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Fc Receptors: Regulatory Mechanisms and Function in Antibody Therapy Fc receptors: regulatory mechanisms and function in antibody therapy Arianne M. Brandsma Fc receptors: regulatory mechanisms and function in antibody therapy Thesis with a summary in English and Dutch, Utrecht University © Arianne Brandsma, 2018 The copyrights of published articles have been transferred to the respective journals. All rights reserved. No part of this thesis may be reproduced, stored in a retrieval system, or transmitted in any other form or by any means, without the permission of the author. ISBN: 9789462959323 Cover design: SVDH Media || www.svdhmedia.nl Layout: Kirsten Geneugelijk Printed by: ProefschriftMaken || www.proefschriftmaken.nl Printing of this thesis was financially supported by: Genmab BV, Roche Glycart AG, and Infection & Immunity Utrecht. Fc receptors: regulatory mechanisms and function in antibody therapy Fc receptoren: regulatie en rol in antistoftherapie (met een samenvatting in het Nederlands) Proefschrift ter verkrijging van de graad van doctor aan de Universiteit Utrecht op gezag van de rector magnificus, prof.dr. G.J. van der Zwaan, ingevolge het besluit van het college voor promoties in het openbaar te verdedigen op donderdag 19 april 2018 des middags te 2.30 uur door Arianne Michèle Brandsma geboren op 22 september 1990 te Vlaardingen Promotor: Prof.dr. J.H.E. Küball Copromotor: Dr. J.H.W. Leusen “A healthy person has a thousand wishes, but a sick person has only one.” − Indian Proverb Reading committee: Prof.dr. J.G.J. van de Winkel Prof.dr. C.E. Hack Prof.dr. J.A.G. van Strijp Prof.dr. M. Peipp Dr. A. Ioan-Fascinay Paranimphs: Kirsten Geneugelijk Maaike Nederend TABLE OF CONTENTS Chapter 1 General introduction 9 Chapter 2 Fc receptor inside-out signaling and possible impact on antibody therapy 23 Chapter 3 Mechanisms of inside-out signaling of the high affinity IgG receptor FcγRI 49 Chapter 4 Strategies to generate conformation-specific antibodies against the high affinity IgG receptor FcγRI 79 Chapter 5 Single nucleotide polymorphisms of the high affinity IgG receptor FcγRI reduce immune complex binding and downstream effector functions 101 Chapter 6 Simultaneous targeting of FcγRs and FcαRI enhances tumor cell killing 123 Chapter 7 Clarifying the confusion between cytokine and Fc receptor “common gamma chain” 147 Chapter 8 General discusssion 153 Appendices Summary 184 Nederlandse samenvatting 186 Dankwoord 190 List of publications 194 Curriculum vitae 197 CHAPTER General introduction 1 Chapter 1 mmunoglobulins, better known as antibodies, are an essential part of the immune sys- Item by specifically binding foreign antigens and eliminating them. Antibodies consist of two identical Fab (antigen binding) domains with hypervariable regions at the N-ter- minus which determine the specificity to an antigen and an constant Fc (crystallizable) domain which mediates the effector functions of antibodies (Fig. 1A). B cells can express antibodies on the surface as antigen receptors (BCR) or excrete them to circulate through the body. In humans, five antibody isotypes are known: IgG, IgA, IgE, IgM, and IgD. These isotypes are distinguished by the C-terminus of the heavy chains, which is not variable. The isotypes differ in function, biological properties, and location within the body. The exposure to antigen, the (inflammatory) environment, and interaction of B cells with T helper cells determines the type of humoral (adaptive) immune response. Antibody func- tions include direct neutralization of pathogens, recruitment of the complement system to directly lyse pathogens or infected cells, and cellular effector functions like phagocytosis and antibody-dependent cellular cytotoxicity (ADCC) of infected cells (Fig. 2A). As the name suggests, Fc receptors (FcR) bind to the Fc domain of antibodies. Fc receptors are mainly expressed on cells of the innate immune system, and thereby provide a crucial bridge between the adaptive and innate immune system. Fc receptor family The human FcR family comprises receptors for all five antibody isotypes: FcγR (IgG), FcαR (IgA), FcεR (IgE), FcµR (IgM), and FcδR (IgD). Most leukocyte Fc receptors are hetero-oligomeric complexes with a unique ligand binding α-chain and one or more accessory subunits (β-, γ-, or ζ-chains). The immunoreceptor tyrosine-based activation motif (ITAM) is essential in triggering biological functions of activating FcR. In addition, some FcR induce inhibitory signals via the immunoreceptor tyrosine-based inhibitory motif (ITIM). For multi-chain FcR (FcγRI, FcγRIIIa), the signaling motif is present in the non-covalently associated FcR γ-chain, whereas for single-chain FcR (FcγRIIa, FcγRIIb), this motif is present in its own cytoplasmic domain1,2. The activation of cells via Fc recep- tor crosslinking is regulated by the amount of antibodies bound to FcR and the ratio of activating and inhibitory Fc receptors on immune cells. The FcγR family is the most extensively studied. It comprises the four activating receptors FcγRI, FcγRIIa, FcγRIIc, and FcγRIIIa, as well as one inhibitory receptor, Fcγ- RIIb. In addition, FcγRIIIb is a glycophosphatidylinositol (GPI)-linked receptor without any known intrinsic signaling capacity. These receptors are expressed on most myeloid cells, including monocytes, macrophages, and neutrophils (Table 1). FcγRI is the only -8 -9 receptor with a high affinity for monomeric IgG (KD of 10 -10 M), while the other FcγR have a low affinity for monomeric IgG. The different FcγRs bind the IgG subclasses (IgG1, IgG2, IgG3, and IgG4) with different specificities and avidities (Fig. 1B). FcαRI is the human receptor for IgA1 and IgA2 that poorly binds monomeric IgA but binds multim- eric IgA avidly. FcγRs, as well as FcαRI, will be further discussed in chapter 2. After crosslinking of activating FcR by immune complexes, kinases of the SRC family phosphorylate the tyrosine residues of the ITAM. These phosphotyrosines now provide a 10 General introduction docking site for kinases of the SYK family that bind via their SH2 domains, which in turn become activated3. Via the activation of several downstream targets, SYK activation results in activation of the RAS-MAPK pathway, increased intracellular calcium levels, and ulti- mately activation of NF-κB transcription factors. These signals can activate the immune cell and lead to e.g. phagocytosis, oxidative burst, and cytokine release. Crosslinking of 1 the inhibitory FcγRIIb leads to phosphorylation of the ITIM by LYN and this recruits and activates the SH2-containing phosphatases SHIP and SHP1. These phosphatases will then dephosphorylate the kinases downstream of ITAM signaling4,5. This counterbalances the activating signaling cascades and can abrograte activating FcR effector functions. Antibody therapy Cancer is a group of malignant diseases characterized by abnormal cell growth after cells acquire multiple genetic mutations. Standard care for cancer patients includes surgical removal of the tumor, radiation therapy, and chemotherapy. However, these treatments are not very specific for tumor cells and often healthy tissue is damaged as well. Antibodies are very specific for their target and can make use of the patients’ own immune system to eliminate tumor cells. This makes antibodies promising agents for targeted therapy of cancer. Several decades ago, rituximab was the first monoclonal antibody (mAb) to be FDA-approved for the treatment of cancer patients. Since then, many more mAbs have been developed for cancer therapy. Besides targeting cancer cells, mAbs are also used as prophylaxis/treatment of autoimmune and infectious diseases. All clinically approved mAbs are of the IgG isotype, mostly IgG1. This has also boosted the attention for FcγR, as the activation of FcγR on immune cells can trigger eradication of target cells. The mechanism of action of mAbs involve direct Fab-mediated and indirect Fc-me- diated effects (Fig. 2B). Binding of mAbs to FcγR on immune cells exploits the normal cellular effector functions of antibodies. Examples of Fab-mediated anti-tumor effects include blocking the ligand binding site of growth factor receptors (e.g. anti-EGFR mAb A variable B region antigen binding domain IgG1 IgG2 IgG3 IgG4 IgA1 IgA2 Fab FcγRI +++ - +++ +++ - - fragment FcγRIIa +++ ++/+* +++ ++ - - light FcγRIIb + - ++ + - - chain constant # # FcγRIIIa ++ -/+ +++ -/++ - - { region Fc heavy FcγRIIIb +++ - +++ - - - fragment chain FcαRI - - - - +++ +++ Figure 1. General{ antibody structure and IgG and IgA subclass binding to FcγRs and FcαRI. (A) General antibody structure depicting the Fab and Fc fragments and highlighting the variable and constant regions of antibodies. (B) Binding avidity of the different IgG and IgA subclasses to the human FcγRs and FcαRI. Multivalent binding is depicted. * indicates binding for the FcγRIIa- 131H/R polymorphism, respectively. # indicates binding for the FcγRIIIa-158F/V polymorphism, respectively. Adapted from Bruhns et al.46 and Wines et al.47. 11 Chapter 1 A. Natural antibody functions monocyte/ direct B cell macrophage neutralization antibodies opsonization and phagocytosis pathogen Fc receptor antibody-dependent cellular cytoxicity NK cell direct lysis C1q complement phagocytosis via activation complement fagments C3b receptor production of inflammatory mediators neutrophil B. Therapeutic antibody functions Fab-mediated effects Fc-mediated effects complement-dependent cytotoxicity receptor lysis degradation tumor MAC antigen ligand blockade tumor cell apoptosis antibody-dependent cellular cytotoxicity apoptosis inhibit receptor induction
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