Effective cancer immunotherapy combining mRNA-encoded bispecific antibodies that induce polyclonal T cell engagement and PD-L1-dependent 4-1BB costimulation
BackgroundImmune checkpoint inhibitors have revolutionized cancer therapy, but many patients fail to respond or develop resistance, often due to reduced T cell activity. Costimulation via 4-1BB has emerged as a promising approach to enhance the effector function of antigen-primed T cells. Bispecific...
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2025-01-01
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| author | Oana Hangiu Oana Hangiu Oana Hangiu Rocío Navarro Susana Frago Laura Rubio-Pérez Laura Rubio-Pérez Laura Rubio-Pérez Antonio Tapia-Galisteo Antonio Tapia-Galisteo Antonio Tapia-Galisteo Laura Díez-Alonso Laura Díez-Alonso Laura Díez-Alonso Marina Gómez-Rosel Marina Gómez-Rosel Marina Gómez-Rosel Noelia Silva-Pilipich Noelia Silva-Pilipich Lucía Vanrell Cristian Smerdou Cristian Smerdou Kenneth A. Howard Laura Sanz Luis Álvarez-Vallina Luis Álvarez-Vallina Luis Álvarez-Vallina Marta Compte |
| author_facet | Oana Hangiu Oana Hangiu Oana Hangiu Rocío Navarro Susana Frago Laura Rubio-Pérez Laura Rubio-Pérez Laura Rubio-Pérez Antonio Tapia-Galisteo Antonio Tapia-Galisteo Antonio Tapia-Galisteo Laura Díez-Alonso Laura Díez-Alonso Laura Díez-Alonso Marina Gómez-Rosel Marina Gómez-Rosel Marina Gómez-Rosel Noelia Silva-Pilipich Noelia Silva-Pilipich Lucía Vanrell Cristian Smerdou Cristian Smerdou Kenneth A. Howard Laura Sanz Luis Álvarez-Vallina Luis Álvarez-Vallina Luis Álvarez-Vallina Marta Compte |
| author_sort | Oana Hangiu |
| collection | DOAJ |
| description | BackgroundImmune checkpoint inhibitors have revolutionized cancer therapy, but many patients fail to respond or develop resistance, often due to reduced T cell activity. Costimulation via 4-1BB has emerged as a promising approach to enhance the effector function of antigen-primed T cells. Bispecific T cell-engaging (TCE) antibodies are an effective way to provide tumor-specific T cell receptor-mediated signaling to tumor-infiltrating lymphocytes. mRNA-based delivery of bispecific antibodies, offer a novel approach to enhance tumor-specific immune responses while minimizing adverse effects.MethodsTwo bispecific antibodies were generated: the EGFR x CD3 TCE antibody (LiTE) and the PD-L1 x 4-1BB costimulatory antibody (LiTCo), which was further fused to a high FcRn albumin variant (Albu-LiTCo). The mRNA encoding these bispecific antibodies contains an N1-methylpseudouridine modified nucleoside and regulatory sequences to ensure proper expression and stability. A series of in vitro assays and cell-based analyses were performed to characterize both antibodies. The in vivo efficacy of the mRNA-encoded bispecific antibodies was evaluated in xenograft tumor models expressing EGFR.ResultsWe investigated the combined effect of two mRNA-encoded Fc-free bispecific antibodies with complementary mechanisms of action: an EGFR-targeting TCE and a half-life extended PD-L1 x 4-1BB costimulatory antibody. The mRNAs encoding both bispecific LiTERNA and Albu-LiTCoRNA, showed similar binding specificity and in vitro function to their protein analogues. Pharmacokinetic studies demonstrated sustained expression of both bispecific antibodies following intravenous administration of the mRNAs formulated using a polymer/lipid-based nanoparticle (LNP) but different pharmacokinetic profiles, shorter for the TCE and longer for the PD-L1 x 4-1BB. When administered as a mRNA-LNP combination (ComboRNA), the growth of EGFR-positive tumors in immunocompetent mice was significantly inhibited, resulting in tumor regression in 20% of cases with no associated toxicity. Histological analysis confirmed increased T cell infiltration in the tumors treated with LITERNA and ComboRNA. Repeated administration resulted in sustained production of bispecific antibodies with different exposure cycles and potent antitumor activity with a favorable safety profile.ConclusionsThese results highlight the potential of combining two mRNA-encoded bispecific antibodies with different mechanisms of action and programmable half-life for cancer immunotherapy. |
| format | Article |
| id | doaj-art-0672d849f30349ecbcacc307964727fc |
| institution | Kabale University |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj-art-0672d849f30349ecbcacc307964727fc2025-01-06T06:59:27ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-01-011510.3389/fimmu.2024.14942061494206Effective cancer immunotherapy combining mRNA-encoded bispecific antibodies that induce polyclonal T cell engagement and PD-L1-dependent 4-1BB costimulationOana Hangiu0Oana Hangiu1Oana Hangiu2Rocío Navarro3Susana Frago4Laura Rubio-Pérez5Laura Rubio-Pérez6Laura Rubio-Pérez7Antonio Tapia-Galisteo8Antonio Tapia-Galisteo9Antonio Tapia-Galisteo10Laura Díez-Alonso11Laura Díez-Alonso12Laura Díez-Alonso13Marina Gómez-Rosel14Marina Gómez-Rosel15Marina Gómez-Rosel16Noelia Silva-Pilipich17Noelia Silva-Pilipich18Lucía Vanrell19Cristian Smerdou20Cristian Smerdou21Kenneth A. Howard22Laura Sanz23Luis Álvarez-Vallina24Luis Álvarez-Vallina25Luis Álvarez-Vallina26Marta Compte27Department of Antibody Engineering, Leadartis SL, Tres Cantos, Madrid, SpainCancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario12 de Octubre (H12O), Madrid, SpainImmuno-Oncology and Immunotherapy Group, Instituto de Investigación Sanitaria 12 de Octubre (imas12), Madrid, SpainDepartment of Antibody Engineering, Leadartis SL, Tres Cantos, Madrid, SpainDepartment of Antibody Engineering, Leadartis SL, Tres Cantos, Madrid, SpainCancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario12 de Octubre (H12O), Madrid, SpainImmuno-Oncology and Immunotherapy Group, Instituto de Investigación Sanitaria 12 de Octubre (imas12), Madrid, SpainH12O-CNIO Cancer Immunotherapy Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), Madrid, SpainCancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario12 de Octubre (H12O), Madrid, SpainImmuno-Oncology and Immunotherapy Group, Instituto de Investigación Sanitaria 12 de Octubre (imas12), Madrid, SpainH12O-CNIO Cancer Immunotherapy Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), Madrid, SpainCancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario12 de Octubre (H12O), Madrid, SpainImmuno-Oncology and Immunotherapy Group, Instituto de Investigación Sanitaria 12 de Octubre (imas12), Madrid, SpainH12O-CNIO Cancer Immunotherapy Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), Madrid, SpainDepartment of Antibody Engineering, Leadartis SL, Tres Cantos, Madrid, SpainCancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario12 de Octubre (H12O), Madrid, SpainImmuno-Oncology and Immunotherapy Group, Instituto de Investigación Sanitaria 12 de Octubre (imas12), Madrid, SpainDivision of DNA and RNA Medicine, CIMA Universidad de Navarra, Pamplona, SpainNavarra Institute for Health Research (IDISNA) and Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, SpainNanogrow Biotech, Montevideo, UruguayDivision of DNA and RNA Medicine, CIMA Universidad de Navarra, Pamplona, SpainNavarra Institute for Health Research (IDISNA) and Cancer Center Clínica Universidad de Navarra (CCUN), Pamplona, SpainInterdisciplinary Nanoscience Center (iNANO), Department of Molecular Biology and Genetics, Aarhus University, Aarhus, DenmarkMolecular Immunology Unit, Biomedical Research Institute Hospital Puerta de Hierro, Majadahonda, Madrid, SpainCancer Immunotherapy Unit (UNICA), Department of Immunology, Hospital Universitario12 de Octubre (H12O), Madrid, SpainImmuno-Oncology and Immunotherapy Group, Instituto de Investigación Sanitaria 12 de Octubre (imas12), Madrid, SpainH12O-CNIO Cancer Immunotherapy Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), Madrid, SpainDepartment of Antibody Engineering, Leadartis SL, Tres Cantos, Madrid, SpainBackgroundImmune checkpoint inhibitors have revolutionized cancer therapy, but many patients fail to respond or develop resistance, often due to reduced T cell activity. Costimulation via 4-1BB has emerged as a promising approach to enhance the effector function of antigen-primed T cells. Bispecific T cell-engaging (TCE) antibodies are an effective way to provide tumor-specific T cell receptor-mediated signaling to tumor-infiltrating lymphocytes. mRNA-based delivery of bispecific antibodies, offer a novel approach to enhance tumor-specific immune responses while minimizing adverse effects.MethodsTwo bispecific antibodies were generated: the EGFR x CD3 TCE antibody (LiTE) and the PD-L1 x 4-1BB costimulatory antibody (LiTCo), which was further fused to a high FcRn albumin variant (Albu-LiTCo). The mRNA encoding these bispecific antibodies contains an N1-methylpseudouridine modified nucleoside and regulatory sequences to ensure proper expression and stability. A series of in vitro assays and cell-based analyses were performed to characterize both antibodies. The in vivo efficacy of the mRNA-encoded bispecific antibodies was evaluated in xenograft tumor models expressing EGFR.ResultsWe investigated the combined effect of two mRNA-encoded Fc-free bispecific antibodies with complementary mechanisms of action: an EGFR-targeting TCE and a half-life extended PD-L1 x 4-1BB costimulatory antibody. The mRNAs encoding both bispecific LiTERNA and Albu-LiTCoRNA, showed similar binding specificity and in vitro function to their protein analogues. Pharmacokinetic studies demonstrated sustained expression of both bispecific antibodies following intravenous administration of the mRNAs formulated using a polymer/lipid-based nanoparticle (LNP) but different pharmacokinetic profiles, shorter for the TCE and longer for the PD-L1 x 4-1BB. When administered as a mRNA-LNP combination (ComboRNA), the growth of EGFR-positive tumors in immunocompetent mice was significantly inhibited, resulting in tumor regression in 20% of cases with no associated toxicity. Histological analysis confirmed increased T cell infiltration in the tumors treated with LITERNA and ComboRNA. Repeated administration resulted in sustained production of bispecific antibodies with different exposure cycles and potent antitumor activity with a favorable safety profile.ConclusionsThese results highlight the potential of combining two mRNA-encoded bispecific antibodies with different mechanisms of action and programmable half-life for cancer immunotherapy.https://www.frontiersin.org/articles/10.3389/fimmu.2024.1494206/fullT-cell engagercostimulatory antibodycancer immunotherapymRNA encoded bispecific antibodiescombined RNA |
| spellingShingle | Oana Hangiu Oana Hangiu Oana Hangiu Rocío Navarro Susana Frago Laura Rubio-Pérez Laura Rubio-Pérez Laura Rubio-Pérez Antonio Tapia-Galisteo Antonio Tapia-Galisteo Antonio Tapia-Galisteo Laura Díez-Alonso Laura Díez-Alonso Laura Díez-Alonso Marina Gómez-Rosel Marina Gómez-Rosel Marina Gómez-Rosel Noelia Silva-Pilipich Noelia Silva-Pilipich Lucía Vanrell Cristian Smerdou Cristian Smerdou Kenneth A. Howard Laura Sanz Luis Álvarez-Vallina Luis Álvarez-Vallina Luis Álvarez-Vallina Marta Compte Effective cancer immunotherapy combining mRNA-encoded bispecific antibodies that induce polyclonal T cell engagement and PD-L1-dependent 4-1BB costimulation Frontiers in Immunology T-cell engager costimulatory antibody cancer immunotherapy mRNA encoded bispecific antibodies combined RNA |
| title | Effective cancer immunotherapy combining mRNA-encoded bispecific antibodies that induce polyclonal T cell engagement and PD-L1-dependent 4-1BB costimulation |
| title_full | Effective cancer immunotherapy combining mRNA-encoded bispecific antibodies that induce polyclonal T cell engagement and PD-L1-dependent 4-1BB costimulation |
| title_fullStr | Effective cancer immunotherapy combining mRNA-encoded bispecific antibodies that induce polyclonal T cell engagement and PD-L1-dependent 4-1BB costimulation |
| title_full_unstemmed | Effective cancer immunotherapy combining mRNA-encoded bispecific antibodies that induce polyclonal T cell engagement and PD-L1-dependent 4-1BB costimulation |
| title_short | Effective cancer immunotherapy combining mRNA-encoded bispecific antibodies that induce polyclonal T cell engagement and PD-L1-dependent 4-1BB costimulation |
| title_sort | effective cancer immunotherapy combining mrna encoded bispecific antibodies that induce polyclonal t cell engagement and pd l1 dependent 4 1bb costimulation |
| topic | T-cell engager costimulatory antibody cancer immunotherapy mRNA encoded bispecific antibodies combined RNA |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1494206/full |
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