Immunotherapy of autoimmune disease

• LO:

  • Categorise different immunotherapeutics by therapeutic target, explaining the benefits and limitations of different approaches for the treatment of autoimmune disease
  • Appraise the antigen-specific immunotherapeutic approach, comparing this therapeutic strategy with non-antigen-specific approaches to treating autoimmunity
• Non-specific immunosuppressants


  • Compromise normal immune function - cancer immunosurveillance and resistance to infection
  • Often given for long periods of time
  • Severe toxicity issues associated with use (+ potential carcinogenicity)
  • Many inhibit DNA synthesis: aim to prevent rapid expansion of auto-reactive cells, e.g. Leflunamide/Teriflunomide, Mitoxantrone, Methotrexate, Cyclophosphamide
• Anti-cytokine therapies: targeting the IL-6 receptor


  • IL-6 upregulated during general inflammation; notably implicated in the pathogenesis of rheumatoid arthritis (RA) and also juvenile idiopathic arthritis (JIA)
  • Tocilizumab is a humanised monoclonal anti-IL-6R antibody
  • Binds membrane-bound and soluble IL-6R, global blockade of IL-6 signalling
  • Significantly reduce signs and symptoms of RA, delays progression of disease
  • Effective treatment of JIA
  • Common side effects include: infections, liver enzyme abnormalities, neutropenia, intestinal perforations
• Cytokine administration: another therapeutic strategy


  • IFN-b is the most commonly prescribed disease-modifying therapy for active relapsing-remitting MS
  • Reduces annual relapse rates and lesion load measured by MRI
  • Reduces brain atrophy and disability progression
  • Anti-inflammatory effects include: modulates antigen presentation (thus T cell activation), modifies cytokine production, promotes Treg differentiation
  • Many patients don't respond to IFN-b, some due to production of neutralising antibodies
• Targeting IL-2 to Treg cells via the high affinity IL-2R


  • Monoclonal antibodies: anti-IL-2
  • Protein engineering: modified IL-2 protein sequence "mutein"
• Immunotherapies targeting lymphocytes: Alemtuzumab (Campath-1H)


  • Anti-CD52 monoclonal antibody
  • Depletes lymphocytes (chronic lymphocytic leukaemia)
  • Reduced relapse rate in MS patients, reduced accumulation of disability, reduced lesions (seen by MRI)
  • T cells expand following depletion, triggering secondary autoimmunity (thrombocytopenic purpura/ autoimmune thyroid disorders)
  • Rare/serious- stroke, spontaneous intracranial haemorrhage
  • Reviewed by European Medicines Agency: from 2020, more restrictions and monitoring needed (safety concerns)
• Immunotherapies targeting lymphocytes: B cells


  • Rituximab and Ocrelizumab are anti-CD20 monoclonal antibodies
  • Depletes B cells
  • Reduced production of auto-antibodies
  • B cell presentation of antigen inhibited, reduced T cell activation
  • B-cell derived inflammatory cytokines reduced
  • Rituximab = Licenced for treatment of RA and pemphigus vulgaris
  • Ocrelizumab licenced relapsing remitting MS and primary progressive MS
  • Only effective in some SLE patients
  • May cause increased risk of infection, reactivation of latent infections, cytokine release syndrome
  • Severe adverse effect (rare) reported progressive multifocal leukoencephalopathy (PML)
• Progressive Multifocal Leukoencephalopathy (PML)


  • Reactivation of polyomavirus JC, demyelination, progressive damage
  • Patients present with neurological deficits
  • Uni- or multifocal lesions of the white matter of the brain
  • JC virus present in high percentage of the population, dangerous in immunocompromised individuals (e.g. AIDS or immunosuppressive therapies)
  • No effective treatment, need to reverse immunosuppression (fatal infection)
• Abatacept


  • CTLA-4-Ig fusion protein
  • Aims to block co-stimulation (signal 2) by binding to CD80/CD86 on APC preventing CD28 interaction
  • Licenced RA: large-scale clinical trials = reduced signs and symptoms of RA, slowing disease progression and joint damage
  • Not effective for the treatment of all autoimmune diseases- no benefit in SLE patients
• Natalizumab


  • In MS, VLA4 : VCAM1 interactions are thought to allow myelin-specific T cells to cross the blood-brain barrier
  • Aims to inhibit T cell migration in to the CNS by preventing VLA4 form interacting with VCAM1
  • Licenced for highly active relapsing remitting MS
  • Blocking leukocyte migration inhibits normal immunosurveillance of the CNS - reactivation of the polyomavirus JC PML. 757 cases by 2018, not withdrawn (benefits outweigh risks)
• Efficacy of anti-VLA4


  1. CD4+ T cells with TCR specific for myelin basic protein are labelled with green fluorescent protein

  2. Intravital two-photon microscopy used to visualise cells in blood vessels of the CNS

  3. Mice pre-treated with anti-LFA1 (no effect) then anti-VLA4 administered i.v. to animals

  4. T cell crawling inhibited
• Antigen-specific immunotherapy


  • CD4+ T cells initiate and orchestrate many autoimmune diseases after recognition of self-antigen via the T cell receptor (TCR)
  • By using antigen to target disease-relevant self-reactive TCR, we can silence damaging T cell responses through induction of antigen-specific tolerance
  • Normal immune responses remain intact
• Non-specific immunosuppressive drugs


  • Corticosteroids
  • Anti-cytokine and cytokine therapies
  • Anti-T cell drugs
• Peptide antigens


  Preferable to intact antigen as they can stimulate antibody secretion and activate mast cells and basophils (by cross-linking IgE), and can stimulate cytotoxic T cells
• CD4+ MHC II


  • Soluble peptides mimic the naturally processed antigen when bound to MHC II, specifically target self-reactive T cells for the induction of tolerance
  • Bind to peptide-receptive MHC class II
  • Presented by steady-state/immature DC
  • Dosing regimen is important to drive tolerance induction (e.g. dose escalation is safer)
• Peptide immunotherapy: Tg4 EAE model


  1. TCR transgenic: CD4+ T cells recognise a myelin peptide MBP Ac1-9

  2. Mice are highly susceptible to CNS autoimmunity

  3. Repetitive administration of MBP Ac1-9 peptide (i.n. or s.c. routes)

  4. Antigen-specific tolerance induced in self-reactive CD4+ T cells

  5. Mice no longer susceptible to CNS autoimmunity
• Peptide immunotherapy prevents EAE


  Prophylactically and therapeutically
• Peptide immunotherapy induces expression of genes promoting immunological tolerance

  1. mRNA expression upregulated

  2. mRNA expression downregulated
• Phase 1b protocol (ATX-MS-1467-002)


  1. Subjects: HLA-DR2 positive patients (n=43) with relapsing multiple sclerosis (RMS)

  2. Dose: upward titration 25, 50, 100, 400 followed by repeated 800 μg doses

  3. Dose frequency: 14 days ± 3 days

  4. Primary objective: Assess safety and tolerability of ATX-MS-1467

  5. Secondary objective: Monitor immunological parameters in response to ATX-MS-1467, Monitor disease status in the CNS using Gadolinium-enhanced MRI
• ATX-MS-1467 treatment


  Lesions significantly reduced
• ATX-MS-1467 has been tested in 2 Phase I safety studies, ATX-MS-CS-001 in patients with secondary progressive multiple sclerosis (n=6) and ATX-MS-1467-002 in patients with relapsing multiple sclerosis (n=43)
• The safety data from these 49 patients indicates no evidence of unexpected safety signals with the majority of adverse events relating to the subjects' underlying disease or minor injection site reactions
• Immunotherapy of autoimmune disease


  • Non-specific immunosuppressive drugs
  • Therapies targeting cytokines
  • Therapies targeting lymphocytes
  • Inhibitors of leukocyte migration
  • Epitope mimetics
  • Antigen-specific immunotherapy is the gold standard therapy, inducing antigen-specific tolerance (the Tg4 model and ATX-MS-1467)
• Autoimmune diseases include


  • alopecia areata
  • autoimmune hemolytic anemia
  • autoimmune hepatitis
  • type 1 diabetes
  • juvenile idiopathic arthritis (some forms)
  • glomerulonephritis
  • Graves’ disease
  • Guillain-Barré syndrome
  • myasthenia gravis
  • myocarditis (some forms)
• Therapies for autoimmunity

  
• General immunosuppressants: adverse effects may outweigh benefits


  • Non-specific immunosuppressants compromise normal immune function - cancer immunosurveillance and resistance to infection
  • Often given for long periods of time
  • Severe toxicity issues associated with use (+ potential carcinogenicity)Many inhibit DNA synthesis: aim to prevent rapid expansion of auto-reactive cells
  • Recent analysis showed that use of immunosuppressants (leflunamide and methotrexate) failed in more than 50% of RA patients due to adverse effects
• Glucocorticoids


  • Glucocorticoids (e.g. prednisone and prednisolone) have numerous immunosuppressive effects
  • Inhibit production of pro-inflammatory cytokines, promote anti-inflammatory cytokines
  • Promote apoptosis in macrophages, DC and T cellsXSide-effects may be severe: e.g. immunodeficiency, hyperglycaemia, skin fragility, osteoporosis, muscle break-down

  
• Anti-cytokine therapies


  • Pro-inflammatory cytokines have a central role in autoimmune pathogenesis – immunotherapeutic targets
  • Often exist as part of complex delicately balanced network
  • Inhibiting specific cytokine signalling can inhibit e.g. inflammatory cascades, T cell differentiation

  
• Anti-cytokine therapies: Targeting IL-12/IL-23 p40


  IL-12 and IL-23 share a common p40 subunit. These cytokines are important for Th1 and Th17 differentiation

  Ustekinumab

  • Monoclonal anti-IL-12p40 antibody
  • Blocks both Th1 and Th17 differentiation, through inhibition of IL-12 and IL-23 cytokine signalling
  • Significantly improves psoriasis, benefits demonstrated in Crohn’s, UC, psoriatic arthritis
  • Increased risk of infection (TB), no efficacy MS

  
• Anti-cytokine therapies: targeting TNF

  TNF expression is rate limiting step in pathogenesis of several immune-mediated diseases

  • TNF-blocking is effective in the treatment of RA, JIA, Crohn’s disease, psoriasis, psoriatic arthritis, ulcerative colitis, ankylosing spondylitis
  • Side effects: potential for lethal re-activation of latent infections e.g. TB,HBV, increased risk of lymphoma, pancytopenia
  • Paradoxically, long term use increases risk of other autoimmune disease development, e.g. MS and SLE

  
• Anti-cytokine therapies: targeting the IL-6 receptor

  IL-6 upregulated during general inflammation; notably implicated in the  pathogenesis of rheumatoid arthritis (RA) and also juvenile idiopathic arthritis (JIA)

  Tocilizumab

  • Humanised monoclonal anti-IL-6R antibody
  • Binds membrane-bound and soluble IL-6R -> global blockade of IL-6 signalling
  • Significantly reduce signs and symptoms of RA, delays progression of disease
  • Effective treatment of JIA
  • Common side effects include: infections, liver enzyme abnormalities, neutropenia, intestinal perforations
• Efficacy of anti-cytokine therapies across autoimmune diseases

  
• Low-dose IL-2 to expand Regulatory T cells (Treg)

  • IL-2 administered at low doses aims to expand CD4+ Treg which constitutively express CD25 (the IL-2R a chain)et al., 2019)
  • Treg can suppress many different immune cells; by boosting Treg, IL-2 therapy may be effective in treating a range of immune-mediated disorders
  • Phase I-IIa trials in 11 autoimmune disease show proof of concept:  low-dose IL-2 induces robust expansion of Treg, along with potential improvement of autoimmune symptoms

  
• Targeting IL-2 to Treg cells via the high affinity IL-2R

  
• Immunotherapies targeting lymphocytes: T cells


  Daclizumab

  • Anti-CD25 monoclonal antibody
  • Aims to block recently activated self-reactive T cells expressing CD25

  Reduced relapse rate in MS patients (licenced 2016), reduced disability accumulation, reduced lesions (MRI)

  Increased risk of infection

  Safety concerns-> Withdrawn March 2018
• Immunotherapies targeting lymphocytes: T cells (Otelixizumab)


  • In development
  • Anti-CD3 monoclonal antibody
  • Aims to induce T cell apoptosis and anergy, induce Treg (TGF-b)

  Maintain b-cell function in Type 1 diabetes patients

  Percentage of patients fail to respond to therapy

  Transient EBV-reactivation

  
• Immunotherapies targeting lymphocytes: T cells (Abatacept)


  • CTLA-4-Ig fusion protein
  • Aims to block co-stimulation (signal 2) by binding to CD80/CD86 on APC preventing CD28 interaction

  Licenced RA: large-scale clinical trials = reduced signs and symptoms of RA, slowing disease progression and joint damage

  Not effective for the treatment of all autoimmune diseases- no benefit in SLE patients

  
• Inhibitors of leukocyte migration: anti-VLA4


  Natalizumab

  Anti-VLA4 (a4b1 integrin) monoclonal antibody

  In MS, VLA4 : VCAM1 interactions are thought to allow myelin-specific T cells to cross the blood-brain barrier

  • aims to inhibit T cell migration in to the CNS by preventing VLA4 form interacting with VCAM1

  Licenced for highly active relapsing remitting MSXOpportunistic infection

  Blocking leukocyte migration inhibits normal immunosurveillance of the CNS -> reactivation of the polyomavirus JC -> PML. 757 cases by 2018, not withdrawn (benefits outweigh risks)

  
• Efficacy of anti-VLA4: evidence from an animal model of MS


  • CD4+ T cells with TCR specific for myelin basic protein are labelled with green fluorescent protein
  • Intravital two-photon microscopy used to visualise cells in blood vessels of the CNS
  • Mice pre-treated with anti-LFA1 (no effect) then anti-VLA4 administered i.v. to animals -> T cell crawling inhibited
• Inhibitors of leukocyte migration


  • Naïve and central memory T cells circulate between blood and lymph nodes
  • Home to lymph nodes via CC-chemokine receptor 7 (CCR7)
  • To exit lymph nodes, the sphingosine 1-phosphate receptor 1 (S1P1) must be activated by S1P
  • This overrides CCR7-mediated retention in the lymph nodes, T cells exit lymph node