Targeting RGMb interactions: Discovery and preclinical characterization of potent anti-RGMb antibodies blocking multiple ligand bindings
Therapeutic efficacy with durable responses has been demonstrated with several antibody drugs that block key immune checkpoint receptors, including PD-1, PD-L1, and CTLA-4. Despite the success of these drugs, a substantial proportion of patients do not benefit. Targeting multiple inhibitory pathways...
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2024-12-01
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| Series: | mAbs |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/19420862.2024.2432403 |
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| author | Maria Meira Aurore Frey Neila Chekkat Magda Rybczynska Zaki Sellam Joon Seok Park Francesca Smylie Gazzaniga Alexia Parmentier Marianne Le Gall Gordon James Freeman Dennis Lee Kasper Arlene Helen Sharpe Eric Rambeaux Abdijapar Shamshiev |
| author_facet | Maria Meira Aurore Frey Neila Chekkat Magda Rybczynska Zaki Sellam Joon Seok Park Francesca Smylie Gazzaniga Alexia Parmentier Marianne Le Gall Gordon James Freeman Dennis Lee Kasper Arlene Helen Sharpe Eric Rambeaux Abdijapar Shamshiev |
| author_sort | Maria Meira |
| collection | DOAJ |
| description | Therapeutic efficacy with durable responses has been demonstrated with several antibody drugs that block key immune checkpoint receptors, including PD-1, PD-L1, and CTLA-4. Despite the success of these drugs, a substantial proportion of patients do not benefit. Targeting multiple inhibitory pathways simultaneously to augment anti-tumor immunity has proven to be a promising approach. The emergence of Repulsive Guidance Molecule b (RGMb), a ligand for PD-L2, as a novel co-inhibitory pathway in T cells, together with its regulation by the gut microbiome, encouraged the discovery and development of fully human anti-RGMb antibodies. Here, we describe phage display-derived monoclonal antibodies (mAbs) 2C11 and 5C10 that bind human RGMb with high affinities of 1.4 nM and 0.72 nM, respectively. Both mAbs 2C11 and 5C10 potently inhibited RGMb interaction with PD-L2. MAb 2C11 effectively inhibited RGMb interaction with bone morphogenetic proteins 2 and 4 (BMP2–4), while leaving RGMb interaction with Neogenin 1 (Neo1) unaffected. Conversely, mAb 5C10 disrupted RGMb interaction with Neo1 while maintaining RGMb binding to BMP2–4. These findings map the 2C11 epitope at the membrane-distal N-terminal region of RGMb, which coincides with both PD-L2- and BMP2–4-binding sites. The PD-L2 binding interface is likely positioned between RGMb’s N-terminal BMP-binding and C-terminal Neo1-binding regions. The in vivo activity of mAb 2C11 in combination with anti-PD-1 or anti-PD-L1 was tested in MC38 and B16-OVA cancer models and demonstrated synergistic effects by significantly enhancing anti-tumor responses. These properties make mAb 2C11 a promising candidate for therapeutic use to overcome immune checkpoint inhibitor resistances, warranting further exploration in clinical settings. |
| format | Article |
| id | doaj-art-1d44523d5d454ca5b140916b3cff708f |
| institution | Kabale University |
| issn | 1942-0862 1942-0870 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | mAbs |
| spelling | doaj-art-1d44523d5d454ca5b140916b3cff708f2025-01-31T04:19:37ZengTaylor & Francis GroupmAbs1942-08621942-08702024-12-0116110.1080/19420862.2024.2432403Targeting RGMb interactions: Discovery and preclinical characterization of potent anti-RGMb antibodies blocking multiple ligand bindingsMaria Meira0Aurore Frey1Neila Chekkat2Magda Rybczynska3Zaki Sellam4Joon Seok Park5Francesca Smylie Gazzaniga6Alexia Parmentier7Marianne Le Gall8Gordon James Freeman9Dennis Lee Kasper10Arlene Helen Sharpe11Eric Rambeaux12Abdijapar Shamshiev13R&D Department, IOME Bio SA, Strasbourg, FranceR&D Department, IOME Bio SA, Strasbourg, FranceR&D Department, IOME Bio SA, Strasbourg, FranceR&D Department, IOME Bio SA, Strasbourg, FranceR&D Department, IOME Bio SA, Strasbourg, FranceDepartment of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USADepartment of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USAAntibody Discovery Department, Mabqi, Grabels, FranceAntibody Discovery Department, Mabqi, Grabels, FranceDepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USADepartment of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USADepartment of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USAR&D Department, IOME Bio SA, Strasbourg, FranceR&D Department, IOME Bio SA, Strasbourg, FranceTherapeutic efficacy with durable responses has been demonstrated with several antibody drugs that block key immune checkpoint receptors, including PD-1, PD-L1, and CTLA-4. Despite the success of these drugs, a substantial proportion of patients do not benefit. Targeting multiple inhibitory pathways simultaneously to augment anti-tumor immunity has proven to be a promising approach. The emergence of Repulsive Guidance Molecule b (RGMb), a ligand for PD-L2, as a novel co-inhibitory pathway in T cells, together with its regulation by the gut microbiome, encouraged the discovery and development of fully human anti-RGMb antibodies. Here, we describe phage display-derived monoclonal antibodies (mAbs) 2C11 and 5C10 that bind human RGMb with high affinities of 1.4 nM and 0.72 nM, respectively. Both mAbs 2C11 and 5C10 potently inhibited RGMb interaction with PD-L2. MAb 2C11 effectively inhibited RGMb interaction with bone morphogenetic proteins 2 and 4 (BMP2–4), while leaving RGMb interaction with Neogenin 1 (Neo1) unaffected. Conversely, mAb 5C10 disrupted RGMb interaction with Neo1 while maintaining RGMb binding to BMP2–4. These findings map the 2C11 epitope at the membrane-distal N-terminal region of RGMb, which coincides with both PD-L2- and BMP2–4-binding sites. The PD-L2 binding interface is likely positioned between RGMb’s N-terminal BMP-binding and C-terminal Neo1-binding regions. The in vivo activity of mAb 2C11 in combination with anti-PD-1 or anti-PD-L1 was tested in MC38 and B16-OVA cancer models and demonstrated synergistic effects by significantly enhancing anti-tumor responses. These properties make mAb 2C11 a promising candidate for therapeutic use to overcome immune checkpoint inhibitor resistances, warranting further exploration in clinical settings.https://www.tandfonline.com/doi/10.1080/19420862.2024.2432403Cancer immunotherapyICI resistanceimmune checkpointmonoclonal antibodyRGMb |
| spellingShingle | Maria Meira Aurore Frey Neila Chekkat Magda Rybczynska Zaki Sellam Joon Seok Park Francesca Smylie Gazzaniga Alexia Parmentier Marianne Le Gall Gordon James Freeman Dennis Lee Kasper Arlene Helen Sharpe Eric Rambeaux Abdijapar Shamshiev Targeting RGMb interactions: Discovery and preclinical characterization of potent anti-RGMb antibodies blocking multiple ligand bindings mAbs Cancer immunotherapy ICI resistance immune checkpoint monoclonal antibody RGMb |
| title | Targeting RGMb interactions: Discovery and preclinical characterization of potent anti-RGMb antibodies blocking multiple ligand bindings |
| title_full | Targeting RGMb interactions: Discovery and preclinical characterization of potent anti-RGMb antibodies blocking multiple ligand bindings |
| title_fullStr | Targeting RGMb interactions: Discovery and preclinical characterization of potent anti-RGMb antibodies blocking multiple ligand bindings |
| title_full_unstemmed | Targeting RGMb interactions: Discovery and preclinical characterization of potent anti-RGMb antibodies blocking multiple ligand bindings |
| title_short | Targeting RGMb interactions: Discovery and preclinical characterization of potent anti-RGMb antibodies blocking multiple ligand bindings |
| title_sort | targeting rgmb interactions discovery and preclinical characterization of potent anti rgmb antibodies blocking multiple ligand bindings |
| topic | Cancer immunotherapy ICI resistance immune checkpoint monoclonal antibody RGMb |
| url | https://www.tandfonline.com/doi/10.1080/19420862.2024.2432403 |
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