Selective activation of interleukin-2/interleukin-15 receptor signaling in tumor microenvironment using paired bispecific antibodies
Background Owing to their roles in promoting T cell and natural killer (NK) cell activation and proliferation, interleukins-2 (IL-2) and interleukins-15 (IL-15) have been pursued as promising pathways to target in cancer immunotherapy. Nonetheless, their wider therapeutic application has been hamper...
Saved in:
| Main Authors: | , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMJ Publishing Group
2025-03-01
|
| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/13/3/e010650.full |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850046860960464896 |
|---|---|
| author | Camilla Jandus Walter Ferlin Sébastien Calloud Alizée Viandier Pauline Malinge Nicolas Fischer Limin Shang Krzysztof Masternak Julien Montorfani Eric Hatterer Laurence Chatel Adeline Lesnier Bruno Daubeuf Lise Nouveau |
| author_facet | Camilla Jandus Walter Ferlin Sébastien Calloud Alizée Viandier Pauline Malinge Nicolas Fischer Limin Shang Krzysztof Masternak Julien Montorfani Eric Hatterer Laurence Chatel Adeline Lesnier Bruno Daubeuf Lise Nouveau |
| author_sort | Camilla Jandus |
| collection | DOAJ |
| description | Background Owing to their roles in promoting T cell and natural killer (NK) cell activation and proliferation, interleukins-2 (IL-2) and interleukins-15 (IL-15) have been pursued as promising pathways to target in cancer immunotherapy. Nonetheless, their wider therapeutic application has been hampered by severe dose-limiting toxicities including systemic cytokine release and organ edema for IL-2, and inconvenient intratumoral administration for IL-15. To address these safety issues, we generated IL-2R/IL-15R×TAA (tumor-associated antigen) bispecific antibody (bsAb) pairs to selectively activate IL-2R signaling in the tumor microenvironment.Methods Each bsAb pair is composed of one bsAb targeting CD122 and a TAA epitope, and the other bsAb targeting CD132 and the same or a different TAA epitope. In vitro assays were performed to characterize the IL-2R/IL-15R agonistic activity of the bsAb pairs, as well as their capacity to enhance T-cell-mediated killing of TAA+ malignant cells. Using a syngeneic mouse tumor model, in vivo biological activity and systemic toxicity of the bsAb pairs were assessed in comparison with IL-2. The in vivo antitumor activity was assessed in combination with an anti-mouse programmed cell death protein 1 (mPD-1) monoclonal antibody.Results We demonstrated with two different TAAs (human epidermal growth factor receptor 2 (HER2) and mesothelin (MSLN)) that the CD122×TAA/CD132×TAA bsAb pairs mediate effective activation of immune cells exclusively in the presence of TAA+ tumor cells. In syngeneic hMSLN-MC38 tumor-bearing mice, the CD122×MSLN-1/CD132×MSLN-2 bsAb pair promotes selective activation and expansion of NK cells and central memory CD8+ T cells inside the tumor without inducing organ edema or systemic cytokine release, two well-known manifestations of IL-2 associated toxicity. In combination with checkpoint inhibitor anti-mPD-1, the bsAb pair boosts the accumulation of CD8+ effector T cells and NK cells, leading to a favorable CD8+ T cell to CD4+ regulatory T cell ratio for a more robust inhibition of tumor growth.Conclusions Overall, the findings suggest that this innovative therapeutic approach effectively leverages the antitumor activity of IL-2 and IL-15 pathways while minimizing their associated systemic toxicities. This dual bsAb format holds potential for broader application in other immune-activating pathways. |
| format | Article |
| id | doaj-art-4f8a8ff0aaef4dd2b4b18aec457a488a |
| institution | DOAJ |
| issn | 2051-1426 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-4f8a8ff0aaef4dd2b4b18aec457a488a2025-08-20T02:54:22ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262025-03-0113310.1136/jitc-2024-010650Selective activation of interleukin-2/interleukin-15 receptor signaling in tumor microenvironment using paired bispecific antibodiesCamilla Jandus0Walter Ferlin1Sébastien Calloud2Alizée Viandier3Pauline Malinge4Nicolas Fischer5Limin Shang6Krzysztof Masternak7Julien Montorfani8Eric Hatterer9Laurence Chatel10Adeline Lesnier11Bruno Daubeuf12Lise Nouveau133 Ludwig Institute for Cancer Research Lausanne branch, Lausanne, Vaud, Switzerland1 Light Chain Bioscience - Novimmune S.A, Plan-Les-Ouates, Geneva, Switzerland1 Light Chain Bioscience - Novimmune S.A, Plan-Les-Ouates, Geneva, Switzerland1 Light Chain Bioscience - Novimmune S.A, Plan-Les-Ouates, Geneva, Switzerland1 Light Chain Bioscience - Novimmune S.A, Plan-Les-Ouates, Geneva, Switzerland1 Light Chain Bioscience - Novimmune S.A, Plan-Les-Ouates, Geneva, Switzerland1 Light Chain Bioscience - Novimmune S.A, Plan-Les-Ouates, Geneva, Switzerland1 Light Chain Bioscience - Novimmune S.A, Plan-Les-Ouates, Geneva, Switzerland1 Light Chain Bioscience - Novimmune S.A, Plan-Les-Ouates, Geneva, Switzerland1 Light Chain Bioscience - Novimmune S.A, Plan-Les-Ouates, Geneva, Switzerland1 Light Chain Bioscience - Novimmune S.A, Plan-Les-Ouates, Geneva, Switzerland1 Light Chain Bioscience - Novimmune S.A, Plan-Les-Ouates, Geneva, Switzerland1 Light Chain Bioscience - Novimmune S.A, Plan-Les-Ouates, Geneva, Switzerland1 Light Chain Bioscience - Novimmune S.A, Plan-Les-Ouates, Geneva, SwitzerlandBackground Owing to their roles in promoting T cell and natural killer (NK) cell activation and proliferation, interleukins-2 (IL-2) and interleukins-15 (IL-15) have been pursued as promising pathways to target in cancer immunotherapy. Nonetheless, their wider therapeutic application has been hampered by severe dose-limiting toxicities including systemic cytokine release and organ edema for IL-2, and inconvenient intratumoral administration for IL-15. To address these safety issues, we generated IL-2R/IL-15R×TAA (tumor-associated antigen) bispecific antibody (bsAb) pairs to selectively activate IL-2R signaling in the tumor microenvironment.Methods Each bsAb pair is composed of one bsAb targeting CD122 and a TAA epitope, and the other bsAb targeting CD132 and the same or a different TAA epitope. In vitro assays were performed to characterize the IL-2R/IL-15R agonistic activity of the bsAb pairs, as well as their capacity to enhance T-cell-mediated killing of TAA+ malignant cells. Using a syngeneic mouse tumor model, in vivo biological activity and systemic toxicity of the bsAb pairs were assessed in comparison with IL-2. The in vivo antitumor activity was assessed in combination with an anti-mouse programmed cell death protein 1 (mPD-1) monoclonal antibody.Results We demonstrated with two different TAAs (human epidermal growth factor receptor 2 (HER2) and mesothelin (MSLN)) that the CD122×TAA/CD132×TAA bsAb pairs mediate effective activation of immune cells exclusively in the presence of TAA+ tumor cells. In syngeneic hMSLN-MC38 tumor-bearing mice, the CD122×MSLN-1/CD132×MSLN-2 bsAb pair promotes selective activation and expansion of NK cells and central memory CD8+ T cells inside the tumor without inducing organ edema or systemic cytokine release, two well-known manifestations of IL-2 associated toxicity. In combination with checkpoint inhibitor anti-mPD-1, the bsAb pair boosts the accumulation of CD8+ effector T cells and NK cells, leading to a favorable CD8+ T cell to CD4+ regulatory T cell ratio for a more robust inhibition of tumor growth.Conclusions Overall, the findings suggest that this innovative therapeutic approach effectively leverages the antitumor activity of IL-2 and IL-15 pathways while minimizing their associated systemic toxicities. This dual bsAb format holds potential for broader application in other immune-activating pathways.https://jitc.bmj.com/content/13/3/e010650.full |
| spellingShingle | Camilla Jandus Walter Ferlin Sébastien Calloud Alizée Viandier Pauline Malinge Nicolas Fischer Limin Shang Krzysztof Masternak Julien Montorfani Eric Hatterer Laurence Chatel Adeline Lesnier Bruno Daubeuf Lise Nouveau Selective activation of interleukin-2/interleukin-15 receptor signaling in tumor microenvironment using paired bispecific antibodies Journal for ImmunoTherapy of Cancer |
| title | Selective activation of interleukin-2/interleukin-15 receptor signaling in tumor microenvironment using paired bispecific antibodies |
| title_full | Selective activation of interleukin-2/interleukin-15 receptor signaling in tumor microenvironment using paired bispecific antibodies |
| title_fullStr | Selective activation of interleukin-2/interleukin-15 receptor signaling in tumor microenvironment using paired bispecific antibodies |
| title_full_unstemmed | Selective activation of interleukin-2/interleukin-15 receptor signaling in tumor microenvironment using paired bispecific antibodies |
| title_short | Selective activation of interleukin-2/interleukin-15 receptor signaling in tumor microenvironment using paired bispecific antibodies |
| title_sort | selective activation of interleukin 2 interleukin 15 receptor signaling in tumor microenvironment using paired bispecific antibodies |
| url | https://jitc.bmj.com/content/13/3/e010650.full |
| work_keys_str_mv | AT camillajandus selectiveactivationofinterleukin2interleukin15receptorsignalingintumormicroenvironmentusingpairedbispecificantibodies AT walterferlin selectiveactivationofinterleukin2interleukin15receptorsignalingintumormicroenvironmentusingpairedbispecificantibodies AT sebastiencalloud selectiveactivationofinterleukin2interleukin15receptorsignalingintumormicroenvironmentusingpairedbispecificantibodies AT alizeeviandier selectiveactivationofinterleukin2interleukin15receptorsignalingintumormicroenvironmentusingpairedbispecificantibodies AT paulinemalinge selectiveactivationofinterleukin2interleukin15receptorsignalingintumormicroenvironmentusingpairedbispecificantibodies AT nicolasfischer selectiveactivationofinterleukin2interleukin15receptorsignalingintumormicroenvironmentusingpairedbispecificantibodies AT liminshang selectiveactivationofinterleukin2interleukin15receptorsignalingintumormicroenvironmentusingpairedbispecificantibodies AT krzysztofmasternak selectiveactivationofinterleukin2interleukin15receptorsignalingintumormicroenvironmentusingpairedbispecificantibodies AT julienmontorfani selectiveactivationofinterleukin2interleukin15receptorsignalingintumormicroenvironmentusingpairedbispecificantibodies AT erichatterer selectiveactivationofinterleukin2interleukin15receptorsignalingintumormicroenvironmentusingpairedbispecificantibodies AT laurencechatel selectiveactivationofinterleukin2interleukin15receptorsignalingintumormicroenvironmentusingpairedbispecificantibodies AT adelinelesnier selectiveactivationofinterleukin2interleukin15receptorsignalingintumormicroenvironmentusingpairedbispecificantibodies AT brunodaubeuf selectiveactivationofinterleukin2interleukin15receptorsignalingintumormicroenvironmentusingpairedbispecificantibodies AT lisenouveau selectiveactivationofinterleukin2interleukin15receptorsignalingintumormicroenvironmentusingpairedbispecificantibodies |