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Cd32b) in the Mouse Is Limited by Monoclonal Antibody Consumption and Receptor Internalization This Information Is Current As of September 29, 2021

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Cd32b) in the Mouse Is Limited by Monoclonal Antibody Consumption and Receptor Internalization This Information Is Current As of September 29, 2021 Immunotherapy Targeting Inhibitory Fcγ Receptor IIB (CD32b) in the Mouse Is Limited by Monoclonal Antibody Consumption and Receptor Internalization This information is current as of September 29, 2021. Emily L. Williams, Alison L. Tutt, Stephen A. Beers, Ruth R. French, Claude H. T. Chan, Kerry L. Cox, Ali Roghanian, Christine A. Penfold, Cherié L. Butts, Peter Boross, J. Sjef Verbeek, Mark S. Cragg and Martin J. Glennie J Immunol 2013; 191:4130-4140; Prepublished online 11 Downloaded from September 2013; doi: 10.4049/jimmunol.1301430 http://www.jimmunol.org/content/191/8/4130 http://www.jimmunol.org/ Supplementary http://www.jimmunol.org/content/suppl/2013/09/11/jimmunol.130143 Material 0.DC1 References This article cites 74 articles, 37 of which you can access for free at: http://www.jimmunol.org/content/191/8/4130.full#ref-list-1 by guest on September 29, 2021 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • 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 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 © 2013 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Immunotherapy Targeting Inhibitory Fcg Receptor IIB (CD32b) in the Mouse Is Limited by Monoclonal Antibody Consumption and Receptor Internalization Emily L. Williams,* Alison L. Tutt,* Stephen A. Beers,* Ruth R. French,* Claude H. T. Chan,* Kerry L. Cox,* Ali Roghanian,* Christine A. Penfold,* Cherie´ L. Butts,† Peter Boross,‡ J. Sjef Verbeek,‡ Mark S. Cragg,*,1 and Martin J. Glennie*,1 Genetic deficiency of the inhibitory Fc receptor, FcgRIIB (CD32b), has been shown to augment the activity of activatory FcgR and promote mAb immunotherapy. To investigate whether mAbs capable of blocking FcgRIIB have similar capacity, we recently Downloaded from generated a panel of specific anti-mouse FcgRIIB mAbs that do not cross-react with other FcRs, allowing us to study the potential of FcgRIIB as a therapeutic target. Previous work revealed a number of these mAbs capable of eliciting programmed cell death of targets, and in the present study we demonstrated their ability to promote target cell phagocytosis. However, in a variety of murine tumor models, anti-FcgRIIB mAbs demonstrated limited therapeutic activity despite optimized treatment regimens. Unexpectedly, we observed that the anti-FcgRIIB mAbs are rapidly and extensively consumed in vivo, both by the tumor and host cells, including B cells, leading to a precipitous loss from the circulation. Closer analysis revealed that the anti-FcgRIIB mAbs http://www.jimmunol.org/ become extensively internalized from the cell surface within 24 h in vivo, likely explaining their suboptimal efficacy. Subsequent studies revealed that anti-FcgRIIB mAb immunotherapy was effective when used against FcgRIIB+ tumors in FcgRIIB2/2 recipients, indicating that consumption of the mAb by nontumor cells is the primary limitation of these reagents. Importantly, similar rates of internalization were not seen on human target cells, at least in vitro. These studies further highlight the need to determine the propensity of mAb therapeutics to internalize target receptors and also identify potential key differences between human and mouse cells in this respect. The Journal of Immunology, 2013, 191: 4130–4140. herapeutic Abs such as rituximab, trastuzumab, and bev- the activatory FcgR (FcgR I, III, and IV in the mouse) occurs via acizumab are now established treatments for various an ITAM-containing cytoplasmic tail or association with a com- by guest on September 29, 2021 T cancers (1, 2). A major component of their therapeutic mon ITAM-containing g-chain. Conversely, inhibitory signaling is efficacy is thought to derive from their interaction with FcgRs (3). afforded by the ITIM-containing tail of FcgRIIB/CD32b. With the FcgRs are expressed on a wide range of immune cells such as exception of FcgRI (and IgG2a binding to FcgRIV), the FcgRs 6 –1 macrophages, neutrophils, and NK cells, as well as B cells and have relatively low affinity for monomeric IgG (Kd of ∼10 M ) dendritic cells (DCs) (4, 5). Both human and mouse FcgRs fall and so are unlikely to engage IgG in free solution. into two subgroups; activatory and inhibitory. Signaling through FcgR function varies with the cell type on which they are expressed. Triggering activatory FcgRs on effector cells, such as monocytes or macrophages, results in the release of a spectrum of *Antibody and Vaccine Group, Cancer Sciences Unit, University of Southampton, inflammatory immune modulators, such as cytokines. Conversely, Faculty of Medicine, General Hospital, Southampton SO16 6YD, United Kingdom; †Immunology Research, Biogen Idec, Cambridge, MA 02142; and ‡Department of triggering of FcgRIIB on B cells by IgG-containing immune Human Genetics, Leiden University Medical Center, 2333 ZA Leiden, The Nether- complexes (ICs) serves to inhibit signaling through the BCR, re- lands ducing proliferation, Ab production, and potentially delivering 1 M.S.C. and M.J.G. are cosenior authors and contributed equally to this study. apoptotic signals to the cells (reviewed in Ref. 4). More recently it Received for publication May 30, 2013. Accepted for publication August 7, 2013. has been shown that FcgRIIB is also expressed on plasma cells This work was supported by Leukaemia and Lymphoma Research Grants 07010, (and myeloma cells). In such cases, engagement can also induce 08014, and 09009. apoptosis with potentially important implications for controlling E.L.W. performed experiments, analyzed results, produced figures, and wrote the long-lived plasma cells and shaping the Ab repertoire (6). The paper with M.S.C.; R.R.F. performed experiments, produced figures, and edited the manuscript; A.L.T., S.A.B., K.L.C., C.H.T.C., C.A.P., C.L.B., P.B., and J.S.V. pro- coexpression of both inhibitory and activatory FcgR by cells pro- duced and provided critical reagents; S.A.B. and A.R. performed experiments; M.J.G. vides a mechanism of fine control for cellular activation, where designed the research, analyzed results, and edited the manuscript; and M.S.C. de- signed the research, analyzed results, and wrote the manuscript with E.L.W. engagement of the FcgRIIB counterbalances activatory FcgR ef- fector function. Address correspondence and reprint requests to Prof. Mark Cragg, Antibody and Vaccine Group, Cancer Sciences Unit, Southampton University Faculty of Medicine, Within the field of Ab-based immunotherapy, growing evidence General Hospital, Southampton, SO16 6YD, U.K. E-mail address: [email protected] indicates that FcgRs on innate effector cells are critical for con- The online version of this article contains supplemental material. trolling therapeutic efficacy (7–10). In mouse models the thera- Abbreviations used in this article: ADCC, Ab-dependent cellular cytotoxicity; peutic activity of a range of anti-cancer mAbs correlates with their BMDM, bone marrow–derived macrophage; DC, dendritic cell; h, human; IC, im- ability to bind to activatory FcgR (8, 11–16), and deletion of the mune complex; PCD, programmed cell death; Tg, transgenic; WT, wild-type. FcgR g-chain abrogates therapeutic activity of most anti-cancer Copyright Ó 2013 by The American Association of Immunologists, Inc. 0022-1767/13/$16.00 mAbs (7). In contrast, in their seminal paper, Clynes et al. (7) www.jimmunol.org/cgi/doi/10.4049/jimmunol.1301430 The Journal of Immunology 4131 demonstrated that deleting FcgRIIB enhances the therapeutic ac- human peripheral B cells were purified by negative selection using MACS tivity of a number of different therapeutic mAbs, including 4D5 B cell isolation kits (Miltenyi Biotec). and trastuzumab (17), further alluding to the balance between Generation of bone marrow–derived macrophages FcgRIIB and activatory FcgR being critical for mAb-induced effector function. Murine bone marrow–derived macrophages (BMDMs) were generated Evidence for similar activity in humans has been more difficult from cells isolated from the bone marrow of the femur and tibia of mice. Cells were cultured in RPMI 1640 (Life Technologies Invitrogen, Paisley, to obtain and is largely derived from genetic studies, taking ad- U.K.) enriched with 10% FCS, 2 mM glutamine and 1 mM pyruvate, vantage of the fact that certain FcgRs have polymorphisms that penicillin and streptomycin (each at 100 mg/ml), and 20% L929 cell– affect their affinity for various IgG classes. Polymorphisms that conditioned medium (containing M-CSF). Cells were cultured at 37˚C, 5% increase the interaction between IgG and FcgRIIA or FcgRIIIA CO2 for 10–14 d prior to use. Macrophage differentiation was routinely confirmed by morphological examination and/or flow cytometry for CD11b have been shown to be associated with improved therapeutic efficacy expression. (18–21). Similarly, defucosylated IgG, which binds with a marked increased affinity to the activatory FcgRIIIA, shows ∼50-fold in- Abs and reagents crease in Ab-dependent cellular cytotoxicity (ADCC) activity, which mAbs were typically produced from the culture supernatant of hybridoma is expected to deliver significant improvement in clinical efficacy. In cells or stably transfected Chinese hamster ovary-K1 (AT128 m2a). IgG was both mice and humans, polymorphisms that result in reduced ex- purified on protein A with purity assessed by electrophoresis (Beckman EP pression or activity of the inhibitory FcgRIIB are associated with system; Beckman Coulter) and lack of aggregation was confirmed by increased susceptibility to autoimmune disease (22–28). HPLC. F(ab9)2 fragments were produced as described previously (40).
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