FcγRIIB engagement drives agonistic activity of Fc-engineered αOX40 antibody to stimulate human tumor-infiltrating T cells
Background OX40 (CD134) is a costimulatory molecule of the tumor necrosis factor receptor superfamily that is currently being investigated as a target for cancer immunotherapy. However, despite promising results in murine tumor models, the clinical efficacy of agonistic αOX40 antibodies in the treat...
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BMJ Publishing Group
2020-10-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/8/2/e000816.full |
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| author | Jie Wei Shahram Salek-Ardakani Wenjing Yang Lucia Campos Carrascosa Adriaan A van Beek Valeska de Ruiter Michail Doukas Timothy S Fisher Keith Ching Karlijn van Loon Patrick P C Boor Yannick S Rakké Lisanne Noordam Pascal Doornebosch Dirk Grünhagen Kees Verhoef Wojciech G Polak Jan N M IJzermans Irene Ni Yik Andy Yeung Dave Sprengers Jaap Kwekkeboom |
| author_facet | Jie Wei Shahram Salek-Ardakani Wenjing Yang Lucia Campos Carrascosa Adriaan A van Beek Valeska de Ruiter Michail Doukas Timothy S Fisher Keith Ching Karlijn van Loon Patrick P C Boor Yannick S Rakké Lisanne Noordam Pascal Doornebosch Dirk Grünhagen Kees Verhoef Wojciech G Polak Jan N M IJzermans Irene Ni Yik Andy Yeung Dave Sprengers Jaap Kwekkeboom |
| author_sort | Jie Wei |
| collection | DOAJ |
| description | Background OX40 (CD134) is a costimulatory molecule of the tumor necrosis factor receptor superfamily that is currently being investigated as a target for cancer immunotherapy. However, despite promising results in murine tumor models, the clinical efficacy of agonistic αOX40 antibodies in the treatment of patients with cancer has fallen short of the high expectation in earlier-stage trials.Methods Using lymphocytes from resected tumor, tumor-free (TF) tissue and peripheral blood mononuclear cells (PBMC) of 96 patients with hepatocellular and colorectal cancers, we determined OX40 expression and the in vitro T-cell agonistic activity of OX40-targeting compounds. RNA-Seq was used to evaluate OX40-mediated transcriptional changes in CD4+ and CD8+ human tumor-infiltrating lymphocytes (TILs).Results Here, we show that OX40 was overexpressed on tumor-infiltrating CD4+ T cells compared with blood and TF tissue-derived T cells. In contrast to a clinical candidate αOX40 antibody, treatment with an Fc-engineered αOX40 antibody (αOX40_v12) with selectively enhanced FcγRIIB affinity, stimulated in vitro CD4+ and CD8+ TIL expansion, as well as cytokine and chemokine secretions. The activity of αOX40_v12 was dependent on FcγRIIB engagement and intrinsic CD3/CD28 signals. The transcriptional landscape of CD4+ and CD8+ TILs shifted toward a prosurvival, inflammatory and chemotactic profile on treatment with αOX40_v12.Conclusions OX40 is overexpressed on CD4+ TILs and thus represents a promising target for immunotherapy. Targeting OX40 with currently used agonistic antibodies may be inefficient due to lack of OX40 multimerization. Thus, Fc engineering is a powerful tool in enhancing the agonistic activity of αOX40 antibody and may shape the future design of antibody-mediated αOX40 immunotherapy. |
| format | Article |
| id | doaj-art-e56e3eb9973e485888dbd8bd5af2b0dc |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2020-10-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-e56e3eb9973e485888dbd8bd5af2b0dc2024-11-10T05:20:08ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262020-10-018210.1136/jitc-2020-000816FcγRIIB engagement drives agonistic activity of Fc-engineered αOX40 antibody to stimulate human tumor-infiltrating T cellsJie Wei0Shahram Salek-Ardakani1Wenjing Yang2Lucia Campos Carrascosa3Adriaan A van Beek4Valeska de Ruiter5Michail Doukas6Timothy S Fisher7Keith Ching8Karlijn van Loon9Patrick P C Boor10Yannick S Rakké11Lisanne Noordam12Pascal Doornebosch13Dirk Grünhagen14Kees Verhoef15Wojciech G Polak16Jan N M IJzermans17Irene Ni18Yik Andy Yeung19Dave Sprengers20Jaap Kwekkeboom21Hunan Key Laboratory of Joint Degeneration and Injury, Xiangya Hospital, Central South University, Changsha, Hunan, ChinaCancer Immunology Discovery, Pfizer Inc, San Diego, California, USAOffice for Cancer Diagnosis and Treatment Quality Control, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People`s Republic of China1 Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, Netherlands1 Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, Netherlands1 Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, Netherlands2 Pathology, Erasmus MC-University Medical Center, Rotterdam, Netherlands3 Pfizer Cancer Immunology Discovery, Pfizer Inc, San Diego, California, USA3 Pfizer Cancer Immunology Discovery, Pfizer Inc, San Diego, California, USA1 Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, NetherlandsDepartment of Gastroenterology and Hepatology, Erasmus MC-University Medical Center Rotterdam, Rotterdam, Netherlands1 Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, Netherlands1 Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, Netherlands4 Surgery, IJsselland Hospital, Capelle aan den IJssel, NetherlandsDepartment of Surgical Oncology and Gastrointestinal Surgery, Erasmus MC, Rotterdam, The Netherlands5 Surgery, Erasmus MC-University Medical Center, Rotterdam, Netherlands6 Department of Surgery, Division of HPB and Transplant Surgery, Erasmus University Medical Center, Rotterdam, The Netherlands1 Erasmus MC Transplant Institute, department of Surgery, division of Hepatobiliary and Transplantation Surgery, University Medical Center Rotterdam, Rotterdam, Zuid-Holland, The Netherlands3 Pfizer Cancer Immunology Discovery, Pfizer Inc, San Diego, California, USAAsher Biotherapeutics, Inc, South San Francisco, CA, USADepartment of Gastroenterology and Hepatology, Erasmus MC-University Medical Center Rotterdam, Rotterdam, Netherlands1 Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, NetherlandsBackground OX40 (CD134) is a costimulatory molecule of the tumor necrosis factor receptor superfamily that is currently being investigated as a target for cancer immunotherapy. However, despite promising results in murine tumor models, the clinical efficacy of agonistic αOX40 antibodies in the treatment of patients with cancer has fallen short of the high expectation in earlier-stage trials.Methods Using lymphocytes from resected tumor, tumor-free (TF) tissue and peripheral blood mononuclear cells (PBMC) of 96 patients with hepatocellular and colorectal cancers, we determined OX40 expression and the in vitro T-cell agonistic activity of OX40-targeting compounds. RNA-Seq was used to evaluate OX40-mediated transcriptional changes in CD4+ and CD8+ human tumor-infiltrating lymphocytes (TILs).Results Here, we show that OX40 was overexpressed on tumor-infiltrating CD4+ T cells compared with blood and TF tissue-derived T cells. In contrast to a clinical candidate αOX40 antibody, treatment with an Fc-engineered αOX40 antibody (αOX40_v12) with selectively enhanced FcγRIIB affinity, stimulated in vitro CD4+ and CD8+ TIL expansion, as well as cytokine and chemokine secretions. The activity of αOX40_v12 was dependent on FcγRIIB engagement and intrinsic CD3/CD28 signals. The transcriptional landscape of CD4+ and CD8+ TILs shifted toward a prosurvival, inflammatory and chemotactic profile on treatment with αOX40_v12.Conclusions OX40 is overexpressed on CD4+ TILs and thus represents a promising target for immunotherapy. Targeting OX40 with currently used agonistic antibodies may be inefficient due to lack of OX40 multimerization. Thus, Fc engineering is a powerful tool in enhancing the agonistic activity of αOX40 antibody and may shape the future design of antibody-mediated αOX40 immunotherapy.https://jitc.bmj.com/content/8/2/e000816.full |
| spellingShingle | Jie Wei Shahram Salek-Ardakani Wenjing Yang Lucia Campos Carrascosa Adriaan A van Beek Valeska de Ruiter Michail Doukas Timothy S Fisher Keith Ching Karlijn van Loon Patrick P C Boor Yannick S Rakké Lisanne Noordam Pascal Doornebosch Dirk Grünhagen Kees Verhoef Wojciech G Polak Jan N M IJzermans Irene Ni Yik Andy Yeung Dave Sprengers Jaap Kwekkeboom FcγRIIB engagement drives agonistic activity of Fc-engineered αOX40 antibody to stimulate human tumor-infiltrating T cells Journal for ImmunoTherapy of Cancer |
| title | FcγRIIB engagement drives agonistic activity of Fc-engineered αOX40 antibody to stimulate human tumor-infiltrating T cells |
| title_full | FcγRIIB engagement drives agonistic activity of Fc-engineered αOX40 antibody to stimulate human tumor-infiltrating T cells |
| title_fullStr | FcγRIIB engagement drives agonistic activity of Fc-engineered αOX40 antibody to stimulate human tumor-infiltrating T cells |
| title_full_unstemmed | FcγRIIB engagement drives agonistic activity of Fc-engineered αOX40 antibody to stimulate human tumor-infiltrating T cells |
| title_short | FcγRIIB engagement drives agonistic activity of Fc-engineered αOX40 antibody to stimulate human tumor-infiltrating T cells |
| title_sort | fcγriib engagement drives agonistic activity of fc engineered αox40 antibody to stimulate human tumor infiltrating t cells |
| url | https://jitc.bmj.com/content/8/2/e000816.full |
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