A novel IgG-based FLT3xCD3 bispecific antibody for the treatment of AML and B-ALL
Background In lymphoid malignancies, the introduction of chimeric antigen receptor T (CAR-T) cells and bispecific antibodies (bsAbs) has achieved remarkable clinical success. However, such immunotherapeutic strategies are not yet established for acute myeloid leukemia (AML), the most common form of...
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BMJ Publishing Group
2022-03-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/10/3/e003882.full |
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| author | Melanie Märklin Gundram Jung Jonas S Heitmann Joseph Kauer Helmut R Salih Stefanie Mueller Bochong Li Latifa Zekri Naveen K Mehta Martin Pfluegler Kristan Meetze Isabelle Sindel Fabian Vogt Lukas Osburg Hans-Jörg Bühring Sebastian Hörner Patrick A Baeuerle Jennifer S Michaelson |
| author_facet | Melanie Märklin Gundram Jung Jonas S Heitmann Joseph Kauer Helmut R Salih Stefanie Mueller Bochong Li Latifa Zekri Naveen K Mehta Martin Pfluegler Kristan Meetze Isabelle Sindel Fabian Vogt Lukas Osburg Hans-Jörg Bühring Sebastian Hörner Patrick A Baeuerle Jennifer S Michaelson |
| author_sort | Melanie Märklin |
| collection | DOAJ |
| description | Background In lymphoid malignancies, the introduction of chimeric antigen receptor T (CAR-T) cells and bispecific antibodies (bsAbs) has achieved remarkable clinical success. However, such immunotherapeutic strategies are not yet established for acute myeloid leukemia (AML), the most common form of acute leukemia in adults. Common targets in AML such as CD33, CD123, and CLEC12A are highly expressed on both AML blasts and on normal myeloid cells and hematopoietic stem cells (HSCs), thereby raising toxicity concerns. In B-cell acute lymphoblastic leukemia (B-ALL), bsAbs and CAR-T therapy targeting CD19 and CD22 have demonstrated clinical success, but resistance via antigen loss is common, motivating the development of agents focused on alternative targets. An attractive emerging target is FLT3, a proto-oncogene expressed in both AML and B-ALL, with low and limited expression on myeloid dendritic cells and HSCs.Methods We developed and characterized CLN-049, a T cell-activating bsAb targeting CD3 and FLT3, constructed as an IgG heavy chain/scFv fusion. CLN-049 binds the membrane proximal extracellular domain of the FLT3 protein tyrosine kinase, which facilitates the targeting of leukemic blasts regardless of FLT3 mutational status. CLN-049 was evaluated for preclinical safety and efficacy in vitro and in vivo.Results CLN-049 induced target-restricted activation of CD4+ and CD8+ T cells. AML cell lines expressing a broad range of surface levels of FLT3 were efficiently lysed on treatment with subnanomolar concentrations of CLN-049, whereas FLT3-expressing hematopoietic progenitor cells and dendritic cells were not sensitive to CLN-049 killing. Treatment with CLN-049 also induced lysis of AML and B-ALL patient blasts by autologous T cells at the low effector-to-target ratios typically observed in patients with overt disease. Lysis of leukemic cells was not affected by supraphysiological levels of soluble FLT3 or FLT3 ligand. In mouse xenograft models, CLN-049 was highly active against human leukemic cell lines and patient-derived AML and B-ALL blasts.Conclusions CLN-049 has a favorable efficacy and safety profile in preclinical models, warranting evaluation of its antileukemic activity in the clinic. |
| format | Article |
| id | doaj-art-3b2e9606c0a24dee884cff6451dd74fe |
| institution | DOAJ |
| issn | 2051-1426 |
| language | English |
| publishDate | 2022-03-01 |
| publisher | BMJ Publishing Group |
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| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-3b2e9606c0a24dee884cff6451dd74fe2025-08-20T03:05:14ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262022-03-0110310.1136/jitc-2021-003882A novel IgG-based FLT3xCD3 bispecific antibody for the treatment of AML and B-ALLMelanie Märklin0Gundram Jung1Jonas S Heitmann2Joseph Kauer3Helmut R Salih4Stefanie Mueller5Bochong Li6Latifa Zekri7Naveen K Mehta8Martin Pfluegler9Kristan Meetze10Isabelle Sindel11Fabian Vogt12Lukas Osburg13Hans-Jörg Bühring14Sebastian Hörner15Patrick A Baeuerle16Jennifer S Michaelson17Cluster of Excellence iFIT (EXC 2180) Image-Guided and Functionally Instructed Tumor Therapies, University of Tübingen, Tübingen, Germany2Cluster of Excellence iFIT (EXC2180) ‘Image-Guided and Functionally Instructed Tumor Therapies’, University of Tübingen, Tübingen, Baden-Württemberg, Germany2Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Tübingen, Baden-Württemberg, Germany1 Heidelberg University Hospital Department of Hematology Oncology and Rheumatology, Heidelberg, Germany1Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, Tübingen, Baden-Württemberg, GermanyClinical Collaboration Unit Translational Immunology, University Hospitals Tubingen, Tubingen, GermanyCullinan Oncology Inc, Cambridge, Massachusetts, USA1Cluster of Excellence iFIT (EXC2180) ‘Image-Guided and Functionally Instructed Tumor Therapies’, University of Tübingen, Tübingen, Baden-Württemberg, GermanyCullinan Oncology Inc, Cambridge, Massachusetts, USAImmunology, Eberhard Karls Universitat Tubingen, Tubingen, GermanyCullinan Florentine Corp, Cambridge, Massachusetts, USAImmunology, Eberhard Karls Universitat Tubingen, Tubingen, GermanyImmunology, Eberhard Karls Universitat Tubingen, Tubingen, GermanyImmunology, Eberhard Karls Universitat Tubingen, Tubingen, GermanyInternal Medicine, Eberhard Karls Universitat Tubingen, Tubingen, Germany1Cluster of Excellence iFIT (EXC2180) ‘Image-Guided and Functionally Instructed Tumor Therapies’, University of Tübingen, Tübingen, Baden-Württemberg, GermanyCullinan Oncology Inc, Cambridge, Massachusetts, USA6Cullinan Oncology, Cambridge, MA, USABackground In lymphoid malignancies, the introduction of chimeric antigen receptor T (CAR-T) cells and bispecific antibodies (bsAbs) has achieved remarkable clinical success. However, such immunotherapeutic strategies are not yet established for acute myeloid leukemia (AML), the most common form of acute leukemia in adults. Common targets in AML such as CD33, CD123, and CLEC12A are highly expressed on both AML blasts and on normal myeloid cells and hematopoietic stem cells (HSCs), thereby raising toxicity concerns. In B-cell acute lymphoblastic leukemia (B-ALL), bsAbs and CAR-T therapy targeting CD19 and CD22 have demonstrated clinical success, but resistance via antigen loss is common, motivating the development of agents focused on alternative targets. An attractive emerging target is FLT3, a proto-oncogene expressed in both AML and B-ALL, with low and limited expression on myeloid dendritic cells and HSCs.Methods We developed and characterized CLN-049, a T cell-activating bsAb targeting CD3 and FLT3, constructed as an IgG heavy chain/scFv fusion. CLN-049 binds the membrane proximal extracellular domain of the FLT3 protein tyrosine kinase, which facilitates the targeting of leukemic blasts regardless of FLT3 mutational status. CLN-049 was evaluated for preclinical safety and efficacy in vitro and in vivo.Results CLN-049 induced target-restricted activation of CD4+ and CD8+ T cells. AML cell lines expressing a broad range of surface levels of FLT3 were efficiently lysed on treatment with subnanomolar concentrations of CLN-049, whereas FLT3-expressing hematopoietic progenitor cells and dendritic cells were not sensitive to CLN-049 killing. Treatment with CLN-049 also induced lysis of AML and B-ALL patient blasts by autologous T cells at the low effector-to-target ratios typically observed in patients with overt disease. Lysis of leukemic cells was not affected by supraphysiological levels of soluble FLT3 or FLT3 ligand. In mouse xenograft models, CLN-049 was highly active against human leukemic cell lines and patient-derived AML and B-ALL blasts.Conclusions CLN-049 has a favorable efficacy and safety profile in preclinical models, warranting evaluation of its antileukemic activity in the clinic.https://jitc.bmj.com/content/10/3/e003882.full |
| spellingShingle | Melanie Märklin Gundram Jung Jonas S Heitmann Joseph Kauer Helmut R Salih Stefanie Mueller Bochong Li Latifa Zekri Naveen K Mehta Martin Pfluegler Kristan Meetze Isabelle Sindel Fabian Vogt Lukas Osburg Hans-Jörg Bühring Sebastian Hörner Patrick A Baeuerle Jennifer S Michaelson A novel IgG-based FLT3xCD3 bispecific antibody for the treatment of AML and B-ALL Journal for ImmunoTherapy of Cancer |
| title | A novel IgG-based FLT3xCD3 bispecific antibody for the treatment of AML and B-ALL |
| title_full | A novel IgG-based FLT3xCD3 bispecific antibody for the treatment of AML and B-ALL |
| title_fullStr | A novel IgG-based FLT3xCD3 bispecific antibody for the treatment of AML and B-ALL |
| title_full_unstemmed | A novel IgG-based FLT3xCD3 bispecific antibody for the treatment of AML and B-ALL |
| title_short | A novel IgG-based FLT3xCD3 bispecific antibody for the treatment of AML and B-ALL |
| title_sort | novel igg based flt3xcd3 bispecific antibody for the treatment of aml and b all |
| url | https://jitc.bmj.com/content/10/3/e003882.full |
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