Cytokine Therapeutics PDF

Cytokine therapeutics Image by Creative Biolabs (www.creative-biolabs.com) Christina Sakellariou, PhD Department of Immunotechnology November 2024 [email protected] ...

Cytokine therapeutics Image by Creative Biolabs (www.creative-biolabs.com) Christina Sakellariou, PhD Department of Immunotechnology November 2024 [email protected]  Lecture’s objectives To: Understand what a cytokine is, its role, its mechanisms of action, its traits Recognise cytokines of the innate and of the adaptive immune system Understand the role of cytokines in inflammation; pro- vs anti- inflammatory cytokines Be able to describe the effects of different cytokines in disease Know at least two examples of cytokine therapeutics used for the treatment of diseases Department of Immunotechnology, Lund University Cytokine biology Cytokine : cyto + kinos (Greek) cell + movement Low molecular weight ( Produced by macrophages Fig. 3.27. Immunobiology, 9th ed. (©Garland Science 2017) Department of Immunotechnology, Lund University > Produced by T cells IL-5 Eosinophil growth factor IL-2 T cell growth factor IL-3 (by Th cells) mast cell growth factor IL-17 T cell activation Neutrophil mobilization, T cell activation IL-4 IFNγ B cell activator Anti-viral effects IL-10 Immunosuppressive Department of Immunotechnology, Lund University  Cytokine signalling Department of Immunotechnology, Lund University  Cytokines signal via their receptors Signal via type I transmembrane proteins trimeric Ligands bind to receptors in extracellular domain Signal transduction initiated by intracellular domain Schematic by (Turner, Nedjai et al. 2014) IGDs: extracellular immunoglobulin domains CRDs: cysteine-rich domains Cytokines belong to families of receptor proteins, each with a distinctive structure. Fig. 3.25 Immunobiology, 9th ed. (©Garland Science 2017)  Cytokine effects in disease Department of Immunotechnology, Lund University IL-1 family Comprised of 11 members (incl. IL-1α, IL-1β, IL-18, IL-33), both pro- and anti- inflammatory members Promote the activity of cells of the innate immune system (e.g. neutrophils, eosinophils, basophils etc) Activate and reinforce T cell function T helper 17 (TH17) cells require IL-1 to differentiate from naïve T cells TH17 cells mediate autoimmune and chronic inflammatory diseases TH1 cells are mainly affected by IL-18 TH2 cells are mainly affected by IL-33 Closely related receptors – signalling! Interleukin-1 family members, processing, receptors and regulation (Sims and Smith 2010) Department of Immunotechnology, Lund University IL-1α and IL-1β Signal through the same receptor IL-1β is secreted and circulates systemically IL-1α is generally associated with the plasma membrane of the producing cell and so acts locally IL-1β is mainly produced by monocytes and macrophages IL-1α expression is highly expressed by keratinocytes and endothelial cells Different functional contributions during immune responses Knockout mice studies show that IL-1α is important for priming T cells during contact hypersensitivity and for the induction of high levels of serum IgE following immunization with ovalbumin IL-1β can circulate to the brain and is more important for the induction of fever Dysregulation of their expression leads to pathobiological diseases Interleukin-1 family members, processing, receptors and regulation (Sims and Smith 2010) Department of Immunotechnology, Lund University IL-18 and IL-33 IL-18 is expressed by macrophages, dendritic cells (DCs), epithelial cells (e.g. keratinocytes) Pro-IL-18 is constitutively expressed, but requires Caspase 1 processing to be fully activated Signalling is initiated when IL-18R binds to IL-18RAP (ie initiated by two subunits) Activity is regulated by the soluble IL-18 binding protein (IL-18BP) when IL-18 binds to IL-18BP, then it cannot bind to its receptors In inflammatory conditions there is much more IL-18 production compared to IL-18BP In circulation (normal conditions) there is much more IL-18BP IL-33 Expressed by many human and mouse tissues, including endothelial, epithelial and fibroblast-like cells Leads to the production of TH2-associated cytokines and increased serum immunoglobulin levels in vitro polarized TH2 cells upon re-stimulation respond to IL-33 by significantly increasing secretion of IL-5 and IL-13 (Schmitz, Owyang et al. 2005) Displays strong immunomodulatory functions Contributes to tissue homeostasis and responses to environmental stresses Interleukin-1 family members, processing, receptors and regulation (Sims and Smith 2010) ST2 is its primary receptor Department of Immunotechnology, Lund University IL-1 and immune-mediated diseases Systemic Lupus Crohn’s disease and Psoriasis Asthma Erythomatosus (SLE) Ulcerative Colitis (UC) (abnormal epidermal differentiation that leads (autoimmune disease involving auto- (Two forms of inflammatory (syndrome of reduced airway flow to redness and scaling of the skin) antibody production and subsequent tissue bowel disease (IBD) characterized by and bronchial remodelling that is driven in destruction in many organs) destructive granulomatous inflammation of part by unregulated and excessive pulmonary the gasterointestinal tract (Crohn’s disease) or inflammation) IL-1, IL-18, IL-1F6 and IL-1F9 Increased amounts of IL-18 in more superficial inflammation of the large are increased in the skin bowel (ulcerative colitis)) Expression of IL-1β by the plasma and skin of patients lesions of patients macrophages in the alveoli and The circulating concentrations IL-1α and IL-1β expression are airway submucosa is increased of both total and free IL-18 enhanced in the inflamed in patients positively correlate with intestinal mucosa of patients disease activity and renal with IBD IL-18-deficient mice have less damage severe lung pathology Inhibition of IL-1 is beneficial compared with wild-type mice in several models of IBD following chronic administration of allergen IL-18 serum concentrations are increased in proportion to Soluble ST2 concentrations are disease severity in Crohn’s increased in asthmatics disease Department of Immunotechnology, Lund University IL-1 family in the clinic Department of Immunotechnology, Lund University IL-1 family in the clinic Department of Immunotechnology, Lund University IL-6 IL-6 and IL-11 belong to the same family Expressed by mononuclear phagocytes, T cells, B cells, fibroblasts, endothelial cells and many more Involved in haematopoiesis maturation of B cells into antibody producing plasma cells T cell activation differentiation and regulation of Th2 and Treg phenotypes Signals through a ligand-binding IL-6 receptor (IL-6R) α chain (gp80, CD126) and the signal-transducing component gp130 (CD130) Pleiotropic activity of IL-6 (Tanaka and Kishimoto 2014) Department of Immunotechnology, Lund University IL-6 and immune-mediated diseases Castleman disease: Pathologic role in disease development lymphoproliferative disorder-> overgrowth of cells in a lymph node Dysregulated IL-6 production occurs in synovial fluids of rheumatoid arthritis, swollen lymph nodes of Castleman disease, myeloma cells, peripheral blood cells or tissues from patients with other diseases, and in many tumour cells Systemic and local inflammatory effects Systemic and local inflammation effects of IL-6 (Choy, De Benedetti et al. 2020) Department of Immunotechnology, Lund University IL-6 and IL-6R blockade IL-6 blockade inhibits disease development in animal models of SLE, rheumatoid arthritis and others IL-6R blockade leads to relief of symptoms from many diseases (Choy, De Benedetti et al. 2020) Department of Immunotechnology, Lund University IL-6 in the clinic IL-6R inhibitors: Tocilizumab Sarilumab IL-6 inhibitor: Siltuximab (Choy, De Benedetti et al. 2020) Department of Immunotechnology, Lund University  (Choy, De Benedetti et al. 2020) Department of Immunotechnology, Lund University Department of Immunotechnology, Lund University TNFα Originally described as an endotoxin induced serum factor responsible for the necrosis of in vitro and in vivo tumours Pro-inflammatory mediator Stimulates cell proliferation Exerts cytolytic and cytostatic activity against tumour cells Anti-viral and immunoregulatory effects Linked to coagulation, insulin resistance, endothelial function PLEIOTROPIC cytokine! Member of the TNF superfamily of type II transmembrane proteins Mainly secreted from activated macrophages; monocytes, NK cells, T cells, neurons and others. Schematic by (Turner, Nedjai et al. 2014) Department of Immunotechnology, Lund University TNFa and immune-mediated diseases In Rheumatoid arthritis: Many pro-inflammatory cytokines, including IL-1, IL-6, TNF and GM-CSF, are produced within the inflamed joints Neutralizing TNF with either anti-TNF antibody or a recombinant soluble TNF receptor ameliorates joint disease in a murine model of collagen-induced arthritis In Psoriasis: TNF, TNFR1 and TNFR2 are upregulated in dermal blood vessels in involved skin from patients with psoriasis Anti-TNF therapies have showed rapid and significant improvement of patient plaques In Cardiovascular disease (e.g. atherosclerosis, heart failure): vascular endothelial cell responses to TNF may underlie the vascular pathology TNF-blockade hasn’t proved clinically beneficial Department of Immunotechnology, Lund University Anti-TNF therapies: mainly for autoimmune diseases (Rheumatoid arthritis (RA), psoriasis, IBD and others) Humira® (adalibumab): fully human monoclonal antibody (mAb) Remicade ® (infliximab): chimeric IgG anti-human mAb Enbrel ® (etanercept): a TNFR2 dimeric fusion protein, with an IgG1 Fc Simponi Aria ® (Golimumab): fully human mAb Cimzia ® (Certolizumab pegol): PEGylated Fab fragment Schematic by https://musculoskeletalkey.com/anti-tnf-therapy/ Department of Immunotechnology, Lund University IL-2 By Steven Rosenberg Department of Immunotechnology, Lund University IL-2 Pleiotropic cytokine, originally discovered as T cell growth factor Secreted predominantly by antigen stimulated CD4+ T cells Produced also by CD8 T cells, NK cells, activated DCs Mediates differentiation of naïve CD8 T cells, into memory T cells IL-2 receptors: a – unique β – shared with IL-15 γ – shared with IL-15, IL-4, IL-7, IL-9, IL-21 Schematic by Waldman 2006 Department of Immunotechnology, Lund University IL-2 therapy Key factor for Treg cell survival and maintenance in vivo studies: mice deficient in IL-2/receptors, lacked Treg cells Low dose IL-2 proven efficient in GVHD, transplantation and others – Short half life leads to repeated injections Department of Immunotechnology, Lund University IL-2 therapy in cancer Approved treatment for metastatic melanoma and renal cell carcinoma - ALDESLEUKIN Systemically injected Department of Immunotechnology, Lund University The other side of the coin… Department of Immunotechnology, Lund University Cytokine release syndrome Systemic inflammatory response, triggered by infections, drugs and other factors Described after infusion of several antibody based, protein and non-protein-based drugs Observed in the setting of transplantation and GVHD Massive T cell stimulation! One of the most frequent adverse events of such therapies Theralizumab (by TeGenero) Anti-CD28 Activated all T cells Cytokine storm! Department of Immunotechnology, Lund University A long way to go.. Cytokines’ half life is small – limits their efficacy Systemic administration? Limited efficacy More toxicities! Why are many immunotherapies given at a late disease stage? Why are they given to specific subcategories of diseased patients? Department of Immunotechnology, Lund University References 1. Kany, S., J.T. Vollrath, and B. Relja, Cytokines in Inflammatory Disease. Int J Mol Sci, 2019. 20(23). 2. Cavaillon, J.M., Pro- versus anti-inflammatory cytokines: myth or reality. Cell Mol Biol (Noisy-le-grand), 2001. 47(4): p. 695-702. 3. Turner, M. D., et al. (2014). "Cytokines and chemokines: At the crossroads of cell signalling and inflammatory disease." Biochim Biophys Acta 1843(11): 2563-2582. 4. Sims, J. E. and D. E. Smith (2010). "The IL-1 family: regulators of immunity." Nat Rev Immunol 10(2): 89-102. 5. Tanaka, T. and T. Kishimoto (2014). "The biology and medical implications of interleukin-6." Cancer Immunol Res 2(4): 288-294. 6. Choy, E. H., et al. (2020). "Translating IL-6 biology into effective treatments." Nat Rev Rheumatol 16(6): 335-345. 7. Waldmann, T. A. (2006). "The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine design." Nat Rev Immunol 6(8): 595-601. 8. Feldmann, M. (2008). "Many cytokines are very useful therapeutic targets in disease." J Clin Invest 118(11): 3533-3536. 9. Donnelly, R. P., et al. (2009). "An overview of cytokines and cytokine antagonists as therapeutic agents." Ann N Y Acad Sci 1182: 1- 13. Department of Immunotechnology, Lund University Questions to think and reflect upon Are there “good” and “bad” cytokines? Can we use one cytokine therapy to treat many different types of diseases? Any other reason that cytokine therapeutics are not as efficacious as desired? (Think of pleiotropy) How else can we use the cytokine therapeutics, to take a greater advantage of them? Why are many immunotherapies given at a late disease stage? Why are they given to specific subcategories of diseased patients?