Regulation of Monoclonal Antibody Immunotherapy by FcγRIIB

Stopforth, Richard J.; Cleary, Kirstie L.S.; Cragg, Mark S.

doi:10.1007/s10875-016-0247-8

Cited by 12 publications

(13 citation statements)

References 47 publications

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“…Our group further demonstrated this in the context of therapeutic mAb internalization upon binding to B cell surface Ags, where mAb was mainly internalized in the presence of the human FcγRIIB2 isoform . FcγRIIB1 is predominantly expressed on B cells, whereas myeloid cells express predominantly the B2 isoform …”

Section: Fcγriib Structurementioning

confidence: 69%

“…Recent studies investigating mechanisms underlying the efficacy and function of various therapeutic mAbs have also shed new light into novel functions of FcγRIIB (reviewed in Refs. ). On normal and malignant B cells, FcγRIIB has been shown to be involved in removing the clinically relevant CD20 mAb, rituximab, from the B cell surface, effectively abrogating its cell‐mediated anticancer mechanisms .…”

Section: Fcγriib‐mediated Crosslinking Of Therapeutic Antibodiesmentioning

confidence: 97%

“…FcγRIIB can be targeted by specific blocking mAbs or its expression regulated by modulating the tumor microenvironment . Alternatively, engineering therapeutic mAbs to reduce their binding to FcγRIIB has been proposed as an approach to overcome such resistance …”

Section: Fcγriib As a Therapeutic Targetmentioning

confidence: 99%

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New revelations from an old receptor: Immunoregulatory functions of the inhibitory Fc gamma receptor, FcγRIIB (CD32B)

Roghanian

Stopforth

Dahal

et al. 2018

Journal of Leukocyte Biology

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The Fc gamma receptor IIB (FcγRIIB/CD32B) was generated million years ago during evolution. It is the sole inhibitory receptor for IgG, and has long been associated with the regulation of humoral immunity and innate immune homeostasis. However, new and surprising functions of FcγRIIB are emerging. In particular, FcγRIIB has been shown to perform unexpected activatory roles in both immune-signaling and monoclonal antibody (mAb) immunotherapy. Furthermore, although ITIM signaling is an integral part of FcγRIIB regulatory activity, it is now clear that inhibition/activation of immune responses can occur independently of the ITIM. In light of these new findings, we present an overview of the established and noncanonical functions of FcγRIIB and discuss how this knowledge might be exploited therapeutically.

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Section: Fcγriib Structurementioning

confidence: 69%

Section: Fcγriib‐mediated Crosslinking Of Therapeutic Antibodiesmentioning

confidence: 97%

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New revelations from an old receptor: Immunoregulatory functions of the inhibitory Fc gamma receptor, FcγRIIB (CD32B)

Roghanian

Stopforth

Dahal

et al. 2018

Journal of Leukocyte Biology

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“…35,36 It is likely that PBMCs comprise multiple types of immune effector cells, and the lower ADCC activity of aglycosylated Fc variants compared with Herceptin might be derived from the increased binding affinity to FcgRIIb, an inhibitory receptor for downregulating immune cell activation for antitumor activity. 37,38 Further engineering to reduce binding to inhibitory FcgRIIb will generate Fc variants that exhibit improved ADCC and tumor cell-killing activities.…”

Section: Discussionmentioning

confidence: 99%

Engineered aglycosylated full-length IgG Fc variants exhibiting improved FcγRIIIa binding and tumor cell clearance

Kwon²,

Lee

et al. 2017

mAbs

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FcγRIIIa, which is predominantly expressed on the surface of natural killer cells, plays a key role in antibody-dependent cell-mediated cytotoxicity (ADCC), a major effector function of therapeutic IgG antibodies that results in the death of aberrant cells. Despite the potential uses of aglycosylated IgG antibodies, which can be easily produced in bacteria and do not have complicated glycan heterogeneity issues, they show negligible binding to FcγRIIIa and abolish the activation of immune leukocytes for tumor cell clearance, in sharp contrast to most glycosylated IgG antibodies used in the clinical setting. For directed evolution of aglycosylated Fc variants that bind to FcγRIIIa and, in turn, exert potent ADCC effector function, we randomized the aglycosylated Fc region of full-length IgG expressed on the inner membrane of Escherichia coli. Multiple rounds of high-throughput screening using flow cytometry facilitated the isolation of aglycosylated IgG Fc variants that exhibited higher binding affinity to FcγRIIIa-158V and FcγRIIIa-158F compared with clinical-grade trastuzumab (Herceptin®). The resulting aglycosylated trastuzumab IgG antibody Fc variants could elicit strong peripheral blood mononuclear cell-mediated ADCC without glycosylation in the Fc region.

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“…In relation to alloimmune thrombocytopenia of pregnancy, they discussed a role of CRP and oxidative stress in increased clearance of platelets. Mark Cragg and his associates [15] discussed the biology of FcγRIIB and how that could be used to modify monoclonal antibodies in order to improve efficacy of monoclonal antibodies in the treatment of autoimmune diseases and cancer; in the case of autoimmune diseases, by delivering inhibitory signals and inducing apoptosis in autoantibody-producing B cells, and mediating apoptotic signal in malignant B cells. They discussed their work on antigenic modulation of CD20:IgG complexes.…”

mentioning

confidence: 99%

Ins and Outs of Antibodies

Gupta

2016

J Clin Immunol

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In recent years, there have been major developments in the understanding of the mechanisms of assembly, intracellular transport, antibody secretion, and B cell differentiation into antibody-producing plasma cells. These, along with use of FcRs as targets for therapy for human diseases, were the main theme of the 4th International Forum on Immunology Research held at Berlin on October 7-10, 2015.The endoplasmic reticulum (ER) plays a critical role in biogenesis of secretory and membrane proteins, in which Sec61 complex in the ER membrane represents a polypeptide-conducting channel. In the last decade, a number of human diseases have been linked to the components of the protein translocation machinery. These disorders have been grouped as Sec61-channelopathies. The mutations in the gene encoding Sec61α-subunit are associated with a common variable immunodeficiency. Zimmerman [1] reviewed the chaperone network of immunoglobulin heavy chain binding protein (BiP) and its co-chaperones (ERjs or ERdjs) and nucleotide exchange factors and its role in correct folding and assembly of polypeptides that are delivered to their functional location in the cell or outside of the cell by vesicular transport. He discussed in detail the mechanisms of Sec61 mutation resulting in inefficient gating of Sec61 channel resulting in sustained leakage of ER Ca ++ , resulting in apoptosis of plasma cells. It is also interesting to entertain a possibility of defect (s) in the assembly, folding, degradation, and transport out of the cells of secreted IgM or IgA in patients with selective IgM deficiency and selective IgA deficiency, respectively.There has been major progress in understanding transcriptional regulation of terminal differentiation of mature naïve B cells to antibody-secreting B cells; however, only recently attention has been directed towards metabolic regulation of plasma cell differentiation. Aronov and Tirosh [2] reviewed a link between transcriptional and metabolic control of plasma cells. While mature naïve B cells express approximately equal amounts of secreted μ heavy chain (μs) and the transmembrane μ heavy chain (μm), B cells express membrane IgM but do not secrete IgM. μs molecules are continuously degraded by the proteasome-dependent ER-dependent associated degradation pathway (ERDA), whereas μm molecules assemble into BCR and are transported to the cell surface. During B cell differentiation to plasma cells, this process is reversed. Three major transcription factors, IRF4, Blimp1, and XBP1 regulate stepwise differentiation of plasma cells. These include three parallel signaling pathways, IRE1, PERK, and AFT6. Perhaps, there are additional signaling pathways. A role of each of these ER-resident sensors in protein folding, autophagy, and apoptosis of plasma cells is reviewed. Autophagy is a highly conserved intracellular digestive pathway that plays a role in the engulfment of unwanted substrates and directs them to the lysosome for degradation and recycling. Autophagy plays a role in the regulation of both innate an...

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Regulation of Monoclonal Antibody Immunotherapy by FcγRIIB

Cited by 12 publications

References 47 publications

New revelations from an old receptor: Immunoregulatory functions of the inhibitory Fc gamma receptor, FcγRIIB (CD32B)

New revelations from an old receptor: Immunoregulatory functions of the inhibitory Fc gamma receptor, FcγRIIB (CD32B)

Engineered aglycosylated full-length IgG Fc variants exhibiting improved FcγRIIIa binding and tumor cell clearance

Ins and Outs of Antibodies

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