Abstract |
The Bruton tyrosine kinase inhibitor (BTKi) ibrutinib has transformed chronic lymphocytic leukemia (CLL) therapy but requires continuous administration. These factors have spurred interest in combination treatments. Unlike with chemotherapy, CD20-directed antibody therapy has not improved the outcome of BTKi treatment. Whereas CD20 antigen density on CLL cells decreases during ibrutinib treatment, the B-cell activating factor (BAFF) and its receptor (BAFF-R) remain elevated. Furthermore, BAFF signaling via noncanonical NF-κB remains elevated with BTKi treatment. Blocking BAFF interaction with BAFF-R by using VAY-736, a humanized defucosylated engineered antibody directed against BAFF-R, antagonized BAFF-mediated apoptosis protection and signaling at the population and single-cell levels in CLL cells. Furthermore, VAY-736 showed superior antibody-dependent cellular cytotoxicity compared with CD20- and CD52-directed antibodies used in CLL. VAY-736 exhibited in vivo activity as a monotherapy and, when combined with ibrutinib, produced prolonged survival compared with either therapy alone. The in vivo activity of VAY-736 is dependent upon immunoreceptor tyrosine-based activation motif (ITAM)-mediated activation of effector cells as shown by using an ITAM-deficient mouse model. Collectively, our findings support targeting the BAFF signaling pathway with VAY-736 to more effectively treat CLL as a single agent and in combination with ibrutinib.
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Authors | Emily M McWilliams, Christopher R Lucas, Timothy Chen, Bonnie K Harrington, Ronni Wasmuth, Amanda Campbell, Kerry A Rogers, Carolyn M Cheney, Xiaokui Mo, Leslie A Andritsos, Farrukh T Awan, Jennifer Woyach, William E Carson 3rd, Jonathan Butchar, Susheela Tridandapani, Erin Hertlein, Carlos E Castro, Natarajan Muthusamy, John C Byrd |
Journal | Blood advances
(Blood Adv)
Vol. 3
Issue 3
Pg. 447-460
(02 12 2019)
ISSN: 2473-9537 [Electronic] United States |
PMID | 30737226
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Copyright | © 2019 by The American Society of Hematology. |
Chemical References |
- Antibodies, Monoclonal, Humanized
- Piperidines
- Pyrazoles
- Pyrimidines
- ibrutinib
- Adenine
- ianalumab
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Topics |
- Adenine
(analogs & derivatives)
- Animals
- Antibodies, Monoclonal, Humanized
(metabolism)
- Humans
- Leukemia, Lymphocytic, Chronic, B-Cell
(drug therapy)
- Mice
- Piperidines
- Pyrazoles
(pharmacology, therapeutic use)
- Pyrimidines
(pharmacology, therapeutic use)
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