Abstract
The critical role of IgE in allergic diseases is well-documented and clinically proven. Omalizumab, a humanized anti-IgE antibody, was the first approved antibody for the treatment of allergic diseases. Nevertheless, omalizumab still has some limitations, such as product instability and dosage restriction in clinical application. In this study, we attempted to develop an omalizumab biobetter antibody with the potential to overcome its limitations. We removed two aspartic acid isomerization hotspots in CDRs of omalizumab to improve antibody candidate’s stability. Meanwhile, several murine amino acids in the framework region of omalizumab were replaced with human source to reduce the potential immunogenicity. Yeast display technology was then applied to screen antibody candidates with high binding affinity to IgE. Moreover, YTE mutation in Fc fragment was introduced into the candidates for extending their serum half-life. A lead candidate, AB1904Am15, was screened out, which showed desired biophysical properties and improved stability, high binding affinity and elevated potency in vitro, prolonged half-life in human FcRn transgenic mouse, and enhanced in vivo efficacy in cynomolgus monkey asthma model. Overall, our study developed a biobetter antibody of omalizumab, AB1904Am15, which has the potential to show improved clinical benefit in the treatment of allergic diseases.
Highlights
Allergic diseases, such as allergic asthma, atopic dermatitis, allergic rhinitis and food allergy, represent a chronic disorder of the immune system to various environmental allergens, for example, house dust mites, pollens and animal dander
To improve the antigen affinity of antibody candidates, yeast surface display technology was used for affinity maturation
The results showed the KD values of AB1904Am1 and AB1904Am8 were higher than L0H0, which indicating the lower affinity of AB1904Am1 and AB1904Am8 to L0H0
Summary
Allergic diseases, such as allergic asthma, atopic dermatitis, allergic rhinitis and food allergy, represent a chronic disorder of the immune system to various environmental allergens, for example, house dust mites, pollens and animal dander. Omalizumab has exhibited robust clinical efficacy, and showed potential to treat a wide range of other allergic diseases [19,20,21,22]. It binds to the constant region of free IgE and prevents free IgE binding to IgE receptors [23, 24]. The reduction of serum free IgE levels results in downregulation of FcεRI expression on effector cells [24, 25], further dampening the effector cell response to allergens [26]. We applied antibody engineering technology to optimize omalizumab sequence to reduce the potential immunogenicity risk, and remove the two typical Asp isomerization hotspots in CDRs to improve stability. The biophysical properties, stability profile and biological activity as well as efficacy of candidates were evaluated
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