Abstract
Over the last couple of decades, a demographic transition towards an aging population has occurred. This has been accompanied by an increase in chronic inflammatory disorders like atopic dermatitis, rheumatoid arthritis, and diabetic ulcers, as many of these are strongly age related. There is thus an increasing demand to develop better therapeutic strategies to manage and cure chronic diseases. In many of these diseases, the trigger for onset of the inflammation is diverse, but their chronic, non-resolving phases share many similarities like, e.g. composition of the cellular infiltrate and cytokine milieu. One of the main constituents of the cellular infiltrate are macrophages (MØs), and these have been recognised as key players in chronicity. In particular, the pro-inflammatory M1 subpopulations has been ascribed a role in persistence, whereas the M2 population is involved in tissue remodeling and resolution. The high expression of the high affinity receptor for IgG is specific for M1. In this chapter, we describe the preclinical development of immunotoxins, targeting CD64 on M1, for the treatment of the chronic phase of chronic inflammatory diseases. Although ADCs using a protein toxin as effector molecule, also known as immunotoxins, were mainly developed for life-threatening disease like cancer, the ongoing improvement on these therapeutics has broadened their potential clinical application. Preclinical data on immunotoxins targeting CD64 show that targeting M1 cells through CD64 in chronic inflammation has a beneficial effect on course and development of the disease and leads to resolution of the inflammation, both in vivo in preclinical animal models and ex vivo on patient-derived cells and biopsies. This efficacy, combined with the improved safety profile of the latest generation immunotoxins, qualifies these CD64-targeted agents for M1-specific therapeutic intervention in chronic inflammatory disease.
Theo Thepen (Corresponding author: CD64) and Stefan Barth (Corresponding author: rec. IT).
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References
Balce DR, Li B, Allan ERO et al (2011) Alternative activation of macrophages by IL-4 enhances the proteolytic capacity of their phagosomes through synergistic mechanisms. Blood 118:4199–4208. doi:10.1182/blood-2011-01-328906
Barth S, Huhn M, Matthey B et al (2000) Compatible-solute-supported periplasmic expression of functional recombinant proteins under stress conditions. Appl Environ Microbiol 66:1572–1579. doi:10.1128/AEM.66.4.1572-1579.2000
Baxi EG, DeBruin J, Tosi DM et al (2015) Transfer of myelin-reactive Th17 cells impairs endogenous remyelination in the central nervous system of cuprizone-fed mice. J Neurosci 35:8626–8639. doi:10.1523/JNEUROSCI.3817-14.2015
Beekman JM, van der Poel CE, van der Linden JA et al (2008) Filamin A stabilizes Fc gamma RI surface expression and prevents its lysosomal routing. J Immunol 180:3938–3945
Berges N, Hehmann-Titt G, Hristodorov D et al (2014) Human cytolytic fusion proteins: modified versions of human granzyme B and angiogenin have the potential to replace bacterial toxins in targeted therapies against CD64+ diseases. Antibodies 3:92–115. doi:10.3390/antib3010092
Boros P, Bromberg JS (2006) New cellular and molecular immune pathways in ischemia/reperfusion injury. Am J Transplant 6:652–658. doi:10.1111/j.1600-6143.2005.01228.x
Challa DK, Velmurugan R, Ober RJ, Sally Ward E (2014) FcRn: from molecular interactions to regulation of IgG pharmacokinetics and functions. Curr Top Microbiol Immunol 382:249–272. doi:10.1007/978-3-319-07911-0_12
Chan AC, Carter PJ (2010) Therapeutic antibodies for autoimmunity and inflammation. Nat Rev Immunol 10:301–316. doi:10.1038/nri2761
Coutinho AE, Chapman KE (2011) The anti-inflammatory and immunosuppressive effects of glucocorticoids, recent developments and mechanistic insights. Mol Cell Endocrinol 335:2–13. doi:10.1016/j.mce.2010.04.005
de Vries IJ, Langeveld-Wildschut EG, van Reijsen FC et al (1997) Nonspecific T-cell homing during inflammation in atopic dermatitis: expression of cutaneous lymphocyte-associated antigen and integrin alphaE beta7 on skin-infiltrating T cells. J Allergy Clin Immunol 100:694–701
Fet NG, Fiebeler A, Klinge U et al (2012) Reduction of activated macrophages after ischaemia-reperfusion injury diminishes oxidative stress and ameliorates renal damage. Nephrol Dial Transplant 27:3149–3155. doi:10.1093/ndt/gfr792
Fischer R, Stoger E, Schillberg S et al (2004) Plant-based production of biopharmaceuticals. Curr Opin Plant Biol 7:152–158. doi:10.1016/j.pbi.2004.01.007
Fridman WH (1991) Fc receptors and immunoglobulin binding factors. FASEB J 5:2684–2690
Gordon S, Taylor PR (2005) Monocyte and macrophage heterogeneity. Nat Rev Immunol 5:953–964. doi:10.1038/nri1733
Goswami S, Wang W, Arakawa T, Ohtake S (2013) Developments and challenges for mAb-based therapeutics. Antibodies 2:452–500. doi:10.3390/antib2030452
Graziano RF, Tempest PR, White P et al (1995) Construction and characterization of a humanized anti-gamma-Ig receptor type I (Fc gamma RI) monoclonal antibody. J Immunol 155:4996–5002
Grewe M, Bruijnzeel-Koomen CA, Schöpf E et al (1998) A role for Th1 and Th2 cells in the immunopathogenesis of atopic dermatitis. Immunol Today 19:359–361
Guyre PM, Graziano RF, Vance BA et al (1989) Monoclonal antibodies that bind to distinct epi topes on Fc gamma RI are able to trigger receptor function. J Immunol 143:1650–1655
Heijnen IA, van de Winkel JGJ (1995) A human Fc gamma RI/CD64 transgenic model for in vivo analysis of (bispecific) antibody therapeutics. J Hematother 4:351–356
Heijnen IA, van Vugt MJ, Fanger NA et al (1996) Antigen targeting to myeloid-specific human Fc gamma RI/CD64 triggers enhanced antibody responses in transgenic mice. J Clin Invest 97:331–338. doi:10.1172/JCI118420
Himmelweit F (1960) The collected papers of paul ehrlich in four volumes including a complete bibliography. Pergamon Press, Oxford
Hristodorov D, Mladenov R, Huhn M et al (2012) Macrophage-targeted therapy: CD64-based immunotoxins for treatment of chronic inflammatory diseases. Toxins (Basel) 4:676–694. doi:10.3390/toxins4090676
Hristodorov D, Mladenov R, Felbert von V et al (2015) Targeting CD64 mediates elimination of M1 but not M2 macrophages in vitro and in cutaneous inflammation in mice and patient biopsies. MAbs:00–00. doi:10.1080/19420862.2015.1066950
Italiani P (2014) From monocytes to M1/M2 macrophages: phenotypical vs. functional differentiation. Front Immunol 5:514. doi:10.3389/fimmu.2014.00514/abstract
Kiekens RC, Thepen T, Bihari IC et al (2000) Expression of Fc receptors for IgG during acute and chronic cutaneous inflammation in atopic dermatitis. Br J Dermatol 142:1106–1113
Klimka A, Barth S, Matthey B et al (1999) An anti-CD30 single-chain Fv selected by phage display and fused to Pseudomonas exotoxin A (Ki-4(scFv)-ETÁ) is a potent immunotoxin against a Hodgkin-derived cell line. Br J Cancer 80:1214. doi:10.1038/sj.bjc.6690488
Köhler G, Milstein C (1975) Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 256:495–497
Langeveld-Wildschut EG, Thepen T, Bihari IC et al (1996) Evaluation of the atopy patch test and the cutaneous late-phase reaction as relevant models for the study of allergic inflammation in patients with atopic eczema. J Allergy Clin Immunol 98:1019–1027
Li J, Hsu H-C, Mountz JD (2013) The dynamic duo-inflammatory M1 macrophages and Th17 cells in Rheumatic Diseases. J Orthop Rheumatol 1(4). doi:10.13188/2334-2846.1000002
Liu Y-C, Zou X-B, Chai Y-F, Yao Y-M (2014) Macrophage polarization in inflammatory diseases. Int J Biol Sci 10:520–529. doi:10.7150/ijbs.8879
Mantovani A, Sica A, Sozzani S et al (2004) The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol 25:677–686. doi:10.1016/j.it.2004.09.015
Metchnikoff É (1892) Leçons sur la pathologie comparée de l’inflammation. Masson
Mills CD (2015) Anatomy of a discovery: M1 and M2 macrophages. Front Immunol 6:212. doi:10.3389/fimmu.2015.00212
Mills CD, Kincaid K, Alt JM et al (2000) M-1/M-2 Macrophages and the Th1/Th2 paradigm. J Immunol 164:6166–6173. doi:10.4049/jimmunol.164.12.6166
Mosser DM, Edwards JP (2008) Exploring the full spectrum of macrophage activation. Nat Rev Immunol 8:958–969. doi:10.1038/nri2448
Perco P, Pleban C, Kainz A et al (2007) Gene expression and biomarkers in renal transplant ischemia reperfusion injury. Transpl Int 20:2–11. doi:10.1111/j.1432-2277.2006.00376.x
Ravetch JV, Kinet JP (1991) Fc receptors. Annu Rev Immunol 9:457–492. doi:10.1146/annurev.iy.09.040191.002325
Reichert J (2015) Approved_mAbs. http://www.antibodysociety.org.newsapprovedmabs.php, 1–2.
Ribbert T, Thepen T, Tur MK et al (2010) Recombinant, ETA′-based CD64 immunotoxins: improved efficacy by increased valency, both in vitro and in vivo in a chronic cutaneous inflammation model in human CD64 transgenic mice. Br J Dermatol 163:279–286. doi:10.1111/j.1365-2133.2010.09824.x
Robbe P, Draijer C, Borg TR et al (2015) Distinct macrophage phenotypes in allergic and nonallergic lung inflammation. Am J Physiol Lung Cell Mol Physiol 308:L358–L367. doi:10.1152/ajplung.00341.2014
Sean Eardley K, Cockwell P (2005) Macrophages and progressive tubulointerstitial disease. Kidney Int 68:437–455. doi:10.1111/j.1523-1755.2005.00422.x
Sica A, Mantovani A (2012) Macrophage plasticity and polarization: in vivo veritas. J Clin Invest 122:787–795. doi:10.1172/JCI59643
Sodoyer R (2004) Expression systems for the production of recombinant pharmaceuticals. BioDrugs 18:51–62
Thepen T, Langeveld-Wildschut EG, Bihari IC et al (1996) Biphasic response against aeroallergen in atopic dermatitis showing a switch from an initial TH2 response to a TH1 response in situ: an immunocytochemical study. J Allergy Clin Immunol 97:828–837
Thepen T, van Vuuren AJ, Kiekens RC et al (2000) Resolution of cutaneous inflammation after local elimination of macrophages. Nat Biotechnol 18:48–51. doi:10.1038/71908
Tur MK, Huhn M, Thepen T et al (2003) Recombinant CD64-specific single chain immunotoxin exhibits specific cytotoxicity against acute myeloid leukemia cells. Cancer Res 63:8414–8419
Van De Winkel JG, Capel PJ (1993) Human IgG Fc receptor heterogeneity: molecular aspects and clinical implications. Immunol Today 14:215–221. doi:10.1016/0167-5699(93)90166-I
van der Poel CE, Karssemeijer RA, Boross P et al (2010) Cytokine-induced immune complex binding to the high-affinity IgG receptor, FcγRI, in the presence of monomeric IgG. Blood 116:5327–5333. doi:10.1182/blood-2010-04-280214
van der Poel CE, Spaapen RM, van de Winkel JGJ, Leusen JHW (2011) Functional characteristics of the high affinity IgG receptor, FcγRI. J Immunol 186:2699–2704. doi:10.4049/jimmunol.1003526
van Roon JAG, van Vuuren AJ, Wijngaarden S et al (2003) Selective elimination of synovial inflammatory macrophages in rheumatoid arthritis by an Fcgamma receptor I-directed immunotoxin. Arthritis Rheum 48:1229–1238. doi:10.1002/art.10940
van Vuuren AJ, van Roon JAG, Walraven V et al (2006) CD64-directed immunotoxin inhibits arthritis in a novel CD64 transgenic rat model. J Immunol 176:5833–5838
Vitetta ES, Krolick KA, Miyama-Inaba M et al (1983) Immunotoxins: a new approach to cancer therapy. Science 219:644–650
Wang Y, Harris DCH (2011) Macrophages in renal disease. J Am Soc Nephrol 22:21–27. doi:10.1681/ASN.2010030269
Weiner GJ (2015) Building better monoclonal antibody-based therapeutics. Nat Rev Cancer 15:361–370. doi:10.1038/nrc3930
Werfel T, Morita A, Grewe M et al (1996) Allergen specificity of skin-infiltrating T cells is not restricted to a type-2 cytokine pattern in chronic skin lesions of atopic dermatitis. J Invest Dermatol 107:871–876
Xue J, Schmidt SV, Sander J et al (2014) Transcriptome-based network analysis reveals a spectrum model of human macrophage activation. Immunity 40:274–288. doi:10.1016/j.immuni.2014.01.006
Yates RM, Hermetter A, Taylor GA, Russell DG (2007) Macrophage activation downregulates the degradative capacity of the phagosome. Traffic 8:241–250. doi:10.1111/j.1600-0854.2006.00528.x
Zhong RK, Van De Winkel JG, Thepen T et al (2001) Cytotoxicity of anti-CD64-ricin a chain immunotoxin against human acute myeloid leukemia cells in vitro and in SCID mice. J Hematother Stem Cell Res 10:95–105. doi:10.1089/152581601750098318
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Thepen, T., Barth, S. (2017). Recombinant Immunotoxins for Chronic Inflammatory Disease. In: Grawunder, U., Barth, S. (eds) Next Generation Antibody Drug Conjugates (ADCs) and Immunotoxins. Milestones in Drug Therapy. Springer, Cham. https://doi.org/10.1007/978-3-319-46877-8_7
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