Enhanced potency of immunotherapy against B‐cell precursor acute lymphoblastic leukemia by combination of an Fc‐engineered CD19 antibody and CD47 blockade
Abstract CD19‐directed immunotherapy has become a cornerstone in the therapy of B‐cell precursor acute lymphoblastic leukemia (BCP‐ALL). CD19‐directed cellular and antibody‐based therapeutics have entered therapy of primary and relapsed disease and contributed to improved outcomes in relapsed diseas...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2024-02-01
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| Series: | HemaSphere |
| Online Access: | https://doi.org/10.1002/hem3.48 |
| _version_ | 1797234781115645952 |
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| author | Denis M. Schewe Fotini Vogiatzi Ira A. Münnich Tobias Zeller Roland Windisch Christian Wichmann Kristina Müller Hilal Bhat Elisa Felix Dimitrios Mougiakakos Heiko Bruns Lennart Lenk Thomas Valerius Andreas Humpe Matthias Peipp Christian Kellner |
| author_facet | Denis M. Schewe Fotini Vogiatzi Ira A. Münnich Tobias Zeller Roland Windisch Christian Wichmann Kristina Müller Hilal Bhat Elisa Felix Dimitrios Mougiakakos Heiko Bruns Lennart Lenk Thomas Valerius Andreas Humpe Matthias Peipp Christian Kellner |
| author_sort | Denis M. Schewe |
| collection | DOAJ |
| description | Abstract CD19‐directed immunotherapy has become a cornerstone in the therapy of B‐cell precursor acute lymphoblastic leukemia (BCP‐ALL). CD19‐directed cellular and antibody‐based therapeutics have entered therapy of primary and relapsed disease and contributed to improved outcomes in relapsed disease and lower therapy toxicity. However, efficacy remains limited in many cases due to a lack of therapy response, short remission phases, or antigen escape. Here, BCP‐ALL cell lines, patient‐derived xenograft (PDX) samples, human macrophages, and an in vivo transplantation model in NOD.Cg‐PrkdcscidIl2rgtm1Wjl/SzJ (NSG) mice were used to examine the therapeutic potency of a CD19 antibody Fc‐engineered for improved effector cell recruitment (CD19‐DE) and antibody‐dependent cellular phagocytosis (ADCP), in combination with a novel modified CD47 antibody (Hu5F9‐IgG2σ). For the in vivo model, only samples refractory to CD19‐DE monotherapy were chosen. Hu5F9‐IgG2σ enhanced ADCP by CD19‐DE in various BCP‐ALL cell line models with varying CD19 surface expression and cytogenetic backgrounds, two of which contained the KMT2A‐AFF1 fusion. Also, the antibody combination was efficient in inducing ADCP by human macrophages in pediatric PDX samples with and adult samples with and without KMT2A‐rearrangement in vitro. In a randomized phase 2‐like PDX trial using seven KMT2A‐rearranged BCP‐ALL samples in NSG mice, the CD19/CD47 antibody combination proved highly efficient. Our findings support that the efficacy of Fc‐engineered CD19 antibodies may be substantially enhanced by a combination with CD47 blockade. This suggests that the combination may be a promising therapy option for BCP‐ALL, especially in relapsed patients and/or patients refractory to CD19‐directed therapy. |
| first_indexed | 2024-03-07T19:48:36Z |
| format | Article |
| id | doaj.art-9fd66e3abc514ac88a3fe38bc7edfa67 |
| institution | Directory Open Access Journal |
| issn | 2572-9241 |
| language | English |
| last_indexed | 2024-04-24T16:37:31Z |
| publishDate | 2024-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | HemaSphere |
| spelling | doaj.art-9fd66e3abc514ac88a3fe38bc7edfa672024-03-29T13:51:20ZengWileyHemaSphere2572-92412024-02-0182n/an/a10.1002/hem3.48Enhanced potency of immunotherapy against B‐cell precursor acute lymphoblastic leukemia by combination of an Fc‐engineered CD19 antibody and CD47 blockadeDenis M. Schewe0Fotini Vogiatzi1Ira A. Münnich2Tobias Zeller3Roland Windisch4Christian Wichmann5Kristina Müller6Hilal Bhat7Elisa Felix8Dimitrios Mougiakakos9Heiko Bruns10Lennart Lenk11Thomas Valerius12Andreas Humpe13Matthias Peipp14Christian Kellner15Medical Faculty Otto‐von‐Guericke University Magdeburg GermanyDepartment of Pediatrics, ALL‐BFM Study Group Christian‐Albrechts University and University Hospital Schleswig‐Holstein Kiel GermanyDivision of Transfusion Medicine, Cell Therapeutics and Haemostaseology LMU University Hospital, LMU Munich Munich GermanyDivision of Transfusion Medicine, Cell Therapeutics and Haemostaseology LMU University Hospital, LMU Munich Munich GermanyDivision of Transfusion Medicine, Cell Therapeutics and Haemostaseology LMU University Hospital, LMU Munich Munich GermanyDivision of Transfusion Medicine, Cell Therapeutics and Haemostaseology LMU University Hospital, LMU Munich Munich GermanyDepartment of Pediatrics, ALL‐BFM Study Group Christian‐Albrechts University and University Hospital Schleswig‐Holstein Kiel GermanyMedical Faculty Otto‐von‐Guericke University Magdeburg GermanyMedical Faculty Otto‐von‐Guericke University Magdeburg GermanyDepartment of Hematology/Oncology Otto‐von‐Guericke University Magdeburg GermanyDepartment of Internal Medicine 5, Hematology and Oncology Friedrich‐Alexander‐University Erlangen‐Nürnberg Erlangen GermanyDepartment of Pediatrics, ALL‐BFM Study Group Christian‐Albrechts University and University Hospital Schleswig‐Holstein Kiel GermanyDivision of Stem Cell Transplantation and Immunotherapy, Department of Medicine II Christian‐Albrechts University and University Hospital Schleswig‐Holstein Kiel GermanyDivision of Transfusion Medicine, Cell Therapeutics and Haemostaseology LMU University Hospital, LMU Munich Munich GermanyDivision of Antibody‐Based Immunotherapy, Department of Medicine II Christian‐Albrechts University and University Hospital Schleswig‐Holstein Kiel GermanyDivision of Transfusion Medicine, Cell Therapeutics and Haemostaseology LMU University Hospital, LMU Munich Munich GermanyAbstract CD19‐directed immunotherapy has become a cornerstone in the therapy of B‐cell precursor acute lymphoblastic leukemia (BCP‐ALL). CD19‐directed cellular and antibody‐based therapeutics have entered therapy of primary and relapsed disease and contributed to improved outcomes in relapsed disease and lower therapy toxicity. However, efficacy remains limited in many cases due to a lack of therapy response, short remission phases, or antigen escape. Here, BCP‐ALL cell lines, patient‐derived xenograft (PDX) samples, human macrophages, and an in vivo transplantation model in NOD.Cg‐PrkdcscidIl2rgtm1Wjl/SzJ (NSG) mice were used to examine the therapeutic potency of a CD19 antibody Fc‐engineered for improved effector cell recruitment (CD19‐DE) and antibody‐dependent cellular phagocytosis (ADCP), in combination with a novel modified CD47 antibody (Hu5F9‐IgG2σ). For the in vivo model, only samples refractory to CD19‐DE monotherapy were chosen. Hu5F9‐IgG2σ enhanced ADCP by CD19‐DE in various BCP‐ALL cell line models with varying CD19 surface expression and cytogenetic backgrounds, two of which contained the KMT2A‐AFF1 fusion. Also, the antibody combination was efficient in inducing ADCP by human macrophages in pediatric PDX samples with and adult samples with and without KMT2A‐rearrangement in vitro. In a randomized phase 2‐like PDX trial using seven KMT2A‐rearranged BCP‐ALL samples in NSG mice, the CD19/CD47 antibody combination proved highly efficient. Our findings support that the efficacy of Fc‐engineered CD19 antibodies may be substantially enhanced by a combination with CD47 blockade. This suggests that the combination may be a promising therapy option for BCP‐ALL, especially in relapsed patients and/or patients refractory to CD19‐directed therapy.https://doi.org/10.1002/hem3.48 |
| spellingShingle | Denis M. Schewe Fotini Vogiatzi Ira A. Münnich Tobias Zeller Roland Windisch Christian Wichmann Kristina Müller Hilal Bhat Elisa Felix Dimitrios Mougiakakos Heiko Bruns Lennart Lenk Thomas Valerius Andreas Humpe Matthias Peipp Christian Kellner Enhanced potency of immunotherapy against B‐cell precursor acute lymphoblastic leukemia by combination of an Fc‐engineered CD19 antibody and CD47 blockade HemaSphere |
| title | Enhanced potency of immunotherapy against B‐cell precursor acute lymphoblastic leukemia by combination of an Fc‐engineered CD19 antibody and CD47 blockade |
| title_full | Enhanced potency of immunotherapy against B‐cell precursor acute lymphoblastic leukemia by combination of an Fc‐engineered CD19 antibody and CD47 blockade |
| title_fullStr | Enhanced potency of immunotherapy against B‐cell precursor acute lymphoblastic leukemia by combination of an Fc‐engineered CD19 antibody and CD47 blockade |
| title_full_unstemmed | Enhanced potency of immunotherapy against B‐cell precursor acute lymphoblastic leukemia by combination of an Fc‐engineered CD19 antibody and CD47 blockade |
| title_short | Enhanced potency of immunotherapy against B‐cell precursor acute lymphoblastic leukemia by combination of an Fc‐engineered CD19 antibody and CD47 blockade |
| title_sort | enhanced potency of immunotherapy against b cell precursor acute lymphoblastic leukemia by combination of an fc engineered cd19 antibody and cd47 blockade |
| url | https://doi.org/10.1002/hem3.48 |
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