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      Phage Display Derived Monoclonal Antibodies: From Bench to Bedside

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          Abstract

          Monoclonal antibodies (mAbs) have become one of the most important classes of biopharmaceutical products, and they continue to dominate the universe of biopharmaceutical markets in terms of approval and sales. They are the most profitable single product class, where they represent six of the top ten selling drugs. At the beginning of the 1990s, an in vitro antibody selection technology known as antibody phage display was developed by John McCafferty and Sir. Gregory Winter that enabled the discovery of human antibodies for diverse applications, particularly antibody-based drugs. They created combinatorial antibody libraries on filamentous phage to be utilized for generating antigen specific antibodies in a matter of weeks. Since then, more than 70 phage–derived antibodies entered clinical studies and 14 of them have been approved. These antibodies are indicated for cancer, and non-cancer medical conditions, such as inflammatory, optical, infectious, or immunological diseases. This review will illustrate the utility of phage display as a powerful platform for therapeutic antibodies discovery and describe in detail all the approved mAbs derived from phage display.

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          Most cited references431

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          Vascular Endothelial Growth Factor (VEGF) and Its Receptor (VEGFR) Signaling in Angiogenesis: A Crucial Target for Anti- and Pro-Angiogenic Therapies.

          The vascular endothelial growth factor (VEGF) and its receptor (VEGFR) have been shown to play major roles not only in physiological but also in most pathological angiogenesis, such as cancer. VEGF belongs to the PDGF supergene family characterized by 8 conserved cysteines and functions as a homodimer structure. VEGF-A regulates angiogenesis and vascular permeability by activating 2 receptors, VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk1 in mice). On the other hand, VEGF-C/VEGF-D and their receptor, VEGFR-3 (Flt-4), mainly regulate lymphangiogenesis. The VEGF family includes other interesting variants, one of which is the virally encoded VEGF-E and another is specifically expressed in the venom of the habu snake (Trimeresurus flavoviridis). VEGFRs are distantly related to the PDGFR family; however, they are unique with respect to their structure and signaling system. Unlike members of the PDGFR family that strongly stimulate the PI3K-Akt pathway toward cell proliferation, VEGFR-2, the major signal transducer for angiogenesis, preferentially utilizes the PLCγ-PKC-MAPK pathway for signaling. The VEGF-VEGFR system is an important target for anti-angiogenic therapy in cancer and is also an attractive system for pro-angiogenic therapy in the treatment of neuronal degeneration and ischemic diseases.
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            Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders.

            Vascular endothelial growth factor (VEGF) is a major mediator of angiogenesis associated with tumors and other pathological conditions, including proliferative diabetic retinopathy and age-related macular degeneration. The murine anti-human VEGF monoclonal antibody (muMAb VEGF) A.4.6.1 has been shown to potently suppress angiogenesis and growth in a variety of human tumor cells lines transplanted in nude mice and also to inhibit neovascularization in a primate model of ischemic retinal disease. In this report, we describe the humanization of muMAb VEGF A.4.6.1. by site-directed mutagenesis of a human framework. Not only the residues involved in the six complementarity-determining regions but also several framework residues were changed from human to murine. Humanized anti-VEGF F(ab) and IgG1 variants bind VEGF with affinity very similar to that of the original murine antibody. Furthermore, recombinant humanized MAb VEGF inhibits VEGF-induced proliferation of endothelial cells in vitro and tumor growth in vivo with potency and efficacy very similar to those of muMAb VEGF A.4.6.1. Therefore, recombinant humanized MAb VEGF is suitable to test the hypothesis that inhibition of VEGF-induced angiogenesis is a valid strategy for the treatment of solid tumors and other disorders in humans.
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              Diversity in the CDR3 region of V(H) is sufficient for most antibody specificities.

              J. Xu, M Davis (2000)
              All rearranging antigen receptor genes have one or two highly diverse complementarity determining regions (CDRs) among the six that typically form the ligand binding surface. We report here that, in the case of antibodies, diversity at one of these regions, CDR3 of the V(H) domain, is sufficient to permit otherwise identical IgM molecules to distinguish between a variety of hapten and protein antigens. Furthermore, we find that somatic mutation can allow such antibodies to achieve surprisingly high affinities. These results are consistent with a model in which the highly diverse CDR3 loops are the key determinant of specificity in antigen recognition in both T cell receptors (TCR) and antibodies, whereas the germline-encoded CDR1 and CDR2 sequences are much more cross-reactive.
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                Author and article information

                Contributors
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                28 August 2020
                2020
                : 11
                : 1986
                Affiliations
                [1] 1Faculty of Pharmacy, King Abdulaziz University , Jeddah, Saudi Arabia
                [2] 2Vaccines and Immunotherapy Unit, King Fahd Medical Research Center, King Abdulaziz University , Jeddah, Saudi Arabia
                [3] 3Department of Pharmaceutics and Pharmaceutical Technology, College of Pharmacy, Taif University , Taif, Saudi Arabia
                [4] 4College of Applied Medical Sciences, Taibah University , Medina, Saudi Arabia
                [5] 5Department of Medical Laboratory Technology, University of Tabuk , Tabuk, Saudi Arabia
                [6] 6Australian Institute for Bioengineering and Nanotechnology, The University of Queensland , Brisbane, QLD, Australia
                [7] 7Australian Research Council Training Centre for Biopharmaceutical Innovation, The University of Queensland , Brisbane, QLD, Australia
                [8] 8Department of Medical Microbiology and Parasitology, Faculty of Medicine, King Abdulaziz University , Jeddah, Saudi Arabia
                Author notes

                Edited by: Rajko Reljic, St. George's, University of London, United Kingdom

                Reviewed by: Victor Greiff, University of Oslo, Norway; Fatima Ferreira, University of Salzburg, Austria

                *Correspondence: Anwar M. Hashem amhashem@ 123456kau.edu.sa

                This article was submitted to Vaccines and Molecular Therapeutics, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2020.01986
                7485114
                32983137
                6c1b6a4d-74f0-4cf3-aaca-a7c8a931036a
                Copyright © 2020 Alfaleh, Alsaab, Mahmoud, Alkayyal, Jones, Mahler and Hashem.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 29 May 2020
                : 23 July 2020
                Page count
                Figures: 5, Tables: 2, Equations: 0, References: 569, Pages: 37, Words: 29303
                Categories
                Immunology
                Review

                Immunology
                monoclonal antibodies,phage display,antibody libraries,biopanning,biopharmaceuticals
                Immunology
                monoclonal antibodies, phage display, antibody libraries, biopanning, biopharmaceuticals

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