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      Stimulation of natural killer cells with rhCD137 ligand enhances tumor-targeting antibody efficacy in gastric cancer

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          Abstract

          Although many anticancer agents for gastric cancer have been developed, the prognosis for many patients remains poor. Recently, costimulatory immune molecules that reactivate antitumor immune responses by utilizing the host immune system have attracted attention as new therapeutic strategies. CD137 is a costimulatory molecule that reportedly potentiates the antitumor activity of tumor-targeting monoclonal antibodies (mAbs) by enhancing antibody-dependent cellular cytotoxicity. However, it remains unclear whether CD137 stimulates tumor-regulatory activity in gastric cancer. In this study, we investigated the antitumor effects of CD137 stimulation on gastric cancer cells administered tumor-targeting mAbs. Our results showed that human natural killer (NK) cells were activated by expressing CD137 after encountering trastuzumab-coated gastric cancer cells, and that stimulation of activated NK cells in the presence of trastuzumab and recombinant human CD137 ligand (rhCD137L) enhanced cytotoxicity and release of cytokines (IFN-γ, TNF, granzyme A, or granzyme B) as compared with activated NK cells with trastuzumab alone ( p < 0.05). By combination treatment with rhCD137L, similar effects were obtained regarding cancer cell cytotoxicity in the presence of cetuximab ( p < 0.01). Moreover, we revealed that CD137 expression was dependent upon the affinity between the Fc portion of the antibodies and FcγRIIIa of NK cells based on results indicating that human IgG1 and IgG3 subclasses enhanced CD137 expression ( p < 0.001). These results confirmed that FcγRIIIA polymorphisms (158 V/V) enhanced CD137 expression to a greater degree than 158 F polymorphisms ( p = 0.014). Our results suggested that CD137 stimulation could promote the effects of tumor-targeting mAbs in gastric cancer, and that further investigation of antibody binding affinity and in vivo activities might improve therapeutic strategies related to the treatment of gastric cancer patients.

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          Properties of mouse and human IgG receptors and their contribution to disease models.

          Pierre Bruhns (2012)
          Impressive advances in defining the properties of receptors for the Fc portion of immunoglobulins (FcR) have been made over the past several years. Ligand specificities were systematically analyzed for both human and mouse FcRs that revealed novel receptors for specific IgG subclasses. Expression patterns were redefined using novel specific anti-FcR mAbs that revealed major differences between human and mouse systems. The in vivo roles of IgG receptors have been addressed using specific FcR knockout mice or in mice expressing a single FcR, and have demonstrated a predominant contribution of mouse activating IgG receptors FcγRIII and FcγRIV to models of autoimmunity (eg, arthritis) and allergy (eg, anaphylaxis). Novel blocking mAbs specific for these activating IgG receptors have enabled, for the first time, the investigation of their roles in vivo in wild-type mice. In parallel, the in vivo properties of human FcRs have been reported using transgenic mice and models of inflammatory and allergic reactions, in particular those of human activating IgG receptor FcγRIIA (CD32A). Importantly, these studies led to the identification of specific cell populations responsible for the induction of various inflammatory diseases and have revealed, in particular, the unexpected contribution of neutrophils and monocytes to the induction of anaphylactic shock.
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            Randomized phase III trial of high-dose interleukin-2 versus subcutaneous interleukin-2 and interferon in patients with metastatic renal cell carcinoma.

            Shelly K Weiss, John Clark, Janice Dutcher … (2005)
            The Cytokine Working Group conducted a randomized phase III trial to determine the value of outpatient interleukin-2 (IL-2) and interferon alfa-2b (IFN) relative to high-dose (HD) IL-2 in patients with metastatic renal cell carcinoma. Patients were stratified for bone and liver metastases, primary tumor in place, and Eastern Cooperative Oncology Group performance status 0 or 1 and then randomly assigned to receive either IL-2 (5 MIU/m(2) subcutaneously every 8 hours for three doses on day 1, then daily 5 days/wk for 4 weeks) and IFN (5 MIU/m(2) subcutaneously three times per week for 4 weeks) every 6 weeks or HD IL-2 (600,000 U/kg/dose intravenously every 8 hours on days 1 through 5 and 15 to 19 [maximum 28 doses]) every 12 weeks. One hundred ninety-two patients were enrolled between April 1997 and July 2000. Toxicities were as anticipated for these regimens. The response rate was 23.2% (22 of 95 patients) for HD IL-2 versus 9.9% (nine of 91 patients) for IL-2/IFN (P = .018). Ten patients receiving HD IL-2 were progression-free at 3 years versus three patients receiving IL-2 and IFN (P = .082). The median response durations were 24 and 15 [corrected] months (P = .18) [corrected] and median survivals were 17.5 and 13 months (P = .24). For patients with bone or liver metastases (P = .001) or a primary tumor in place (P = .040), survival was superior with HD IL-2. This randomized phase III trial provides additional evidence that HD IL-2 should remain the preferred therapy for selected patients with metastatic renal cell carcinoma.
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              Establishment of FUT8 knockout Chinese hamster ovary cells: an ideal host cell line for producing completely defucosylated antibodies with enhanced antibody-dependent cellular cytotoxicity.

              Naoko Yamane-Ohnuki, Satoko Kinoshita, Miho Inoue-Urakubo … (2004)
              To generate industrially applicable new host cell lines for antibody production with optimizing antibody-dependent cellular cytotoxicity (ADCC) we disrupted both FUT8 alleles in a Chinese hamster ovary (CHO)/DG44 cell line by sequential homologous recombination. FUT8 encodes an alpha-1,6-fucosyltransferase that catalyzes the transfer of fucose from GDP-fucose to N-acetylglucosamine (GlcNAc) in an alpha-1,6 linkage. FUT8(-/-) cell lines have morphology and growth kinetics similar to those of the parent, and produce completely defucosylated recombinant antibodies. FUT8(-/-)-produced chimeric anti-CD20 IgG1 shows the same level of antigen-binding activity and complement-dependent cytotoxicity (CDC) as the FUT8(+/+)-produced, comparable antibody, Rituxan. In contrast, FUT8(-/-)-produced anti-CD20 IgG1 strongly binds to human Fcgamma-receptor IIIa (FcgammaRIIIa) and dramatically enhances ADCC to approximately 100-fold that of Rituxan. Our results demonstrate that FUT8(-/-) cells are ideal host cell lines to stably produce completely defucosylated high-ADCC antibodies with fixed quality and efficacy for therapeutic use.
              Article 0 comments Cited 140 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Toshihiro Misumi: Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ResourcesRole: SoftwareRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Kazuaki Tanabe:
                ORCID: http://orcid.org/0000-0002-8650-2735
                Role: ConceptualizationRole: Funding acquisition
                Nobuaki Fujikuni: Role: InvestigationRole: Methodology
                Hideki Ohdan: Role: Project administrationRole: Supervision
                Pier Giorgio Petronini: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, CA USA )
                ISSN (Electronic): 1932-6203
                Publication date (Electronic): 15 October 2018
                Publication date Collection: 2018
                Volume: 13
                Issue: 10
                Electronic Location Identifier: e0204880
                Affiliations
                [001]Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
                Universita degli Studi di Parma, ITALY
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                https://orcid.org/http://orcid.org/0000-0002-8650-2735
                Article
                Publisher ID: PONE-D-18-24604
                DOI: 10.1371/journal.pone.0204880
                PMC ID: 6188629
                PubMed ID: 30321186
                SO-VID: 9311fd00-62cc-4794-a7f7-0bfd7dc82b16
                Copyright statement: © 2018 Misumi et al
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 21 August 2018
                Date accepted : 14 September 2018
                Page count
                Figures: 7, Tables: 0, Pages: 19
                Product
                Funding
                The Japan Society for the Promotion of Science (JSPS) KAKENHI (grant No. 25462023) The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Subject: Research Article
                Subject: Biology and life sciences
                Subject: Cell biology
                Subject: Cellular types
                Subject: Animal cells
                Subject: Blood cells
                Subject: White blood cells
                Subject: NK cells
                Subject: Biology and life sciences
                Subject: Cell biology
                Subject: Cellular types
                Subject: Animal cells
                Subject: Immune cells
                Subject: White blood cells
                Subject: NK cells
                Subject: Biology and life sciences
                Subject: Immunology
                Subject: Immune cells
                Subject: White blood cells
                Subject: NK cells
                Subject: Medicine and health sciences
                Subject: Immunology
                Subject: Immune cells
                Subject: White blood cells
                Subject: NK cells
                Subject: Medicine and Health Sciences
                Subject: Oncology
                Subject: Cancers and Neoplasms
                Subject: Gastrointestinal Tumors
                Subject: Gastric Cancer
                Subject: Biology and Life Sciences
                Subject: Toxicology
                Subject: Cytotoxicity
                Subject: Medicine and Health Sciences
                Subject: Pathology and Laboratory Medicine
                Subject: Toxicology
                Subject: Cytotoxicity
                Subject: Biology and Life Sciences
                Subject: Physiology
                Subject: Immune Physiology
                Subject: Cytokines
                Subject: Medicine and Health Sciences
                Subject: Physiology
                Subject: Immune Physiology
                Subject: Cytokines
                Subject: Biology and Life Sciences
                Subject: Immunology
                Subject: Immune System
                Subject: Innate Immune System
                Subject: Cytokines
                Subject: Medicine and Health Sciences
                Subject: Immunology
                Subject: Immune System
                Subject: Innate Immune System
                Subject: Cytokines
                Subject: Biology and Life Sciences
                Subject: Developmental Biology
                Subject: Molecular Development
                Subject: Cytokines
                Subject: Medicine and Health Sciences
                Subject: Oncology
                Subject: Cancer Treatment
                Subject: Research and Analysis Methods
                Subject: Spectrum Analysis Techniques
                Subject: Spectrophotometry
                Subject: Cytophotometry
                Subject: Flow Cytometry
                Subject: Biology and Life Sciences
                Subject: Toxicology
                Subject: Cytotoxicity Assay
                Subject: Medicine and Health Sciences
                Subject: Pathology and Laboratory Medicine
                Subject: Toxicology
                Subject: Cytotoxicity Assay
                Subject: Biology and Life Sciences
                Subject: Physiology
                Subject: Physiological Processes
                Subject: Secretion
                Subject: Medicine and Health Sciences
                Subject: Physiology
                Subject: Physiological Processes
                Subject: Secretion
                Custom metadata
                Data Availability All relevant data are within the manuscript and its Supporting Information files.

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