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.