T cell–independent B cell activation induces immunosuppressive sialylated IgG antibodies

Hess, Constanze; Winkler, André; Lorenz, Alexandra; Holecska, Vivien; Blanchard, Véronique; Eiglmeier, Susanne; Schoen, Anna Lena; Bitterling, Josephine; Stoehr, Alexander D.; Petzold, Dominique; Schommartz, Tim; Mertes, Maria M.M.; Schoen, Carolin T.; Tiburzy, Ben; Herrmann, Anne; Köhl, Jörg; Manz, Rudolf A.; Madaio, Michael P.; Berger, Markus; Wardemann, Hedda; Ehlers, Marc

doi:10.1172/jci65938

Cited by 115 publications

(100 citation statements)

References 65 publications

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“…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). Notably, none of the previous studies used precisely the same protocols for enriching or depleting sialic acid-containing IgG glycoforms, which may partially explain the discrepancies of these studies.…”

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

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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

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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

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“…More recently, it has been demonstrated that IgG Fc sialylation acts as a negative regulator of B cell proliferation independent of FcγRIIB expression (14,15). Here, we show that Fc sialylation inhibits immediate proinflammatory IgG effector functions through impairment of complement-mediated cytotoxicity.…”

Section: Introductionmentioning

confidence: 48%

Sialylation of IgG Fc domain impairs complement-dependent cytotoxicity

Quast¹,

Keller²,

Maurer³

et al. 2015

Journal of Clinical Investigation

229

198

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“…In addition to the decreased levels of fucosylation, Env-specific Abs from GagPol-primed animals also showed an increased prevalence of bisected glycans, further supporting their enhanced capacity to mediate protective mechanisms dependent on FcgRs (67,68). Given its regulatory property (69)(70)(71), only the concomitant increase in sialic acid could reduce the functionality of these Abs (72) but may as well be a compensatory mechanism to avoid Abs with an excessive inflammatory profile that could cause immune pathology.…”

Section: Discussionmentioning

confidence: 95%

Enhancing the Quality of Antibodies to HIV-1 Envelope by GagPol-Specific Th Cells

Bonsmann

Niezold

Temchura

et al. 2015

The Journal of Immunology

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The importance of Fc-dependent effector functions of Abs induced by vaccination is increasingly recognized. However, vaccination of mice against HIV envelope (Env) induced a skewed Th cell response leading to Env-specific Abs with reduced effector function. To overcome this bias, GagPol-specific Th cells were harnessed to provide intrastructural help for Env-specific B cells after immunization with virus-like particles containing GagPol and Env. This led to a balanced Env-specific humoral immune response with a more inflammatory Fc glycan profile. The increased quality in the Ab response against Env was confirmed by FcγR activation assays. Because the Env-specific Th cell response was also biased in human vaccinees, intrastructural help is an attractive novel approach to increase the efficacy of prophylactic HIV Env-based vaccines and may also be applicable to other particulate vaccines.

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T cell–independent B cell activation induces immunosuppressive sialylated IgG antibodies

Cited by 115 publications

References 65 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

Sialylation of IgG Fc domain impairs complement-dependent cytotoxicity

Enhancing the Quality of Antibodies to HIV-1 Envelope by GagPol-Specific Th Cells

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