Antagonistic Human FcγRIIB (CD32B) Antibodies Have Anti-Tumor Activity and Overcome Resistance to Antibody Therapy In Vivo

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 rece...

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Published in:	Cancer cell Vol. 27; no. 4; pp. 473 - 488
Main Authors:	Roghanian, Ali, Teige, Ingrid, Mårtensson, Linda, Cox, Kerry L., Kovacek, Mathilda, Ljungars, Anne, Mattson, Jenny, Sundberg, Annika, Vaughan, Andrew T., Shah, Vallari, Smyth, Neil R., Sheth, Bhavwanti, Chan, H.T. Claude, Li, Zhan-Chun, Williams, Emily L., Manfredi, Giusi, Oldham, Robert J., Mockridge, C. Ian, James, Sonya A., Dahal, Lekh N., Hussain, Khiyam, Nilsson, Björn, Verbeek, J. Sjef, Juliusson, Gunnar, Hansson, Markus, Jerkeman, Mats, Johnson, Peter W.M., Davies, Andrew, Beers, Stephen A., Glennie, Martin J., Frendéus, Björn, Cragg, Mark S.
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 13-04-2015
Subjects:	Animals Antibodies, Monoclonal - pharmacology Antibodies, Monoclonal - therapeutic use Antibodies, Monoclonal, Murine-Derived - metabolism Antibodies, Monoclonal, Murine-Derived - pharmacology Antibodies, Monoclonal, Murine-Derived - therapeutic use Cancer and Oncology Cancer och onkologi Clinical Medicine Drug Synergism Humans Klinisk medicin Medical and Health Sciences Medicin och hälsovetenskap Mice Neoplasms - drug therapy Neoplasms - immunology Receptors, IgG - antagonists & inhibitors Receptors, IgG - physiology Rituximab
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Summary:	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. [Display omitted] •Fully human hFcγRIIB (CD32B) antibodies overcome resistance to therapeutic antibodies•hFcγRIIB mAbs augment standard-of-care anti-CD20 therapy in vitro and in vivo•hFcγRIIB mAbs restore drug responsiveness in refractory CLL cells in vivo•hFcγRIIB mAbs help overcome cell- and niche-specific resistance mechanisms Roghanian et al. show that antibodies blocking FcγRIIB prevent internalization of anti-CD20 antibody rituximab, thereby maximizing immune effector cell-mediated antitumor activity. Combined targeting of FcγRIIB and CD20 is effective in xenografts from human malignancies clinically relapsed/refractory to rituximab.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1535-6108 1878-3686 1878-3686
DOI:	10.1016/j.ccell.2015.03.005