An antibody-drug conjugate targeting VpreB1 for the treatment of B-cell acute lymphoblastic leukemia
Abstract: B-lineage acute lymphoblastic leukemia (B-ALL) therapy is being transformed by therapies targeting antigens such as CD19, CD20, and CD22 on the surface of B-ALL cells. Moreover, having therapies targeting these different B-ALL antigens has helped address challenges associated with both int...
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| Format: | Article |
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Elsevier
2025-08-01
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| Series: | Blood Neoplasia |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S295032802500055X |
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| author | Peter M. Gordon Robin L. Williams Jason Ostergaard Keegan C. Lee Hannah N. Bui Joseph M. Muretta Bridget S. Wilson Thomas Beder Claudia D. Baldus Luke Lambert Benjamin E. Deonovic Timothy Singleton Sarah K. Tasian Stuart S. Winter |
| author_facet | Peter M. Gordon Robin L. Williams Jason Ostergaard Keegan C. Lee Hannah N. Bui Joseph M. Muretta Bridget S. Wilson Thomas Beder Claudia D. Baldus Luke Lambert Benjamin E. Deonovic Timothy Singleton Sarah K. Tasian Stuart S. Winter |
| author_sort | Peter M. Gordon |
| collection | DOAJ |
| description | Abstract: B-lineage acute lymphoblastic leukemia (B-ALL) therapy is being transformed by therapies targeting antigens such as CD19, CD20, and CD22 on the surface of B-ALL cells. Moreover, having therapies targeting these different B-ALL antigens has helped address challenges associated with both intra- and inter-patient variability in targeted antigen expression levels and antigen loss as mechanisms of therapy resistances. To further expand the range of targetable antigens in B-ALL therapy, we developed a novel antibody-drug conjugate (ADC) that targets the VpreB1 (CD179a) component of the surrogate light chain. VpreB1 is expressed across most B-ALL molecular subtypes but otherwise has expression limited to precursor B cells, but not mature B cells. Our VpreB1 antibody demonstrated high affinity for its target protein and when conjugated to the toxin calicheamicin (VpreB1-ADC) exhibited significant in vitro toxicity against B-ALL cells harboring a range of genomic alterations. In vivo, the VpreB1-ADC was well tolerated in mice, with modest weight loss and decreased white blood cell counts. When tested against a B-ALL cell line and multiple B-ALL patient-derived xenograft models, the VpreB1-ADC significantly reduced leukemia burden, prolonged survival, and cured a subset of mice. These promising results support further investigation of the VpreB1 component of the surrogate light chain as a therapeutic target, including the VpreB1-ADC in preclinical and clinical trials, with the goal of expanding the arsenal of immunoconjugates available for the treatment of B-ALL. |
| format | Article |
| id | doaj-art-da3e4836deb14fa8a3d6f5511e2a8f5f |
| institution | DOAJ |
| issn | 2950-3280 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Blood Neoplasia |
| spelling | doaj-art-da3e4836deb14fa8a3d6f5511e2a8f5f2025-08-20T03:14:02ZengElsevierBlood Neoplasia2950-32802025-08-012310012010.1016/j.bneo.2025.100120An antibody-drug conjugate targeting VpreB1 for the treatment of B-cell acute lymphoblastic leukemiaPeter M. Gordon0Robin L. Williams1Jason Ostergaard2Keegan C. Lee3Hannah N. Bui4Joseph M. Muretta5Bridget S. Wilson6Thomas Beder7Claudia D. Baldus8Luke Lambert9Benjamin E. Deonovic10Timothy Singleton11Sarah K. Tasian12Stuart S. Winter13Division of Pediatric Hematology/Oncology, Department of Pediatrics, University of Minnesota, Minneapolis, MNDivision of Pediatric Hematology/Oncology, Department of Pediatrics, University of Minnesota, Minneapolis, MNDivision of Pediatric Hematology/Oncology, Department of Pediatrics, University of Minnesota, Minneapolis, MNDepartment of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MNDepartment of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MNDepartment of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MNDepartment of Pathology, The University of New Mexico, Albuquerque, NMMedical Department II, Hematology and Oncology, University Hospital Schleswig-Holstein, Kiel, GermanyMedical Department II, Hematology and Oncology, University Hospital Schleswig-Holstein, Kiel, GermanyDepartment of Pathology, Children’s Minnesota, Minneapolis, MNDivision of Design and Analytics, The Research Institute, Children’s Minnesota, Minneapolis, MNDepartment of Pathology, Children’s Minnesota, Minneapolis, MNDivision of Oncology and Center for Childhood Cancer Research, Children’s Hospital of Philadelphia, Philadelphia, PA; Department of Pediatrics and Abramson Cancer Center, University of Pennsylvania School of Medicine, Philadelphia, PADepartment of Cancer and Blood Disorders, Children’s Minnesota, Minneapolis, MN; Correspondence: Stuart S. Winter, Children’s Minnesota, Research Institute, 2525 Chicago Ave South, Minneapolis, MN 55404;Abstract: B-lineage acute lymphoblastic leukemia (B-ALL) therapy is being transformed by therapies targeting antigens such as CD19, CD20, and CD22 on the surface of B-ALL cells. Moreover, having therapies targeting these different B-ALL antigens has helped address challenges associated with both intra- and inter-patient variability in targeted antigen expression levels and antigen loss as mechanisms of therapy resistances. To further expand the range of targetable antigens in B-ALL therapy, we developed a novel antibody-drug conjugate (ADC) that targets the VpreB1 (CD179a) component of the surrogate light chain. VpreB1 is expressed across most B-ALL molecular subtypes but otherwise has expression limited to precursor B cells, but not mature B cells. Our VpreB1 antibody demonstrated high affinity for its target protein and when conjugated to the toxin calicheamicin (VpreB1-ADC) exhibited significant in vitro toxicity against B-ALL cells harboring a range of genomic alterations. In vivo, the VpreB1-ADC was well tolerated in mice, with modest weight loss and decreased white blood cell counts. When tested against a B-ALL cell line and multiple B-ALL patient-derived xenograft models, the VpreB1-ADC significantly reduced leukemia burden, prolonged survival, and cured a subset of mice. These promising results support further investigation of the VpreB1 component of the surrogate light chain as a therapeutic target, including the VpreB1-ADC in preclinical and clinical trials, with the goal of expanding the arsenal of immunoconjugates available for the treatment of B-ALL.http://www.sciencedirect.com/science/article/pii/S295032802500055X |
| spellingShingle | Peter M. Gordon Robin L. Williams Jason Ostergaard Keegan C. Lee Hannah N. Bui Joseph M. Muretta Bridget S. Wilson Thomas Beder Claudia D. Baldus Luke Lambert Benjamin E. Deonovic Timothy Singleton Sarah K. Tasian Stuart S. Winter An antibody-drug conjugate targeting VpreB1 for the treatment of B-cell acute lymphoblastic leukemia Blood Neoplasia |
| title | An antibody-drug conjugate targeting VpreB1 for the treatment of B-cell acute lymphoblastic leukemia |
| title_full | An antibody-drug conjugate targeting VpreB1 for the treatment of B-cell acute lymphoblastic leukemia |
| title_fullStr | An antibody-drug conjugate targeting VpreB1 for the treatment of B-cell acute lymphoblastic leukemia |
| title_full_unstemmed | An antibody-drug conjugate targeting VpreB1 for the treatment of B-cell acute lymphoblastic leukemia |
| title_short | An antibody-drug conjugate targeting VpreB1 for the treatment of B-cell acute lymphoblastic leukemia |
| title_sort | antibody drug conjugate targeting vpreb1 for the treatment of b cell acute lymphoblastic leukemia |
| url | http://www.sciencedirect.com/science/article/pii/S295032802500055X |
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