In:
The Journal of Immunology, The American Association of Immunologists, Vol. 184, No. 1_Supplement ( 2010-04-01), p. 145.30-145.30
Kurzfassung:
The T cell receptor complex (TCR) is a powerful therapeutic target for modulating autoimmunity and transplantation biology. A number of studies have shown that TCR/CD3-directed molecules are beneficial in mouse models of disease (e.g, acute graft vs host disease, aGVHD). However, both 145-2C11 (anti-CD3ϵ) and H57-597 (anti-TCRβ) are T cell mitogens and stimulate the activation of T cells and cytokine release in vitro and in vivo . In contrast to conventional antibodies, SMIP molecules are single chain binding proteins based on a scFv-CH2-CH3 format. Compared to their corresponding parent antibodies, SMIP molecules utilizing the 2C11 and H57 binding domains demonstrate a more robust down modulation of the TCR complex, enhanced efficacy in in vitro assays of T cell function, and significantly reduced levels of pro-inflammatory cytokines. Administration of these compounds in vivo results in significantly lower levels of cytokine release with no measurable changes in animal weight loss or adverse clinical symptoms despite dosage of 60 fold molar excess compared to the original full-length antibody. In addition, our SMIPs significantly abrogate donor cell engraftment in spleens of host animals in a parent into F1 model of aGVHD. These observations indicate that features in the SMIP format could generate novel anti-human CD3-directed therapeutics with greatly reduced levels of cytokine release in vivo.
Materialart:
Online-Ressource
ISSN:
0022-1767
,
1550-6606
DOI:
10.4049/jimmunol.184.Supp.145.30
Sprache:
Englisch
Verlag:
The American Association of Immunologists
Publikationsdatum:
2010
ZDB Id:
1475085-5
