| Id |
Subject |
Object |
Predicate |
Lexical cue |
| T309 |
0-102 |
Sentence |
denotes |
Improved recruitment of FcγRIIb immunoreceptor tyrosine inhibition motif‐dependent inhibitory function |
| T310 |
103-589 |
Sentence |
denotes |
Harnessing the physiological inhibitory function of FcγRIIb by mAbs that target ITAM receptors has the potential to shut down ITAM‐dependent signaling pathways of major importance in antibody pathologies.32, 108 Such ITAM signaling receptors include the BCR complex on B cells which is active in systemic lupus erythematosus, the FcεRI on basophils and mast cell subsets in allergies or the activating‐type FcγR on a variety of innate leukocytes in antibody‐mediated tissue destruction. |
| T311 |
590-754 |
Sentence |
denotes |
In such scenarios, the ITAM signaling receptor complex that is targeted by the therapeutic mAb must be co‐expressed on the cell surface with the inhibitory FcγRIIb. |
| T312 |
755-958 |
Sentence |
denotes |
This permits coengagement with ITAM signaling receptor by the Fab of the mAb and inhibitory FcγRIIb by its Fc which is the critical requirement in the inhibitory MOA for such therapeutic mAbs (Figure 1). |
| T313 |
959-1384 |
Sentence |
denotes |
Obexelimab (also known as XmAb5871; Table 4), currently in early clinical testing in inflammatory autoimmune disease, is an IgG1 mAb that targets CD19 of the BCR complex.19 It contains two Fc modifications, S267E and L328F (also known as “SELF” mutations), that selectively increased FcγRIIb binding by 400‐fold to about 1 nm, which results in powerful suppression of BCR signaling and the proliferation of primary B cells.19 |
| T314 |
1385-2349 |
Sentence |
denotes |
The anti‐IgE mAb omalizumab is an IgG1 mAb approved for the treatment of allergic disorders.110, 111 A similar but Fc‐engineered IgG1 mAb XmAb7195, currently in early clinical testing, contains the affinity‐enhancing SELF modifications.112 Both mAbs sterically neutralize the interaction between IgE and its high‐affinity receptor FcεRI to prevent basophil and mast cell activation.113, 114 However, XmAb7195 exhibited more efficient removal (sweeping; discussed later) of circulating IgE and also inhibited B‐cell IgE production, presumably by binding to the IgE BCR on the B‐cell surface and coclustering with FcγRIIb via its affinity‐enhanced Fc domain.112 Thus, XmAb7195’s selective modulation of IgE production by IgE+ B cells in addition to its enhanced clearance of IgE may offer significantly improved therapeutic benefits in allergy therapy beyond simple IgE neutralization.112 The “SELF” mutations have also been used in agonistic mAbs (discussed later). |
| T315 |
2350-2581 |
Sentence |
denotes |
One cautionary note is that the arginine 131 (R131) of the IgG‐binding site in FcγRIIb is critical for the enhanced affinity binding of “SELF”‐mutated Fcs but it is also present in the activating‐type “high responder” FcγRIIa‐R131. |
| T316 |
2582-2844 |
Sentence |
denotes |
Thus, antibodies modified with “SELF” have very‐high‐affinity binding to FcγRIIa‐R131 115 with a potentially increased risk of FcγRIIa‐dependent complications in patients expressing this allelic form, although, so far, none have been reported in clinical trials. |
| T317 |
2845-3035 |
Sentence |
denotes |
However, an alternative set of six Fc mutations, termed “V12” (P238D, E233D, G237D, H268D, P271G and A330R), potently enhanced FcγRIIb binding without increasing FcγRIIa–R131 interaction.115 |
