Abstract:
: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.
journal_name
Bloodjournal_title
Bloodauthors
Leong SR,Sukumaran S,Hristopoulos M,Totpal K,Stainton S,Lu E,Wong A,Tam L,Newman R,Vuillemenot BR,Ellerman D,Gu C,Mathieu M,Dennis MS,Nguyen A,Zheng B,Zhang C,Lee G,Chu YW,Prell RA,Lin K,Laing ST,Polson AGdoi
10.1182/blood-2016-08-735365subject
Has Abstractpub_date
2017-02-02 00:00:00pages
609-618issue
5eissn
0006-4971issn
1528-0020pii
blood-2016-08-735365journal_volume
129pub_type
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