6. IgE and IgE-receptor targeting therapies for treating
allergies
Another group of antibodies that
prevent histamine release by basophils and mast cells are the anti-IgE
antibodies. They exert their effect by preventing IgE from binding to
FcεRI and CD23 (Figure 1 and 2). Binding of IgE to CD23 may involve
different portions of CD23 and, interestingly can be blocked with
Omailizumab which also blocks IgE binding to the high affinity receptor
for IgE 71. In addition, anti-IgE has a similar
inhibitory effect as AIT-induced IgG and IgA antibodies that block
IgE-mediated T cell activation130.
The structures of the ectodomain regions of FcεRI and CD23 in complexes
with IgE-Fc have revealed how these two distinct receptors interact with
IgE97,131,132. IgE binding to its two receptors is
regulated through unique conformational changes in the IgE-Fc domain
that enable an allosteric competition between low and high-affinity
receptors131,133. IgE binding to FcεRI occurs through
the tips of the two IgE Cε3 domains, engaging both antibody heavy chains
in an asymmetric ”open” conformation 132,133 In
contrast, CD23 binding occurs to a distinct surface of the IgE-Fc at the
junction between Cε3-Cε4 domains and favours a ”closed” conformation
that inhibits FcεRI binding131. High affinity binding
to FcεRI leads to the prebinding of serum IgE to receptor-expressing
cells, sensitizing them to respond upon allergen exposure and
cross-linking. In contrast, IgE binding to CD23 is of lower affinity and
is stabilised through avidity effects, most notably by IgE-allergen
complex formation. Strikingly, IgE bound to FcεRI is incredibly stable,
persisting on peripheral mast cells for weeks-months and impacting the
safety and speed of AIT/OIT approaches.
Two anti-IgE antibodies, omalizumab and
ligelizumab134,135 have been advanced as therapeutics
for the treatment of allergic diseases, including allergic asthma,
chronic spontaneous urticaria, chronic rhinosinusitis and food
allergies. However, other anti-IgE antibodies are in clinical
development (e.g. Xmab7195/UB221/omalizumab biosimilars). Omalizumab and
ligelizumab highlight the impressive impact that anti-IgE can have in
allergy treatment136. Omalizumab was the first
anti-IgE developed as a therapeutic, initially for the treatment of
severe allergic asthma in 2003. Since then, omalizumab has shown
efficacy in treating CSU, food allergy and chronic
rhinosinusitis137. As discussed elsewhere in this
review, omalizumab enhanced OIT treatment in food allergy clinical
trials, reducing allergen challenge reactions and enabling a more rapid
increase in allergen dosing and simultaneous tolerization for multiple
allergens138. Ligelizumab is a next-generation, higher
affinity anti-IgE that shows an improved ability to suppress free IgE in
patients135. Despite having an
~100-fold higher affinity for IgE, ligelizumab
surprisingly did not show improved efficacy in treating allergic asthma
patients139,140. However, in phase II clinical
studies, ligelizumab showed improved efficacy over omalizumab for the
treatment of CIU141. It remains to be established
whether ligelizumab will have a significant benefit in OIT/AIT relative
to omalizumab.
The structures and mechanisms of omalizumab vs ligelizumab are revealing
and provide insight into the possible differences in their therapeutic
impact. Omalizumab and ligelizumab both engage epitopes in the IgE Cε3
domains adjacent to the binding site for FcεRI139,142,143. Despite the substantial overlap in their
epitopes, ligelizumab binds across the IgE dimer engaging residues in
both Cε3 domains and overlapping the space that would be occupied by
FcεRI. In contrast, omalizumab engages an epitope towards an outer face
of the Cε3 domains, does not bind across the IgE dimer and lies somewhat
peripherally to FcεRI. One of the consequences of these distinct binding
interactions is that omalizumab can effectively inhibit binding to FcεRI
and CD23, while ligelizumab shows preferential inhibition of
FcεRI139. The ability of ligelizumab to block CD23
binding is weaker than omalizumab, despite its much higher IgE affinity.
The weaker inhibition of IgE:CD23 interactions exhibited by ligelizumab
may account for its failure to outperform omalizumab in clinical trials
for allergic asthma 139,140, where CD23 is thought to
play an essential role in disease through antigen presentation and or
antigen transport144,145. CD23 has also been studied
as a target in allergic diseases. However, although a phase 1/2 study
with the anti-CD23 mAb Lumiliximab in asthma patients showed a good
safety profile, anti-CD23 has not been developed further in asthma or
allergy 146.
It will be exciting and informative to compare the activities of
omalizumab and ligelizumab in AIT, which may help assess the clinical
importance of the inhibition of CD23 and FcεRI interactions during
tolerization to food or other allergens.
The rationale of combining anti-IgE with AIT or OIT is that the
combination may prevent allergic side effects of
AIT130 and OIT, allow more rapid updosing of allergen,
and will provide immediate clinical benefit. Since 2007, several studies
have addressed this combination treatment. These are reviewed in detail
in 138,148. Overall, both these combination treatments
have shown promising results, especially evidenced by decreased adverse
reactions to AIT and OIT. Larger follow up studies are needed to define
the optimal dosing and target groups for this type of combination
treatment.
Finally, a class of ”disruptive” IgE inhibitors has been described
based on Designed Ankyrin Repeat Proteins (DARPins), which can rapidly
dissociate FcεRI-bound IgE in vitro and in vivo149,150. Such kinetically active anti-IgE inhibitors
may have the potential to rapidly desensitise peripheral mast cells and
significantly accelerate the timelines for AIT in the future.