Overcoming leukemia heterogeneity by combining T cell engaging bispecific antibodies
Background Leukemia represents about 5% of all human cancers. Despite advances in therapeutics, a substantial number of patients succumb to the disease. Several subtypes of leukemia are inherently more resistant to treatment despite intensive chemotherapy or targeted therapy.Methods Here we describe...
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doaj-663e5da6089b4d33b0204bb1e5e7d4472021-07-13T15:02:27ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262020-07-018210.1136/jitc-2020-001626Overcoming leukemia heterogeneity by combining T cell engaging bispecific antibodiesBrian Alexander0Lajos Pusztai1David L Rimm2Priti Hegde3Mariya Rozenblit4Richard Huang5Natalie Danziger6Shakti Ramkissoon7Kim Blenman8Jeffrey S Ross9R&D, Foundation Medicine Inc, Cambridge, Massachusetts, USADepartment of Medical Oncology, Yale University School of Medicine, New Haven, Connecticut, USADepartment of Medical Oncology, Yale University School of Medicine, New Haven, Connecticut, USAR&D, Foundation Medicine Inc, Cambridge, Massachusetts, USADepartment of Medical Oncology, Yale University School of Medicine, New Haven, Connecticut, USAR&D, Foundation Medicine Inc, Cambridge, Massachusetts, USAR&D, Foundation Medicine Inc, Cambridge, Massachusetts, USAR&D, Foundation Medicine Inc, Cambridge, Massachusetts, USADepartment of Medical Oncology, Yale University School of Medicine, New Haven, Connecticut, USAR&D, Foundation Medicine Inc, Cambridge, Massachusetts, USABackground Leukemia represents about 5% of all human cancers. Despite advances in therapeutics, a substantial number of patients succumb to the disease. Several subtypes of leukemia are inherently more resistant to treatment despite intensive chemotherapy or targeted therapy.Methods Here we describe the generation of T cell engaging (CD3) bispecific antibodies (BsAbs) built on humanized IgG frameworks using the IgG(L)-scFv format against two targets expressed on acute lymphoblastic leukemia (ALL) and on acute myeloid leukemia (AML).Results Each BsAb mediated potent anti-leukemia effect against ALL (CD19) and AML (CD33) in vitro and in xenograft models. Importantly, the CD19-specific BsAb (BC250) was effective against hematogenous spread preventing metastases to liver and kidney in mice bearing ALL and Burkitt’s lymphoma xenografts. BC250 was more potent than the The Food and Drug Administration (FDA)-approved BsAb blinatumomab against ALL xenografts in vivo as measured by tumor bioluminescence and mouse survival. Furthermore, the combination of the CD19 and CD33 BsAbs in two xenograft models of mixed phenotype acute leukemia (biphenotypic and bilineal leukemia) was far superior than monotherapy with either of the BsAbs alone.Conclusions Selective combinations of these leukemia-specific BsAb offer the potential to overcome tumor heterogeneity or clonal escape in the modern era of antibody-based T cell-driven immunotherapy.https://jitc.bmj.com/content/8/2/e001626.full |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Brian Alexander Lajos Pusztai David L Rimm Priti Hegde Mariya Rozenblit Richard Huang Natalie Danziger Shakti Ramkissoon Kim Blenman Jeffrey S Ross |
spellingShingle |
Brian Alexander Lajos Pusztai David L Rimm Priti Hegde Mariya Rozenblit Richard Huang Natalie Danziger Shakti Ramkissoon Kim Blenman Jeffrey S Ross Overcoming leukemia heterogeneity by combining T cell engaging bispecific antibodies Journal for ImmunoTherapy of Cancer |
author_facet |
Brian Alexander Lajos Pusztai David L Rimm Priti Hegde Mariya Rozenblit Richard Huang Natalie Danziger Shakti Ramkissoon Kim Blenman Jeffrey S Ross |
author_sort |
Brian Alexander |
title |
Overcoming leukemia heterogeneity by combining T cell engaging bispecific antibodies |
title_short |
Overcoming leukemia heterogeneity by combining T cell engaging bispecific antibodies |
title_full |
Overcoming leukemia heterogeneity by combining T cell engaging bispecific antibodies |
title_fullStr |
Overcoming leukemia heterogeneity by combining T cell engaging bispecific antibodies |
title_full_unstemmed |
Overcoming leukemia heterogeneity by combining T cell engaging bispecific antibodies |
title_sort |
overcoming leukemia heterogeneity by combining t cell engaging bispecific antibodies |
publisher |
BMJ Publishing Group |
series |
Journal for ImmunoTherapy of Cancer |
issn |
2051-1426 |
publishDate |
2020-07-01 |
description |
Background Leukemia represents about 5% of all human cancers. Despite advances in therapeutics, a substantial number of patients succumb to the disease. Several subtypes of leukemia are inherently more resistant to treatment despite intensive chemotherapy or targeted therapy.Methods Here we describe the generation of T cell engaging (CD3) bispecific antibodies (BsAbs) built on humanized IgG frameworks using the IgG(L)-scFv format against two targets expressed on acute lymphoblastic leukemia (ALL) and on acute myeloid leukemia (AML).Results Each BsAb mediated potent anti-leukemia effect against ALL (CD19) and AML (CD33) in vitro and in xenograft models. Importantly, the CD19-specific BsAb (BC250) was effective against hematogenous spread preventing metastases to liver and kidney in mice bearing ALL and Burkitt’s lymphoma xenografts. BC250 was more potent than the The Food and Drug Administration (FDA)-approved BsAb blinatumomab against ALL xenografts in vivo as measured by tumor bioluminescence and mouse survival. Furthermore, the combination of the CD19 and CD33 BsAbs in two xenograft models of mixed phenotype acute leukemia (biphenotypic and bilineal leukemia) was far superior than monotherapy with either of the BsAbs alone.Conclusions Selective combinations of these leukemia-specific BsAb offer the potential to overcome tumor heterogeneity or clonal escape in the modern era of antibody-based T cell-driven immunotherapy. |
url |
https://jitc.bmj.com/content/8/2/e001626.full |
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