-sized mAb, F(ab)2 microarpenetration. These small molecules, thus, may be applied for rays showed an improvement in not only the sensitivity, but monitoring therapy of cancer in addition to the application of also the specificity, of the detection [71]. Innovation in the immobilization surfaces and detection the imaging diagnosis [67]. With the improved tumor penetration, rapid blood clearance and high affinity of cryptic epito- strategies leads to development of microrray, such as planar pes, use of antibody Fab and scFv fragments can enhance the arrays and bead-based antibody arrays. Planar arrays are antibody arrays in which all of the elements (i.e., antibody quality of the diagnostic imaging [68–70]. www.expert-reviews.com
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Table 1. The application of monoclonal antibodies to the existing biomarkers in cancer diagnosis during the last 5 years. Antibody
Biomarker
Detect method
Cancer early diagnosis
Ref.
Angiotensin II
ELISA
Early breast cancer
[7]
Antibody toward pAktser473
pAktser473
Dual near-infrared immunofluorescent imaging method
Basal-like breast cancer
[8]
Mouse anti-human monoclonal (CRCT5.1)
MCM2
Immunohistochemistry
Gastric cardiac cancer
[13]
FRA-specific monoclonal antibody (mAb 26B3)
FRA
Immunohistochemistry
Gynecologic tumors
[48]
NSE
Multiplex suspension bead array
Lung cancer
[57]
CYFRA21-1
Multiplex suspension bead array
Lung cancer
[57]
AFP
Multiplex suspension bead array
Liver cancer
[57]
CA242
Multiplex suspension bead array
Pancreatic, gastric, rectum cancer, cholangiocarcinoma
[57]
Free b-hCG
Multiplex suspension bead array
Ovarian cancer
[57]
Free-PSA, total-PSA
Multiplex suspension bead array
Prostate cancer
[57]
PSA
Rapid bead-based immunoassay
Prostate carcinoma
[60]
VCAM-1/PAI-1
Antibody suspension bead arrays
Post-operative recurrence in patients with colorectal cancer
[63]
MCP-1
Sandwich ELISA
Hepatocellular carcinoma
[71]
HE4
Sandwich ELISA
Ovarian and endometrial cancer
[76]
CA-125
Sandwich ELISA
Ovarian cancer
[76]
Four biomarkers panel (CA125, HE4, CEA and VCAM1)
Multiplex xMAP beadbased immunoassays
Early-stage ovarian cancer
[77]
R21, a mouse mAb against sAC
Human sAC protein
Immunohistochemistry
Lentigo maligna
[78]
Antibodies against MAPKAPK3 and ACVR2B
MAPKAPK3/ ACVR2B
ELISA
Colorectal cancer
[79]
Full-sized antibody
Mouse monoclonal anti-PSA antibodies (5G6 and 8A6) for coating; mouse monoclonal anti-PSA antibody (5A6) for detection
FRA: Folate receptor-a; hCE1: Human carboxylesterase 1; mAb: Monoclonal antibody; NSCLC: Non-small cell lung cancer; PSA: Prostate-specific antigen.
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Table 1. The application of monoclonal antibodies to the existing biomarkers in cancer diagnosis during the last 5 years (cont.). Antibody
Biomarker
Detect method
Cancer early diagnosis
Ref.
hCE1 mAb and biotinylated polyclonal anti-hCE1 antibody
hCE1
Sandwich ELISA
Hepatocellular carcinoma
[80]
Rabbit anti-ERG antibody (clone ID: EPR3864)
ERG protein
Immunohistochemistry
Prostate carcinoma
[81]
CA-S27-mAb
CA-S27
Sandwich ELISA
Cholangiocarcinoma
[82]
B6 scFv for IgM
Lung cancerassociated IgM autoantibodies
Electrochemiluminescent assay
NSCLC
[83]
Alexa-conjugated scFv
HER2 receptor
Flow cytometer
Human breast adenocarcinoma
[84]
Full-sized antibody (cont.)
Minimized antibody
FRA: Folate receptor-a; hCE1: Human carboxylesterase 1; mAb: Monoclonal antibody; NSCLC: Non-small cell lung cancer; PSA: Prostate-specific antigen.
fragments) are in one plane. Planar antibody array has been extensively used in clinical research for discovery of drug targets and biomarkers. The planar arrays comprise single label-based antibody array and ‘sandwich’-type assay [52]. The former requires a direct target labeling with fluorophores, which often leads to poor quality of the image due to potential perturbation of antibody–antigen interactions. ‘Sandwich’ assays can provide better results than the single labeled array due to a significant improvement in the specificity and the sensitivity of the detection. Recently, serum monocyte chemoattractant protein-1 and prolactin developed by using ‘sandwich’ array were used for diagnosis of hepatocellular carcinoma [72]. Adapted from planar antibody arrays, bead-based antibody array offers a fast, flexible and multiplexed procedure to screen larger numbers of samples without extensive sample preparation by utilizing microparticles [73]. Breast cancer serum markers were identified by bead-based immunoassay successfully. Several proteins were found to be increased significantly, including epidermal growth factor, soluble CD40-ligand and proapolipoprotein A1. These proteins were demonstrated to be able to distinguish primary breast cancer patients from healthy controls with higher accuracy [62]. Because of the advantages of the F(ab)2, the sensitivity of F(ab)2-based microarray assays is higher than that of ELISA. The use of F(ab)2 fragments as capturing probes is an important feature of this antibody microarray platform. Removal of species-specific Fc fragments minimizes the cross-reaction and provides a rationale for development of antibody-based diagnosis of cancer (FIGURE 3). Currently, there are many of these products in clinical and preclinical studies. Several recombinant Fabs and scFvs have been approved by the US FDA for molecular diagnosis of cancer [65].
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Biosensors are designed for detection of cancer biomarkers and for determination of drug efficacy at different target sites. It provides fast and accurate detection, reliable imaging of cancer cells and monitoring of angiogenesis and cancer metastasis [45,74]. Fab antibody fragments would be ideal reagents since they are small, stable, high specificity and can be developed as novel biosensing devices used for molecular diagnosis of cancer. This technology has been successfully applied to diagnosis of cancer [71,75,76]. In addition, the exquisite selectivity and easy manipulation of the Fab fragments facilitate more exotic applications including targeting quantum dots and therapeutic delivery vehicles. Recombinant mAb Fab fragments are now extensively used in design of multiplexed arrays for gene expression analysis and discovery of novel biomarkers. As new biomarkers have been generating by an integrated omics technologies, novel small mAb Fab reagents with high affinity can be developed as effective diagnostic tools used for early diagnosis and therapy of cancer [69]. The antibody-based cancer diagnoses to the existing biomarkers developed in the last 5 years are summarized in TABLE 1. Expert commentary
Molecular oncologic pathology has become an alternative approach for early diagnosis of cancer and for prediction of the biological behavior of a tumor and for better understanding of tumor therapy. As an important dimension in molecular diagnosis of cancer, a mAb Fab-based microarray platform due to its high sensitivity and the specificity for detection of antigens will provide an effective approach for development of novel biomarkers used for early diagnosis of cancer. In addition, it may also provide unique approach for development of the mAb Fab-based biosensor used for determination of novel drug effectiveness, monitoring disease progression and intervention. 103
Review
Zhang, Soori, Dobleman & Xiao
Five-year view
Financial & competing interests disclosure
The mAb fragments, because of their chemical properties, such as small, stable, high affinity against the tumor-associated antigen, provide valuable alternative approach for development of new biosensor devices with high sensitivity and specificity [62]. Such antibody bioassays will have an important impact on early diagnosis and therapeutic administration of cancer [47,68]. Thus, development of these new bioassay reagents (mAb Fabs) are anticipated to be new trend for early diagnose of cancer over next 5 years. It may be developed as a breakthrough approach for early diagnosis of cancer with improvement of sensitivity and specificity that cannot be achieved by other methods in the coming years.
This research was supported by a grant of Chinese National Technology R&D Program for the 11th five-year plan (2009BAK61B04) and the Dobleman Head and Neck Cancer Foundation in the USA. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties. No writing assistance was utilized in the production of this manuscript.
Key issues • Quantitative proteomics and biomarker discovery in human cancer. • The promise of biomarkers in cancer screening and detection. • Novel antibody vectors for imaging. • Monoclonal antibodies: diagnostic uses. • Protein-based tumor imaging probes. • Monoclonal antibody arrays as an emerging tool for discovery of cancer biomarkers. • Antibody arrays: technical considerations and clinical applications in cancer. • A monoclonal antibody Fabs microarray platform and its clinical applications.
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