Inhibition of TNF by a TNF receptor immunoadhesin. Comparison to an anti-TNF monoclonal antibody.
TNF is an important mediator of inflammation, which can have deleterious effects when produced inappropriately. We have described a recombinant inhibitor of TNF, termed TNFR-IgG, or TNFR immunoadhesin, composed of the extracellular portion of the type 1 (p55) TNF receptor (TNFR) linked to the hinge and Fc regions of IgG heavy chain. This bivalent, Ab-like molecule is a potent inhibitor of TNF, exhibiting significantly higher affinity for the cytokine than soluble TNFR. Here, we compare the TNF-neutralizing capacity of TNFR-IgG to that of an anti-TNF mAb. In vitro, TNFR-IgG was 10- to 50-fold more potent than anti-TNF mAb at blocking the cytotoxic effect of exogenous TNF on actinomycin D-treated murine L-M cells. In vivo, the plasma half-life of TNFR-IgG in mice was approximately 6 days, similar to that reported for the anti-TNF mAb. However, the immunoadhesin was approximately 10-fold more effective than the Ab at neutralizing the activity of endogenous TNF, as assessed in a model for murine listeriosis. These results demonstrate a markedly greater potency of the TNFR immunoadhesin compared with the anti-TNF mAb at inhibiting TNF activity in vitro and in vivo.
Haak-Frendscho
M
M
Department of Molecular Biology, Genentech, Inc., South San Francisco, CA 94080.
Marsters
S A
SA
Mordenti
J
J
Brady
S
S
Gillett
N A
NA
Chen
S A
SA
Ashkenazi
A
A
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D008088:Listeriosis / Q000276:immunology / Q000473:pathology; D008099:Liver / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018124:Receptors, Tumor Necrosis Factor / Q000737:chemistry*; D011993:Recombinant Fusion Proteins / Q000493:pharmacokinetics / Q000494:pharmacology*; D013154:Spleen / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
D000911:Antibodies, Monoclonal; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha