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A patient process of establishing proof-of-principle for the effectiveness of targeting radiolabelled monoclonal antibodies to virally infected cells and then identifying monoclonal antibodies that would be effective against HIV infected cells is bearing fruit for researchers from Albert Einstein College of Medicine in New York in the USA. The group presented their findings on radioimmunotherapy (RIT) treatment of HIV-infected lymphocytes from patients previously treated with highly active antiretroviral therapy (HAART) at the Annual Meeting of the Radiological Society of North America (RSNA) today.

RIT is traditionally used in cancer treatment, but in 2006 the group published the findings of a proof-of-principle study in in vitro in chronically HIV-1-infected human T cells and acutely HIV-1-infected human peripheral blood mononuclear cells and in vivo in a severe combined immunodeficiency (SCID) mouse model in which there were acutely HIV-1-infected human peripheral blood mononuclear cells in the spleen. The group showed that using mAbs against HIV glycoproteins gp120 and gp41 labelled with bismuth 213 ((213)Bi) or rhenium 188 ((188)Re) resulted in killing of the HIV-1 infected cells and suggested that HIV-targeted RIT had potential as a co-treatment option along with HAART for HIV infection. The group then built on this proof-of-principle study to try to identify a mAb to HIV gp41 which would be suitable for preclinical development. mAB 2556 was identified as being a high affinity antibody which reacted with gp41 both on viral particle surfaces and infected cells. (213)Bi-2556 efficiently killed ACH-2 human lymphocytes chronically infected with HIV-1, and HIV-1 infected human peripheral blood mononuclear cells (hPBMCs) in vitro. In two in vivo HIV-1 mouse models, splenic and intraperitoneal, (213)Bi-2556 decreased HIV-1 infected hPBMCs from the spleens and peritoneum, respectively.

RIT had already been successfully adapted for the treatment of other pathogens such as experimental fungal (C. neoformans and H. capsulatum), bacterial (S. pneumoniae and B. anthracis), and viral (HIV-1) infections with negligible haematological toxicity in experimental animals. Depending on whether mAbs were radiolabeled with either alpha- or beta-emitters, infected cells succumbed to apoptosis-like cell death (both alpha- or beta-emitters), while mAbs radiolabeled with alpha-emitter (213)Bi also decreased the metabolic activity of microbial cells.

In the results presented in the Annual Meeting of the Radiological Society of North America (RSNA) the group reported that RIT killed previously HAART-treated HIV-infected lymphocytes and reduced HIV infection in the blood samples to undetectable levels. Their studies have also used an in vitro human blood brain barrier model to show that (213)Bi-2556 could cross the blood-brain barrier, thus potentially overcoming a limitation of anti-retroviral therapy, which can only partially cross the blood-brain barrier.

The effectiveness of this therapy lies in the fact that unlike HAART, the RIT can actually kill HIV-1-infected cells and eliminate reservoirs of latently HIV-infected cells that may persist even after HAART treatment. The group is preparing to move to clinical trials in patients to try out a strategy that may finally provide a cure for HIV infection.

Sources

DADACHOVA, E. and CASADEVALL, A., 2009. Radioimmunotherapy of infectious diseases. Seminars in nuclear medicine, 39(2), pp. 146-153.

DADACHOVA, E., KITCHEN, S.G., BRISTOL, G., BALDWIN, G.C., REVSKAYA, E., EMPIG, C., THORNTON, G.B., GORNY, M.K., ZOLLA-PAZNER, S. and CASADEVALL, A., 2012. Pre-clinical evaluation of a 213Bi-labeled 2556 antibody to HIV-1 gp41 glycoprotein in HIV-1 mouse models as a reagent for HIV eradication. Plos One, 7(3), pp. e31866-e31866.

DADACHOVA, E., PATEL, M.C., TOUSSI, S., APOSTOLIDIS, C., MORGENSTERN, A., BRECHBIEL, M.W., GORNY, M.K., ZOLLA-PAZNER, S., CASADEVALL, A. and GOLDSTEIN, H., 2006. Targeted killing of virally infected cells by radiolabeled antibodies to viral proteins. Plos Medicine, 3(11), pp. e427-e427.

http://www.sciencedaily.com/releases/201...091601.htm [Accessed 3 December 2013].