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      Humanization of fibroblast growth factor 1 single‐chain antibody and validation for its antitumorigenic efficacy in breast cancer and glioma cells

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          Abstract

          Single‐chain variable fragment (scFv) antibodies are the smallest immunoglobulins with high antigen‐binding affinity. We have previously reported that fibroblast growth factor 1 played pivotal roles in cancer development and generated a mouse scFv (mscFv1C9) could effectively prohibit cancer cell proliferation in vitro and in vivo. Here, we further humanized this scFv (hscFv1C9) using a structure‐guided complementarity determining region grafting strategy. The purified hscFv1C9 maintained similar antigen‐binding affinity and specificity as mscFv1C9, and it was capable of inhibiting growth of different tumours in vitro and in vivo. These data strongly suggested that hscFv1C9 has antitumour potentials.

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          Crystal structure of an angiogenesis inhibitor bound to the FGF receptor tyrosine kinase domain.

          Aaron M Hamby, Susan Hubbard, Anna V Eliseenkova … (1998)
          Angiogenesis, the sprouting of new blood vessels from pre-existing ones, is an essential physiological process in development, yet also plays a major role in the progression of human diseases such as diabetic retinopathy, atherosclerosis and cancer. The effects of the most potent angiogenic factors, vascular endothelial growth factor (VEGF), angiopoietin and fibroblast growth factor (FGF) are mediated through cell surface receptors that possess intrinsic protein tyrosine kinase activity. In this report, we describe a synthetic compound of the pyrido[2,3-d]pyrimidine class, designated PD 173074, that selectively inhibits the tyrosine kinase activities of the FGF and VEGF receptors. We show that systemic administration of PD 173074 in mice can effectively block angiogenesis induced by either FGF or VEGF with no apparent toxicity. To elucidate the determinants of selectivity, we have determined the crystal structure of PD 173074 in complex with the tyrosine kinase domain of FGF receptor 1 at 2.5 A resolution. A high degree of surface complementarity between PD 173074 and the hydrophobic, ATP-binding pocket of FGF receptor 1 underlies the potency and selectivity of this inhibitor. PD 173074 is thus a promising candidate for a therapeutic angiogenesis inhibitor to be used in the treatment of cancer and other diseases whose progression is dependent upon new blood vessel formation.
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            Antibody-based targeting of FGFR3 in bladder carcinoma and t(4;14)-positive multiple myeloma in mice.

            Jing Qing, Xiangnan Du, Yongmei Chen … (2009)
            Overexpression of FGF receptor 3 (FGFR3) is implicated in the development of t(4;14)-positive multiple myeloma. While FGFR3 is frequently overexpressed and/or activated through mutations in bladder cancer, the functional importance of FGFR3 and its potential as a specific therapeutic target in this disease have not been elucidated in vivo. Here we report that inducible knockdown of FGFR3 in human bladder carcinoma cells arrested cell-cycle progression in culture and markedly attenuated tumor progression in xenografted mice. Further, we developed a unique antibody (R3Mab) that inhibited not only WT FGFR3, but also various mutants of the receptor, including disulfide-linked cysteine mutants. Biochemical analysis and 2.1-A resolution crystallography revealed that R3Mab bound to a specific FGFR3 epitope that simultaneously blocked ligand binding, prevented receptor dimerization, and induced substantial conformational changes in the receptor. R3Mab exerted potent antitumor activity against bladder carcinoma and t(4;14)-positive multiple myeloma xenografts in mice by antagonizing FGFR3 signaling and eliciting antibody-dependent cell-mediated cytotoxicity (ADCC). These studies provide in vivo evidence demonstrating an oncogenic role of FGFR3 in bladder cancer and support antibody-based targeting of FGFR3 in hematologic and epithelial cancers driven by WT or mutant FGFR3.
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              Humanizing murine IgG3 anti-GD2 antibody m3F8 substantially improves antibody-dependent cell-mediated cytotoxicity while retaining targeting in vivo

              Nai-Kong V. Cheung, Hongfen Guo, Jian Hu … (2012)
              Murine IgG3 anti-GD2 antibody m3F8 has shown anti-neuroblastoma activity in Phase I/II studies, where antibody-dependent cell-mediated cytotoxicity (ADCC) played a key role. Humanization of m3F8 should circumvent human anti-mouse antibody (HAMA) response and enhance its ADCC properties to reduce dosing and pain side effect. Chimeric 3F8 (ch3F8) and humanized 3F8 (hu3F8-IgG1 and hu3F8-IgG4) were produced and purified by protein A affinity chromatography. In vitro comparison was made with m3F8 and other anti-GD2 antibodies in binding, cytotoxicity, and cross-reactivity assays. In GD2 binding studies by SPR, ch3F8 and hu3F8 maintained KD comparable to m3F8. Unlike other anti-GD2 antibodies, m3F8, ch3F8 and hu3F8 had substantially slower koff.. Similar to m3F8, both ch3F8 and hu3F8 inhibited tumor cell growth in vitro, while cross-reactivity with other gangliosides was comparable to that of m3F8. Both peripheral blood mononuclear cell (PBMC)-ADCC and polymorphonuclear leukocytes (PMN)-ADCC of ch3F8 and hu3F8-IgG1 were more potent than m3F8. This superiority was consistently observed in ADCC assays, irrespective of donors or NK-92MI-transfected human CD16 or CD32, whereas complement mediated cytotoxicity (CMC) was reduced. As expected, hu3F8-IgG4 had near absent PBMC-ADCC and CMC. Hu3F8 and m3F8 had similar tumor-to-non tumor ratios in biodistribution studies. Anti-tumor effect against neuroblastoma xenografts was better with hu3F8-IgG1 than m3F8. In conclusion, humanizing m3F8 produced next generation anti-GD2 antibodies with substantially more potent ADCC in vitro and anti-tumor activity in vivo. By leveraging ADCC over CMC, they may be clinically more effective, while minimizing pain and HAMA side effects. A Phase I trial using hu3F8-IgG1 is ongoing.
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                Author and article information

                Contributors
                Qing‐Chuan Zheng: zhengqc@jlu.edu.cn
                Xiao‐Juan Zhu: zhuxj720@nenu.edu.cn
                Journal
                Journal ID (nlm-ta): J Cell Mol Med
                Journal ID (iso-abbrev): J. Cell. Mol. Med
                Journal ID (doi): 10.1111/(ISSN)1582-4934
                Journal ID (publisher-id): JCMM
                Title: Journal of Cellular and Molecular Medicine
                Publisher: John Wiley and Sons Inc. (Hoboken )
                ISSN (Print): 1582-1838
                ISSN (Electronic): 1582-4934
                Publication date (Electronic): 24 March 2018
                Publication date (Print): June 2018
                Volume: 22
                Issue: 6 ( doiID: 10.1111/jcmm.2018.22.issue-6 )
                Pages: 3259-3263
                Affiliations
                [ 1 ] Key Laboratory of Molecular Epigenetics of Ministry of Education Institute of Genetics and Cytology Northeast Normal University Changchun China
                [ 2 ] Department of Hand Surgery China‐Japan Union Hospital of Jilin University Changchun China
                [ 3 ] Laboratory of Theoretical and Computational Chemistry Institute of Theoretical Chemistry Jilin University Changchun China
                Author notes
                [*] [* ] Correspondence

                Xiao‐Juan Zhu and Qing‐Chuan Zheng

                Emails: zhuxj720@ 123456nenu.edu.cn (X‐JZ) and zhengqc@ 123456jlu.edu.cn (Q‐CZ)

                Author information
                http://orcid.org/0000-0002-9455-1182
                Article
                Publisher ID: JCMM13547
                DOI: 10.1111/jcmm.13547
                PMC ID: 5980129
                PubMed ID: 29575613
                SO-VID: d42675f0-ecb5-4a76-91e0-c1f19fee6928
                Copyright © © 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.
                License:

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 14 August 2017
                Date accepted : 19 December 2017
                Page count
                Figures: 2, Tables: 0, Pages: 5, Words: 2440
                Funding
                Funded by: Program of International S and T Cooperation
                Award ID: 2015DFA31580
                Funded by: National Natural Science Foundation of China
                Award ID: 31401192
                Award ID: 31671065
                Award ID: 31601128
                Funded by: Jilin Provincial Key Laboratory of Neural Plasticity
                Award ID: 20160622020JC
                Funded by: Science and Technology Development Plan of Jilin Province
                Award ID: 20160204032GX
                Award ID: 20140203002YY
                Award ID: 20150520031JH
                Categories
                Subject: Short Communication
                Subject: Short Communication
                Custom metadata
                source-schema-version-number 2.0
                component-id jcmm13547
                cover-date June 2018
                details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.4.0 mode:remove_FC converted:31.05.2018

                ScienceOpen disciplines: Molecular medicine
                Keywords: antibody humanization,cancer treatment,fibroblast growth factor 1,monoclonal antibody,single‐chain variable fragment
                Data availability:
                ScienceOpen disciplines: Molecular medicine
                Keywords: antibody humanization, cancer treatment, fibroblast growth factor 1, monoclonal antibody, single‐chain variable fragment

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