Obinutuzumab activates FcγRI more potently than other anti-CD20 antibodies in chronic lymphocytic leukemia (CLL)
Treatment with monoclonal antibodies has revolutionized clinical medicine, especially in the fields of cancer and immunology. One of the oldest antibodies, which is widely used for the treatment of lymphomas and autoimmune diseases, is the anti-CD20 antibody rituximab. In recent years, new antibodie...
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Taylor & Francis Group
2018-06-01
|
| Series: | OncoImmunology |
| Subjects: | |
| Online Access: | http://dx.doi.org/10.1080/2162402X.2018.1428158 |
| _version_ | 1818478185278341120 |
|---|---|
| author | Shlomo Elias Shira Kahlon Rebecca Kotzur Noah Kaynan Ofer Mandelboim |
| author_facet | Shlomo Elias Shira Kahlon Rebecca Kotzur Noah Kaynan Ofer Mandelboim |
| author_sort | Shlomo Elias |
| collection | DOAJ |
| description | Treatment with monoclonal antibodies has revolutionized clinical medicine, especially in the fields of cancer and immunology. One of the oldest antibodies, which is widely used for the treatment of lymphomas and autoimmune diseases, is the anti-CD20 antibody rituximab. In recent years, new antibodies against CD20 have been developed including ofatumumab and obinutuzumab. An important mechanism of action of therapeutic monoclonal antibodies is activation of immune cells via Fc receptors (FcγRs). However, surprisingly, little is known about triggering of FcγRs by different therapeutic antibodies in general and anti-CD20 antibodies in particular. Here we establish a reporter assay to assess whether a particular antibody activates a certain Fc receptor. Using this assay we corroborated previous reports demonstrating obinutuzumab's ability to highly activate FcγRIIIa (CD16a). Importantly, we discovered that obinutuzumab also activates FcγRI (CD64) significantly more than rituximab and ofatumumab in response to chronic lymphocytic leukemia (CLL) cells obtained from patients. Mechanistically we show that this is due to the lack of FcγRIIb-mediated internalization of obinutuzumab following binding to CD20. Moreover, we show that obinutuzumab induces increased phagocytosis by primary macrophages in an FcγRI-dependent manner. Beyond the discovery of a new mechanism of obinutuzumab activity, the reporter assay can be applied to other therapeutic antibodies and may assist in developing antibodies with improved immunological properties. |
| first_indexed | 2024-12-10T09:45:12Z |
| format | Article |
| id | doaj.art-19f4fa8ec319414693ca0e420faa11d6 |
| institution | Directory Open Access Journal |
| issn | 2162-402X |
| language | English |
| last_indexed | 2024-12-10T09:45:12Z |
| publishDate | 2018-06-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | OncoImmunology |
| spelling | doaj.art-19f4fa8ec319414693ca0e420faa11d62022-12-22T01:53:51ZengTaylor & Francis GroupOncoImmunology2162-402X2018-06-017610.1080/2162402X.2018.14281581428158Obinutuzumab activates FcγRI more potently than other anti-CD20 antibodies in chronic lymphocytic leukemia (CLL)Shlomo Elias0Shira Kahlon1Rebecca Kotzur2Noah Kaynan3Ofer Mandelboim4Hadassah – Hebrew University Medical CenterInstitute for Medical Research Israel Canada (IMRIC), Hebrew University-Hadassah Medical SchoolInstitute of Immunogenetics, Hannover Medical SchoolInstitute for Medical Research Israel Canada (IMRIC), Hebrew University-Hadassah Medical SchoolInstitute for Medical Research Israel Canada (IMRIC), Hebrew University-Hadassah Medical SchoolTreatment with monoclonal antibodies has revolutionized clinical medicine, especially in the fields of cancer and immunology. One of the oldest antibodies, which is widely used for the treatment of lymphomas and autoimmune diseases, is the anti-CD20 antibody rituximab. In recent years, new antibodies against CD20 have been developed including ofatumumab and obinutuzumab. An important mechanism of action of therapeutic monoclonal antibodies is activation of immune cells via Fc receptors (FcγRs). However, surprisingly, little is known about triggering of FcγRs by different therapeutic antibodies in general and anti-CD20 antibodies in particular. Here we establish a reporter assay to assess whether a particular antibody activates a certain Fc receptor. Using this assay we corroborated previous reports demonstrating obinutuzumab's ability to highly activate FcγRIIIa (CD16a). Importantly, we discovered that obinutuzumab also activates FcγRI (CD64) significantly more than rituximab and ofatumumab in response to chronic lymphocytic leukemia (CLL) cells obtained from patients. Mechanistically we show that this is due to the lack of FcγRIIb-mediated internalization of obinutuzumab following binding to CD20. Moreover, we show that obinutuzumab induces increased phagocytosis by primary macrophages in an FcγRI-dependent manner. Beyond the discovery of a new mechanism of obinutuzumab activity, the reporter assay can be applied to other therapeutic antibodies and may assist in developing antibodies with improved immunological properties.http://dx.doi.org/10.1080/2162402X.2018.1428158anti-cd20cllfc receptorsobinutuzumabrituximab |
| spellingShingle | Shlomo Elias Shira Kahlon Rebecca Kotzur Noah Kaynan Ofer Mandelboim Obinutuzumab activates FcγRI more potently than other anti-CD20 antibodies in chronic lymphocytic leukemia (CLL) OncoImmunology anti-cd20 cll fc receptors obinutuzumab rituximab |
| title | Obinutuzumab activates FcγRI more potently than other anti-CD20 antibodies in chronic lymphocytic leukemia (CLL) |
| title_full | Obinutuzumab activates FcγRI more potently than other anti-CD20 antibodies in chronic lymphocytic leukemia (CLL) |
| title_fullStr | Obinutuzumab activates FcγRI more potently than other anti-CD20 antibodies in chronic lymphocytic leukemia (CLL) |
| title_full_unstemmed | Obinutuzumab activates FcγRI more potently than other anti-CD20 antibodies in chronic lymphocytic leukemia (CLL) |
| title_short | Obinutuzumab activates FcγRI more potently than other anti-CD20 antibodies in chronic lymphocytic leukemia (CLL) |
| title_sort | obinutuzumab activates fcγri more potently than other anti cd20 antibodies in chronic lymphocytic leukemia cll |
| topic | anti-cd20 cll fc receptors obinutuzumab rituximab |
| url | http://dx.doi.org/10.1080/2162402X.2018.1428158 |
| work_keys_str_mv | AT shlomoelias obinutuzumabactivatesfcgrimorepotentlythanotheranticd20antibodiesinchroniclymphocyticleukemiacll AT shirakahlon obinutuzumabactivatesfcgrimorepotentlythanotheranticd20antibodiesinchroniclymphocyticleukemiacll AT rebeccakotzur obinutuzumabactivatesfcgrimorepotentlythanotheranticd20antibodiesinchroniclymphocyticleukemiacll AT noahkaynan obinutuzumabactivatesfcgrimorepotentlythanotheranticd20antibodiesinchroniclymphocyticleukemiacll AT ofermandelboim obinutuzumabactivatesfcgrimorepotentlythanotheranticd20antibodiesinchroniclymphocyticleukemiacll |