1. Academic Validation
  2. Anti-BAFF-R antibody VAY-736 demonstrates promising preclinical activity in CLL and enhances effectiveness of ibrutinib

Anti-BAFF-R antibody VAY-736 demonstrates promising preclinical activity in CLL and enhances effectiveness of ibrutinib

  • Blood Adv. 2019 Feb 12;3(3):447-460. doi: 10.1182/bloodadvances.2018025684.
Emily M McWilliams 1 2 Christopher R Lucas 3 Timothy Chen 1 2 Bonnie K Harrington 2 4 Ronni Wasmuth 2 Amanda Campbell 1 Kerry A Rogers 2 Carolyn M Cheney 2 Xiaokui Mo 5 Leslie A Andritsos 2 Farrukh T Awan 2 Jennifer Woyach 2 William E Carson 3rd 6 Jonathan Butchar 2 Susheela Tridandapani 2 Erin Hertlein 2 Carlos E Castro 3 Natarajan Muthusamy 2 John C Byrd 2 7
Affiliations

Affiliations

  • 1 Biomedical Sciences Graduate Program, College of Medicine.
  • 2 Division of Hematology, Department of Internal Medicine, College of Medicine and OSU Comprehensive Cancer Center.
  • 3 Department of Mechanical and Aerospace Engineering, College of Engineering.
  • 4 Department of Veterinary Biosciences, College of Veterinary and Comparative Medicine.
  • 5 Center for Biostatistics.
  • 6 Division of Surgical Oncology, Department of Surgery, College of Medicine and OSU Comprehensive Cancer Center, and.
  • 7 Division of Medicinal Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH.
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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