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

摘要

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