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Antibodies Targeting Chemokine Receptors CXCR4 and ACKR3

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Antibodies Targeting Chemokine Receptors CXCR4 and ACKR3 1521-0111/96/6/753–764$35.00 https://doi.org/10.1124/mol.119.116954 MOLECULAR PHARMACOLOGY Mol Pharmacol 96:753–764, December 2019 Copyright ª 2019 by The Author(s) This is an open access article distributed under the CC BY-NC Attribution 4.0 International license. Special Section: From Insight to Modulation of CXCR4 and ACKR3 (CXCR7) Function – Minireview Antibodies Targeting Chemokine Receptors CXCR4 and ACKR3 Vladimir Bobkov, Marta Arimont, Aurélien Zarca, Timo W.M. De Groof, Bas van der Woning, Hans de Haard, and Martine J. Smit Division of Medicinal Chemistry, Amsterdam Institute for Molecules Medicines and Systems, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands (V.B., M.A., A.Z., T.W.M.D.G., M.J.S.); and argenx BVBA, Zwijnaarde, Belgium (V.B., B.W., H.H.) Downloaded from Received April 22, 2019; accepted July 3, 2019 ABSTRACT Dysregulation of the chemokine system is implicated in a number CXCR4 and ACKR3, formerly referred to as CXCR7. We of autoimmune and inflammatory diseases, as well as cancer. discuss their unique properties and advantages over small- molpharm.aspetjournals.org Modulation of chemokine receptor function is a very promising molecule compounds, and also refer to the molecules in approach for therapeutic intervention. Despite interest from preclinical and clinical development. We focus on single- academic groups and pharmaceutical companies, there are domain antibodies and scaffolds and their utilization in GPCR currently few approved medicines targeting chemokine recep- research. Additionally, structural analysis of antibody binding tors. Monoclonal antibodies (mAbs) and antibody-based mole- to CXCR4 is discussed. cules have been successfully applied in the clinical therapy of cancer and represent a potential new class of therapeutics SIGNIFICANCE STATEMENT targeting chemokine receptors belonging to the class of G Modulating the function of GPCRs, and particularly chemokine protein–coupled receptors (GPCRs). Besides conventional receptors, draws high interest. A comprehensive review is mAbs, single-domain antibodies and antibody scaffolds provided for monoclonal antibodies, antibody fragments, and at ASPET Journals on September 29, 2021 are also gaining attention as promising therapeutics. In this variants directed at CXCR4 and ACKR3. Their advantageous review, we provide an extensive overview of mAbs, single- functional properties, versatile applications as research tools, domain antibodies, and other antibody fragments targeting and use in the clinic are discussed. Introduction Gprotein–independent systems and are, therefore, referred to as atypical chemokine receptors (Nibbs and Graham, CXCR4 and ACKR3: Role in Physiology and Diseases. 2013). CXCR4 activates the G family of heterotrimeric Chemokines and chemokine receptors play key roles in i G proteins, while ACKR3, previously known as CXCR7, immune system homeostasis, controlling the activation, dif- signals in a G protein–independent and b-arrestin–dependent ferentiation, migration, and survival of leukocytes and other manner. ACKR3 downregulates CXCR4 signaling by either hematopoietic cells (Scholten et al., 2012). Due to their role in scavenging its ligand CXCL12 or forming heterodimers leukocyte migration, the chemokine receptor system is an with CXCR4 (Rajagopal et al., 2010); there may also important mediator of inflammation. Prolonged or deregu- be crosstalk between CXCR4 and ACKR3 upon ligand lated expression of chemokines or chemokine receptors pro- binding that is mediated by intracellular signaling effectors motes abnormal infiltration of leukocytes into inflamed tissue. (Zabel et al., 2009). This may result in inflammation, autoimmune diseases, CXCR4 and ACKR3 have been widely studied in relation to tumor growth, survival, and metastasis (Scholten et al., their role in a large number of diseases. CXCR4 was the first 2012). Most chemokine receptors, belonging to the superfam- human immunodeficiency virus (HIV) coreceptor discovered ily of G protein–coupled receptors (GPCRs), activate G and has since then become an interesting target for the – protein dependent signaling pathways upon agonist binding. treatment of AIDS (De Clercq, 2003). X4 HIV strains bind to However, there are some chemokine receptors that signal via CD4 and CXCR4 through the envelope glycoprotein gp120 to infect the target cell (Murphy and Heusinkveld, 2018). This research was funded by the European Union’s Horizon 2020 Marie Skłodowska-Curie Actions Program under ONCORNET Grant 641833. Mutations truncating the C-terminus of CXCR4 also cause https://doi.org/10.1124/mol.119.116954. the rare immunodeficiency warts, hypogammaglobulinemia, ABBREVIATIONS: ADCC, antibody-dependent cell-mediated cytotoxicity; CDC, complement-dependent cytotoxicity; CDR, complementarity determining region; CGRP, calcitonin gene-related peptide; ECL, extracellular loop; Fab, antigen-binding fragment; Fc, fragment crystallizable; FDA, Food and Drug Administration; GPCR, G protein–coupled receptor; mAb, monoclonal antibody; Nb, nanobody. 753 754 Bobkov et al. infections, and myelokathexis syndrome. The CXCR4-CXCL12 data (Burns et al., 2006; Peled et al., 2012; Scholten et al., axis is also implicated in chronic inflammatory diseases such as 2012; Teixidó et al., 2018). Thus, a specific blockage of asthma and rheumatoid arthritis (Tamamura et al., 2004). CXCR4 and/or ACKR3 function has a great potential for Multiple cancer cells show elevated expression of CXCR4, clinical therapy of cancer and other disorders. Antibodies including breast, ovarian, and prostate cancer cells, mela- and their fragments can be ideal candidates for such clinical nomas, gliomas, neuroblastomas, osteosarcomas, leukemia, interventions and serve as important tools in fundamental T- and B-cell lymphomas, colorectal, pancreatic, and uter- research. ine cancers, among others (Peled et al., 2012). ACKR3 Monoclonal Antibodies and Their First Approvals for expression is also increased in a number of cancer types Targeting GPCRs. In 1985, the United States Food and including leukemia, breast, pancreatic, colon, and lung Drug Administration (FDA) approved the first monoclonal (Miao et al., 2007; Melo et al., 2014; D’Alterio et al., 2016; antibody (mAb) directed against CD3, muromonab (Ortho- Guo et al., 2016). Both receptors are involved in different clone OKT3), for the treatment of kidney transplant rejection stages of tumorigenesis including growth, survival, and (Smith, 1996). Since then, 76 mAbs have received marketing metastasis, according to in vitro and in vivo experimental approval by the European Medicines Agency and FDA, with Downloaded from molpharm.aspetjournals.org at ASPET Journals on September 29, 2021 Fig. 1. Overview of antibody formats. (A) Schematic representation of the structure of a conventional antibody (Conv. Ab), heavy chain–only antibody (HCAb), and immunoglobulin new antigen receptor (IgNAR). The antibodies consist of constant domains [constant heavy (CH) and constant light (CL)] and variable domains [variable heavy (VH), variable light (VL), variable heavy chain region of a heavy chain–only antibody (VHH), or variable fragment of immunoglobulin new antigen receptor (VNAR)], which make up the Fc region and Fab domains. (B) Overview of commonly used fragments derived from Conv. Abs, HCAbs, or IgNARs. Bispec. Nb, bispecific nanobody; Biv. Nb, bivalent nanobody; Nb, nanobody; Nb-Fc, nanobody-Fc fusion protein; scFv, single-chain variable fragment. Antibodies Targeting CXCR4 and ACKR3 755 around 30 mAbs approved for oncological indications (http:// for the treatment of CCR4-positive adult T-cell leukemia/ www.ema.europa.eu, www.fda.gov; as of April 2019). mAbs lymphoma (Beck and Reichert, 2012). In May 2018, the FDA and antibody-based therapeutics is a relatively young but fast- approved another GPCR-targeting mAb, erenumab (Aimovig), growing field with approximately 30 candidates in late-stage a fully human antagonistic antibody against the calcitonin clinical trials for cancer therapy and many more in earlier gene-related peptide (CGRP) receptor for prevention of mi- phases of development, indicating a further increase in graine (Dolgin, 2018). Erenumab is a highly potent antibody, approvals in the upcoming years (Kaplon and Reichert, 2018). and in comparison with small-molecule compounds targeting Antibodies are normally produced by B-cells of the immune the CGRP receptor, e.g., telcagepant [N-[(3R,6S)-6-(2,3- system to regulate immune response and specifically bind and difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4- neutralize foreign pathogens and microbes. Specific target (2-oxo-3H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide], recognition is mediated by variable fragments located on the it offers greater specificity with no measurable activity on ends of two antigen-binding fragment (Fab) arms composed of other receptors in the family, thus reducing possible off-target heavy and light chains (Figs. 1 and 2). Fabs are connected to effects (Walker et al., 2015; Shi et al., 2016). CGRP has an the fragment crystallizable (Fc) region, and the resulting extensive binding epitope on the receptor. Therefore, a broad molecule features a Y-shaped heterotetrameric structure with coverage of the extracellular sites with multiple interactions an approximate molecular weight of 150 kDa. In 1975, Köhler on both subunits of the CGRP receptor by erenumab can offer and Milstein introduced the first technique for isolating superior specificity and potency in competing with CGRP over
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