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 mon ocytes in the inflammatory infiltrate of diseases such as rheumatoid arthri tis, renal diseases, and multiple sclerosis, In contrast, little expression of CCR5 is found on peripheral blood leukocytes. A specific depletion of C CR5(+) cells could therefore be a useful strategy to reduce the cellular in filtrate in chronic inflammations. Moreover, CCR5 is the major coreceptor f or hi-tropic EW-I strains, Depletion of CCR5+ leukocytes may help to elimin ate cells latently infected with HIV-1. We designed two constructs that spe cifically 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 C CR5(+) T cells and monocytes, but is inactive against cells that do not exp ress 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 truncate d version of Pseudomonas exotoxin A. The fusion protein binds to CCR5 and d own-modulates the receptor from the cell surface, The chemokine toxin compl etely destroyed CCR5(+) Chinese hamster ovary cells at a concentration of 1 0 nM, whereas no cytotoxic effect was detectable against CCR5(-)Chinese ham ster 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 infe cted cells. The Journal of Immunology, 2001, 166: 2420-2426.