An anti-CD3/anti–CLL-1 bispecific antibody for the treatment of acute myeloid leukemia
In: Blood, Jg. 129 (2017-02-02), S. 609-618
Online
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Zugriff:
Acute myeloid leukemia (AML) is a major unmet medical need. Most patients have poor long-term survival, and treatment has not significantly changed in 40 years. Recently, bispecific antibodies that redirect the cytotoxic activity of effector T cells by binding to CD3, the signaling component of the T-cell receptor, and a tumor target have shown clinical activity. Notably, blinatumomab is approved to treat relapsed/refractory acute lymphoid leukemia. Here we describe the design, discovery, pharmacologic activity, pharmacokinetics, and safety of a CD3 T cell-dependent bispecific (TDB) full-length human IgG1 therapeutic antibody targeting CLL-1 that could potentially be used in humans to treat AML. CLL-1 is prevalent in AML and, unlike other targets such as CD33 and CD123, is not expressed on hematopoietic stem cells providing potential hematopoietic recovery. We selected a high-affinity monkey cross-reactive anti-CLL-1 arm and tested several anti-CD3 arms that varied in affinity, and determined that the high-affinity CD3 arms were up to 100-fold more potent in vitro. However, in mouse models, the efficacy differences were less pronounced, probably because of prolonged exposure to TDB found with lower-affinity CD3 TDBs. In monkeys, assessment of safety and target cell depletion by the high- and low-affinity TDBs revealed that only the low-affinity CD3/CLL1 TDB was well tolerated and able to deplete target cells. Our data suggest that an appropriately engineered CLL-1 TDB could be effective in the treatment of AML.
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An anti-CD3/anti–CLL-1 bispecific antibody for the treatment of acute myeloid leukemia
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Autor/in / Beteiligte Person: | Polson, Andrew ; Steven T Laing ; Lu, Elizabeth ; Totpal, Klara ; Tam, Lucinda ; Lee, Genee ; Zhang, Crystal ; Nguyen, Allen ; Dennis, Mark S. ; Lin, Kedan ; Chu, Yu-Waye ; Mathieu, Mary ; Newman, Robert J. ; Wong, Alfred ; Zheng, Bing ; Prell, Rodney A. ; Hristopoulos, Maria ; Vuillemenot, Brian R. ; Ellerman, Diego ; Sukumaran, Siddharth ; Leong, Steven R. ; Gu, Chen ; Stainton, Shannon |
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Zeitschrift: | Blood, Jg. 129 (2017-02-02), S. 609-618 |
Veröffentlichung: | American Society of Hematology, 2017 |
Medientyp: | unknown |
ISSN: | 1528-0020 (print) ; 0006-4971 (print) |
DOI: | 10.1182/blood-2016-08-735365 |
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