Depletion of CCR5-Expressing Cells with Bispecific Antibodies and Chemokine Toxins: A New Strategy in the Treatment of Chronic Inflammatory Diseases and HIV

• Published in: The Journal of immunology (1950) 2001-02, Vol.166 (4), p.2420-2426
• Main Authors: Bruhl, Hilke, Cihak, Josef, Stangassinger, Manfred, Schlondorff, Detlef, Mack, Matthias
• Format: Article
• Language: English
• Subjects: ADP Ribose Transferases; Animals; Antibodies, Bispecific - biosynthesis; Antibodies, Bispecific - genetics; Antibodies, Bispecific - metabolism; Antibodies, Bispecific - toxicity; Arthritis, Rheumatoid - immunology; Arthritis, Rheumatoid - pathology; Arthritis, Rheumatoid - therapy; Bacterial Toxins; CCR5 protein; CD3 antigen; CD3 Complex - immunology; Cell Separation; Cells, Cultured; Chemokine CCL5 - genetics; Chemokine CCL5 - immunology; Chemokines - genetics; Chemokines - metabolism; Chemokines - therapeutic use; Chemokines - toxicity; CHO Cells; Chronic Disease; Cricetinae; Cytotoxicity, Immunologic - genetics; Exotoxins - chemical synthesis; Exotoxins - genetics; Exotoxins - immunology; HIV Infections - immunology; HIV Infections - pathology; HIV Infections - therapy; Human immunodeficiency virus; Humans; Immunotoxins - genetics; Immunotoxins - metabolism; Immunotoxins - therapeutic use; Immunotoxins - toxicity; Lymphocyte Depletion; Monocytes - immunology; Monocytes - metabolism; Pseudomonas aeruginosa - genetics; Pseudomonas aeruginosa - immunology; Pseudomonas aeruginosa Exotoxin A; Receptors, CCR5 - biosynthesis; Receptors, CCR5 - immunology; Receptors, CCR5 - metabolism; Recombinant Fusion Proteins - immunology; Recombinant Fusion Proteins - metabolism; Recombinant Fusion Proteins - toxicity; Synovial Fluid - cytology; Synovial Fluid - immunology; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; T-Lymphocytes - pathology; Virulence Factors
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.166.4.2420

The chemokine receptor CCR5 is expressed on the majority of T cells and monocytes in the inflammatory infiltrate of diseases such as rheumatoid arthritis, renal diseases, and multiple sclerosis. In contrast, little expression of CCR5 is found on peripheral blood leukocytes. A specific depletion of CCR5(+) cells could therefore be a useful strategy to reduce the cellular infiltrate in chronic inflammations. Moreover, CCR5 is the major coreceptor for M-tropic HIV-1 strains. Depletion of CCR5(+) leukocytes may help to eliminate cells latently infected with HIV-1. We designed two constructs that specifically destroy chemokine receptor-positive cells. The first construct, a bispecific Ab, binds simultaneously to CCR5 and CD3. Thereby it redirects CD3(+) T cells against CCR5(+) target cells. The Ab specifically depletes CCR5(+) T cells and monocytes, but is inactive against cells that do not express CCR5. Furthermore, ex vivo the bispecific Ab eliminated >95% of CCR5(+) monocytes and T cells from the synovial fluid of patients with arthritis. Also, we designed a fusion protein of the chemokine RANTES and a truncated version of Pseudomonas. exotoxin A. The fusion protein binds to CCR5 and down-modulates the receptor from the cell surface. The chemokine toxin completely destroyed CCR5(+) Chinese hamster ovary cells at a concentration of 10 nM, whereas no cytotoxic effect was detectable against CCR5(-) Chinese hamster ovary cells. Both constructs efficiently deplete CCR5-positive cells, appear as useful agents in the treatment of chronic inflammatory diseases, and may help to eradicate HIV-1 by increasing the turnover of latently infected cells.