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Analyzing Complex Polygenic Traits
Published in Richard K. Burt, Alberto M. Marmont, Stem Cell Therapy for Autoimmune Disease, 2019
Bernard R. Lauwerys, Edward K. Wakeland
In SLE, several genes located on chromosome 1 have been extensively tested for their association with disease: Feγ receptors, T cell receptor zeta chain, interleukin-10, poly (ADP-ribose) polymerase (PARP) and tumor necrosis factor receptor 2 (TNFR2). The genes encoding the low-affinity Fcγ receptors FcγRIIa, FcγRIIb, FcγRIIc, FcγRIIIa and FcγRIIIb are tightly clustered at 1q23.16 FcγRIIa-R/H131 polymorphism was reported in several studies to represent a significant risk factor for SLE.17-19 Interestingly, the FcγRIIa-131R/R genotype, which is enriched in SLE patients, is also associated with a significant decrease in the clearance of immune complexes in vivo, a finding that could be relevant for the pathogenesis of the disease.20 Other polymorphisms in FcyRIIb and FcyRIIIa genotypes have been reported as risk factors for SLE.21,22 However, the results of these studies could be affected by linkage disequilibrium within this region.
Immunoglobulins: Metabolism and biological properties
Published in Gabriel Virella, Medical Immunology, 2019
One notable exception to the ability to induce cell activation is the opposite effect mediated by FcγRIIb receptors. These receptors have mmunoreceptor tyrosine-based inhibitory motifs (ITIM) in their intracellular portion. These receptors are expressed on B lymphocytes and may play a critical role in the downregulation of humoral immune responses as a consequence of the formation of circulating immune complexes.
Fc Receptors
Published in Maurizio Zanetti, J. Donald Capra, The Antibodies, 1999
Genes encoding FcR bear the name of their products, usually written in italics. When several genes encode receptors of a single class for the same isotype of immunoglobulins, they are identified by the capital letters A, B or C, as well as corresponding receptors. Thus, three human genes for high-affinity IgG receptors were found, FcγRIA, FcyRIB and FcyRIC [29], but only one protein, FcγRIA, was found to be expressed on cell membranes. Three genes encode human FcγRII: FcyRΠA, FcyRIIB and FcyRIIC [30], which encode FcγRIIA, FcγRIIB and FcγRIIC. One gene only encodes murine FcγRII [30, 31]. Because this receptor is the homologue of human FcγRIIB, it is referred to as FcγRIIB, even though no FcγRIIA or C exist in mice. Two genes encode human FcγRIII: FcyRIIIA and FcyRIIIB, whereas there is a single FcyRIII gene in mice [30]. The murine FcγRIII being the homologue of human FcγRIIIA, it is referred to as FcγRIIIA.
The emerging landscape of novel 4-1BB (CD137) agonistic drugs for cancer immunotherapy
Published in mAbs, 2023
Christina Claus, Claudia Ferrara-Koller, Christian Klein
Human IgG2 (used in utomilumab) displays a lower hinge flexibility as human IgG4 (used in urelumab), which was correlated with a higher agonistic activity for CD40 agonistic antibodies.27–29 Therefore, the hinge flexibility may not explain the higher agonistic activity of urelumab. Fc-mediated cross-linking, especially binding to Fc gamma receptor IIB (FcγRIIB) has been reported to promote the activity of agonistic antibodies.27,30,31 As an IgG4, urelumab has higher affinity to FcγRIIB, and therefore may mediate stronger FcγRIIB-dependent agonistic activity, but this may not be the only factor related to the agonistic differences between urelumab and utomilumab. Nevertheless, FcγRIIB crosslinking in the liver has been associated with hepatitis induction by anti-Fas or anti-4-1BB agonistic antibodies.26,32,33
Elimination of plasma soluble antigen in cynomolgus monkeys by combining pH-dependent antigen binding and novel Fc engineering
Published in mAbs, 2022
Yuji Hori, Ken Ohmine, Hitoshi Katada, Yuki Noguchi, Kazuki Sato, Takeru Nambu, Lam Runyi Adeline, Gan Siok Wan, Kenta Haraya, Kazuhisa Ozeki, Masahiko Nanami, Tatsuhiko Tachibana, Zenjiro Sampei, Taichi Kuramochi, Junichi Nezu, Kunihiro Hattori, Tomoyuki Igawa
Previously, we reported that Fc variants with enhanced binding to FcγRIIb showed increased clearance of the soluble antigen in mice.17 Although a few Fc variants had enhanced human FcγRIIb (huFcγRIIb) binding, none of them is reported to cross-react with cynomolgus FcγRIIb (cyFcγRIIb).25–27 To predict the sweeping efficacy in humans, we tried to develop a new human Fc variant whose binding levels to huFcγRIIb and cyFcγRIIb were similarly enhanced. This was also needed to reduce binding to activating Fcγ receptors such as FcγRIIIa because it could potentially induce immune activation or cause unwanted adverse effects, depending on the disease or the mode of action of the antibody. Therefore, to make an Fc variant with the desired binding to each FcγR, we selected substitutions G236N, H268D, and A330K, based on our previous work, and introduced them in the Fc region of IgG1.25 The IgG1 variants V1 (G236N), V2 (G236N/H268D), and V3 (G236N/H268D/A330K) were then produced and their binding activity to each Fcγ receptor was measured (Table 2). V3 showed enhanced binding to both huFcγRIIb and cyFcγIIb, and importantly, the levels of enhancement were comparable (by 3.06-fold and 2.86-fold, respectively). Although the affinity to cyFcγRIIa of V3 was also enhanced because of the high homology between cyFcγRIIa and cyFcγRIIb, this Fc variant could be useful for predicting the sweeping efficacy of the antibodies in humans based on cynomolgus monkey pharmacokinetics studies.
CLEC5a-directed bispecific antibody for effective cellular phagocytosis
Published in mAbs, 2022
Vivekananda Kedage, Diego Ellerman, Mingjian Fei, Wei-Ching Liang, Gu Zhang, Eric Cheng, Juan Zhang, Yongmei Chen, Haochu Huang, Wyne P. Lee, Yan Wu, Minhong Yan
A role of CLEC5A in proinflammatory responses has been observed in a variety of settings, during infections with CLEC5A-binding virus such as influenza,14 dengue7 and Japanese encephalitis virus,33 in chronic obstructive pulmonary disease8 and in inflammatory colon diseases.31 Interestingly, an activating mutation in CLEC5A was associated with Crohn’s disease.34 In one study, the proinflammatory responses mediated by CLEC5A led to an increase of immune cell infiltration in the lungs of mice infected with influenza virus.14 Similarly, a CLEC5A-blocking antibody prevented the infiltration of immune cells in the brains of mice infected with Japanese encephalitis virus.33 In this study, we show that agonism of CLEC5A using a bispecific antibody also resulted in the secretion of proinflammatory cytokines. In addition to the direct cancer cell elimination by phagocytosis, the concurrent release of proinflammatory chemokines and cytokines could have additive antitumor effects by recruiting other immune cells. It is known that FcγRIIB, in addition to negatively regulating phagocytosis, also dampens secretion of proinflammatory cytokines.35 On the other hand, activation mediated by DAP10/DAP12 is not as sensitive to ITIM-inhibition as those initiated by ITAM-containing receptors, at least in the context of NKG2D.36,37 Thus, a CLEC5A-based bispecific antibody could lead to a more robust antitumor response.