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Focus on Approved and In-Clinical-Trial Monoclonal Antibodies Journal name: Drug Design, Development and Therapy Article Designation: Review Year: 2017 Volume: 11 Drug Design, Development and Therapy Dovepress Running head verso: Françoso and Simioni Running head recto: Monoclonal antibodies to colorectal tumors open access to scientific and medical research DOI: http://dx.doi.org/10.2147/DDDT.S119036 Open Access Full Text Article REVIEW Immunotherapy for the treatment of colorectal tumors: focus on approved and in-clinical-trial monoclonal antibodies Alex Françoso1 Abstract: Colorectal cancer is considered a disease of the elderly population. Since the number Patricia Ucelli Simioni1–3 of geriatric patients continues to rise, monoclonal antibody therapy is the most promising therapy in the recent research. Presently, the monoclonal antibodies most frequently used in the 1Department of Biomedical Science, Faculty of Americana, Americana, treatment of colorectal tumors are bevacizumab, cetuximab, panitumumab, and ramucirumab. 2Department of Genetics, Evolution Bevacizumab is a monoclonal antibody that acts on VEGF. Cetuximab and panitumumab act and Bioagents, Institute of Biology, University of Campinas, Campinas, on EGFR. Ramucirumab binds directly to the ligand-binding pocket of VEGFR-2 to block 3Department of Biochemistry and the binding of VEGF-A, VEGF-C, and VEGF-D. These monoclonal antibodies, alone or in Microbiology, Institute of Biosciences, association with radiotherapy or chemotherapy, are presenting good results and are increasing Universidade Estadual Paulista, Rio Claro, São Paulo, Brazil patient survival, despite the side effects. Due to the limited number of molecules available, For personal use only. several studies are trying to develop new monoclonal antibodies for the treatment of colorec- tal tumors. Among those being studied, some recent molecules are in phase I and/or II trials and are yielding advantageous results, such as anti-DR5, anti-Fn14, anti-IGF-1R, anti-EGFR, anti-NRP1, and anti-A33 antibodies. This has been successful in reducing side effects and in treating nonresponsive patients. Keywords: monoclonal antibodies, colorectal tumor, bevacizumab, cetuximab, panitumumab, ramucirumab Colorectal tumor Colorectal cancer is considered a heterogeneous disease, both in relation to the pathogenesis and the clinical signals.1 The incidence of colorectal cancer is higher in people between 60 and 70 years of age. Twenty percent of cases occur before the Drug Design, Development and Therapy downloaded from https://www.dovepress.com/ by 137.108.70.13 on 14-Jan-2020 age of 50. Colorectal cancer is more prevalent in the US, Canada, Australia, New Zealand, Denmark, Sweden, and other developed countries. The incidence is 30 times lower in India, South America, and Africa. In Japan, the incidence is increas- ing gradually, reaching similar rates in the UK, presumably as a result of changes in lifestyle and diet.2–7 The discovery of sequences of genes associated with adenoma–carcinoma has contributed to understanding the genetic and epigenetic alterations that drive the for- mation of colorectal cancer. Among the genetic alterations associated with colorectal cancer, abnormal activation of the Wnt/β-catenin signaling pathway has an important role, because Wnt pathway is crucial in cell proliferation and migration.8 Correspondence: Patricia Ucelli Simioni Somatic mutations may play an important role as prognostic or predictive mark- Faculdade de Americana, FAM, Rua Joaquim Boer, 733, Jardim Luciene, ers for the development of specific therapies in colorectal cancer. These mutations 13477-360, Americana, São Paulo, Brazil involve genes such as KRAS, BRAF, PIK3CA, AKT1, PTEN, NRAS, and TGFBR2.9–15 Tel +55 19 9 9699 1899 Email [email protected] Therefore, epigenetic and gene silencing events may increase the progression of submit your manuscript | www.dovepress.com Drug Design, Development and Therapy 2017:11 177–184 177 Dovepress © 2017 Françoso and Simioni. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you http://dx.doi.org/10.2147/DDDT.S119036 hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Powered by TCPDF (www.tcpdf.org) 1 / 1 Françoso and Simioni Dovepress colorectal cancer.16 This finding opens new possibilities regions. It recognizes the extracellular domain of the EGFR for high-precision laboratory tests such as the identification and therefore can block the tumor growth.47 of molecular markers in screening tests for noninvasive After binding to the extracellular domain of EGFR, this colorectal adenocarcinoma.17 antibody prevents the signaling and ligand-induced dimeriza- tion of the receptor. In this way, it blocks the signals of cell Supporting treatment with growth and tumor survival. Cetuximab may have the function monoclonal antibodies of mediating antibody-dependent cellular cytotoxicity Approved monoclonal antibodies (ADCC). This monoclonal antibody only achieves dynamic for therapy equilibrium after the third week of infusion.48–56 In addition, Several monoclonal antibodies for different therapeutic this biological molecule was approved by the US Food and targets have already been approved for use in patients with Drug Administration (FDA) for patients with metastatic tumors. For example, cetuximab and panitumumab are mono- colorectal cancer (mCRC), especially for patients who do not clonal antibodies directed at the EGFR.4,18,19 Bevacizumab is tolerate irinotecan (a chemotherapeutic drug), and was also targeted to the VEGF.20,21 Ramucirumab inhibits VEGF and associated with irinotecan for patients who do not tolerate 57,58 VEGF receptor.22,23 Moreover, for the CD20 target, rituximab, oxaliplatin, irinotecan, and 5-fluorouracil (5-FU). ofatumumab, tositumomab, and ibritumomab tiuxetan24–26 are Some patients present an anaphylactic reaction. A study used. The antibodies trastuzumab, pertuzumab, trastuzumab, has shown that there is a higher incidence of anaphylaxis and emtansine are directed HER2/neu.27–33 The monoclonal in people who have a history of allergies to red meat and 59 antibody that targets the CD33 molecule is gemtuzumab tick bites. Cutaneous reactions are considered severe with ozogamicin.31,34 Alemtuzumab binds to CD52,35,36 while cetuximab. Cytokine release syndrome occurs usually 1 hour brentuximab vedotin is directed at the CD30 molecule.37 after the infusion. This reaction is usually more severe after 60 Ipilimumab binds to the CTLA4 molecule, among others.38,39 the first infusion. Electrolyte disturbances and neutropenia events may be related to the associated chemotherapy using For personal use only. Still under development are monoclonal antibodies directed at new or older potential targets, but are not yet approved for platinum-based compounds. Eye infections such as ulcerative 61 use in patients.18,25,40–43 dermatitis can also occur. Cetuximab has demonstrated benefits only in a small Approved monoclonal antibodies for subset of metastatic patients (KRAS wild-type patients colorectal tumors and patients with limited metastatic disease). Alterna- At present, among biological molecules, a few antibodies tive strategies that demonstrate promising results for have their use approved for the treatment of colorectal tumors the treatment of rectal cancer during stage II/III include (Table 1). The four approved monoclonal antibodies showing short-course radiotherapy with adjuvant chemotherapy and favorable results for use in the treatment of colorectal cancer neoadjuvant FOLFOX (folinic acid, 5-FU, and oxaliplatin)– 62 are bevacizumab, cetuximab, panitumumab, and ramuci- bevacizumab without radiotherapy. rumab, which are detailed in the following section.42,44–46 Drug Design, Development and Therapy downloaded from https://www.dovepress.com/ by 137.108.70.13 on 14-Jan-2020 Panitumumab Cetuximab Panitumumab is a humanized IgG2 kappa antibody with com- Cetuximab is a monoclonal antibody, IgG1 kappa human/ plementary determining regions (CDRs) of murine origin. It is murine chimeric, with constant regions and murine variable directed against the EGFR. When compared with cetuximab, Table 1 Approved antibodies for the treatment of colorectal tumor Monoclonal antibody Therapeutic target Mechanism of action Indication approved (FDA) Bevacizumab VEGF Inhibition of VEGF Colorectal cancer – palliative treatment (humanized IgG1) Cetuximab (humanized/ EGFR (ErbB1) Inhibition of EGFR; ADCC Colorectal cancer – palliative treatment murine chimeric IgG1) Panitumumab EGFR Inhibition of EGFR Metastatic colorectal carcinoma – with EGFR expression Ramucirumab VEGF receptor-2 Blockage of VEGF-A, VEGF-C, mCRC – in combination with FOLFIRI and binding of VEGF-D (irinotecan, folinic acid, and 5-fluorouracil) Abbreviations: ADCC, antibody-dependent cellular cytotoxicity; FDA, US Food and Drug Administration; mCRC, metastatic colorectal cancer. 178 submit your manuscript | www.dovepress.com Drug Design, Development and Therapy 2017:11 Dovepress Powered by TCPDF (www.tcpdf.org) 1 / 1 Dovepress Monoclonal antibodies to colorectal tumors it is a murine
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