title: Anti-Thy-1 Antibody-mediated Complement-dependent Cytotoxicity is Regulated by the Distribution of Antigen, Antibody and Membrane Complement Regulatory Proteins in Rats.
abstract: Some therapeutic antibodies as anticancer agents exert their effects through the host immune system, but the factors that predict their cytotoxicity, including complement-dependent cytotoxicity (CDC), are unclear. In the present study, we attempted to elucidate some of these factors in a preclinical model. CDC-related mesangiolysis caused by administration of the anti-Thy-1.1 antibody can be studied in the rat anti-Thy-1 glomerulonephritis model, so the model was used in this study. Three animals each were sacrificed at 0.5, 1, 8, 24 and 48 hours after i.v. administration of the anti-Thy-1.1 antibody at 1mg/kg. The distribution of the Thy-1.1 antigen and 2 membrane complement regulatory proteins (mCRPs), Crry and CD55, in three non-treated animals and the distribution of the injected antibody and C3 in the model was studied by immunohistochemistry. In the mesangial cells of the kidney, both expression of the antigen and distribution of the antibody with C3 deposition were observed with weak expression of mCRPs. There was also antigen and antibody distribution in the medullary cells of the adrenal gland and in the lymphocytes of the thymus but no C3 deposition, which was thought to be related to high expression of mCRPs. The antigen was observed in several other organs and tissues without distribution of the antibody. Cell death was only observed in the mesangial cells. These results clearly demonstrate that activation of CDC is regulated by several factors, such as distribution of the target molecule, antibody distribution and the balance among the molecules of the CDC cascade and mCRPs.
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd., 200 Kajiwara, Kamakura, Kanagawa 247-8530, Japan.
authors.forename: Chie
authors.initials: C
authors.lastname: Kato
authors.forename: Atsuhiko
authors.initials: A
authors.lastname: Kato
authors.forename: Kenji
authors.initials: K
authors.lastname: Adachi
authors.forename: Etsuko
authors.initials: E
authors.lastname: Fujii
authors.forename: Kaori
authors.initials: K
authors.lastname: Isobe
authors.forename: Tomochika
authors.initials: T
authors.lastname: Matsushita
authors.forename: Takeshi
authors.initials: T
authors.lastname: Watanabe
authors.forename: Masami
authors.initials: M
authors.lastname: Suzuki
keywords: antibody; antigen; complement-dependent cytotoxicity; membrane complement regulatory protein; rat anti-Thy-1 glomerulonephritis model