Role of Fcγ receptors in HER2-targeted breast cancer therapy
Several therapeutic monoclonal antibodies (mAbs), including those targeting epidermal growth factor receptor, human epidermal growth factor receptor 2 (HER2), and CD20, mediate fragment crystallizable gamma receptor (FcγR)–dependent activities as part of their mechanism of action. These activities i...
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2022-01-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/10/1/e003171.full |
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| author | Hope S Rugo Antonino Musolino William J Gradishar Jeffrey L Nordstrom Edwin P Rock Fernanda Arnaldez Mark D Pegram |
| author_facet | Hope S Rugo Antonino Musolino William J Gradishar Jeffrey L Nordstrom Edwin P Rock Fernanda Arnaldez Mark D Pegram |
| author_sort | Hope S Rugo |
| collection | DOAJ |
| description | Several therapeutic monoclonal antibodies (mAbs), including those targeting epidermal growth factor receptor, human epidermal growth factor receptor 2 (HER2), and CD20, mediate fragment crystallizable gamma receptor (FcγR)–dependent activities as part of their mechanism of action. These activities include induction of antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP), which are innate immune mechanisms of cancer cell elimination. FcγRs are distinguished by their affinity for the Fc fragment, cell distribution, and type of immune response they induce. Activating FcγRIIIa (CD16A) on natural killer cells plays a crucial role in mediating ADCC, and activating FcγRIIa (CD32A) and FcγRIIIa on macrophages are important for mediating ADCP. Polymorphisms in FcγRIIIa and FcγRIIa generate variants that bind to the Fc portion of antibodies with different affinities. This results in differential FcγR-mediated activities associated with differential therapeutic outcomes across multiple clinical settings, from early stage to metastatic disease, in patients with HER2+ breast cancer treated with the anti-HER2 mAb trastuzumab. Trastuzumab has, nonetheless, revolutionized HER2+ breast cancer treatment, and several HER2-directed mAbs have been developed using Fc glyco-engineering or Fc protein-engineering to enhance FcγR-mediated functions. An example of an approved anti-HER2 Fc-engineered chimeric mAb is margetuximab, which targets the same epitope as trastuzumab, but features five amino acid substitutions in the IgG 1 Fc domain that were deliberately introduced to increase binding to activating FcγRIIIa and decrease binding to inhibitory FcγRIIb (CD32B). Margetuximab enhances Fc-dependent ADCC in vitro more potently than the combination of pertuzumab (another approved mAb directed against an alternate HER2 epitope) and trastuzumab. Margetuximab administration also enhances HER2-specific B cell and T cell–mediated responses ex vivo in samples from patients treated with prior lines of HER2 antibody-based therapies. Stemming from these observations, a worthwhile future goal in the treatment of HER2+ breast cancer is to promote combinatorial approaches that better eradicate HER2+ cancer cells via enhanced immunological mechanisms. |
| format | Article |
| id | doaj-art-84020c9f8fdf4430910e9aaa577cdc59 |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2022-01-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-84020c9f8fdf4430910e9aaa577cdc592025-02-09T17:55:09ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262022-01-0110110.1136/jitc-2021-003171Role of Fcγ receptors in HER2-targeted breast cancer therapyHope S Rugo0Antonino Musolino1William J Gradishar2Jeffrey L Nordstrom3Edwin P Rock4Fernanda Arnaldez5Mark D Pegram6Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California, USADepartment of Medicine and Surgery, University of Parma, Parma, ItalyDivision of Hematology/Oncology, Northwestern University, Chicago, Illinois, USAMacroGenics, Inc, Rockville, Maryland, USAMacroGenics, Inc, Rockville, Maryland, USAClinical Development, Oncology R&D, AstraZeneca R&D Gaithersburg, Gaithersburg, Maryland, USA1Stanford University School of Medicine, Palo Alto, CA, USASeveral therapeutic monoclonal antibodies (mAbs), including those targeting epidermal growth factor receptor, human epidermal growth factor receptor 2 (HER2), and CD20, mediate fragment crystallizable gamma receptor (FcγR)–dependent activities as part of their mechanism of action. These activities include induction of antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP), which are innate immune mechanisms of cancer cell elimination. FcγRs are distinguished by their affinity for the Fc fragment, cell distribution, and type of immune response they induce. Activating FcγRIIIa (CD16A) on natural killer cells plays a crucial role in mediating ADCC, and activating FcγRIIa (CD32A) and FcγRIIIa on macrophages are important for mediating ADCP. Polymorphisms in FcγRIIIa and FcγRIIa generate variants that bind to the Fc portion of antibodies with different affinities. This results in differential FcγR-mediated activities associated with differential therapeutic outcomes across multiple clinical settings, from early stage to metastatic disease, in patients with HER2+ breast cancer treated with the anti-HER2 mAb trastuzumab. Trastuzumab has, nonetheless, revolutionized HER2+ breast cancer treatment, and several HER2-directed mAbs have been developed using Fc glyco-engineering or Fc protein-engineering to enhance FcγR-mediated functions. An example of an approved anti-HER2 Fc-engineered chimeric mAb is margetuximab, which targets the same epitope as trastuzumab, but features five amino acid substitutions in the IgG 1 Fc domain that were deliberately introduced to increase binding to activating FcγRIIIa and decrease binding to inhibitory FcγRIIb (CD32B). Margetuximab enhances Fc-dependent ADCC in vitro more potently than the combination of pertuzumab (another approved mAb directed against an alternate HER2 epitope) and trastuzumab. Margetuximab administration also enhances HER2-specific B cell and T cell–mediated responses ex vivo in samples from patients treated with prior lines of HER2 antibody-based therapies. Stemming from these observations, a worthwhile future goal in the treatment of HER2+ breast cancer is to promote combinatorial approaches that better eradicate HER2+ cancer cells via enhanced immunological mechanisms.https://jitc.bmj.com/content/10/1/e003171.full |
| spellingShingle | Hope S Rugo Antonino Musolino William J Gradishar Jeffrey L Nordstrom Edwin P Rock Fernanda Arnaldez Mark D Pegram Role of Fcγ receptors in HER2-targeted breast cancer therapy Journal for ImmunoTherapy of Cancer |
| title | Role of Fcγ receptors in HER2-targeted breast cancer therapy |
| title_full | Role of Fcγ receptors in HER2-targeted breast cancer therapy |
| title_fullStr | Role of Fcγ receptors in HER2-targeted breast cancer therapy |
| title_full_unstemmed | Role of Fcγ receptors in HER2-targeted breast cancer therapy |
| title_short | Role of Fcγ receptors in HER2-targeted breast cancer therapy |
| title_sort | role of fcγ receptors in her2 targeted breast cancer therapy |
| url | https://jitc.bmj.com/content/10/1/e003171.full |
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