Targeting IgE in non-allergic diseases
Several anti-IgE monoclonal antibodies (mAbs) are at various stages of
pre-clinical and clinical development. These mAbs have been extensively
reviewed in the context of allergic diseases137,138.
Three anti-IgE mAbs that have been tested so far in patients with
autoallergic and autoimmune diseases: Omalizumab (OMZ) and its
biosimilars, Ligelizumab (LGZ) and UB-221.
Omalizumab. OMZ (Xolair®) is a
humanized anti-IgE mAb that was first approved in 2003 for the treatment
of moderate-to-severe asthma. In 2014, it became the first FDA-approved
mAb for the treatment of CSU139-141. OMZ targets free
IgE and precludes binding of IgE to both FcεRI and
CD23142-144. OMZ recognizes structural epitopes in the
Cε3 domain of the constant region of IgE that also contains key epitopes
for binding of IgE to both FcεRI and CD23, thus preventing their binding
to these receptors142-144. Importantly, OMZ poorly
recognizes IgE already bound to FcεRI. This represents an essential
safety feature as it does not induce activation of mast cells and
basophils through FcεRI-crosslinking143,145. However,
it also implies that repeated injections of OMZ are required in order to
trap IgE as it slowly detaches from FcεRI. Several OMZ biosimilars such
as GBR 310, CT-P39 and CMA007 are now at various stages of clinical
development146-148.
Ligelizumab. LGZ is an anti-IgE mAb with aK D of
35 pM, which is 88-fold stronger than the K D of
OMZ149. LGZ
also recognizes epitopes in the Cε3 domain of free IgE and thereby
impairs binding of IgE to both FcεRI and CD23150.
However, OMZ and LGZ have distinct inhibition profiles, due to their
differences in affinity and epitopes recognized in the IgE Cε3
domain149. LGZ shows higher potency than OMZ at
preventing binding of IgE to FcεRI, but is less potent at blocking
binding of IgE to CD23149.
UB-221. More recently, a novel anti-IgE mAb,UB-221, was
tested in CSU in a first-in-human trial151. Unlike OMZ
and LGZ, monomeric UB-221, in vitro , binds to CD23-bound IgE, and
UB-221-IgE complexes freely engage CD23. These features may allow UB-221
to inhibit IgE production through CD23 engagement unlike LGZ and OMZ, at
least ex vivo 151. UB-221 binds IgE with a
strong intermediate affinity as compared to OMZ and LGZ
(LGZ>UB-221>OMZ), is also able to prevent
FcԑRI-mediated basophils/mast cells activation and degranulation induced
by IgE/antigen complexes, and, like LGZ, exhibits superior
IgE-neutralizing activity than OMZ.
All three anti-IgE mAbs induce a rapid and pronounced serum-IgE
reduction, and their efficacy have been and/or are currently being
tested in the following AbAID.