Highly Effective Poly(Ethylene Glycol) Architectures for Specific Inhibition of Immune Receptor Activation

Emily Baird, David Holowka, Geoffrey W. Coates, Barbara Baird

Research output: Contribution to journalArticle

44 Citations (Scopus)

Abstract

Architectural features of synthetic ligands were systematically varied to optimize inhibition of mast cell degranulation initiated by multivalent crossing of IgE-receptor complexes. A series of ligands were generated by end-capping poly(ethylene glycol) (PEG) polymers and amine-based dendrimers with the hapten 2,4-dinitrophenyl (DNP). These were used to explore the influence of polymeric backbone length, valency, and hapten presentation on binding to anti-DNP IgE and inhibition of stimulated activation of RBL cells. Monovalent MPEG5000-DNP (IC50 = 50 nM), bivalent DNP-PEG3350-DNP (IC50 = 8 nM), bismonovalent MPEG 5000-DNP2 (IC50 = 20 nM), bisbivalent DNP 2-PEG3350-DNP2 (IC50 = 3nM) and DNP4-dendrimer ligands (IC50 = 50 nM) all effectively inhibit cellular activation caused by multivalent antigen, DNP-bovine serum albumin. For different DNP ligands, we provide evidence for more effective inhibition due to (i) preferential formation of intra-IgE cross-links by bivalent ligands of sufficient length, (ii) self-association of monovalent ligands with longer tails, and (iii) higher probability of binding for bisvalent ligands. We also show that larger DNP16-dendrimers of higher valency trigger degranulation by cross-linking IgE-receptor complexes, whereas smaller DNP-dendrimers are inhibitory. Thus, features of synthetic ligands can be manipulated to control receptor occupation, aggregation, and inhibition of the cellular response.

Original languageEnglish (US)
Pages (from-to)12739-12748
Number of pages10
JournalBiochemistry
Volume42
Issue number44
DOIs
StatePublished - Nov 11 2003
Externally publishedYes

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Ethylene Glycol
Polyethylene glycols
Chemical activation
Ligands
Dendrimers
Inhibitory Concentration 50
IgE Receptors
Haptens
Immunoglobulin E
Receptor Aggregation
Cell Degranulation
Mast Cells
Amines
Polymers
Agglomeration
Association reactions
Antigens

ASJC Scopus subject areas

  • Biochemistry

Cite this

Highly Effective Poly(Ethylene Glycol) Architectures for Specific Inhibition of Immune Receptor Activation. / Baird, Emily; Holowka, David; Coates, Geoffrey W.; Baird, Barbara.

In: Biochemistry, Vol. 42, No. 44, 11.11.2003, p. 12739-12748.

Research output: Contribution to journalArticle

Baird, Emily ; Holowka, David ; Coates, Geoffrey W. ; Baird, Barbara. / Highly Effective Poly(Ethylene Glycol) Architectures for Specific Inhibition of Immune Receptor Activation. In: Biochemistry. 2003 ; Vol. 42, No. 44. pp. 12739-12748.
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