Therapeutically targeting type I interferon directly to XCR1+ dendritic cells reveals the role of cDC1s in anti-drug antibodies
Conventional type 1 dendritic cells (cDC1s) are superior in antigen cross-presentation and priming CD8+ T cell anti-tumor immunity and thus, are a target of high interest for cancer immunotherapy. Type I interferon (IFN) is a potent inducer of antigen cross-presentation, but, unfortunately, shows on...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2023-10-01
|
| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1272055/full |
| _version_ | 1797650800545103872 |
|---|---|
| author | Paul Noe Joy H. Wang Kyu Chung Zhiyong Cheng Jessica J. Field Xiaomeng Shen Christa L. Cortesio Cinthia V. Pastuskovas Hyewon Phee Kristin V. Tarbell Jackson G. Egen Amy-Jo Casbon |
| author_facet | Paul Noe Joy H. Wang Kyu Chung Zhiyong Cheng Jessica J. Field Xiaomeng Shen Christa L. Cortesio Cinthia V. Pastuskovas Hyewon Phee Kristin V. Tarbell Jackson G. Egen Amy-Jo Casbon |
| author_sort | Paul Noe |
| collection | DOAJ |
| description | Conventional type 1 dendritic cells (cDC1s) are superior in antigen cross-presentation and priming CD8+ T cell anti-tumor immunity and thus, are a target of high interest for cancer immunotherapy. Type I interferon (IFN) is a potent inducer of antigen cross-presentation, but, unfortunately, shows only modest results in the clinic given the short half-life and high toxicity of current type I IFN therapies, which limit IFN exposure in the tumor. CD8+ T cell immunity is dependent on IFN signaling in cDC1s and preclinical studies suggest targeting IFN directly to cDC1s may be sufficient to drive anti-tumor immunity. Here, we engineered an anti-XCR1 antibody (Ab) and IFN mutein (IFNmut) fusion protein (XCR1Ab-IFNmut) to determine whether systemic delivery could drive selective and sustained type I IFN signaling in cDC1s leading to anti-tumor activity and, in parallel, reduced systemic toxicity. We found that the XCR1Ab-IFNmut fusion specifically enhanced cDC1 activation in the tumor and spleen compared to an untargeted control IFN. However, multiple treatments with the XCR1Ab-IFNmut fusion resulted in robust anti-drug antibodies (ADA) and loss of drug exposure. Using other cDC1-targeting Ab-IFNmut fusions, we found that localizing IFN directly to cDC1s activates their ability to promote ADA responses, regardless of the cDC1 targeting antigen. The development of ADA remains a major hurdle in immunotherapy drug development and the cellular and molecular mechanisms governing the development of ADA responses in humans is not well understood. Our results reveal a role of cDC1s in ADA generation and highlight the potential ADA challenges with targeting immunostimulatory agents to this cellular compartment. |
| first_indexed | 2024-03-11T16:06:51Z |
| format | Article |
| id | doaj.art-03541fea0c654008afc71aef6450c703 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-03-11T16:06:51Z |
| publishDate | 2023-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-03541fea0c654008afc71aef6450c7032023-10-24T22:01:05ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-10-011410.3389/fimmu.2023.12720551272055Therapeutically targeting type I interferon directly to XCR1+ dendritic cells reveals the role of cDC1s in anti-drug antibodiesPaul Noe0Joy H. Wang1Kyu Chung2Zhiyong Cheng3Jessica J. Field4Xiaomeng Shen5Christa L. Cortesio6Cinthia V. Pastuskovas7Hyewon Phee8Kristin V. Tarbell9Jackson G. Egen10Amy-Jo Casbon11Oncology Research, Amgen Research, South San Francisco, CA, United StatesOncology Research, Amgen Research, South San Francisco, CA, United StatesOncology Research, Amgen Research, South San Francisco, CA, United StatesOncology Research, Amgen Research, South San Francisco, CA, United StatesPharmacokinetics and Drug Metabolism, Amgen Research, South San Francisco, CA, United StatesPharmacokinetics and Drug Metabolism, Amgen Research, South San Francisco, CA, United StatesTherapeutics Discovery, Amgen Research, South San Francisco, CA, United StatesPharmacokinetics and Drug Metabolism, Amgen Research, South San Francisco, CA, United StatesOncology Research, Amgen Research, South San Francisco, CA, United StatesOncology Research, Amgen Research, South San Francisco, CA, United StatesOncology Research, Amgen Research, South San Francisco, CA, United StatesOncology Research, Amgen Research, South San Francisco, CA, United StatesConventional type 1 dendritic cells (cDC1s) are superior in antigen cross-presentation and priming CD8+ T cell anti-tumor immunity and thus, are a target of high interest for cancer immunotherapy. Type I interferon (IFN) is a potent inducer of antigen cross-presentation, but, unfortunately, shows only modest results in the clinic given the short half-life and high toxicity of current type I IFN therapies, which limit IFN exposure in the tumor. CD8+ T cell immunity is dependent on IFN signaling in cDC1s and preclinical studies suggest targeting IFN directly to cDC1s may be sufficient to drive anti-tumor immunity. Here, we engineered an anti-XCR1 antibody (Ab) and IFN mutein (IFNmut) fusion protein (XCR1Ab-IFNmut) to determine whether systemic delivery could drive selective and sustained type I IFN signaling in cDC1s leading to anti-tumor activity and, in parallel, reduced systemic toxicity. We found that the XCR1Ab-IFNmut fusion specifically enhanced cDC1 activation in the tumor and spleen compared to an untargeted control IFN. However, multiple treatments with the XCR1Ab-IFNmut fusion resulted in robust anti-drug antibodies (ADA) and loss of drug exposure. Using other cDC1-targeting Ab-IFNmut fusions, we found that localizing IFN directly to cDC1s activates their ability to promote ADA responses, regardless of the cDC1 targeting antigen. The development of ADA remains a major hurdle in immunotherapy drug development and the cellular and molecular mechanisms governing the development of ADA responses in humans is not well understood. Our results reveal a role of cDC1s in ADA generation and highlight the potential ADA challenges with targeting immunostimulatory agents to this cellular compartment.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1272055/fullimmunogenicityinterferonimmunotherapydendritic cellsconventional type I DCsantibody IFN fusion |
| spellingShingle | Paul Noe Joy H. Wang Kyu Chung Zhiyong Cheng Jessica J. Field Xiaomeng Shen Christa L. Cortesio Cinthia V. Pastuskovas Hyewon Phee Kristin V. Tarbell Jackson G. Egen Amy-Jo Casbon Therapeutically targeting type I interferon directly to XCR1+ dendritic cells reveals the role of cDC1s in anti-drug antibodies Frontiers in Immunology immunogenicity interferon immunotherapy dendritic cells conventional type I DCs antibody IFN fusion |
| title | Therapeutically targeting type I interferon directly to XCR1+ dendritic cells reveals the role of cDC1s in anti-drug antibodies |
| title_full | Therapeutically targeting type I interferon directly to XCR1+ dendritic cells reveals the role of cDC1s in anti-drug antibodies |
| title_fullStr | Therapeutically targeting type I interferon directly to XCR1+ dendritic cells reveals the role of cDC1s in anti-drug antibodies |
| title_full_unstemmed | Therapeutically targeting type I interferon directly to XCR1+ dendritic cells reveals the role of cDC1s in anti-drug antibodies |
| title_short | Therapeutically targeting type I interferon directly to XCR1+ dendritic cells reveals the role of cDC1s in anti-drug antibodies |
| title_sort | therapeutically targeting type i interferon directly to xcr1 dendritic cells reveals the role of cdc1s in anti drug antibodies |
| topic | immunogenicity interferon immunotherapy dendritic cells conventional type I DCs antibody IFN fusion |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1272055/full |
| work_keys_str_mv | AT paulnoe therapeuticallytargetingtypeiinterferondirectlytoxcr1dendriticcellsrevealstheroleofcdc1sinantidrugantibodies AT joyhwang therapeuticallytargetingtypeiinterferondirectlytoxcr1dendriticcellsrevealstheroleofcdc1sinantidrugantibodies AT kyuchung therapeuticallytargetingtypeiinterferondirectlytoxcr1dendriticcellsrevealstheroleofcdc1sinantidrugantibodies AT zhiyongcheng therapeuticallytargetingtypeiinterferondirectlytoxcr1dendriticcellsrevealstheroleofcdc1sinantidrugantibodies AT jessicajfield therapeuticallytargetingtypeiinterferondirectlytoxcr1dendriticcellsrevealstheroleofcdc1sinantidrugantibodies AT xiaomengshen therapeuticallytargetingtypeiinterferondirectlytoxcr1dendriticcellsrevealstheroleofcdc1sinantidrugantibodies AT christalcortesio therapeuticallytargetingtypeiinterferondirectlytoxcr1dendriticcellsrevealstheroleofcdc1sinantidrugantibodies AT cinthiavpastuskovas therapeuticallytargetingtypeiinterferondirectlytoxcr1dendriticcellsrevealstheroleofcdc1sinantidrugantibodies AT hyewonphee therapeuticallytargetingtypeiinterferondirectlytoxcr1dendriticcellsrevealstheroleofcdc1sinantidrugantibodies AT kristinvtarbell therapeuticallytargetingtypeiinterferondirectlytoxcr1dendriticcellsrevealstheroleofcdc1sinantidrugantibodies AT jacksongegen therapeuticallytargetingtypeiinterferondirectlytoxcr1dendriticcellsrevealstheroleofcdc1sinantidrugantibodies AT amyjocasbon therapeuticallytargetingtypeiinterferondirectlytoxcr1dendriticcellsrevealstheroleofcdc1sinantidrugantibodies |