The mechanistic and functional profile of the therapeutic anti-IgE antibody ligelizumab differs from omalizumab

Abstract

Targeting of immunoglobulin E (IgE) represents an interesting approach for the treatment of allergic disorders. A high-affinity monoclonal anti-IgE antibody, ligelizumab, has recently been developed to overcome some of the limitations associated with the clinical use of the therapeutic anti-IgE antibody, omalizumab. Here, we determine the molecular binding profile and functional modes-of-action of ligelizumab. We solve the crystal structure of ligelizumab bound to IgE, and report epitope differences between ligelizumab and omalizumab that contribute to their qualitatively distinct IgE-receptor inhibition profiles. While ligelizumab shows superior inhibition of IgE binding to FcεRI, basophil activation, IgE production by B cells and passive systemic anaphylaxis in an in vivo mouse model, ligelizumab is less potent in inhibiting IgE:CD23 interactions than omalizumab. Our data thus provide a structural and mechanistic foundation for understanding the efficient suppression of FcεRI-dependent allergic reactions by ligelizumab in vitro as well as in vivo.

Urticaria: Collegium Internationale Allergologicum (CIA) Update 2020

“…Phase III studies are ongoing in adults and adolescents with CSU. This clinical efficacy of ligelizumab may involve effects of this molecule on IgE production by B cells [93].…”

Targeted Therapy for Chronıc Spontaneous Urtıcarıa: Ratıonale and Recent Progress

“…Recently, a mechanistic and functional comparison of ligelizumab and omalizumab showed epitope differences that contribute to their qualitative distinct IgE-receptor profiles. Liguelizumab shows better suppression of IgE binding to FcεRI, basophil activation, and IgE secretion by B cells [82]. The research also showed inhibition of IgE-FcεRII (CD23) interaction was stronger for omalizumab.…”

“…The research also showed inhibition of IgE-FcεRII (CD23) interaction was stronger for omalizumab. Considering the role of CD23 in lung inflammation, the authors suggested that the lack of superiority of ligelizumab compared to placebo/omalizumab in a phase II trial (NCT01716754) conducted in patients with allergic asthma might be explained by this difference [82]. A phase IIb dose-finding trial compared the efficacy and safety of ligelizumab 24 mg, 72 mg, and 240 mg every 4 weeks with omalizumab 300 mg every 4 weeks and placebo in 382 adult patients with CSU.…”

A highly sensitive bioluminescent method for measuring allergen‐specific IgE in microliter samples

“…The IgE LuLISA allows bioluminescent detection of sIgE using an anti‐IgE nanobody (single variable heavy immunoglobulin domain [sdAb] or V H H) which recognizes the constant Cε3 region of human IgE 3 and is expressed in tandem with the catalytic domain of the enzyme luciferase (nanoKAZ) 4 (Figure 1A and Figure ). The anti‐IgE nanobody we used for this assay (sdAb026) has an affinity for IgE similar to that of the therapeutic anti‐IgE antibody omalizumab (K D 1.4 nM vs 2.6 nM, respectively 3,5 ) and was reported to inhibit interactions between IgE and the two receptors FcεRI and CD23 3 …”