Unique Epitopes on CεmX in IgE–B Cell Receptors Are Potentially Applicable for Targeting IgE-Committed B Cells

Chen, Jiun-Bo; Wu, Pheidias C.; Hung, Alfur Fu-Hsin; Chu, Chia-Yu; Tsai, Tsen‐Fang; Yu, Hon‐Tsen; Chang, Hwan‐You; Chang, Tse Wen

doi:10.4049/jimmunol.0902437

Cited by 40 publications

(40 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In contrast, h4B12 and h47H4 bind to the same CemX peptide segment of native mIgE in quite different conformations with high affinity and specificity. Furthermore, they cause the lysis of mIgE-expressing B cells, thus downregulating IgE production 17,18 . Notably, h47H4 has advanced to phase IIb clinical trial.…”

Section: Discussionmentioning

confidence: 99%

“…Notably, h47H4 has advanced to phase IIb clinical trial. Both h4B12 and h47H4 can bind to mIgE on B lymphocytes and mediate cytolytic mechanisms on mIgE-expressing B cells through apoptosis and antibody-dependent cellular cytotoxicity 17,18 . The antigenic sites for those two mAbs are not blocked by possible CemX-binding partner(s) or by associated molecules on the cell surface.…”

Section: Discussionmentioning

confidence: 99%

“…The antigenic sites for those two mAbs are not blocked by possible CemX-binding partner(s) or by associated molecules on the cell surface. This is important since not all regions of CemX are accessible to mAbs 17 . The IDR algorithms (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…CemX is thought to play a role in determining the outcome of cell signaling, following B cell receptor engagement 16 ; however, its function has not been fully elucidated. Unlike omalizumab that binds to both membrane-bound IgE (mIgE) and free IgE, an anti-CemX antibody targets only mIgE and therefore can target mIgEexpressing B lymphoblasts and memory B cells to downregulate IgE production 17,18 without being neutralized by free IgE. Thus, a therapeutic anti-CemX antibody could potentially be administered less frequently at smaller doses than omalizumab.…”

mentioning

confidence: 99%

“…The antibody h4B12 from our group, derived from the parental murine mAb 4B12 (ref. 17), is in preparation to enter human clinical studies. The antibody h47H4 (quilizumab) from Genentech, derived from the parental murine mAb 47H4 (ref.…”

mentioning

confidence: 99%

See 4 more Smart Citations

Two potential therapeutic antibodies bind to a peptide segment of membrane-bound IgE in different conformations

et al. 2014

Self Cite

View full text Add to dashboard Cite

IgE mediates hypersensitivity reactions responsible for most allergic diseases, which affect 20-40% of the population in developed countries. A 52-residue domain of membrane-bound IgE (mIgE) called CemX is currently a target for developing therapeutic antibodies; however, its structure is unknown. Here we show that two antibodies with therapeutic potential in IgE-mediated allergic diseases, which can cause cytolytic effects on mIgE-expressing B lymphocytes and downregulate IgE production, target different conformations of an intrinsically disordered region (IDR) in the extracellular CemX domain. We provide an important example of antibodies targeting an extracellular IDR of a receptor on the surface of intended target cells. We also provide fundamental structural characteristics unique to human mIgE, which may stimulate further studies to investigate whether other monoclonal antibodies (mAbs) targeting intrinsically disordered peptide segments or vaccine-like products targeting IDRs of a membrane protein can be developed.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Two potential therapeutic antibodies bind to a peptide segment of membrane-bound IgE in different conformations

et al. 2014

Self Cite

View full text Add to dashboard Cite

show abstract

Genetic variations in the CεmX domain of human membrane-bound IgE

Wan

Chen

et al. 2010

Immunogenetics

View full text Add to dashboard Cite

The epsilon chain of membrane-bound IgE (mIgE) is expressed predominantly as a "long" isoform, containing an extra segment of 52 amino acid (a.a.) residues, referred to as C epsilon mX, between the CH4 domain and the C-terminal membrane-anchoring transmembrane peptide. C epsilon mX results from an alternative splicing of the epsilon RNA transcript at 156-bp upstream of the splicing acceptor site used by the "short" isoform. Here, based on an analysis of the C epsilon mX genomic DNA sequences of 320 subjects residing in Taiwan, we report that single-nucleotide polymorphisms have been found at two positions, namely, G/T at #46 and A/G at #93 (along the 156 bp of C epsilon mX), with the former creating an amino acid change from Val to Leu at #16 (along the 52 a.a. of C epsilon mX) and the latter resulting in no change (Gly). Among the 640 C epsilon mX sequences identified, the previously known 46G93A allelic form appeared 293 times, the newly discovered 46T93A allelic form (GeneBank accession no. GU208817) 26 times, and the 46G93G allelic form (GU208818) 321 times. No 46T93G allelic form was found. Serum IgE measurements showed that the polymorphisms did not correlate with the levels of serum IgE. The anti-C epsilon mX monoclonal antibody, 4B12, could bind equally well to mIgE.Fc(L)(16V) and mIgE.Fc(L)(16L). While genetic variation of C epsilon mX of broader populations should also be investigated, these newly discovered genetic variants of C epsilon mX in the Taiwanese population do not seem to affect the feasibility of using an anti-C epsilon mX mAb, such as 4B12, to target mIgE-expressing B cells.

show abstract

The IgE gene in primates exhibits extraordinary evolutionary diversity

Chen

Kawamura

et al. 2011

Immunogenetics

View full text Add to dashboard Cite

Membrane-bound IgE (mIgE) on B lymphocytes is essential for IgE production. Earlier studies showed that the ε chain of mIgE (mε) on human B cells has a "long" isoform, with an extra "CεmX" domain of 52 amino acid (aa) residues between the CH4 domain and the membrane-anchor segment, as compared to the conventional "short" isoform. Because CεmX provides an antigenic site for targeting IgE-expressing B cells to down-regulate IgE production in patients with allergy, analysis of CεmX in various animals is of great interest. Hence, we analyzed the ε Ig gene, in particular, its membrane exon regions encoding the membrane anchor peptide segment and CεmX domain, of 26 species of the order Primates and 12 species of seven non-Primate orders using data obtained experimentally or retrieved from GenBank. Our analyses reveal the unexpected finding that the genes of three extant tarsier species do not contain the membrane exons for mIgE. Another striking finding is that early evolved Strepsirhini primates such as lemurs and lorises do not have gene segments for the long isoform, whereas New World monkeys such as marmosets and squirrel monkeys allow the transcription of only the long isoform. In Old World monkeys and apes, including humans, the ε gene allows the transcription of both isoforms. This work thus reveals the dramatic differences in the gene segment encoding the mε C terminal region among the four major primate lineages: the Strepsirhini primates, the tarsiers, New World monkeys, and Old World monkeys and apes/humans.

show abstract

Unique Epitopes on CεmX in IgE–B Cell Receptors Are Potentially Applicable for Targeting IgE-Committed B Cells

Abstract: Material Supplementary 7.DC1http://www.jimmunol.org/content/suppl/2010/01/13/jimmunol.090243References

Cited by 40 publications

References 51 publications

Two potential therapeutic antibodies bind to a peptide segment of membrane-bound IgE in different conformations

Two potential therapeutic antibodies bind to a peptide segment of membrane-bound IgE in different conformations

Genetic variations in the CεmX domain of human membrane-bound IgE

The IgE gene in primates exhibits extraordinary evolutionary diversity

Contact Info

Product

Resources

About