Effectorless Fc-fusion improves FLT3L drug-like properties for cancer immunotherapy combinationsResearch in context
Summary: Background: Conventional dendritic cells (cDCs), are central to antitumour immunity, but their low prevalence in tumours limits the efficacy of immunotherapies. FLT3L is a key growth factor regulating cDCs development in the bone marrow. It expands cDCs when administered exogenously, favou...
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Elsevier
2025-08-01
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S235239642500266X |
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| author | Jérémie Decalf Evangeline Toy Dongping He Radhika Kenkre Amy M. Berkley Devon Wong Mandy Kwong Yee-Seir Kee Yue Sun Srividya Myneni Xiangdan Wang Ahmad Ebtikar Anthony Ancheta Yanli Yang Hok Seon Kim Nga Tang Debarko Banerji Elaine Mai Pranay Dogra Meredith McLerie Alan G. Gutierrez Geraldine Strasser Gautham K. Rao Matt Betzenhauser Wilson Phung Peter Day Wendy Sandoval Ayse Meric Ovacik Pamela Chan Shomyseh Sanjabi Laetitia Comps-Agrar Sivan Cohen James A. Ernst Greg A. Lazar Christopher C. Kemball Iraj Hosseini Yichin Liu Jill M. Schartner Travis W. Bainbridge Christine Moussion |
| author_facet | Jérémie Decalf Evangeline Toy Dongping He Radhika Kenkre Amy M. Berkley Devon Wong Mandy Kwong Yee-Seir Kee Yue Sun Srividya Myneni Xiangdan Wang Ahmad Ebtikar Anthony Ancheta Yanli Yang Hok Seon Kim Nga Tang Debarko Banerji Elaine Mai Pranay Dogra Meredith McLerie Alan G. Gutierrez Geraldine Strasser Gautham K. Rao Matt Betzenhauser Wilson Phung Peter Day Wendy Sandoval Ayse Meric Ovacik Pamela Chan Shomyseh Sanjabi Laetitia Comps-Agrar Sivan Cohen James A. Ernst Greg A. Lazar Christopher C. Kemball Iraj Hosseini Yichin Liu Jill M. Schartner Travis W. Bainbridge Christine Moussion |
| author_sort | Jérémie Decalf |
| collection | DOAJ |
| description | Summary: Background: Conventional dendritic cells (cDCs), are central to antitumour immunity, but their low prevalence in tumours limits the efficacy of immunotherapies. FLT3L is a key growth factor regulating cDCs development in the bone marrow. It expands cDCs when administered exogenously, favouring antitumour T cell priming and tumour control. Currently, FLT3L pharmacokinetic (PK) and pharmacodynamic (PD) properties require daily dosing for up to 14 days, which may limit its clinical use. In the present study, we developed and characterised a therapeutic modality named FLT3L-Fc NG2LH. Methods: We improved human FLT3L PK properties by fusing it with a modified fragment crystallisable (Fc) domain of IgG1. To prevent Fc gamma receptor (FcγR) mediated effector function, we engineered an effectorless Fc format called NG2LH, consisting of the aglycosylation substitution N297G, combined with a graft of the lower hinge region of IgG2 onto an otherwise IgG1 Fc. Findings: FLT3L-Fc NG2LH had limited binding to FcγRs and failed to elicit antibody dependent cellular cytotoxicity (ADCC) and cellular phagocytosis (ADCP). PK/PD studies using a mouse effectorless equivalent, mFLT3L-Fc, showed that a single injection of mFLT3L-Fc leads to sustained expansion of cDCs in blood, spleen, and B16F10 tumours. When combined with polyI:C and anti-PD-L1, a single mFLT3L-Fc injection delays the growth of B16F10 tumours and reinvigorates CD8+ T cell immunity. Interpretation: The improved properties of FLT3L-Fc NG2LH are expected to mitigate the practical limitations of FLT3L usage in the clinic, and constitute an asset for future cancer immunotherapy combination regimens leveraging cDC biology in situ. Funding: This work was performed at, and funded by Genentech Inc. South San Francisco, CA 94080, USA. |
| format | Article |
| id | doaj-art-9b71b4e0a8a6441bb7377eeecd7bab97 |
| institution | DOAJ |
| issn | 2352-3964 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj-art-9b71b4e0a8a6441bb7377eeecd7bab972025-08-20T03:04:57ZengElsevierEBioMedicine2352-39642025-08-0111810582210.1016/j.ebiom.2025.105822Effectorless Fc-fusion improves FLT3L drug-like properties for cancer immunotherapy combinationsResearch in contextJérémie Decalf0Evangeline Toy1Dongping He2Radhika Kenkre3Amy M. Berkley4Devon Wong5Mandy Kwong6Yee-Seir Kee7Yue Sun8Srividya Myneni9Xiangdan Wang10Ahmad Ebtikar11Anthony Ancheta12Yanli Yang13Hok Seon Kim14Nga Tang15Debarko Banerji16Elaine Mai17Pranay Dogra18Meredith McLerie19Alan G. Gutierrez20Geraldine Strasser21Gautham K. Rao22Matt Betzenhauser23Wilson Phung24Peter Day25Wendy Sandoval26Ayse Meric Ovacik27Pamela Chan28Shomyseh Sanjabi29Laetitia Comps-Agrar30Sivan Cohen31James A. Ernst32Greg A. Lazar33Christopher C. Kemball34Iraj Hosseini35Yichin Liu36Jill M. Schartner37Travis W. Bainbridge38Christine Moussion39Department of Cancer Immunology, Genentech Inc., South San Francisco, CA, 94080, USADepartment of Translational Oncology, Genentech Inc., South San Francisco, CA, 94080, USADepartment of Biochemical and Cellular Pharmacology, Genentech Inc., South San Francisco, CA, 94080, USADepartment of Pharmacokinetics and Pharmacodynamics, Genentech Inc., South San Francisco, CA, 94080, USADepartment of Translational Oncology, Genentech Inc., South San Francisco, CA, 94080, USADepartment of Biochemical and Cellular Pharmacology, Genentech Inc., South San Francisco, CA, 94080, USADepartment of Biochemical and Cellular Pharmacology, Genentech Inc., South San Francisco, CA, 94080, USADepartment of Antibody Engineering, Genentech Inc., South San Francisco, CA, 94080, USADepartment of Bioanalytical Sciences, Genentech Inc., South San Francisco, CA, 94080, USADepartment of Bioanalytical Sciences, Genentech Inc., South San Francisco, CA, 94080, USADepartment of Bioanalytical Sciences, Genentech Inc., South San Francisco, CA, 94080, USADepartment of Analytical and Quality Control, Genentech Inc., South San Francisco, CA, 94080, USADepartment of Biological Technologies, Genentech Inc., South San Francisco, CA, 94080, USADepartment of Antibody Engineering, Genentech Inc., South San Francisco, CA, 94080, USADepartment of Antibody Engineering, Genentech Inc., South San Francisco, CA, 94080, USADepartment of Biochemical and Cellular Pharmacology, Genentech Inc., South San Francisco, CA, 94080, USADepartment of Biochemical and Cellular Pharmacology, Genentech Inc., South San Francisco, CA, 94080, USADepartment of Biochemical and Cellular Pharmacology, Genentech Inc., South San Francisco, CA, 94080, USADepartment of Oncology Biomarker Development, Genentech Inc., South San Francisco, CA, 94080, USADiscovery Biology, Curia Global Inc., Buffalo, NY, 14203, USADepartment of Cancer Immunology, Genentech Inc., South San Francisco, CA, 94080, USADepartment of Cancer Immunology, Genentech Inc., South San Francisco, CA, 94080, USADepartment of Translational Safety, Genentech Inc., South San Francisco, CA, 94080, USADiscovery Biology, Curia Global Inc., Buffalo, NY, 14203, USADepartment of Microchemistry Proteomic and Lipidomic, Genentech Inc., South San Francisco, CA, 94080, USADepartment of Biological Technologies, Genentech Inc., South San Francisco, CA, 94080, USADiscovery Biology, Curia Global Inc., Buffalo, NY, 14203, USADepartment of Microchemistry Proteomic and Lipidomic, Genentech Inc., South San Francisco, CA, 94080, USADepartment of Biochemical and Cellular Pharmacology, Genentech Inc., South San Francisco, CA, 94080, USADepartment of Oncology Biomarker Development, Genentech Inc., South San Francisco, CA, 94080, USADepartment of Biochemical and Cellular Pharmacology, Genentech Inc., South San Francisco, CA, 94080, USADepartment of Bioanalytical Sciences, Genentech Inc., South San Francisco, CA, 94080, USADepartment of Microchemistry Proteomic and Lipidomic, Genentech Inc., South San Francisco, CA, 94080, USADepartment of Antibody Engineering, Genentech Inc., South San Francisco, CA, 94080, USADepartment of Biochemical and Cellular Pharmacology, Genentech Inc., South San Francisco, CA, 94080, USADepartment of Pharmacokinetics and Pharmacodynamics, Genentech Inc., South San Francisco, CA, 94080, USADepartment of Biochemical and Cellular Pharmacology, Genentech Inc., South San Francisco, CA, 94080, USADepartment of Translational Oncology, Genentech Inc., South San Francisco, CA, 94080, USADepartment of Protein Chemistry, Genentech Inc., South San Francisco, CA, 94080, USA; Corresponding author.Department of Cancer Immunology, Genentech Inc., South San Francisco, CA, 94080, USA; Corresponding author.Summary: Background: Conventional dendritic cells (cDCs), are central to antitumour immunity, but their low prevalence in tumours limits the efficacy of immunotherapies. FLT3L is a key growth factor regulating cDCs development in the bone marrow. It expands cDCs when administered exogenously, favouring antitumour T cell priming and tumour control. Currently, FLT3L pharmacokinetic (PK) and pharmacodynamic (PD) properties require daily dosing for up to 14 days, which may limit its clinical use. In the present study, we developed and characterised a therapeutic modality named FLT3L-Fc NG2LH. Methods: We improved human FLT3L PK properties by fusing it with a modified fragment crystallisable (Fc) domain of IgG1. To prevent Fc gamma receptor (FcγR) mediated effector function, we engineered an effectorless Fc format called NG2LH, consisting of the aglycosylation substitution N297G, combined with a graft of the lower hinge region of IgG2 onto an otherwise IgG1 Fc. Findings: FLT3L-Fc NG2LH had limited binding to FcγRs and failed to elicit antibody dependent cellular cytotoxicity (ADCC) and cellular phagocytosis (ADCP). PK/PD studies using a mouse effectorless equivalent, mFLT3L-Fc, showed that a single injection of mFLT3L-Fc leads to sustained expansion of cDCs in blood, spleen, and B16F10 tumours. When combined with polyI:C and anti-PD-L1, a single mFLT3L-Fc injection delays the growth of B16F10 tumours and reinvigorates CD8+ T cell immunity. Interpretation: The improved properties of FLT3L-Fc NG2LH are expected to mitigate the practical limitations of FLT3L usage in the clinic, and constitute an asset for future cancer immunotherapy combination regimens leveraging cDC biology in situ. Funding: This work was performed at, and funded by Genentech Inc. South San Francisco, CA 94080, USA.http://www.sciencedirect.com/science/article/pii/S235239642500266XDendritic cellsCancer immunotherapyFLT3LInnate immunityAdaptive immunity |
| spellingShingle | Jérémie Decalf Evangeline Toy Dongping He Radhika Kenkre Amy M. Berkley Devon Wong Mandy Kwong Yee-Seir Kee Yue Sun Srividya Myneni Xiangdan Wang Ahmad Ebtikar Anthony Ancheta Yanli Yang Hok Seon Kim Nga Tang Debarko Banerji Elaine Mai Pranay Dogra Meredith McLerie Alan G. Gutierrez Geraldine Strasser Gautham K. Rao Matt Betzenhauser Wilson Phung Peter Day Wendy Sandoval Ayse Meric Ovacik Pamela Chan Shomyseh Sanjabi Laetitia Comps-Agrar Sivan Cohen James A. Ernst Greg A. Lazar Christopher C. Kemball Iraj Hosseini Yichin Liu Jill M. Schartner Travis W. Bainbridge Christine Moussion Effectorless Fc-fusion improves FLT3L drug-like properties for cancer immunotherapy combinationsResearch in context EBioMedicine Dendritic cells Cancer immunotherapy FLT3L Innate immunity Adaptive immunity |
| title | Effectorless Fc-fusion improves FLT3L drug-like properties for cancer immunotherapy combinationsResearch in context |
| title_full | Effectorless Fc-fusion improves FLT3L drug-like properties for cancer immunotherapy combinationsResearch in context |
| title_fullStr | Effectorless Fc-fusion improves FLT3L drug-like properties for cancer immunotherapy combinationsResearch in context |
| title_full_unstemmed | Effectorless Fc-fusion improves FLT3L drug-like properties for cancer immunotherapy combinationsResearch in context |
| title_short | Effectorless Fc-fusion improves FLT3L drug-like properties for cancer immunotherapy combinationsResearch in context |
| title_sort | effectorless fc fusion improves flt3l drug like properties for cancer immunotherapy combinationsresearch in context |
| topic | Dendritic cells Cancer immunotherapy FLT3L Innate immunity Adaptive immunity |
| url | http://www.sciencedirect.com/science/article/pii/S235239642500266X |
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