Monoclonal Antibody Therapy for Allergy: History
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Contributor:
Henry C. Ezechukwu
,
Oyelola A. Adegboye
,
Wahab O. Okunowo
,
Theophilus I. Emeto

Allergic inflammation is a type 2 immune disorder traditionally treated with epinephrine and glucorticosteroids in the short term. In extreme cases, current treatment options include the use of monoclonal antibodies targeting the pathological pathways of inflammation. However, this is impeded by the cost of production, host immunogenicity, safety, and the efficacy of these antibodies, and by their availability in developing countries. The use of purified monoclonal antibodies for treating severe allergic responses and the associated limitations are described. 

  • allergy
  • inflammation
  • gene
  • antibodies

1. Introduction

Allergic inflammation is a type 2 immune disorder [1] and it is characterized by an abnormal immune response against potentially harmless substances [2]. This response is often classified into three phases: the early phase reaction, which occurs within seconds to minutes, the late phase reaction, which occurs within several hours, and the chronic phase, characterized by persistent exposure to inflammatory mediators and stimuli [2]. Tissue mast cells, blood basophils, and eosinophils are important immune cells that play a crucial role in the allergic-inflammatory response [3][4]. Hallmarks of allergy and allergic inflammation include a rise in serum immunoglobulin E (IgE) (with an exception for contact dermatitis), eosinophilia, cytokine and chemokine secretion, and airway mucus production depending on the site of the inflammation [4][5].
Glucocorticosteroids are commonly prescribed for short-term relief of allergies [6][7] because their prolonged use had previously been associated with several adverse outcomes, such as increased predisposition to diabetes, osteoporosis, and cardiovascular pathologies [8][9]. There are conflicting evidence on corticosteroids efficacy in short-term relief of allergy [7][10].The effectiveness of glucocorticoids as a treatment for allergies remains unclear and controversial in the literature. Therefore, alternative therapeutic strategies have been investigated, such as immunotherapy and antibody gene therapy. These novel methods have provided new insights and opportunities for allergy therapy research.
The early phase of allergen-specific immunotherapy was hypo-sensitization, which began in the first half of the 20th century [11]. This method involves tricking the immune cells not to react to allergens responsible for hypersensitivity or allergic reaction via oral or intravenous administration of high doses of the inert allergen extract. This method is credited to Leonard Noon, who demonstrated that subcutaneous administration of pollen extract could suppress immediate conjunctival sensitivity to the pollen [12]. This therapy was promising in inducing a state of specific immune tolerance to selected allergens. However, caution and close monitoring of patients taking such therapy is required in cases of severe reactions.

2. Mechanism of an Allergic Reaction

Allergic reaction is a fundamental pathological condition that encompasses type 1 hypersensitivity involving innate and adaptive immune cells [13]. There are three steps involved in an allergic-inflammatory response: the sensitization step, also known as the induction phase, the effector step, and the clinical outcome or manifestation step, as depicted in Figure 1. Most allergens including Aspergillus fumigatus and house dust mite (Der p 1 and Der p 5) possess proteolytic activities that disrupt the epithelial barrier and promote antibody IgE/IgG1 production, eosinophilia, as well as the release of inflammatory mediators such as cytokines and histamine [14]. The interaction of histamine, and other inflammatory mediators with their respective receptors expressed on immune cells and epithelial cells are key to allergic clinical manifestation.
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Figure 1. Mechanism of an allergic reaction. An allergy event involves three phases: sensitization phase, effector phase, and clinical manifestation/outcome. The sensitization phase includes the proteolytic activity of allergen disrupting the tight epithelial junction to gain entry, and on the first contact with antigen-presenting cells (APC, such as dendritic cells (DC) and macrophages (MØ)), follows allergen processing and presentation to Th-2 cells, thus producing chemokines (such as CXCL 10) and cytokines such as IL-4. IL-4 acts on B-cells to induce B-cell Ig class switching to produce IgE, which binds to FcεRI on mast cells. The effector phase includes the second exposure to the same allergen, allergen-antibody cross-linking occurs, and mast cell degranulation results in the release of inflammatory mediators that facilitate effector cells (such as eosinophils) recruitment. The contributory responses of these effector cells and mediators present clinical outcomes such as itching and eczema dependent on the exposure surface. When multiple organs are involved, anaphylaxis sets in. This image was created in bio render.

3. Histamine, Histamine Receptors, and Clinical Outcome

Histamine is one of the inflammatory mediators released during basophils or mast cell degranulation. Histamine is a key to the induction of allergic inflammation [15] through its interaction with its respective receptors expressed on several immune cells (mast cells, eosinophils, basophils, dendritic cells, and T cells), on endothelial and epithelial cells, and even on some tissues such as skin and lungs [15][16]. Aside from immune cells, histamine can be secreted by brain neurons [16], which makes histamine a multi-functional biomolecule that can regulate both the central and peripheral nervous systems. Histamine receptors (H1R, H2R, H3R, and H4R) are all members of the G-protein coupled receptor family [15][17]. The binding of histamine to its receptor, [18] leads to several clinical manifestations or outcomes [15][17][19][20][21], as depicted in Table 1.
Table 1. Histamine, its receptors, and associated clinical outcome.
Receptors Effects Clinical Manifestation References
H1 Stimulates nociceptive nerve fiber; bronchoconstriction; increase mucus secretion Itching; urticaria; allergic rhinoconjunctivitis; allergic asthma [15][17]
H2 Gastric acid secretion;
arrhythmia; increased intracellular cAMP		 Peptic ulcer anaphylaxis;
negative feedback on mast cell activation		 [15][20]
H3 Inflammation on the neurons Neuro-inflammatory diseases
such as epilepsy; CNS disorder		 [15][21]
H4 Induce eosinophil shape change; activates eosinophils Lung asthma [19]
Lippert et al. [22] demonstrated that H2R and H4R are highly expressed in human dermal mast cells, while Xu et al. [23] reported that H1R, H2R, and H3R are upregulated in brain astrocytes following histamine treatment. Although Xu et al. reported a neuroprotective role of histamine on astrocytes, several studies highlight the importance of mast cells in histamine–microglial crosstalk in inducing neuroinflammation [24][25]. The expression of histamine receptors is altered during an episode of allergy, and this may be one of the enabling hallmarks of allergic-inflammatory diseases, including allergic rhinitis, and eosinophilic esophagitis [26][27]. Merves et al. [27] demonstrated that H2R is highly expressed in the esophageal biopsies of a patient with active eosinophilic esophagitis, followed by H1R and H4R. These biopsies are comprised of esophageal resident mast cells, circulating basophils, and epithelial cells. Further, Merves et al. [27] also showed that treatment with histamine induces cytokine release in primary human esophageal epithelial cell lines in an H1R-dependent manner. This suggests that histamine–histamine receptor interaction might be associated with a different form of allergy, such as asthma, rhinitis, and conjunctivitis, as depicted in Table 1. The expression of histamine receptors on a wide range of cells and or tissue contributes to the clinical outcome (see Table 1).

4. Possible therapeutic targets that alleviate allergic diseases

The search for an effective therapeutic target against endotype-specific markers (such as free serum IgE, and cytokines) in allergic asthma has long been an active area of allergology research, and most developed biologics are still in clinical trials. Inhaled corticosteroids (ICS) are the first line-medication for both asthmatic children [28] and adults [29]. ICS helps to modulate blood eosinophil levels [29] and improve lung function. The drawback of this treatment is its inherent heterogeneity and patients’ genetic variation [30], toxicity [31][32], such as adrenal complications, muscle weakness, osteoporosis [33], and impaired immunity against pneumonia and tuberculosis [34]. In April 2019, the Global Initiative for Asthma (GINA), no longer recommended the use of asthma-only short-term bronchodilators in its guidelines [35]. This is because the administration of only beta-2 agonist bronchodilators increases the risk for asthma and its comorbidities such as hypertension [36].

4.1. Targeting IgE in Allergic Inflammation

Omalizumab is now used to treat moderate-to-severe asthma patients where bronchodilators and ICS have failed [37][38][39]. Omalizumab is a recombinant humanized mAb that suppresses both the early and the late asthmatic responses by preventing the interaction of serum IgE with FcεR1 on mast cells, blood basophils, and eosinophils [40][41]. Omalizumab has also been reported to effectively reduce respiratory symptoms associated with allergic asthma in a randomized control trial [42]. Likewise, Esquivel et al. [43] reported that omalizumab reduces serum IgE levels and promotes viral load clearance in asthmatic children infected with rhinovirus. In a separate study, omalizumab was found to reduce platelets and leukocytes count, and C-reactive protein (CRP) levels in chronic urticaria patients [44]. Furthermore, omalizumab was shown to substantially reduce nasal and bronchial mucosal inflammation in patients with rhinitis experiencing severe allergic asthma [45]. Omalizumab is also promising in older patients with asthma-associated COPD [46]. Patients receiving omalizumab show improved asthma control test (ACT) scores accompanied by a reduced number of exacerbations [46].

4.2. Targeting Th2-Associated Cytokines in Allergic Disease

IL-4 is a crucial cytokine involved in the differentiation of naïve CD4+ T cells into Th-2 effector cells, and it is an essential signature of type II inflammatory response [5][47]. Murine model studies have revealed that IL-4 but not IL-5 is central to both inducing Th-2 cell activation/response and airway eosinophilic recruitment/inflammation [48][49]. Blockade of IL-4 is a possible target for alleviating most allergic diseases such as asthma, rhinitis, and eczema. Studies have shown that both altrakincept and pascolizumab reduce the recruitment of eosinophils at the site of allergic inflammation by masking the patient’s serum IL-4 (Figure 2), but with low clinical efficacy [31][50][51]. Both altrakincept and pascolizumab could not make it through phase III clinical trials and, as such, were suspended from being launched into the market [52]. Similar to IL-4, IL-13 is also a central mediator of allergic inflammation. IL-13 can induce most of the key characteristic features of experimental asthma and allergy, including allergen-induced airway hypersensitivity, goblet cell hyperplasia with mucus hyper-production, and eosinophilia [53][54][55]. Lebrikizumab is a humanized mAb that blocks IL-13 functionality (Figure 2) [31][56].
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Figure 2. Targeting IgE, and Th-2 (IL-4, IL-5, IL-13) in an allergic inflammatory response. Monoclonal antibodies that target these biomarkers can alleviate symptoms associated with allergies. DC: Dendritic cells. This image was created in bio render.

4.3. Monoclonal Antibodies Targeting Dual Inflammatory Mediators

Emerging reports on the development of mAb targeting multiple Th-2 cytokine responses during allergy episodes have achieved a milestone. For example, Kasaian et al. [57] developed a murine IL-4/IL-13 antagonist that efficiently neutralizes IL-4 and IL-13, as well as reduces serum IgE, lung eosinophilia, lung Mu5ac expression, and airway resistance in OVA-challenged mice. Dupilumab is the only approved mAb with the capability to inhibit the IL-4/IL-13 pathway in patients with atopic dermatitis [58], and allergic asthma [59], via IL-4Rα blockade [60]. Dupilumab neutralizes IL-4 and IL-13 cytokines (Figure 2). Dupilumab received this approval because it improves the quality of patient’s life where other treatments had failed [58]. It has also been reported that dupilumab modulates eosinophils infiltration, B-cells activation, Th2cell-driven dendritic cell activation and blocks the expression of pro-inflammatory cytokines (Il4, Il13, Il5, Il1α) and chemokines in mouse asthma model [61]. Further, Jonstam et al. [62] reported that dupilumab reduces type 2 inflammatory biomarkers such as serum IgE, and eosinophil chemokine release in patients suffering from multiple allergic chronic rhino-sinusitis with nasal polyposis.

4.4. Setbacks and Limitations

Despite the successes in the current mAb therapy for mild-to-severe allergy, there is a range of side effects associated with mAb intake. These include serum sickness, headaches, mild gastrointestinal symptoms, itching, cardiac toxicity, and anaphylaxis which could be life-threatening [63]. For example, a side effect of omalizumab is the induction of immunogenicity and anaphylaxis [64][65]. Other limitations include the inconsistencies in mAb, the cost of mAb production, including its purification, efficacy, and safety [66][67], as well as the skewed results from inconclusive clinical trials. Taken together, cost-effectiveness, inherent factors, and host genetic variation play a crucial role in utilizing mAb in mild-to-severe allergy treatment.

5. Antibody Gene Therapy: The Future for Antibody Therapy

The transfer of genes into host cells began in the late quarter of the 20th century using suitable vectors such as the Adeno-associated virus (AAV) vector, which were thought not to be associated with any illness in the human population [68][69]. Ever since then, it became possible to transfer mAb and/or any therapeutic proteins of interest using an AAV vector, and the use of this approach in several studies has been well-described [70][71]. The use of AVV coding antibody to reduce allergic events have been extensively studied in animal models [72][73][74]. For example, AAV vector coding for high-affinity anti-IgE reduces IgE-mediated peanut histamine release and anaphylaxis score in NOD scid gamma mice [73].
However, this approach became a major concern when Nault et al. [75] reported clonal integration of AAV genomes in tumor-driver genes of hepatocellular carcinomas, suggesting that the use of AAV may induce mutagenesis. Other setbacks include the possibility of the host developing an immune response against AAV capsid in patients who had been predisposed to the wild-type AAV [68]. The involvement of Toll-like receptor (TLR)9 and MyD88-mediated pathways in CD8+ T cells mediated responses to AAV-mediated gene transfer in mice had already been reported [76]. Emerging clinical trials also show similar findings of the host inducing an immune response to AAV [77][78].
These discoveries led to the birth of an alternative route of producing and delivering antibodies with fewer challenges. Studies on the delivery of mRNA-mediated antibody gene into host cells for passive immunity against pathogenic infection, vaccination against tumor growth, and allergy management are still evolving. In contrast to the manufacturing of purified monoclonal antibodies for severe allergy treatment, mRNA-directed antibody therapy can be cost-effective and safe and might only require a single local or systemic targeted shot to exert its therapeutic function [79][80].
Currently, there are only a few preclinical studies on mRNA-encoding antibodies [80]. The use of mRNA-mediated antibodies against viral infection has been extensively studied [79][81]. Thran et al. [79] reported that a single shot of mRNA-LNP encoding anti-rabies antibody provides complete protection against rabies infection even when pre-exposed and/or after several post-exposed challenges with rabies virus. The authors [79] further compared the efficacy of mRNA-LNP encoding rituximab to that of recombinant rituximab administration on tumor growth and found that the anti-tumor effect of mRNA-LNP encoding rituximab was higher than recombinant rituximab. This suggests a promising therapeutic option for the future. Further, Pardi et al. [81] also reported that a single injection of a modified mRNA encoding the light and heavy chain of an anti-HIV1 antibody, VRC01, in mice confers full protection against SF162 and JR-CSF HIV-1 isolates challenge. This suggests that the mRNA-LNP encoding VRCO1 used in their study successfully integrated into host cells and directs the synthesis of broadly neutralizing anti-HIV antibody, VRCO1, capable of conferring host-passive immunity against HIV-1 infection [81]. To date, there are limited/or no studies on the use of mRNA-encoding antibodies for protection against allergy. The current literature on mRNA encoding antibodies on other disease models has been described elsewhere [82][83]. The application of mRNA as a vaccine has also been successful in conferring protection against the dreadful SARS-CoV-2 virus.
Despite this, a few challenges may affect antibody gene therapy for allergy. These include: (1) the potential dangers associated with implanting genes into human hosts to express antibodies against host-inherent allergy biomarkers; (2) this implanted gene may induce endogenous pathogenic viruses’ reactivation and mutagenesis; (3) problems related to large-scale good manufacturing practice production; (4) the half-life of the antibodies encoded by mRNA; and (5) the safety and efficacy of antibody gene therapy for allergies in humans have not translated to its use clinically.
Gene therapy in allergy is an emerging and exciting field, but with limited data. Hopefully, future studies on mRNA encoding either monospecific or bispecific antibodies against allergy biomarkers will continue to evolve and improve in the coming years.

6. Conclusions

Monoclonal antibodies that target serum IgE and Th-2 cytokines have shown potential to reduce the severity of allergic asthma, atopic dermatitis, and rhinitis. However, the therapeutic use of purified mAb faces several challenges, such as the heterogeneity of allergy phenotypes, the efficacy and safety of mAb in clinical trials, the high cost of mAb production, and the limited availability of mAb. Gene therapy using AAV vector was initially promising, but later revealed adverse effects, such as host immune response against AAV. This led to the exploration of mRNA-mediated antibody gene therapy as a novel approach for antibody delivery. The mRNA-mediated antibody has several advantages over conventional mAb, such as requiring only a single injection and periodic boosters. Therefore, future research should focus on developing and optimizing mRNA-mediated antibody gene therapy for a wide range of atopic diseases/allergies

This entry is adapted from the peer-reviewed paper 10.3390/allergies3020007

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