Autoimmune Disorders PDF

AUTOIMMUNE DISORDERS Characterized by a loss or failure of self-tolerance ▪ More than 80 known autoimmune disorders ▪ May affect a wide range of organ systems ▪ Both cellular and humoral components of the immune syste...

AUTOIMMUNE DISORDERS Characterized by a loss or failure of self-tolerance ▪ More than 80 known autoimmune disorders ▪ May affect a wide range of organ systems ▪ Both cellular and humoral components of the immune system may be implicated  COMMON AUTOIMMUNE MECHANISMS ▪ Each autoimmune disease likely has specific triggers and pathogenesis ▪ Common mechanisms include development of autoantibodies and aberrant cytokine signaling ▪ Therapeutic strategies focus on dampening the aberrant immune response JM Anaya. Autoimmunity Rev. 11(11);781-784 (2012).  EARLY TREATMENT STRATEGIES Dr. Kersley recommended the following: 1. Complete physical and mental rest (bed rest), good nourishing diet with plenty of vitamins and iron, and live under best hygienic conditions 2. Eliminate any sepsis that is found in the body 3. Physical and orthopedic treatment: balancing of rest and exercise, re-education of capillary circulation (contrast heat and cold followed by rub-down), counter-irritation, X-ray therapy, correction of deformity 4. Analgesics to promote sleep and relieve pain: aspirin, phenacetin, caffeine GD Kersley. Bristol Med Chir J (1883). 63(225);11-15 (1945).  THERAPEUTIC TARGETS IN AUTOIMMUNITY ▪ Many potential therapeutic targets for autoimmune disorders ▪ Targets include cell surface markers, cytokines, and autoantibodies ▪ Selection of optimal target will depend on the disease pathology IB McInnes, EM Gravallese. Nat Rev Immunol. 21;680-686 (2021).  EVOLUTION OF RHEUMATOID ARTHRITIS TREATMENT ▪ Therapies have evolved from broadly acting drugs (e.g., NSAIDs, steroids) to specific inhibitors ▪ Diagnostic tools have improved in parallel with treatment strategies G Burmester, J Bijlsma et al. Nat Rev Rheumatol. 13;443-448 (2017). DISEASE MODIFYING AGENTS ▪ Frequently referred to as ‘disease modifying anti-rheumatic drugs’ ▪ Synthetic agents (sDMARD) ▪ Conventional: Methotrexate, Sulfasalazine, Leflunomide, etc. ▪ Targeted: Tofacitinib, etc. ▪ Biological (bDMARD) ▪ Original: Anti-TNF mAbs, anti-CD20 mAbs, anti-IL-6R mAbs, IL-1 inhibitor, etc. ▪ Biosimilars: Generic versions of original bDMARD ▪ These act to slow disease progression (hence the name!) ▪ Drugs such as NSAIDs and steroids treat symptoms but do not slow disease progression ▪ Wide range of therapies give providers many options to treat patients if they relapse or are refractory to a given therapy  ROLE OF CYTOKINES IN AUTOIMMUNITY Pro-inflammatory cytokines contribute to Numerous cytokine blocking mAbs have pathogenesis and propagation of disease been approved to treat autoimmune conditions Y Lai, C Dong. Int Immunol. 28(4);181-188 (2015).  RHEUMATOID ARTHRITIS ▪ Autoimmune condition that leads to joint destruction ▪ Affects >20 million people globally ▪ Incidence is 2.5-fold higher in women vs. men ▪ Treated with a wide range of agents A Sharma, A Goel. Mol Biol Rep. 50;4587-4706 (2023).  EXAMPLE: TNF BLOCKERS IN RHEUMATOID ARTHRITIS ▪ Etanercept: TNF Receptor fused to Fc of IgG ▪ Infliximab, Adalimumab: Anti-TNF mAb ▪ Directly inhibit pro-inflammatory TNF signaling via TNF Receptor DL Scott, GH Kingsley. N Engl J Med. 355;704-712 (2006). V Gerriets, A Goyal et al. Tumor Necrosis Factor Inhibitors. (2023).  EFFICACY OF TNF BLOCKERS ▪ Patients treated with anti-TNF have significant reduction in rheumatoid arthritis severity compared to placebo ▪ Efficacy is seen in other autoimmune conditions (TNF signaling is important in many diseases!) ▪ Cytokine blockade may lead to unwanted complications – increased infection susceptibility, cancer, etc. B Bain, M Brazil. Nat Rev Drug Discov. 2;693-694 (2003). Humira Package Insert  KINASE INHIBITORS ▪ Kinases are intracellular molecules that participate in the signal transduction cascade after receptor activation ▪ Kinase inhibition could be used to inhibit signaling from multiple receptors simultaneously ▪ Many kinase inhibitors are orally available so they would not require injections (advantage over biologics) ▪ Many approved and investigational kinase inhibitors for autoimmunity AA Zarrin, K Bao et al. Nat Rev Drug Discov. 20;39-63 (2021).  KINASE INHIBITORS IN RHEUMATOID ARTHRITIS ▪ Approved kinase inhibitors are not specific to a single kinase ▪ Associated with side effects such as infections and hypercholesterolemia ▪ Reactivation of herpes zoster is reported MC Genovese, J Kremer et al. N Engl J Med. 374;1243-1252 (2016). PC Taylor, C Laedermann et al. J Clin Med. 12;4527 (2023).  ROLE OF B CELLS IN AUTOIMMUNITY ▪ B cells have been implicated in the pathology of numerous autoimmune conditions ▪ B cells can lead to disease via: ▪ Production of autoantibodies (plasma cells) ▪ Secretion of pro-inflammatory cytokines ▪ Other antibody-independent effects ▪ Can B cell function be modulated as a treatment strategy? DSW Lee, OL Rojas et al. Nat Rev Drug Discov. 20;179-199 (2021).  B CELL DEPLETING ANTIBODIES Anti-B cell mAbs are regularly used in autoimmunity ▪ B cell depleting mAbs were often first developed for treatment of B cell malignancies ▪ These deplete all cells expressing the target antigen ▪ When are they used? ▪ Example: Rituximab is used in rheumatoid arthritis in patients with inadequate response to anti-TNF therapy Z Zhang, Q Xu et al. Front Immunol. 14;1126421 (2023).  HOW DO B CELL DEPLETING MABS WORK? ▪ Rituximab leads to death of CD20-expressing B cells by 3 mechanisms ▪ Direct lysis ▪ Antibody-dependent cellular cytotoxicity ▪ Complement-dependent cytotoxicity ▪ This significantly reduces circulating B cells and therefore reduces B cell-dependent autoimmunity RP Taylor, MA Lindorfer. Nat Rev Rheumatol. 3;86-95 (2007). JCW Edwards, L Szczepanski et al. N Engl J Med. 350;2572-2581 (2004).  INTRAVENOUS IMMUNOGLOBULIN (IVIG) ▪ Immunoglobulin replacement, either intravenous (IVIG) or subcutaneous (SCIG) ▪ Initially developed (and still used) for treatment of primary immunodeficiencies ▪ Reconstitution of ‘missing’ antibody pool ▪ Used to treat autoimmune conditions at very high doses (1-3 g/kg) ▪ As this is a plasma-derived product, costs are very high (~$10,000/dose) VB Arumugham, A Rayi. Intravenous Immunoglobulin (IVIG). (2023).  HOW DOES IVIG WORK IN AUTOIMMUNITY? ▪ IVIG has many likely mechanisms by which it acts in autoimmune conditions ▪ Direct neutralization of autoantibodies and cytokines is possible ▪ Altered function of effector mechanisms (FcR) – biased towards anti-inflammatory ▪ Accelerated elimination of pathogenic antibodies N Nikolov, J Reisinger et al. Immunotherapy. 8(8);923-940 (2016).  THE NEONATAL FC RECEPTOR ▪ There is an inverse relationship between circulating IgG concentrations and half-life ▪ The neonatal Fc receptor (FcRn) serves as a ‘salvage’ system to protect IgG from degradation Thomas Waldmann ▪ Could saturation of this system lead to accelerated elimination of antibodies at high concentrations? A Morell, WD Terry et al. J Clin Invest. 49(4);673-680 (1970). RP Junghans, CL Anderson. Proc Natl Acad Sci USA. 93;5512-5516 (1996).  IMPACTS OF IVIG ON ‘AUTOANTIBODY’ ELIMINATION ▪ In rodents, increasing doses of IVIG leads to accelerated elimination of a tracer antibody ▪ Tracer antibody used to understand effects on endogenous IgG concentrations ▪ IVIG only affected tracer antibody elimination in mice where FcRn function was intact ▪ Compare open vs. closed symbols to see this! ▪ Saturation of FcRn function by IVIG is the likely mechanism underlying accelerated elimination of autoantibodies by IVIG ▪ Suggested direct inhibition of FcRn as a novel strategy RJ Hansen, JP Balthasar. Thromb Haemost. 88;898-899 (2002).  INHIBITING FCRN – AN ALTERNATIVE TO IVIG? ▪ Specific FcRn inhibitors impact tracer antibody pharmacokinetics at much lower doses than IVIG (15- 60 mg/kg vs. 1-3 g/kg) ▪ This data is shown as it is the first example of a specific FcRn inhibitor in the literature ▪ These results were published in 2005 KE Getman, JP Balthasar. J Pharm Sci. 94(4);718-729 (2005).  EFGARTIGIMOD (VYVGART) – FIRST FCRN INHIBITOR (2021) ▪ First-in-human study showed sustained reduction in circulating IgG concentrations in healthy humans ▪ Maximal effect was ~75-85% reduction in IgG ▪ Possible physiological limitation? ▪ No increased risk in infections observed in this trial P Ulrichts, A Guglietta et al. J Clin Invest. 128(10);4372-4386 (2018).  MYASTHENIA GRAVIS ▪ Autoimmune condition characterized by autoantibody development against acetylcholine receptors ▪ Antibodies lead to loss of post-synaptic neuronal structures ▪ Symptoms are largely related to muscle weakness ▪ Treatments have largely been via general immunosuppressives or IVIG ▪ Good candidate for anti-FcRn NE Gilhus, S Tzartos et al. Nat Rev Dis Primers. 5;30 (2019).  EFGARTIGIMOD IN MYASTHENIA GRAVIS ▪ Efgartigimod significantly reduced circulating anti- acetylcholine receptor antibodies in patients ▪ This led to improvements in disease score ▪ Direct evidence of FcRn inhibition as a therapeutic approach JF Howard, V Bril et al. Neurology. 92(23);e2661-e2673 (2019).  CHIMERIC AUTOANTIBODY RECEPTOR T-CELLS (CAAR-T) ▪ Analogous to CAR-T therapy for cancer ▪ T cells engineered to attack and clear autoreactive B cells ▪ Instead of an scFv presented used in the ‘CAR’, an autoantigen is used to achieve activation ▪ Autoantibodies and B Cell Receptors recognizing the antigen bind to the CAAR-T and lead to activation ▪ More specific than any of the therapies described so far ▪ Possibly curative – remains to be seen! L Chatenoud. Nat Biotechnol. 34;930-932 (2016). https://ascenion.de/en/technology-offers/nmdar-targeted-caar-t-cell-therapy-6684  CHIMERIC ANTIGEN RECEPTOR REGULATORY T CELL (CAR-TREG) ▪ Reminder: Treg are tolerogenic T cells and promote anti-inflammatory responses ▪ CAR-Treg can be made either by selectively transducing isolated Treg or by including FoxP3 (marker of Treg) in the CAR gene construct ▪ ‘CAR’ component recognizes the autoantigen of interest ▪ Knowledge of specific autoantigen is key ▪ Allows induction/restoration of tolerance to the specific antigen M Fransson, E Piras et al. J Neuroinflammation. 9;112 (2012). CLINICAL TRIALS OF CELL THERAPIES FOR AUTOIMMUNITY CAR-T CAAR-T SUMMARY ▪ Disease modifying treatments for autoimmune disorders often rely on modulating cytokine signaling and/or cell functions ▪ These include kinase inhibitors, cytokine inhibitor mAbs, and B cell depleting mAbs ▪ One mechanism of IVIG efficacy in autoimmune disorders is saturation of FcRn ▪ This led to the development of FcRn inhibitors as a therapeutic class ▪ Next generation agents for autoimmune disorders may include cell therapies