9
Human Antibodies 22 (2013) 9–13 DOI 10.3233/HAB-130266 IOS Press
Future prospects of monoclonal antibodies as magic bullets in Immunotherapy Leili Aghebati Malekia,b , Behzad Baradarana,b,∗, Jafar Majidia,b,∗ , Mozhdeh Mohammadiana and Fatemeh Zare Shahneha,b a
b
Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
Abstract. Monoclonal antibody therapy has become a critical component of clinical treatment procedure for a variety of indications. Therapeutic antibodies have made the transition from conception to clinical reality over the past two decades. Now, many of mAbs are being tested as adjuvant or first-line therapies to determine their efficacy in improving survival. In the future, the information drawn from genomemedical science and genome-informatics, that list the disease-related antigens useful for medical treatment, should be essential to develop the therapy using mAbs. Currently, the more attention is getting paid toward monoclonal antibody therapy. Several monoclonal antibodies, alone and in combination with other conventional therapies, are being tested in phase I and phase II clinical trials at the moment. Monoclonal antibody therapy can be done by using antibody fragments, antibody fusions with effector proteins and intrabodies. The large size and the long half-life of full-length antibody make them an inappropriate tool for radioimmunotherapy. Therefore, scientists produced some antibody fragments including scFv, Diabody and Nanobodies (sdAbs) which have smaller size besides maintaining the binding activity of the full-length molecule. Immunotoxin and Immunocytokines are consisting of toxin and cytokines fused to antibody fragments. An intrabody is produced by entering antibody into the cell and act against intracellular compartments. Keywords: Monoclonal antibody, prospects, Immunotherapy, cancer
1. Therapeutic antibodies: coming of age Monoclonal antibody therapy has become a critical component of clinical treatment procedure for a variety of indications. The application of mAb ranges from inflammation diseases, cancer, cardiovascular diseases, and transplant rejection to infectious and metabolic and degenerative nervous diseases [1]. Drugs like trastuzumab and infliximab have demonstrated that mAbs can be utilized as extremely specific therapeutics tool, able to elicit significant, important and prolonged clinical responses [2]. ∗ Corresponding authors: Behzad Baradaran, Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. Tel.: +98 411 3364665; Fax: +98 411 3364665; E-mail: behzad_ [email protected]; Jafar Majidi, Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. Tel.: +98 411 3364665; Fax: +98 411 3364665; E-mail: [email protected].
The development of hybridoma technology has allowed the production of large amounts of highly specific antibodies licensed for use against a broad spectrum of diseases. The therapeutic efficacy of mAbs is dependent on their ability to trigger effect or activity as well as their antigen-binding ability. For example, mAbs exert their effects via mechanisms which include triggering apoptosis, activating Ab-dependent cellular cytotoxicity (ADCC), blockade of growth factor receptors and the activation of complement-dependent cytotoxicity (CDC) [3]. Now, mAbs play crucial roles in diagnosis, disease monitoring, identifying prognostic markers and therapy. Monoclonal Antibodies can be produced, alone; tagged with cytotoxic agents; and labeled with radioisotopes. Until now, close to twenty Nobel prizes have been awarded in the field of immunology and allied branches [4].
c 2013 – IOS Press and the authors. All rights reserved ISSN 1093-2607/13/$27.50
10
L.A. Maleki et al. / Future prospects of monoclonal antibodies as magic bullets in Immunotherapy
Paul-Ehrlich thought of developing “magic bullet” against most diseases, including cancer in the last decade of nineteenth century. Accordingly, most biologists prefer to credit Ehrlich for propounding the theory of immunotherapy [3]. The first therapeutic mAb was orthoclone OKT3 (muromonab), a murine mAb directed against CD3 T-cells. It was licensed in 1986 for acute kidney graft rejection and in steroidresistant graft rejection in cardiac and liver transplant patients. The first therapeutic mAbs used in clinical trials were murine in origin (indicated by the suffix -omab in INN nomenclature), and it became clear early on that patients developed human anti-mouse antibody (HAMA) responses against the therapeutic agents that limited both efficacy of the mAb by rapidly clearing it from the body and the number of times the therapy could be administered. To tackle this problem, molecular biological approaches were used to replace part of the rodent antibody sequence for human sequences, resulting in chimeric or humanized molecules (suffixes –ximab and –zumab in INN nomenclature, respectively). Even better, technologies now exist to generate fully human antibodies (suffix –umab) [4,5]. Monoclonal antibody therapy is having a significant impression on many disease processes, especially malignancies arisen from solid tissues and hematological origin. Therapeutic antibodies have made the transition from conception to clinical reality over the past two decades. Now, many of mAbs are being tested as adjuvant or first line therapies to determine their efficacy in improving survival [4,5]. Currently, combination therapy is a well-established strategy in tumor therapy, and mAb are increasingly emerging as a powerful component of many therapeutic protocols. MAbs have been reconfigured, and new therapeutic approaches have emerged. The future role of mAb may thus best envisage as an adjunct to conventional therapy [6]. Several reagents have received FDA approval; a number of mAb and mAb derivatives are being adopted in advanced clinical trials and are also due to receive approval (Table 1). So, the rapid pace of advances in cellular and molecular biology, immunology and protein engineering assures the essential futility of any prognostication attempts regarding antibody-based therapy of human cancer [7]. Recently, the relevance of understanding the receptor-mediated signaling events was highlighted as a new opportunity for mAb-mediated tumor therapy. Eventually, the ability of antibodies to promote ADCC and inflammation offers an as yet unexploited mechanism for improving cancer therapy. Current attention
is focused on defining the possibilities offered by the new targets and new agents being generated by recombinant engineering techniques in order to develop more effective anti-cancer therapies in the near future. In the future, the information drawn from genomemedical science and genome-informatics, that list the diseaserelated antigens useful for medical treatment, should be essential to develop the therapy using mAbs [8].
2. New avenues Taken together, biology and technology are converging to overcome current obstacles to successful mAb therapy in oncology. As shown by the relatively recent increase in trials using humanized mAbs and human antibodies generated in transgenic mice with human immunoglobulin genes, clinical studies typically lag a decade or more behind the wave front of new technology. It therefore follows that new classes of genetically engineered mAbs and modified antibody structures, like bispecific antibodies or smaller antibody fragments will enter clinical trials in the next decade. Improved conjugation technologies will facilitate the development of immunoconjugates [9]. More efficient ADCC will be achieved by overcoming the response variability caused by Fc-receptor polymorphisms using IgGs with alterations in their glycosylation or Fcdomain amino acid sequences. Antibody affinity will be regulated and customized to inhibit binding to normal tissues, improve tumor penetration, retention and optimize anti-tumor effects [10]. The specificity, size, capacity and structure of these mAbs also will be modified to increase tumor specificity by accelerating systemic clearance of mAbs that have failed to bind the target of choice (non-targeted antibodies) [11]. More precise identification of potentially responsive tumors will lead to improved patient selection. Notably, the identification of new functional targets and epitopes on existing targets will expand the range of cancers that can be effectively attacked by exploiting mAb technology [9]. The large size of antibodies reduces tumour penetration and long half-life of full-length antibody in serum is not appropriate for radioimmunotherapy, as it may cause adverse effects on normal tissues too. Therefore, many studies done in order to produce antibody fragments that beside maintaining the binding activity of the full-length molecule, can be use for certain particular applications like radioimmunotherapy short half-life which has the binding activity of the full
L.A. Maleki et al. / Future prospects of monoclonal antibodies as magic bullets in Immunotherapy
11
Table 1 Examples of clinical application of monoclonal antibodies in cancer treatment Generic name
Trade name
Type
Muromomab• Edrecolomab Abciximab• Rituximab• Daclizumab• Basiliximab• Palivizumab• Infliximab• Trastuzumab• Nimotuzumab Gemtuzumab• Alemtuzumab• Ibritomomab• Adalimumab• Omalizumab• Tositumomab• Efalizumab• Cetuximab• Bevacizumab• Natalizumab• Epratuzumab Ranibizumab• Panitumumab• Eculizumab• Certolizumab• Zanolimumab Ofatumumab Ipilimumab Mogamulizumab Pertuzumab
Orthoclone Panorex ReoPro Rituxan MabThera Zenapax Simulect Synagis Remicade Herceptin TheraCIM Mylotarg Mabcampath Campath-IH Zevalin 90 Y Trudexa Xolair Bexxar 131 I Raptiva Erbitux Avastin Tysabri Lymphacide Lucentis Vectibis Soliris Cimzia HuMaxCD4 Arzerra Yervoy Poteligeo Perjeta
Murine Murine Chimeric Chimeric Humanized Chimeric Humanized Chimeric Humanized Humanized Humanized Humanized Mouse Human Humanized Murine Humanized Chimeric Humanized Humanized Humanized Humanized Human Humanized Humanized Human Human Human Humanized Humanized
First approval year (Withdrawn) 1986 1995* (2002) 1994 1997 1997 1998 1998 1998 1998 1999* 2000 2001 2001 2002 2003 2003 2003 2004 2004 2004 2005 2006 2006 2007 2008 2008 2009 2011 2012* 2012
Approved clinical indication(s) Allograft rejection in allogeneic renal transplantation CRC Maintenance of coronary patency NHL, RA Allograft rejection Allograft rejection Respiratory syncytial virus (RSV inhibitor) in children Crohn’s disease and rheumatoid arthritis Metastatic breast Ca, Gastric Ca HNC, Glioma, Lymphoma CD33-positive acute myeloid leukemia CLL B-cell non-Hodgkin’s lymphoma Crohn’s disease and rheumatoid arthritis Treatment of asthma CD20-positive B-cell non-Hodgkin’s lymphoma Moderate to severe plaque psoriasis KRAS wild type CRC, HNC CRC, Ovarian and Lung Ca Multiple sclerosis NHL Wet-type age-related macular degeneration Metastatic colorectal carcinoma Paroxysmal nocturnal haemoglobinuria Crohn’s disease T-cell Lymphoma CLL Melanoma Lymphoma Breast Ca
• FDA approved monoclonal antibodies; ∗ Approval outside of EU/US; Ca: Cancer; CLL: Chronic lymphocytic leukemia; CRC: Colorectal carcinoma; HNC: Head and neck cancer; In: Indium; KRAS: Kirsten rat sarcoma; NHL: Non-Hodgkin’s lymphoma; RA: Rheumatoid arthritis.
molecule, monovalently [12]. Diabody is a compact, medium-sized dimer which produced by decreasing the size of the linker between the two domains. Dimerization increases the molecular weight and provides bivalency which consequently results in a higher avidity and higher tumor penetration while acquiring essential serum half-life. Hence, Diabodies have a great prospective for radioimmunotherapy [4]. Sharks and camelids produce a kind of antibodies [11,12]. scFv (single chain variable fragment) is variable domains of both heavy and light chains which connected by a flexible linker. scFv is small antibody fragment with a very without light chains which respectively named new antigen receptor antibodies (IgNAR) and heavy chain antibodies (HcAbs). Their single variable domain binds to a large spectrum of antigens with high affinity. Nanobodies or single-domain antibodies (sdAbs), single variable domains derived from shark IgNAR or camel HcAbs, are produced via genetic engineering and recombinant antibody technology [4].Producing human sdAbs would be promising candidate for
radioimmunotherapy, because they have very useful characteristics such as very high stability, high affinity, high specificity and binding to non accessible epitopes like enzyme active sites (Fig. 1). Antibody engineering helps us to generate small antibody fragments which can penetrate tumours much more faster than full length antibody; but due to their high rate of catabolism and renal clearance, tumour uptake of these antibody fragments is not that much efficient [12,13]. Chemical addition of polyethylene glycol (PEG) residues and fusion of antibody fragments to human serum albumin (HSA) can be used to increase the size of the fragments, the antibody stability and the serum half-life which subsequently improve anti-tumour activity of the antibody fragment. Overall, multimerization is the most promising method to achieve a good balance between tumour penetration, multivalency and serum half-life. For instance, triabodies or tetrabodies have produced by multimerization using a short or no linker, which results in multivalent
12
L.A. Maleki et al. / Future prospects of monoclonal antibodies as magic bullets in Immunotherapy
Fig. 1. Antibody fragments with therapeutic potential. sdAb, single-domain antibodies; bsAb, bispecific antibodies; bsFab, bispecific Fab fragment; HcAb, heavy chain only antibodies. For more details, reader is directed to see (4). (Colours are visible in the online version of the article; http://dx.doi.org/10.3233/HAB-130266)
fragments with higher molecular weight and increased serum half-lives [4]. Because of the small size and easy production of antibody fragments in yeast or bacteria, several proteins can be fused to them in order to create molecules with novel functions. Immunotoxin is a fusion between a scFv and toxin. It is immunogenic and quickly neutralized by recipients’ immune system. Fusing a human RNase to a human scFv creates more potent immunotoxins which targets a tumor antigen and results in an intense tumor decline [12]. Immunocytokines consisting of cytokines (such as IL-2, IL15, granulocyte-macrophage colonystimulating factor, interferon-γ) fused to tumour-specific antibody fragments. Although systemic administration of cytokines may cause significant side effects, using immunocytokines leads to activate the immune system just in the tumor surrounding area [14]. An intrabody is produced by entering antibody into the cell and act against various intracellular compartments like nucleus, mitochondria, endoplasmic retic-
ulum (ER), cytosol and plasma membrane. Intrabodies has been designed to interact with their intracellular target antigens, and subsequently block or modify particular molecular interactions which may results in interfering with the biological activity of the target protein [14,15]. One type of intrabodies is formed by conjugating antibody to the KDEL peptide signal, which binds to a KDEL receptor on ER, that may leads to keeping the intrabodies inside the ER. Binding the intrabody to its target in the ER leads to avoiding the target protein from departure the ER and being expressed on the cell surface. This process can be useful for reduction of the expression of oncogenic vascular endothelial growth factor receptor on the tumor cell surface, and consequently inhibition of tumor development. dAbs due to their stability, the possibility of binding strongly to epitopes not accessible to conventional antibodies (such as enzyme active sites) and lack of flexible linker are the exceptional applicants for generating intrabodies [15].
L.A. Maleki et al. / Future prospects of monoclonal antibodies as magic bullets in Immunotherapy
3. Conclusion [6]
In summary, monoclonal antibodies, the strongest growth therapeutics in the pharmaceutical industry and marketing, increasingly enter to different stages of clinical trials as alone entities or in combination with other therapies (e.g., traditional cytotoxic chemotherapy, radiation therapy, other antibodies, vaccines and biologic agents).
[7]
[8]
[9]
[10]
References [11] [1]
[2] [3]
[4]
[5]
O.H. Brekke and I. Sandlie, Therapeutic antibodies for human diseases at the dawn of the twenty-first century, Nat Rev Drug Discov 2 (2003), 52–62. R.S. Schwartz, Paul Ehrlich’s magic bullets, N Engl J Med 350 (2004), 1079–1080. J. Majidi, J. Barar, B. Baradaran, J. Abdolalizadeh and Y. Omidia, Target therapy of cancer: Implementation of monoclonal antibodies and nanobodies, Human Antibodies 18 (2009), 81–100. P. Chames, M. Regenmortel, E. Weiss and D. Baty, Therapeutic antibodies: successes, limitations and hopes for the future, British Journal of Pharmacology 157 (2009), 220–233. L.M. Weiner, An overview of monoclonal antibody therapy of
[12]
[13] [14]
[15]
13
cancer, Semin Oncol 26 (1999), 41–50. M.J. Pittet, Behavior of immune players in the tumor microenvironment, Curr Opin Oncol 21 (2009), 53–59. E. Wolf, R. Hofmeister, P. Kufer, B. Schlereth and P. Baeuerle, BiTEs: bispecific antibody constructs with unique anti-tumor activity, Drug Discov Today 10 (2005), 1237–1244. A.J. Korman, K.S. Peggs and J.P. Allison, Checkpoint blockade in cancer immunotherapy, Adv Immunol 90 (2006), 297– 339. T.A. Ferrara, J.W. Hodge and J.L. Gulley, Combining radiation and immunotherapy for synergistic antitumor therapy, Curr Opin Mol Ther 11 (2009), 37–42. S. Demko, J. Summers, P. Keegan and R. Pazdur, FDA Drug approval summary: alemtuzumab as single agent treatment for B cell CLL, Oncologist 13 (2008), 167–174. A.M. Scott, J. Allison and D. Wolchok, Monoclonal antibodies in cancer therapy, Cancer Immunity 12 (2012), 14–22. P. Holliger and P.J. Hudson, Engineered antibody fragments and the rise of single domains, Nat Biotechnol 23 (2005), 1126–1136. G.P. Adams and L.M. Weiner, Monoclonal antibody therapy of cancer, Nature Biotechnol 23 (2005), 1147–1157. P.J. Carter, Introduction to current and future protein therapeutics: A protein engineering perspective, Exp Erimental Cell Research 317 (2011), 1261–1269. A. Beck, T. Wurch and C. Bailly, Strategies and challenges for the next generation of therapeutic antibodies, Nature Reviewes Immunology 10 (2010), 345–352.
Copyright of Human Antibodies is the property of IOS Press and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
Human Antibodies 22 (2013) 9–13 DOI 10.3233/HAB-130266 IOS Press
Future prospects of monoclonal antibodies as magic bullets in Immunotherapy Leili Aghebati Malekia,b , Behzad Baradarana,b,∗, Jafar Majidia,b,∗ , Mozhdeh Mohammadiana and Fatemeh Zare Shahneha,b a
b
Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
Abstract. Monoclonal antibody therapy has become a critical component of clinical treatment procedure for a variety of indications. Therapeutic antibodies have made the transition from conception to clinical reality over the past two decades. Now, many of mAbs are being tested as adjuvant or first-line therapies to determine their efficacy in improving survival. In the future, the information drawn from genomemedical science and genome-informatics, that list the disease-related antigens useful for medical treatment, should be essential to develop the therapy using mAbs. Currently, the more attention is getting paid toward monoclonal antibody therapy. Several monoclonal antibodies, alone and in combination with other conventional therapies, are being tested in phase I and phase II clinical trials at the moment. Monoclonal antibody therapy can be done by using antibody fragments, antibody fusions with effector proteins and intrabodies. The large size and the long half-life of full-length antibody make them an inappropriate tool for radioimmunotherapy. Therefore, scientists produced some antibody fragments including scFv, Diabody and Nanobodies (sdAbs) which have smaller size besides maintaining the binding activity of the full-length molecule. Immunotoxin and Immunocytokines are consisting of toxin and cytokines fused to antibody fragments. An intrabody is produced by entering antibody into the cell and act against intracellular compartments. Keywords: Monoclonal antibody, prospects, Immunotherapy, cancer
1. Therapeutic antibodies: coming of age Monoclonal antibody therapy has become a critical component of clinical treatment procedure for a variety of indications. The application of mAb ranges from inflammation diseases, cancer, cardiovascular diseases, and transplant rejection to infectious and metabolic and degenerative nervous diseases [1]. Drugs like trastuzumab and infliximab have demonstrated that mAbs can be utilized as extremely specific therapeutics tool, able to elicit significant, important and prolonged clinical responses [2]. ∗ Corresponding authors: Behzad Baradaran, Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. Tel.: +98 411 3364665; Fax: +98 411 3364665; E-mail: behzad_ [email protected]; Jafar Majidi, Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. Tel.: +98 411 3364665; Fax: +98 411 3364665; E-mail: [email protected].
The development of hybridoma technology has allowed the production of large amounts of highly specific antibodies licensed for use against a broad spectrum of diseases. The therapeutic efficacy of mAbs is dependent on their ability to trigger effect or activity as well as their antigen-binding ability. For example, mAbs exert their effects via mechanisms which include triggering apoptosis, activating Ab-dependent cellular cytotoxicity (ADCC), blockade of growth factor receptors and the activation of complement-dependent cytotoxicity (CDC) [3]. Now, mAbs play crucial roles in diagnosis, disease monitoring, identifying prognostic markers and therapy. Monoclonal Antibodies can be produced, alone; tagged with cytotoxic agents; and labeled with radioisotopes. Until now, close to twenty Nobel prizes have been awarded in the field of immunology and allied branches [4].
c 2013 – IOS Press and the authors. All rights reserved ISSN 1093-2607/13/$27.50
10
L.A. Maleki et al. / Future prospects of monoclonal antibodies as magic bullets in Immunotherapy
Paul-Ehrlich thought of developing “magic bullet” against most diseases, including cancer in the last decade of nineteenth century. Accordingly, most biologists prefer to credit Ehrlich for propounding the theory of immunotherapy [3]. The first therapeutic mAb was orthoclone OKT3 (muromonab), a murine mAb directed against CD3 T-cells. It was licensed in 1986 for acute kidney graft rejection and in steroidresistant graft rejection in cardiac and liver transplant patients. The first therapeutic mAbs used in clinical trials were murine in origin (indicated by the suffix -omab in INN nomenclature), and it became clear early on that patients developed human anti-mouse antibody (HAMA) responses against the therapeutic agents that limited both efficacy of the mAb by rapidly clearing it from the body and the number of times the therapy could be administered. To tackle this problem, molecular biological approaches were used to replace part of the rodent antibody sequence for human sequences, resulting in chimeric or humanized molecules (suffixes –ximab and –zumab in INN nomenclature, respectively). Even better, technologies now exist to generate fully human antibodies (suffix –umab) [4,5]. Monoclonal antibody therapy is having a significant impression on many disease processes, especially malignancies arisen from solid tissues and hematological origin. Therapeutic antibodies have made the transition from conception to clinical reality over the past two decades. Now, many of mAbs are being tested as adjuvant or first line therapies to determine their efficacy in improving survival [4,5]. Currently, combination therapy is a well-established strategy in tumor therapy, and mAb are increasingly emerging as a powerful component of many therapeutic protocols. MAbs have been reconfigured, and new therapeutic approaches have emerged. The future role of mAb may thus best envisage as an adjunct to conventional therapy [6]. Several reagents have received FDA approval; a number of mAb and mAb derivatives are being adopted in advanced clinical trials and are also due to receive approval (Table 1). So, the rapid pace of advances in cellular and molecular biology, immunology and protein engineering assures the essential futility of any prognostication attempts regarding antibody-based therapy of human cancer [7]. Recently, the relevance of understanding the receptor-mediated signaling events was highlighted as a new opportunity for mAb-mediated tumor therapy. Eventually, the ability of antibodies to promote ADCC and inflammation offers an as yet unexploited mechanism for improving cancer therapy. Current attention
is focused on defining the possibilities offered by the new targets and new agents being generated by recombinant engineering techniques in order to develop more effective anti-cancer therapies in the near future. In the future, the information drawn from genomemedical science and genome-informatics, that list the diseaserelated antigens useful for medical treatment, should be essential to develop the therapy using mAbs [8].
2. New avenues Taken together, biology and technology are converging to overcome current obstacles to successful mAb therapy in oncology. As shown by the relatively recent increase in trials using humanized mAbs and human antibodies generated in transgenic mice with human immunoglobulin genes, clinical studies typically lag a decade or more behind the wave front of new technology. It therefore follows that new classes of genetically engineered mAbs and modified antibody structures, like bispecific antibodies or smaller antibody fragments will enter clinical trials in the next decade. Improved conjugation technologies will facilitate the development of immunoconjugates [9]. More efficient ADCC will be achieved by overcoming the response variability caused by Fc-receptor polymorphisms using IgGs with alterations in their glycosylation or Fcdomain amino acid sequences. Antibody affinity will be regulated and customized to inhibit binding to normal tissues, improve tumor penetration, retention and optimize anti-tumor effects [10]. The specificity, size, capacity and structure of these mAbs also will be modified to increase tumor specificity by accelerating systemic clearance of mAbs that have failed to bind the target of choice (non-targeted antibodies) [11]. More precise identification of potentially responsive tumors will lead to improved patient selection. Notably, the identification of new functional targets and epitopes on existing targets will expand the range of cancers that can be effectively attacked by exploiting mAb technology [9]. The large size of antibodies reduces tumour penetration and long half-life of full-length antibody in serum is not appropriate for radioimmunotherapy, as it may cause adverse effects on normal tissues too. Therefore, many studies done in order to produce antibody fragments that beside maintaining the binding activity of the full-length molecule, can be use for certain particular applications like radioimmunotherapy short half-life which has the binding activity of the full
L.A. Maleki et al. / Future prospects of monoclonal antibodies as magic bullets in Immunotherapy
11
Table 1 Examples of clinical application of monoclonal antibodies in cancer treatment Generic name
Trade name
Type
Muromomab• Edrecolomab Abciximab• Rituximab• Daclizumab• Basiliximab• Palivizumab• Infliximab• Trastuzumab• Nimotuzumab Gemtuzumab• Alemtuzumab• Ibritomomab• Adalimumab• Omalizumab• Tositumomab• Efalizumab• Cetuximab• Bevacizumab• Natalizumab• Epratuzumab Ranibizumab• Panitumumab• Eculizumab• Certolizumab• Zanolimumab Ofatumumab Ipilimumab Mogamulizumab Pertuzumab
Orthoclone Panorex ReoPro Rituxan MabThera Zenapax Simulect Synagis Remicade Herceptin TheraCIM Mylotarg Mabcampath Campath-IH Zevalin 90 Y Trudexa Xolair Bexxar 131 I Raptiva Erbitux Avastin Tysabri Lymphacide Lucentis Vectibis Soliris Cimzia HuMaxCD4 Arzerra Yervoy Poteligeo Perjeta
Murine Murine Chimeric Chimeric Humanized Chimeric Humanized Chimeric Humanized Humanized Humanized Humanized Mouse Human Humanized Murine Humanized Chimeric Humanized Humanized Humanized Humanized Human Humanized Humanized Human Human Human Humanized Humanized
First approval year (Withdrawn) 1986 1995* (2002) 1994 1997 1997 1998 1998 1998 1998 1999* 2000 2001 2001 2002 2003 2003 2003 2004 2004 2004 2005 2006 2006 2007 2008 2008 2009 2011 2012* 2012
Approved clinical indication(s) Allograft rejection in allogeneic renal transplantation CRC Maintenance of coronary patency NHL, RA Allograft rejection Allograft rejection Respiratory syncytial virus (RSV inhibitor) in children Crohn’s disease and rheumatoid arthritis Metastatic breast Ca, Gastric Ca HNC, Glioma, Lymphoma CD33-positive acute myeloid leukemia CLL B-cell non-Hodgkin’s lymphoma Crohn’s disease and rheumatoid arthritis Treatment of asthma CD20-positive B-cell non-Hodgkin’s lymphoma Moderate to severe plaque psoriasis KRAS wild type CRC, HNC CRC, Ovarian and Lung Ca Multiple sclerosis NHL Wet-type age-related macular degeneration Metastatic colorectal carcinoma Paroxysmal nocturnal haemoglobinuria Crohn’s disease T-cell Lymphoma CLL Melanoma Lymphoma Breast Ca
• FDA approved monoclonal antibodies; ∗ Approval outside of EU/US; Ca: Cancer; CLL: Chronic lymphocytic leukemia; CRC: Colorectal carcinoma; HNC: Head and neck cancer; In: Indium; KRAS: Kirsten rat sarcoma; NHL: Non-Hodgkin’s lymphoma; RA: Rheumatoid arthritis.
molecule, monovalently [12]. Diabody is a compact, medium-sized dimer which produced by decreasing the size of the linker between the two domains. Dimerization increases the molecular weight and provides bivalency which consequently results in a higher avidity and higher tumor penetration while acquiring essential serum half-life. Hence, Diabodies have a great prospective for radioimmunotherapy [4]. Sharks and camelids produce a kind of antibodies [11,12]. scFv (single chain variable fragment) is variable domains of both heavy and light chains which connected by a flexible linker. scFv is small antibody fragment with a very without light chains which respectively named new antigen receptor antibodies (IgNAR) and heavy chain antibodies (HcAbs). Their single variable domain binds to a large spectrum of antigens with high affinity. Nanobodies or single-domain antibodies (sdAbs), single variable domains derived from shark IgNAR or camel HcAbs, are produced via genetic engineering and recombinant antibody technology [4].Producing human sdAbs would be promising candidate for
radioimmunotherapy, because they have very useful characteristics such as very high stability, high affinity, high specificity and binding to non accessible epitopes like enzyme active sites (Fig. 1). Antibody engineering helps us to generate small antibody fragments which can penetrate tumours much more faster than full length antibody; but due to their high rate of catabolism and renal clearance, tumour uptake of these antibody fragments is not that much efficient [12,13]. Chemical addition of polyethylene glycol (PEG) residues and fusion of antibody fragments to human serum albumin (HSA) can be used to increase the size of the fragments, the antibody stability and the serum half-life which subsequently improve anti-tumour activity of the antibody fragment. Overall, multimerization is the most promising method to achieve a good balance between tumour penetration, multivalency and serum half-life. For instance, triabodies or tetrabodies have produced by multimerization using a short or no linker, which results in multivalent
12
L.A. Maleki et al. / Future prospects of monoclonal antibodies as magic bullets in Immunotherapy
Fig. 1. Antibody fragments with therapeutic potential. sdAb, single-domain antibodies; bsAb, bispecific antibodies; bsFab, bispecific Fab fragment; HcAb, heavy chain only antibodies. For more details, reader is directed to see (4). (Colours are visible in the online version of the article; http://dx.doi.org/10.3233/HAB-130266)
fragments with higher molecular weight and increased serum half-lives [4]. Because of the small size and easy production of antibody fragments in yeast or bacteria, several proteins can be fused to them in order to create molecules with novel functions. Immunotoxin is a fusion between a scFv and toxin. It is immunogenic and quickly neutralized by recipients’ immune system. Fusing a human RNase to a human scFv creates more potent immunotoxins which targets a tumor antigen and results in an intense tumor decline [12]. Immunocytokines consisting of cytokines (such as IL-2, IL15, granulocyte-macrophage colonystimulating factor, interferon-γ) fused to tumour-specific antibody fragments. Although systemic administration of cytokines may cause significant side effects, using immunocytokines leads to activate the immune system just in the tumor surrounding area [14]. An intrabody is produced by entering antibody into the cell and act against various intracellular compartments like nucleus, mitochondria, endoplasmic retic-
ulum (ER), cytosol and plasma membrane. Intrabodies has been designed to interact with their intracellular target antigens, and subsequently block or modify particular molecular interactions which may results in interfering with the biological activity of the target protein [14,15]. One type of intrabodies is formed by conjugating antibody to the KDEL peptide signal, which binds to a KDEL receptor on ER, that may leads to keeping the intrabodies inside the ER. Binding the intrabody to its target in the ER leads to avoiding the target protein from departure the ER and being expressed on the cell surface. This process can be useful for reduction of the expression of oncogenic vascular endothelial growth factor receptor on the tumor cell surface, and consequently inhibition of tumor development. dAbs due to their stability, the possibility of binding strongly to epitopes not accessible to conventional antibodies (such as enzyme active sites) and lack of flexible linker are the exceptional applicants for generating intrabodies [15].
L.A. Maleki et al. / Future prospects of monoclonal antibodies as magic bullets in Immunotherapy
3. Conclusion [6]
In summary, monoclonal antibodies, the strongest growth therapeutics in the pharmaceutical industry and marketing, increasingly enter to different stages of clinical trials as alone entities or in combination with other therapies (e.g., traditional cytotoxic chemotherapy, radiation therapy, other antibodies, vaccines and biologic agents).
[7]
[8]
[9]
[10]
References [11] [1]
[2] [3]
[4]
[5]
O.H. Brekke and I. Sandlie, Therapeutic antibodies for human diseases at the dawn of the twenty-first century, Nat Rev Drug Discov 2 (2003), 52–62. R.S. Schwartz, Paul Ehrlich’s magic bullets, N Engl J Med 350 (2004), 1079–1080. J. Majidi, J. Barar, B. Baradaran, J. Abdolalizadeh and Y. Omidia, Target therapy of cancer: Implementation of monoclonal antibodies and nanobodies, Human Antibodies 18 (2009), 81–100. P. Chames, M. Regenmortel, E. Weiss and D. Baty, Therapeutic antibodies: successes, limitations and hopes for the future, British Journal of Pharmacology 157 (2009), 220–233. L.M. Weiner, An overview of monoclonal antibody therapy of
[12]
[13] [14]
[15]
13
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