Anti Ig E biologics and allergic diseases

Anti-IgE Biologics
and
Allergic Diseases
PAIRACH SUPSONGSERM
ALLERGY AND CLINICAL IMMUNOLOGY FELLOW
KING CHULALONGKORN MEMORIAL HOSPITAL
18 DECEMBER 2020

Outline
 Introduction
 Role of IgE in allergic pathophysiology
 Anti-IgE biologics
 Role of omalizumab in allergic diseases
 Quiz

Introduction
 The discovery of IgE by Professors Kimishige and
Teruko Ishizaka in 1966
 Omalizumab had been first approved for in
Australia (2002) followed by the United States (2003),
the European Union (2005), and Japan (2009)
 Used for:
> Allergic asthma
> Chronic urticaria
> Other allergic diseases
Okayama Y, et al. Roles of omalizumab in various allergic diseases. Allergology International 2020.

Guntern P, et al. Past, present, and future of anti-IgE biologics. Allergy 2020.

Tan HT, et al. Novel Biologicals for the Treatment of Allergic Diseases and Asthma. Curr Allergy Asthma Rep 2016.

Chronological Appearance of Anti-IgE Compounds

Role of IgE in Allergic Pathophysiology

Multimorbidities Associated with Severe Allergic Asthma
Humbert M, et al. IgE-Mediated Multimorbidities in Allergic Asthma and the Potential for Omalizumab Therapy. J ALLERGY CLIN IMMUNOL PRACT 2019.
Mechanisms of the Development of ALLergy program (MeDALL)
To identify novel mechanisms of allergy initiation during early childhood through to young adulthood
38% of allergic multimorbidities were associated with IgE sensitization

Structure and Receptor Interactions of IgE

Anti-IgE Biologics
 Approved monoclonal anti-IgE antibody
> Omalizumab
 Monoclonal anti-IgE antibody in clinical trials
> Ligelizumab
> Quilizumab
> MEDI4212
> XmAb7195
> Omalizumab biosimilars
 Anti-IgE biologicals in pre-clinical evaluation
> Anti-IgE designed ankyrin repeat proteins
> Monoclonal anti-IgE antibody 8D6
> IgG-Fc-fusion proteins
> Anti-IgE nanobodies

Approved Monoclonal Anti-IgE Antibody:
Omalizumab
 Omalizumab is a recombinant humanized
immunoglobulin (IgG1) monoclonal antibody
 It binds to the same C-epsilon-3 region that
interacts with the IgE receptors forming
complexes with free IgE
 The omalizumab-IgE complexes are
subsequently cleared by the hepatic
reticuloendothelial system
Casale TB, et al. Anti-Immunoglobulin E Therapy. Middleton’s Allergy, 9th Ed, 2019.
Stokes J. Anti-IgE Treatment for Disorders Other Than Asthma. Frontiers in Medicine 2017.

Approved Monoclonal Anti-IgE Antibody:
Omalizumab
 Omalizumab is specific to IgE and does not bind to
IgG or IgA
 It cannot bind to the IgE receptors or to IgE already
attached to Fc-epsilon-RI (does not interact with cell-
bound IgE or activate mast cells or basophils)
 Results:
> Rapid and significant decrease in free IgE levels
> Decreased the expression of the high affinity FcεRI
receptor on the surface of mast cells and basophils

 19 patients with allergic asthma were treated
3 months of omalizumab
 A marker of eosinophil apoptosis (annexin V)
was increased in those patients treated with
omalizamab and annexin-positive eosinophils
were increased compared to baseline
 Cellular production of GM-CSF, used for
eosinophil growth and survival, was decreased

Monoclonal Anti-IgE Antibody in Clinical Trials:
Ligelizumab
 Ligelizumab is a humanized monoclonal IgG1 antibody that binds IgE with an affinity of ∼1.4 χ 10−10 M but
does not interact with FcεRIα-bound IgE
 It does not accelerate dissociation of pre-formed FcεRIα:IgE complexes
 Ligelizumab recognizes a distinct IgE epitope, only partially overlapping with that of omalizumab
 Ligelizumab binds to both Cε3 domains across the IgE-Fc dimer and favors the recognition of IgE in an open
Fc conformation
 It shares significantly more overlap with the binding epitope of FcεRI on IgE than omalizumab and is superior
in inhibiting this interaction
 Ligelizumab shows almost no overlap with the CD23-binding site and is therefore less efficient than
omalizumab in blocking IgE:CD23 interactions

Monoclonal Anti-IgE Antibody in Clinical Trials:
Ligelizumab
 Ligelizumab is predicted to have a therapeutic advantage over omalizumab in FcεRI-driven allergic
disorders
 Ligelizumab showed significantly better symptom control in comparison with omalizumab in a
phase IIb dose-finding trial for CSU
 It was also superior to omalizumab in the inhibition of primary human basophil activation and a
passive systemic anaphylaxis mouse model
 It might be less suitable for the treatment of allergic disorders that heavily rely on CD23-dependent
processes including antigen presentation or trans-epithelial transport (eg, eosinophilic lung
inflammation)
 The distinct receptor inhibition profile provides a plausible explanation as to why ligelizumab lacked
superior efficacy over omalizumab treatment in a phase II clinical trial with allergic asthma patients

Binding Characteristics and Modes-of-Action of Ligelizumab

Binding Characteristics and Modes-of-Action of
Quilizumab/MEDI4212/XmAb7195

Omalizumab Biosimilars

Anti-IgE Biologicals in Pre-Clinical Evaluation

Role of Omalizumab in Allergic Diseases

Role of Omalizumab in Allergic Diseases
 Severe allergic adult asthma
 Severe childhood allergic asthma
 Chronic urticaria
 Allergic rhinitis
 Chronic rhinosinusitis
 Atopic dermatitis
 Food allergies

Efficacy of Omalizumab in
Severe Allergic Adult Asthma
 Omalizumab is the first biologic that was
globally approved for the treatment of severe
or moderate to severe allergic asthma
 Effects:
> Improvement in QOL and pulmonary
function
> Reduction in
>> Asthma symptoms (77%)
>> Asthma exacerbations (43%)
>> Doses of ICS/OCS

 A decline in serum free IgE levels from
baseline to 16 or 32 weeks after treatment
was associated with reduced exacerbation
frequency 2 years after omalizumab
treatment
 Omalizumab discontinuation after 28
weeks of treatment showed that suppressed
free IgE levels returned to baseline within 18-
20 weeks, which was accompanied with re-
emergent of asthma symptoms

 Administered subcutaneously every two or
four weeks
 Dose determined according to the patient's
body weight and serum total IgE levels (30-
1500 IU/mL), ranging from 75 to 600 mg

Responses to Omalizumab Treatment in Atopic
Eosinophilic and Atopic Non-Eosinophilic Patients
 The efficacy of omalizumab may be greater
in more enriched population with high type 2
biomarkers:
> FeNO
> Blood eosinophils
> Serum periostin

Role of Omalizumab in Severe Asthma Comorbidities:
Aspirin-Exacerbated Respiratory Disease
 Omalizumab treatment:
> Reduced daily oral corticosteroid doses and frequency of asthma exacerbations
> Reduction in urinary concentrations of leukotriene E4 and prostaglandin D2 metabolite
> Improved asthma control
> Aspirin tolerance

Allergic Bronchopulmonary Aspergillosis
 A systematic review of 102 cases from 30 published literature summarized beneficial effects of
omalizumab treatment against ABPA:
> Significant improvement in symptoms
> Reduction in frequency of exacerbations
> Reduction of steroid requirement

Asthma-COPD Overlap
> Improvements in asthma outcomes similar to those in patients without ACO

Reports of Omalizumab Treatment in Childhood Asthma
 Omalizumab treatment in children >12 years old:
> Improvement of symptoms/acute exacerbations
> Reduction of ER visits
 Likely to be effective in patients with Th2-type immune response
 Effects of omalizumab:
> Improvement in QOL of asthmatic children and adolescents
> Improvement in QOL of caregivers
> Reduction in ICS use
> No improvement of FEV1

Reports of Omalizumab Treatment in Childhood Asthma:
Viral-Infection Induced Asthma
> Reduced the frequency of acute exacerbation of asthma due to viral infection
> Decreased the duration of rhinovirus (RV) infection/viral shedding/the risk of RV illness

Reports of Omalizumab Treatment in Childhood Asthma:
Laboratory Tests

Omalizumab Dose Adjustment in Pediatric Patients

Role of Omalizumab in Chronic Urticaria
 Urticaria is characterized by repeating emergence of transient
and local edema of the skin or mucosa, mostly with itch
 Up to 40% of CSU may be associated with autoantibodies
against IgE or FcεRI
 Non-sedating 2nd generation antihistamine is the mainstay
treatment
 Omalizumab was approved for treatment of CSU by EMA (EU)
and FDA (USA) in 2014, and PMDA (Japan) in 2017
 The fixed dose of 300 mg of omalizumab every 4 weeks is
optimal for CSU

Mechanisms of Actions of Omalizumab in
The Pathogenesis of Urticaria
 Omalizumab rapidly decreases level of
circulating free IgE, followed by a decrease of
IgE and FcεRI on basophils and mast cells in
the skin
 It may explain the effect of omalizumab on
the mediators release in response to IgG
autoantibodies against IgE or FcεRI (type IIb
autoimmunity)

Treatment of Chronic Urticaria

Prognosis and Parameters to Predict Efficacies of Omalizumab
 The analysis of 50 studies involving 921
patients:
> 89.5% complete or partial response
> 10.5% no response or being refractory
 Clinically apparent improvement of the
symptoms is observed within a week after
the first injection
 Urticaria may relapse in 4-8 weeks after the
last injection

Effects of Omalizumab Against
Allergic Rhinitis in The US and Europe
 Clinical trials of omalizumab treatment
against allergic rhinitis have been conducted for
several years by subcutaneous injection
 Different from doses used in asthma, the
trials for hay fever have been conducted at
single doses of 150 mg or 300 mg of
omalizumab

Effects on Japanese Cedar Pollinosis in Japan
 Placebo-controlled comparative study (2002)
and a comparative study (2003) with an anti-
allergy drug were conducted on JC
 The amount of omalizumab was determined
according to body weight and IgE level
immediately before administration in
December as 0.0016 mg/kg/IgE (IU/mL) and
revised every 4 weeks
 IgE was uniformly reduced to the detection
limit (50 ng/mL) in the administration group

Effects on Japanese Cedar Pollinosis in Japan

Omalizumab in Chronic Rhinosinusitis

Omalizumab in Atopic Dermatitis

Omalizumab in Food Allergies

Anti Ig E biologics and allergic diseases

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