Depletion of CCR5-expressing cells with bispecific antibodies and chemokine toxins: a new strategy in the treatment of chronic inflammatory diseases and HIV.
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.
Brühl
H
H
Medical Policlinic, University of Munich, Munich, Germany. Institute for Animal Physiology, University of Munich, Munich, Germany.
Cihak
J
J
Stangassinger
M
M
Schlöndorff
D
D
Mack
M
M
D036002:ADP Ribose Transferases; D000818:Animals; D018033:Antibodies, Bispecific / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000633:toxicity; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D001427:Bacterial Toxins; D017252:CD3 Complex / Q000276:immunology; D016466:CHO Cells; D002469:Cell Separation; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000235:genetics / Q000276:immunology; D018925:Chemokines / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use / Q000633:toxicity*; D002908:Chronic Disease; D006224:Cricetinae; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D005098:Exotoxins / Q000138:chemical synthesis / Q000235:genetics / Q000276:immunology; D015658:HIV Infections / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D006801:Humans; D000922:Immunotoxins / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use / Q000633:toxicity*; D008212:Lymphocyte Depletion; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism; D011550:Pseudomonas aeruginosa / Q000235:genetics / Q000276:immunology; D019713:Receptors, CCR5 / Q000096:biosynthesis* / Q000276:immunology / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000378:metabolism / Q000633:toxicity; D013582:Synovial Fluid / Q000166:cytology / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A
D036002:ADP Ribose Transferases; D018033:Antibodies, Bispecific; D001427:Bacterial Toxins; D017252:CD3 Complex; D018946:Chemokine CCL5; D018925:Chemokines; D005098:Exotoxins; D000922:Immunotoxins; D019713:Receptors, CCR5; D011993:Recombinant Fusion Proteins; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A