XTX101, a tumor-activated, Fc-enhanced anti-CTLA-4 monoclonal antibody, demonstrates tumor-growth inhibition and tumor-selective pharmacodynamics in mouse models of cancer
Introduction The clinical benefit of the anti-CTLA-4 monoclonal antibody (mAb) ipilimumab has been well established but limited by immune-related adverse events, especially when ipilimumab is used in combination with anti-PD-(L)1 mAb therapy. To overcome these limitations, we have developed XTX101,...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMJ Publishing Group
2023-12-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/11/12/e007785.full |
| _version_ | 1797366022809845760 |
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| author | Zhen Liu Wilson Guzman Parker Johnson Megan McLaughlin Caitlin O’Toole Magali Pederzoli-Ribeil Huawei Qiu Margaret Karow Tim Clackson Jennifer O’Neil Ugur Eskiocak Miso Park Benjamin Nicholson John C Williams Kurt A Jenkins Deborah Moore-Lai Veronica Flesch Ronan C O’Hagan Ulrich Rodeck |
| author_facet | Zhen Liu Wilson Guzman Parker Johnson Megan McLaughlin Caitlin O’Toole Magali Pederzoli-Ribeil Huawei Qiu Margaret Karow Tim Clackson Jennifer O’Neil Ugur Eskiocak Miso Park Benjamin Nicholson John C Williams Kurt A Jenkins Deborah Moore-Lai Veronica Flesch Ronan C O’Hagan Ulrich Rodeck |
| author_sort | Zhen Liu |
| collection | DOAJ |
| description | Introduction The clinical benefit of the anti-CTLA-4 monoclonal antibody (mAb) ipilimumab has been well established but limited by immune-related adverse events, especially when ipilimumab is used in combination with anti-PD-(L)1 mAb therapy. To overcome these limitations, we have developed XTX101, a tumor-activated, Fc-enhanced anti-CTLA-4 mAb.Methods XTX101 consists of an anti-human CTLA-4 mAb covalently linked to masking peptides that block the complementarity-determining regions, thereby minimizing the mAb binding to CTLA-4. The masking peptides are designed to be released by proteases that are typically dysregulated within the tumor microenvironment (TME), resulting in activation of XTX101 intratumorally. Mutations within the Fc region of XTX101 were included to enhance affinity for FcγRIII, which is expected to enhance potency through antibody-dependent cellular cytotoxicity.Results Biophysical, biochemical, and cell-based assays demonstrate that the function of XTX101 depends on proteolytic activation. In human CTLA-4 transgenic mice, XTX101 monotherapy demonstrated significant tumor growth inhibition (TGI) including complete responses, increased intratumoral CD8+T cells, and regulatory T cell depletion within the TME while maintaining minimal pharmacodynamic effects in the periphery. XTX101 in combination with anti-PD-1 mAb treatment resulted in significant TGI and was well tolerated in mice. XTX101 was activated in primary human tumors across a range of tumor types including melanoma, renal cell carcinoma, colon cancer and lung cancer in an ex vivo assay system.Conclusions These data demonstrate that XTX101 retains the full potency of an Fc-enhanced CTLA-4 antagonist within the TME while minimizing the activity in non-tumor tissue, supporting the further evaluation of XTX101 in clinical studies. |
| first_indexed | 2024-03-08T16:58:19Z |
| format | Article |
| id | doaj.art-d160ab0121654c39a0d99d2106b97ef4 |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-03-08T16:58:19Z |
| publishDate | 2023-12-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-d160ab0121654c39a0d99d2106b97ef42024-01-04T19:05:09ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262023-12-01111210.1136/jitc-2023-007785XTX101, a tumor-activated, Fc-enhanced anti-CTLA-4 monoclonal antibody, demonstrates tumor-growth inhibition and tumor-selective pharmacodynamics in mouse models of cancerZhen Liu0Wilson Guzman1Parker Johnson2Megan McLaughlin3Caitlin O’Toole4Magali Pederzoli-Ribeil5Huawei Qiu6Margaret Karow7Tim Clackson8Jennifer O’Neil9Ugur Eskiocak10Miso Park11Benjamin Nicholson12John C Williams13Kurt A Jenkins14Deborah Moore-Lai15Veronica Flesch16Ronan C O’Hagan17Ulrich Rodeck18Xilio Therapeutics, Waltham, Massachusetts, USAXilio Therapeutics, Waltham, Massachusetts, USAXilio Therapeutics, Waltham, Massachusetts, USAXilio Therapeutics, Waltham, Massachusetts, USAXilio Therapeutics, Waltham, Massachusetts, USAXilio Therapeutics, Waltham, Massachusetts, USAXilio Therapeutics, Waltham, Massachusetts, USATentarix Biotherapeutics, San Diego, CA, USAXilio Therapeutics, Waltham, Massachusetts, USAXilio Therapeutics, Waltham, Massachusetts, USAXilio Therapeutics, Waltham, Massachusetts, USAMolecular Medicine, City of Hope National Medical Center, Beckman Research Institute, Duarte, California, USAXilio Therapeutics, Waltham, Massachusetts, USAMolecular Medicine, City of Hope National Medical Center, Beckman Research Institute, Duarte, California, USAXilio Therapeutics, Waltham, Massachusetts, USAXilio Therapeutics, Waltham, Massachusetts, USAMolecular Medicine, City of Hope National Medical Center, Beckman Research Institute, Duarte, California, USAXilio Therapeutics, Waltham, Massachusetts, USADepartment of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USAIntroduction The clinical benefit of the anti-CTLA-4 monoclonal antibody (mAb) ipilimumab has been well established but limited by immune-related adverse events, especially when ipilimumab is used in combination with anti-PD-(L)1 mAb therapy. To overcome these limitations, we have developed XTX101, a tumor-activated, Fc-enhanced anti-CTLA-4 mAb.Methods XTX101 consists of an anti-human CTLA-4 mAb covalently linked to masking peptides that block the complementarity-determining regions, thereby minimizing the mAb binding to CTLA-4. The masking peptides are designed to be released by proteases that are typically dysregulated within the tumor microenvironment (TME), resulting in activation of XTX101 intratumorally. Mutations within the Fc region of XTX101 were included to enhance affinity for FcγRIII, which is expected to enhance potency through antibody-dependent cellular cytotoxicity.Results Biophysical, biochemical, and cell-based assays demonstrate that the function of XTX101 depends on proteolytic activation. In human CTLA-4 transgenic mice, XTX101 monotherapy demonstrated significant tumor growth inhibition (TGI) including complete responses, increased intratumoral CD8+T cells, and regulatory T cell depletion within the TME while maintaining minimal pharmacodynamic effects in the periphery. XTX101 in combination with anti-PD-1 mAb treatment resulted in significant TGI and was well tolerated in mice. XTX101 was activated in primary human tumors across a range of tumor types including melanoma, renal cell carcinoma, colon cancer and lung cancer in an ex vivo assay system.Conclusions These data demonstrate that XTX101 retains the full potency of an Fc-enhanced CTLA-4 antagonist within the TME while minimizing the activity in non-tumor tissue, supporting the further evaluation of XTX101 in clinical studies.https://jitc.bmj.com/content/11/12/e007785.full |
| spellingShingle | Zhen Liu Wilson Guzman Parker Johnson Megan McLaughlin Caitlin O’Toole Magali Pederzoli-Ribeil Huawei Qiu Margaret Karow Tim Clackson Jennifer O’Neil Ugur Eskiocak Miso Park Benjamin Nicholson John C Williams Kurt A Jenkins Deborah Moore-Lai Veronica Flesch Ronan C O’Hagan Ulrich Rodeck XTX101, a tumor-activated, Fc-enhanced anti-CTLA-4 monoclonal antibody, demonstrates tumor-growth inhibition and tumor-selective pharmacodynamics in mouse models of cancer Journal for ImmunoTherapy of Cancer |
| title | XTX101, a tumor-activated, Fc-enhanced anti-CTLA-4 monoclonal antibody, demonstrates tumor-growth inhibition and tumor-selective pharmacodynamics in mouse models of cancer |
| title_full | XTX101, a tumor-activated, Fc-enhanced anti-CTLA-4 monoclonal antibody, demonstrates tumor-growth inhibition and tumor-selective pharmacodynamics in mouse models of cancer |
| title_fullStr | XTX101, a tumor-activated, Fc-enhanced anti-CTLA-4 monoclonal antibody, demonstrates tumor-growth inhibition and tumor-selective pharmacodynamics in mouse models of cancer |
| title_full_unstemmed | XTX101, a tumor-activated, Fc-enhanced anti-CTLA-4 monoclonal antibody, demonstrates tumor-growth inhibition and tumor-selective pharmacodynamics in mouse models of cancer |
| title_short | XTX101, a tumor-activated, Fc-enhanced anti-CTLA-4 monoclonal antibody, demonstrates tumor-growth inhibition and tumor-selective pharmacodynamics in mouse models of cancer |
| title_sort | xtx101 a tumor activated fc enhanced anti ctla 4 monoclonal antibody demonstrates tumor growth inhibition and tumor selective pharmacodynamics in mouse models of cancer |
| url | https://jitc.bmj.com/content/11/12/e007785.full |
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