Impact of isotype on the mechanism of action of agonist anti-OX40 antibodies in cancer: implications for therapeutic combinations
Background OX40 has been widely studied as a target for immunotherapy with agonist antibodies taken forward into clinical trials for cancer where they are yet to show substantial efficacy. Here, we investigated potential mechanisms of action of anti-mouse (m) OX40 and anti-human (h) OX40 antibodies,...
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2024-07-01
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| Series: | Journal for ImmunoTherapy of Cancer |
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| author | Junping Jing Laura Bover C Ian Mockridge Kerry L Cox Mark S Cragg Tatyana Inzhelevskaya Chris A Penfold Vikki English Jane E Willoughby Hong Shi Peter J Morley Heather Jackson Roopa Srinivasan Tom Murray Axel Hoos Paul Bojczuk James Smothers Niranjan Yanamandra Lang Dou Sabyasachi Bhattacharya Laura Seestaller-Wehr David Kilian Kui S Voo Mel John Heather Niederer Andrew J Shepherd Laura Hook Stephanie Hopley Sara J Brett Christopher Hopson Elaine Paul Stephen L Martin |
| author_facet | Junping Jing Laura Bover C Ian Mockridge Kerry L Cox Mark S Cragg Tatyana Inzhelevskaya Chris A Penfold Vikki English Jane E Willoughby Hong Shi Peter J Morley Heather Jackson Roopa Srinivasan Tom Murray Axel Hoos Paul Bojczuk James Smothers Niranjan Yanamandra Lang Dou Sabyasachi Bhattacharya Laura Seestaller-Wehr David Kilian Kui S Voo Mel John Heather Niederer Andrew J Shepherd Laura Hook Stephanie Hopley Sara J Brett Christopher Hopson Elaine Paul Stephen L Martin |
| author_sort | Junping Jing |
| collection | DOAJ |
| description | Background OX40 has been widely studied as a target for immunotherapy with agonist antibodies taken forward into clinical trials for cancer where they are yet to show substantial efficacy. Here, we investigated potential mechanisms of action of anti-mouse (m) OX40 and anti-human (h) OX40 antibodies, including a clinically relevant monoclonal antibody (mAb) (GSK3174998) and evaluated how isotype can alter those mechanisms with the aim to develop improved antibodies for use in rational combination treatments for cancer.Methods Anti-mOX40 and anti-hOX40 mAbs were evaluated in a number of in vivo models, including an OT-I adoptive transfer immunization model in hOX40 knock-in (KI) mice and syngeneic tumor models. The impact of FcγR engagement was evaluated in hOX40 KI mice deficient for Fc gamma receptors (FcγR). Additionally, combination studies using anti-mouse programmed cell death protein-1 (mPD-1) were assessed. In vitro experiments using peripheral blood mononuclear cells (PBMCs) examining possible anti-hOX40 mAb mechanisms of action were also performed.Results Isotype variants of the clinically relevant mAb GSK3174998 showed immunomodulatory effects that differed in mechanism; mIgG1 mediated direct T-cell agonism while mIgG2a acted indirectly, likely through depletion of regulatory T cells (Tregs) via activating FcγRs. In both the OT-I and EG.7-OVA models, hIgG1 was the most effective human isotype, capable of acting both directly and through Treg depletion. The anti-hOX40 hIgG1 synergized with anti-mPD-1 to improve therapeutic outcomes in the EG.7-OVA model. Finally, in vitro assays with human peripheral blood mononuclear cells (hPBMCs), anti-hOX40 hIgG1 also showed the potential for T-cell stimulation and Treg depletion.Conclusions These findings underline the importance of understanding the role of isotype in the mechanism of action of therapeutic mAbs. As an hIgG1, the anti-hOX40 mAb can elicit multiple mechanisms of action that could aid or hinder therapeutic outcomes, dependent on the microenvironment. This should be considered when designing potential combinatorial partners and their FcγR requirements to achieve maximal benefit and improvement of patient outcomes. |
| format | Article |
| id | doaj-art-1d4a1e220c0f453894379600a08cb4a4 |
| institution | OA Journals |
| issn | 2051-1426 |
| language | English |
| publishDate | 2024-07-01 |
| publisher | BMJ Publishing Group |
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| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-1d4a1e220c0f453894379600a08cb4a42025-08-20T02:02:09ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262024-07-0112710.1136/jitc-2023-008677Impact of isotype on the mechanism of action of agonist anti-OX40 antibodies in cancer: implications for therapeutic combinationsJunping Jing0Laura Bover1C Ian Mockridge2Kerry L Cox3Mark S Cragg4Tatyana Inzhelevskaya5Chris A Penfold6Vikki English7Jane E Willoughby8Hong Shi9Peter J Morley10Heather Jackson11Roopa Srinivasan12Tom Murray13Axel Hoos14Paul Bojczuk15James Smothers16Niranjan Yanamandra17Lang Dou18Sabyasachi Bhattacharya19Laura Seestaller-Wehr20David Kilian21Kui S Voo22Mel John23Heather Niederer24Andrew J Shepherd25Laura Hook26Stephanie Hopley27Sara J Brett28Christopher Hopson29Elaine Paul30Stephen L Martin312 Immuno-Oncology and Combinations RU, GlaxoSmithKline, Collegeville, Pennsylvania, USAThe University of Texas MD Anderson Cancer Center, Houston, TX, USA1 Antibody and Vaccine Group, Centre for Cancer Immunology, Faculty of Medicine, University of Southampton, Southampton, UK1 Antibody and Vaccine Group, Centre for Cancer Immunology, Faculty of Medicine, University of Southampton, Southampton, UK1 Antibody and Vaccine Group, Centre for Cancer Immunology, Faculty of Medicine, University of Southampton, Southampton, UK1 Antibody and Vaccine Group, Centre for Cancer Immunology, Faculty of Medicine, University of Southampton, Southampton, UK1 Antibody and Vaccine Group, Centre for Cancer Immunology, Faculty of Medicine, University of Southampton, Southampton, UK1 Antibody and Vaccine Group, Centre for Cancer Immunology, Faculty of Medicine, University of Southampton, Southampton, UK1 Antibody and Vaccine Group, Centre for Cancer Immunology, Faculty of Medicine, University of Southampton, Southampton, UKDepartment of Anesthesiology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, China8 Immunology Research Unit, GlaxoSmithKline Research & Development Limited, Gunnels Wood Road, Stevenage, UK2 Immuno-Oncology and Combinations RU, GlaxoSmithKline, Collegeville, Pennsylvania, USA2 Immuno-Oncology and Combinations RU, GlaxoSmithKline, Collegeville, Pennsylvania, USA1 Antibody and Vaccine Group, Centre for Cancer Immunology, Faculty of Medicine, University of Southampton, Southampton, UK2 Immuno-Oncology and Combinations RU, GlaxoSmithKline, Collegeville, Pennsylvania, USA2 Immuno-Oncology and Combinations RU, GlaxoSmithKline, Collegeville, Pennsylvania, USA2 Immuno-Oncology and Combinations RU, GlaxoSmithKline, Collegeville, Pennsylvania, USA2 Immuno-Oncology and Combinations RU, GlaxoSmithKline, Collegeville, Pennsylvania, USA1 Antibody and Vaccine Group, Centre for Cancer Immunology, Faculty of Medicine, University of Southampton, Southampton, UK2 Immuno-Oncology and Combinations RU, GlaxoSmithKline, Collegeville, Pennsylvania, USA2 Immuno-Oncology and Combinations RU, GlaxoSmithKline, Collegeville, Pennsylvania, USA2 Immuno-Oncology and Combinations RU, GlaxoSmithKline, Collegeville, Pennsylvania, USA4 ORBIT, Institute of Applied Cancer Science, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA1 Antibody and Vaccine Group, Centre for Cancer Immunology, Faculty of Medicine, University of Southampton, Southampton, UK5 Biopharm Discovery, GlaxoSmithKline Research & Development Limited, Stevenage, UK6 Protein, Cellular and Structural Sciences, GlaxoSmithKline Research & Development Limited, Gunnels Wood Road, Stevenage, UK5 Biopharm Discovery, GlaxoSmithKline Research & Development Limited, Stevenage, UK5 Biopharm Discovery, GlaxoSmithKline Research & Development Limited, Stevenage, UK2 Immuno-Oncology and Combinations RU, GlaxoSmithKline, Collegeville, Pennsylvania, USA2 Immuno-Oncology and Combinations RU, GlaxoSmithKline, Collegeville, Pennsylvania, USA2 Immuno-Oncology and Combinations RU, GlaxoSmithKline, Collegeville, Pennsylvania, USA5 Biopharm Discovery, GlaxoSmithKline Research & Development Limited, Stevenage, UKBackground OX40 has been widely studied as a target for immunotherapy with agonist antibodies taken forward into clinical trials for cancer where they are yet to show substantial efficacy. Here, we investigated potential mechanisms of action of anti-mouse (m) OX40 and anti-human (h) OX40 antibodies, including a clinically relevant monoclonal antibody (mAb) (GSK3174998) and evaluated how isotype can alter those mechanisms with the aim to develop improved antibodies for use in rational combination treatments for cancer.Methods Anti-mOX40 and anti-hOX40 mAbs were evaluated in a number of in vivo models, including an OT-I adoptive transfer immunization model in hOX40 knock-in (KI) mice and syngeneic tumor models. The impact of FcγR engagement was evaluated in hOX40 KI mice deficient for Fc gamma receptors (FcγR). Additionally, combination studies using anti-mouse programmed cell death protein-1 (mPD-1) were assessed. In vitro experiments using peripheral blood mononuclear cells (PBMCs) examining possible anti-hOX40 mAb mechanisms of action were also performed.Results Isotype variants of the clinically relevant mAb GSK3174998 showed immunomodulatory effects that differed in mechanism; mIgG1 mediated direct T-cell agonism while mIgG2a acted indirectly, likely through depletion of regulatory T cells (Tregs) via activating FcγRs. In both the OT-I and EG.7-OVA models, hIgG1 was the most effective human isotype, capable of acting both directly and through Treg depletion. The anti-hOX40 hIgG1 synergized with anti-mPD-1 to improve therapeutic outcomes in the EG.7-OVA model. Finally, in vitro assays with human peripheral blood mononuclear cells (hPBMCs), anti-hOX40 hIgG1 also showed the potential for T-cell stimulation and Treg depletion.Conclusions These findings underline the importance of understanding the role of isotype in the mechanism of action of therapeutic mAbs. As an hIgG1, the anti-hOX40 mAb can elicit multiple mechanisms of action that could aid or hinder therapeutic outcomes, dependent on the microenvironment. This should be considered when designing potential combinatorial partners and their FcγR requirements to achieve maximal benefit and improvement of patient outcomes.https://jitc.bmj.com/content/12/7/e008677.full |
| spellingShingle | Junping Jing Laura Bover C Ian Mockridge Kerry L Cox Mark S Cragg Tatyana Inzhelevskaya Chris A Penfold Vikki English Jane E Willoughby Hong Shi Peter J Morley Heather Jackson Roopa Srinivasan Tom Murray Axel Hoos Paul Bojczuk James Smothers Niranjan Yanamandra Lang Dou Sabyasachi Bhattacharya Laura Seestaller-Wehr David Kilian Kui S Voo Mel John Heather Niederer Andrew J Shepherd Laura Hook Stephanie Hopley Sara J Brett Christopher Hopson Elaine Paul Stephen L Martin Impact of isotype on the mechanism of action of agonist anti-OX40 antibodies in cancer: implications for therapeutic combinations Journal for ImmunoTherapy of Cancer |
| title | Impact of isotype on the mechanism of action of agonist anti-OX40 antibodies in cancer: implications for therapeutic combinations |
| title_full | Impact of isotype on the mechanism of action of agonist anti-OX40 antibodies in cancer: implications for therapeutic combinations |
| title_fullStr | Impact of isotype on the mechanism of action of agonist anti-OX40 antibodies in cancer: implications for therapeutic combinations |
| title_full_unstemmed | Impact of isotype on the mechanism of action of agonist anti-OX40 antibodies in cancer: implications for therapeutic combinations |
| title_short | Impact of isotype on the mechanism of action of agonist anti-OX40 antibodies in cancer: implications for therapeutic combinations |
| title_sort | impact of isotype on the mechanism of action of agonist anti ox40 antibodies in cancer implications for therapeutic combinations |
| url | https://jitc.bmj.com/content/12/7/e008677.full |
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