Overcoming leukemia heterogeneity by combining T cell engaging bispecific antibodies Journal Article
| Authors: | Hoseini, S. S.; Espinosa-Cotton, M.; Guo, H. F.; Cheung, N. K. V. |
| Article Title: | Overcoming leukemia heterogeneity by combining T cell engaging bispecific antibodies |
| Abstract: | 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. © 2020 Author(s). Published by BMJ. |
| Keywords: | controlled study; unclassified drug; human cell; nonhuman; flow cytometry; neoplasm; cd8 antigen; t-lymphocytes; interleukin 2; tumor volume; animal experiment; animal model; cytotoxicity; enzyme linked immunosorbent assay; acute leukemia; hematologic neoplasms; immunotherapy; antigens; immunoglobulin g; cell therapy; immunophenotyping; cd4 antigen; antibodies; tumor growth; fluorescence activated cell sorting; bioluminescence; bispecific antibody; blinatumomab; human; priority journal; article; mtt assay; ec50; bc250; bv-173 cell line; nalm-6 cell line |
| Journal Title: | Journal for ImmunoTherapy of Cancer |
| Volume: | 8 |
| Issue: | 2 |
| ISSN: | 2051-1426 |
| Publisher: | Biomed Central Ltd |
| Date Published: | 2020-12-01 |
| Start Page: | e001626 |
| Language: | English |
| DOI: | 10.1136/jitc-2020-001626 |
| PUBMED: | 33239418 |
| PROVIDER: | scopus |
| PMCID: | PMC7689592 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 4 January 2021 -- Source: Scopus |
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