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Title

Characterization of a surrogate murine antibody to model anti-human CD3 therapies

Authors
Hatterer, Eric
Daubeuf, Bruno
Cons, Laura
Glatt, Sophie
Kosco-Vilbois, Marie
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Published in mAbs. 2013, vol. 5, no. 4, p. 555-64
Abstract Fc-modified anti-human CD3ε monoclonal antibodies (mAbs) are in clinical development for the treatment of autoimmune diseases. These next generation mAbs have completed clinical trials in patients with type-1 diabetes and inflammatory bowel disease demonstrating a narrow therapeutic window. Lowered doses are ineffective, yet higher pharmacologically-active doses cause an undesirable level of adverse events. Thus, there is a critical need for a return to bench research to explore ways of improving clinical outcomes. Indeed, we recently reported that a short course of treatment affords synergy, providing long-term disease amelioration when combining anti-mouse CD3 and anti-mouse tumor necrosis factor mAbs in experimental arthritis. Such strategies may widen the window between risk and benefit; however, to more accurately assess experimentally the biology and pharmacology, reagents that mimic the current development candidates were required. Consequently, we engineered an Fc-modified anti-mouse CD3ε mAb, 2C11-Novi. Here, we report the functional characterization of 2C11-Novi demonstrating that it does not bind FcγR in vitro and elicits little cytokine release in vivo, while maintaining classical pharmacodynamic effects (CD3-TCR downregulation and T cell killing). Furthermore, we observed that oral administration of 2C11-Novi ameliorated progression of remitting-relapsing experimental autoimmune encephalitis in mice, significantly reducing the primary acute and subsequent relapse phase of the disease. With innovative approaches validated in two experimental models of human disease, 2C11-Novi represents a meaningful tool to conduct further mechanistic studies aiming at exploiting the immunoregulatory properties of Fc-modified anti-CD3 therapies via combination therapy using parenteral or oral routes of administration.
Keywords AnimalsAntibodies, Monoclonal, Murine-Derived/genetics/immunology/pharmacologyAntigens, CD3/immunologyArthritis, Experimental/drug therapy/immunologyEncephalomyelitis, Autoimmune, Experimental/drug therapy/immunologyFemaleHumansMaleMiceProtein EngineeringReceptors, IgG/immunology
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PMID: 23751612
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Article (Published version) (1 MB) - document accessible for UNIGE members only Limited access to UNIGE
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Research group Groupe Reith Walter (pathologie et immunologie) (282)
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DEPIS, Fabien et al. Characterization of a surrogate murine antibody to model anti-human CD3 therapies. In: mAbs, 2013, vol. 5, n° 4, p. 555-64. https://archive-ouverte.unige.ch/unige:41356

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Deposited on : 2014-10-30

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