Dendritic cell immunoreceptor: A novel receptor for intravenous immunoglobulin mediates induction of regulatory T cells

Massoud, Amir Hossein; Yona, Madelaine; Xue, Ding; Chouiali, Fazila; Alturaihi, Haydar; Ablona, Aidan; Mourad, Walid; Piccirillo, Ciriaco A.; Mazer, Bruce

doi:10.1016/j.jaci.2013.09.029

Cited by 135 publications

(116 citation statements)

References 42 publications

Supporting

Mentioning

114

Contrasting

Unclassified

Order By: Relevance

“…For example, studies using desialylated IVIg in immune thrombocytopenic purpura (ITP) models (28) and Sambucus nigra agglutinin (SNA) -enriched IVIg in arthritis models (29) have shown that sialylation does not enhance IVIg activity or that it may even be dispensable for its therapeutic effects. On the contrary, more comprehensive studies performed by several independent laboratories testing desialylated or hypersialylated IVIg across different animal models under preventive and therapeutic treatment modalities have shown that sialylation is critical for the anti-inflammatory activity of IVIg (24)(25)(26)(27)30). Furthermore, T cell-independent vaccinations resulted in the generation of hypersialylated immunomodulatory antibodies that were able to modulate other immune responses, establishing a broad relevance of these sialylated IgG glycoforms as modulators of immune responses (31).…”

Section: Significancementioning

confidence: 99%

Controlled tetra-Fc sialylation of IVIg results in a drug candidate with consistent enhanced anti-inflammatory activity

Washburn

Schwab

Ortiz

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

204

161

View full text Add to dashboard Cite

Despite the beneficial therapeutic effects of intravenous immunoglobulin (IVIg) in inflammatory diseases, consistent therapeutic efficacy and potency remain major limitations for patients and physicians using IVIg. These limitations have stimulated a desire to generate therapeutic alternatives that could leverage the broad mechanisms of action of IVIg while improving therapeutic consistency and potency. The identification of the important anti-inflammatory role of fragment crystallizable domain (Fc) sialylation has presented an opportunity to develop more potent Ig therapies. However, translating this concept to potent anti-inflammatory therapeutics has been hampered by the difficulty of generating suitable sialylated products for clinical use. Therefore, we set out to develop the first, to our knowledge, robust and scalable process for generating a well-qualified sialylated IVIg drug candidate with maximum Fc sialylation devoid of unwanted alterations to the IVIg mixture. Here, we describe a controlled enzymatic, scalable process to produce a tetra-Fc-sialylated (s4-IVIg) IVIg drug candidate and its qualification across a wide panel of analytic assays, including physicochemical, pharmacokinetic, biodistribution, and in vivo animal models of inflammation. Our in vivo characterization of this drug candidate revealed consistent, enhanced anti-inflammatory activity up to 10-fold higher than IVIg across different animal models. To our knowledge, this candidate represents the first s4-IVIg suitable for clinical use; it is also a valuable therapeutic alternative with more consistent and potent anti-inflammatory activity.IVIg | sialylation | antibody | inflammation | autoimmune disease

show abstract

Section: Significancementioning

confidence: 99%

Controlled tetra-Fc sialylation of IVIg results in a drug candidate with consistent enhanced anti-inflammatory activity

Washburn

Schwab

Ortiz

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

204

161

View full text Add to dashboard Cite

show abstract

“…2,3 Several studies have demonstrated that IVIg expands Tregs in both humans and experimental models. 4,5 These findings have also been confirmed in IVIg-treated autoimmune patients. 6,7 Recently, we demonstrated that IVIg-mediated Treg expansion requires the induction COX-2-dependent PGE 2 in human DCs.…”

mentioning

confidence: 53%

Intravenous immunoglobulin-mediated expansion of regulatory T cells in autoimmune patients is associated with increased prostaglandin E2 levels in the circulation

et al. 2014

View full text Add to dashboard Cite

“…In certain mouse models (74,75), but not in others (13,(76)(77)(78), the anti-inflammatory activity of IVIg depends mainly on a fraction of sialylated Abs. These sialylated Abs may interact with C-type lectins (like DC-SIGN, DCIR) and sialic acid-binding Ig-type lectins, such as CD22, at the surface of immune cells (79,80). It was suggested that these lectins interact with Fc-bound sialic acid (74,75), which was further supported by a study that showed that IVIg with fully sialylated Fc glycans has enhanced anti-inflammatory activity compared with IVIg (81).…”

Section: Immune Modulation By Fab Glycansmentioning

confidence: 99%

The Emerging Importance of IgG Fab Glycosylation in Immunity

Bovenkamp

Hafkenscheid

Rispens

et al. 2016

The Journal of Immunology

255

216

View full text Add to dashboard Cite

Human IgG is the most abundant glycoprotein in serum and is crucial for protective immunity. In addition to conserved IgG Fc glycans, ∼15–25% of serum IgG contains glycans within the variable domains. These so-called “Fab glycans” are primarily highly processed complex-type biantennary N-glycans linked to N-glycosylation sites that emerge during somatic hypermutation. Specific patterns of Fab glycosylation are concurrent with physiological and pathological conditions, such as pregnancy and rheumatoid arthritis. With respect to function, Fab glycosylation can significantly affect stability, half-life, and binding characteristics of Abs and BCRs. Moreover, Fab glycans are associated with the anti-inflammatory activity of IVIgs. Consequently, IgG Fab glycosylation appears to be an important, yet poorly understood, process that modulates immunity.

show abstract

Dendritic cell immunoreceptor: A novel receptor for intravenous immunoglobulin mediates induction of regulatory T cells

Cited by 135 publications

References 42 publications

Controlled tetra-Fc sialylation of IVIg results in a drug candidate with consistent enhanced anti-inflammatory activity

Controlled tetra-Fc sialylation of IVIg results in a drug candidate with consistent enhanced anti-inflammatory activity

Intravenous immunoglobulin-mediated expansion of regulatory T cells in autoimmune patients is associated with increased prostaglandin E2 levels in the circulation

The Emerging Importance of IgG Fab Glycosylation in Immunity

Contact Info

Product

Resources

About