TY - JOUR
T1 - Anti–BAFF-R antibody VAY-736 demonstrates promising preclinical activity in CLL and enhances effectiveness of ibrutinib
AU - McWilliams, Emily M.
AU - Lucas, Christopher R.
AU - Chen, Timothy
AU - Harrington, Bonnie K.
AU - Wasmuth, Ronni
AU - Campbell, Amanda
AU - Rogers, Kerry A.
AU - Cheney, Carolyn M.
AU - Mo, Xiaokui
AU - Andritsos, Leslie A.
AU - Awan, Farrukh T.
AU - Woyach, Jennifer
AU - Carson, William E.
AU - Butchar, Jonathan
AU - Tridandapani, Susheela
AU - Hertlein, Erin
AU - Castro, Carlos E.
AU - Muthusamy, Natarajan
AU - Byrd, John C.
N1 - Publisher Copyright:
© 2019 by The American Society of Hematology
PY - 2019/2/12
Y1 - 2019/2/12
N2 - 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-kB 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.
AB - 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-kB 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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U2 - 10.1182/bloodadvances.2018025684
DO - 10.1182/bloodadvances.2018025684
M3 - Article
C2 - 30737226
AN - SCOPUS:85061232265
SN - 2473-9529
VL - 3
SP - 447
EP - 460
JO - Blood Advances
JF - Blood Advances
IS - 3
ER -