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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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2020-10-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/8/2/e001626.full |
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| author | Madelyn Espinosa-Cotton Sayed Shahabuddin Hoseini Hong-fen Guo Nai-Kong V Cheung |
| author_facet | Madelyn Espinosa-Cotton Sayed Shahabuddin Hoseini Hong-fen Guo Nai-Kong V Cheung |
| author_sort | Madelyn Espinosa-Cotton |
| collection | DOAJ |
| 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. |
| format | Article |
| id | doaj-art-663e5da6089b4d33b0204bb1e5e7d447 |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2020-10-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-663e5da6089b4d33b0204bb1e5e7d4472024-11-10T14:35:07ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262020-10-018210.1136/jitc-2020-001626Overcoming leukemia heterogeneity by combining T cell engaging bispecific antibodiesMadelyn Espinosa-Cotton0Sayed Shahabuddin Hoseini1Hong-fen Guo2Nai-Kong V Cheung3Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, USAPediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, USAPediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, USADepartment of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York, 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 |
| spellingShingle | Madelyn Espinosa-Cotton Sayed Shahabuddin Hoseini Hong-fen Guo Nai-Kong V Cheung Overcoming leukemia heterogeneity by combining T cell engaging bispecific antibodies Journal for ImmunoTherapy of Cancer |
| title | 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_short | Overcoming leukemia heterogeneity by combining T cell engaging bispecific antibodies |
| title_sort | overcoming leukemia heterogeneity by combining t cell engaging bispecific antibodies |
| url | https://jitc.bmj.com/content/8/2/e001626.full |
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