Antagonistic human FcγRIIB (CD32B) antibodies have anti-tumor activity and overcome resistance to antibody therapy in vivo

Ali Roghanian, Ingrid Teige, Linda Mårtensson, Kerry L Cox, Mathilda Kovacek, Anne Ljungars, Jenny Mattson, Annika Sundberg, Andrew T Vaughan, Vallari Shah, Neil R Smyth, Bhavwanti Sheth, H T Claude Chan, Zhan-Chun Li, Emily L Williams, Giusi Manfredi, Robert J Oldham, C Ian Mockridge, Sonya A James, Lekh N DahalKhiyam Hussain, Björn Nilsson, J Sjef Verbeek, Gunnar Juliusson, Markus Hansson, Mats Jerkeman, Peter W M Johnson, Andrew Davies, Stephen A Beers, Martin J Glennie, Björn Frendéus, Mark S Cragg

Research output: Contribution to journalArticle (Academic Journal)peer-review

67 Citations (Scopus)

Abstract

Therapeutic antibodies have transformed cancer therapy, unlocking mechanisms of action by engaging the immune system. Unfortunately, cures rarely occur and patients display intrinsic or acquired resistance. Here, we demonstrate the therapeutic potential of targeting human (h) FcγRIIB (CD32B), a receptor implicated in immune cell desensitization and tumor cell resistance. FcγRIIB-blocking antibodies prevented internalization of the CD20-specific antibody rituximab, thereby maximizing cell surface accessibility and immune effector cell mediated antitumor activity. In hFcγRIIB-transgenic (Tg) mice, FcγRIIB-blocking antibodies effectively deleted target cells in combination with rituximab, and other therapeutic antibodies, from resistance-prone stromal compartments. Similar efficacy was seen in primary human tumor xenografts, including with cells from patients with relapsed/refractory disease. These data support the further development of hFcγRIIB antibodies for clinical assessment.

Original languageEnglish
Pages (from-to)473-88
Number of pages17
JournalCancer Cell
Volume27
Issue number4
DOIs
Publication statusPublished - 13 Apr 2015

Keywords

  • Animals
  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Murine-Derived
  • Drug Synergism
  • Humans
  • Mice
  • Neoplasms
  • Receptors, IgG
  • Rituximab

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