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

Washburn N, Schwab I, Ortiz D, Bhatnagar N, Lansing JC, Medeiros A, Tyler S, Mekala D, Cochran E, Sarvaiya H, Garofalo K, Meccariello R, Meador JW, Rutitzky L, Schultes BC, Ling L, Avery W, Nimmerjahn F, Manning AM, Kaundinya GV, Bosques CJ (2015)

Publication Status: Published

Publication Type: Journal article

Publication year: 2015

Journal

Proceedings of the National Academy of Sciences of the United States of America National Academy of Sciences

Book Volume: 112

Pages Range: E1297-306

Journal Issue: 11

DOI: 10.1073/pnas.1422481112

Abstract

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.

Authors with CRIS profile

Falk Nimmerjahn Lehrstuhl für Genetik

Involved external institutions

Momenta Pharmaceuticals US United States (USA) (US)

How to cite

APA:

Washburn, N., Schwab, I., Ortiz, D., Bhatnagar, N., Lansing, J.C., Medeiros, A.,... Bosques, C.J. (2015). Controlled tetra-Fc sialylation of IVIg results in a drug candidate with consistent enhanced anti-inflammatory activity. Proceedings of the National Academy of Sciences of the United States of America, 112(11), E1297-306. https://doi.org/10.1073/pnas.1422481112

MLA:

Washburn, Nathaniel, et al. "Controlled tetra-Fc sialylation of IVIg results in a drug candidate with consistent enhanced anti-inflammatory activity." Proceedings of the National Academy of Sciences of the United States of America 112.11 (2015): E1297-306.

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