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Phagocytosis and Cytotoxicity Enhances Monocyte/Macrophage Glycoengineering of Therapeutic Antibodies Enhances Monocyte/Macrophage-Mediated Phagocytosis and Cytotoxicity This information is current as Sylvia Herter, Martina C. Birk, Christian Klein, Christian of September 25, 2021. Gerdes, Pablo Umana and Marina Bacac J Immunol 2014; 192:2252-2260; Prepublished online 31 January 2014; doi: 10.4049/jimmunol.1301249 http://www.jimmunol.org/content/192/5/2252 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2014/01/31/jimmunol.130124 Material 9.DCSupplemental http://www.jimmunol.org/ References This article cites 44 articles, 22 of which you can access for free at: http://www.jimmunol.org/content/192/5/2252.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 25, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Author Choice Freely available online through The Journal of Immunology Author Choice option Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2014 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Glycoengineering of Therapeutic Antibodies Enhances Monocyte/Macrophage-Mediated Phagocytosis and Cytotoxicity Sylvia Herter, Martina C. Birk, Christian Klein, Christian Gerdes, Pablo Umana, and Marina Bacac Therapeutic Abs possess several clinically relevant mechanisms of action including perturbation of tumor cell signaling, activation of complement-dependent cytotoxicity, Ab-dependent cellular cytotoxicity (ADCC), Ab-dependent cellular phagocytosis (ADCP), and induction of adaptive immunity. In view of the important role of phagocytic lineage cells in the mechanism of action of ther- apeutic Abs, we analyzed FcgR receptor-dependent effector functions of monocytes and macrophages triggered by glycoengi- neered (GE) Abs (having enhanced FcgRIIIa [CD16a] binding affinity) versus their wild-type (WT) counterparts under different Downloaded from experimental conditions. We first defined the precise FcgR repertoire on classical and nonclassical intermediate monocytes—M1 and M2c macrophage populations. We further show that WT and GE Abs display comparable binding and induce similar effector functions (ADCC and ADCP) in the absence of nonspecific, endogenous IgGs. However, in the presence of these IgGs (i.e., in a situation that more closely mimics physiologic conditions), GE Abs display significantly superior binding and promote stronger monocyte and macrophage activity. These data show that in addition to enhancing CD16a-dependent NK cell cytotoxicity, glycoengineering also enhances monocyte and macrophage phagocytic and cytotoxic activities through enhanced binding to http://www.jimmunol.org/ CD16a under conditions that more closely resemble the physiologic setting. The Journal of Immunology, 2014, 192: 2252–2260. ver the past decades, several anticancer Ab therapeutic activating signals through ITAMs or inhibitory signals through agents have been developed and tested in the clinic, and ITIMs. Most Fc-dependent inhibitory signals are transduced via O 12 are currently approved for use in oncology (1–6). FcgRIIb (CD32b), whereas most stimulatory signals are trans- Many of these agents affect tumor growth by interfering with duced by FcgRI (CD64) and CD16a (10). CD64 is a high- receptor signaling. For example, trastuzumab (targeting Her2/neu) affinity receptor expressed by macrophages, DCs, neutrophils, and cetuximab (targeting EGFR) counteract tumor progression by and eosinophils, whereas CD16a is a low-affinity receptor expressed blocking receptor downstream signaling, whereas rituximab (tar- by NK cells, DCs, macrophages, and mast cells; it is required for by guest on September 25, 2021 geting CD20) and alemtuzumab (targeting CD52) induce direct NK cell–mediated ADCC (10). cell death or apoptosis (3, 7, 8). Various engineering technologies have recently been developed In addition to direct antitumor effects, therapeutic mAbs con- to modulate the binding affinity of the Fc region of therapeutic Abs trol tumor progression through additional mechanisms, includ- to different FcgRs to enhance or suppress FcgR-dependent immune ing complement-dependent cytotoxicity, and immune cell effector effector functions. This has been achieved either by modifying the functions such as Ab-dependent cellular cytotoxicity (ADCC) and structure of the Fc-attached oligosaccharides (glycoengineering) Ab-dependent cellular phagocytosis (ADCP) (3). ADCC and ADCP or by engineering the Fc-polypeptide backbone. In particular, are triggered through interaction of the Ab fragment crystallizable glycoengineered (GE) Abs enriched in glycoforms lacking core (Fc) domain with the corresponding Fcg receptors (FcgRs) expressed fucose residue from oligosaccharides attached at Asn297 of the on NK cells, neutrophils, monocytes, macrophages, dendritic cells Fc have significantly enhanced binding affinity to CD16a and are (DCs), and eosinophils (3, 9). Once engaged, FcgRs transduce more potent and efficacious at mediating ADCC (6, 11–14) Although removing the core fucose residue from Fc-oligosaccharides increases the affinity of all IgG subclasses to human activating CD16a Discovery Oncology, Pharma Research and Early Development (pRED), Roche Gly- (and to its mouse ortholog FcgRIV) by 10–50-fold, binding to cart AG, 8952 Schlieren, Zurich, Switzerland other human activating and inhibitory receptors, including CD32a Received for publication May 10, 2013. Accepted for publication December 21, 2013. or CD32b, remains largely unchanged. Despite the overall simi- larity in protein structure, individual FcgRs have unique binding Address correspondence and reprint requests to: Dr. Marina Bacac, Discovery Oncology, Pharma Research and Early Development (pRED), Roche Glycart patterns. In the case of the CD16a-IgG Fc interaction, the car- AG, Wagistrasse 18, 8952 Schlieren, Zurich, Switzerland. E-mail address: marina. bohydrate attached to CD16a at its Fc binding interface, a struc- [email protected] tural element unique to CD16a among FcgRs, is required for the The online version of this article contains supplemental material. increased binding affinity to afucosylated, GE Abs (10, 15–17). Abbreviations used in this article: ABC, Ab-binding capability; ADCC, Ab-dependent Glycoengineering confers two clinically relevant properties: 1) cellular cytotoxicity; ADCP, Ab-dependent cellular phagocytosis; CLL, chronic lympho- cytic leukemia; DC, dendritic cell; LDH, lactate dehydrogenase; M1, type I macrophage; the ability to achieve high levels of ADCC, even in individuals M2, type II macrophage; M-CSF, macrophage CSF; MDM, monocyte-derived macro- harboring the low-affinity CD16a allotype (158Phe), potentially phage; WT, wild type. overcoming the problem of individual heterogeneity in CD16a This article is distributed under The American Association of Immunologists, Inc., polymorphism and therapy response and 2) the ability to preserve Reuse Terms and Conditions for Author Choice articles. activity in the presence of high concentrations of nonspecific serum Copyright Ó 2014 by The American Association of Immunologists, Inc. 0022-1767/14/$16.00 IgGs (.10 mg/ml) that compete with conventional therapeutic www.jimmunol.org/cgi/doi/10.4049/jimmunol.1301249 The Journal of Immunology 2253 Abs for FcgRs and impair their activity. In line with these prop- 10% FCS and N-acetyl-L-alanyl-L-glutamine (2 mM). 1833-PPOP233 cells erties, a number of preclinical studies demonstrated that Ab Fc- (provided by Thomas Weber, Roche Diagnostics, Penzberg, Germany) were afucosylation translates into significantly enhanced activity in vivo cultivated in DMEM containing 10% FCS and N-acetyl-L-alanyl-L-glutamine (2 mM) plus 200 mg/ml G418. (6, 9, 17), and this has led to the approval of new therapeutic GE Abs. GA101 (obinutuzumab) is a GE, type II anti-CD20 mAb that Monocyte isolation and generation of polarized macrophage has recently been approved by the U.S. Food and Drug Admin- subsets istration for the first line treatment of patients with chronic lym- PBMCs were isolated from buffy coats obtained from the Blutspende- phocytic leukemia (CLL) in combination with chlorambucil (18– zentrale Zurich€ (Switzerland). Depending on the assay requirements, mono- 20). In Japan, the GE CCR4 Ab mogamulizumab has been ap- cytes were isolated using the Pan Monocyte Isolation Kit (for pan monocyte proved for treatment of patients with relapsed or refractory CCR4+ isolation), the Monocyte-Isolation Kit II (for classical, CD16 negative monocyte isolation) or CD16+ Monocyte Isolation Kit (for intermediate, T cell leukemia-lymphoma (21). nonclassical, CD16+ monocyte isolation), all from Miltenyi Biotech. For The effector cells contributing to the efficacy of therapeutic monocyte-derived macrophage (MDM) generation, pan monocytes or Abs and their relative contribution in vivo have not been clearly classical monocytes were incubated inRPMI1640supplementedwithhuman defined. NK
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