Abstract 1240: A flexible antibody-based strategy targeting CD71 for the treatment of AIDS-related non-Hodgkin's lymphoma.

AIDS related non-Hodgkin9s lymphoma (AIDS-NHL) remains a significant clinical problem in the era of effective multiple-agent highly active anti-retroviral therapy (HAART). While an overall decrease in the incidence of AIDS-NHL has been seen in the HAART era, the risk for AIDS-NHL remains elevated, and not all AIDS-NHL subtypes have decreased in incidence, with the incidence of Burkitt9s lymphoma (BL) remaining unchanged. In fact, AIDS-NHL is now the most common AIDS-related cancer in developed countries, where NHL accounts for 23-30% of all AIDS-related deaths. We have previously developed an antibody-avidin fusion protein (ch128.1Av) specific for the human transferrin receptor 1 (TfR1/CD71), a receptor that is overexpressed on cancer cells due to their high demand for iron. This fusion protein exhibits an increased in vitro cytotoxicity against malignant hematopoietic cells compared to the parental antibody without avidin (ch128.1). This cytotoxicity is due to the ability of ch128.1Av to decrease cell surface TfR1, triggering its intracellular sequestration and degradation, with the subsequent induction of lethal iron deprivation. However, both ch128.1Av and ch128.1 confer protection in murine models of human disseminated multiple myeloma. ch128.1Av is also a universal delivery system and its cytotoxicity can be further enhanced by its conjugation with biotinylated drugs making it a unique molecule capable of a two-pronged attack against malignant cells through drug delivery and direct cytotoxic activity through iron starvation. The main goal of this study is to evaluate the potential use of ch128.1Av alone and as a delivery vehicle as a possible AIDS-NHL therapy. We found that, when used alone, ch128.1Av exhibits significant cytotoxic activity against two representative AIDS-NHL cell lines: 2F7 (AIDS-Burkitt9s NHL) and RRBL (AIDS-diffuse large B-cell lymphoma). Importantly, the level of cytotoxicity was similar to that observed using the highly sensitive human B lymphoblastoid cell line IM-9. In addition, the cytotoxicity dramatically increases when this fusion protein is conjugated to biotinylated saporin 6 (b-SO6), a plant ribosome inactivating protein that blocks protein synthesis, resulting in an immunotoxin. We also found that non-activated (resting) B cells isolated from the peripheral blood of healthy individuals are resistant to ch128.1Av, but sensitive to ch128.1Av complexed to b-SO6, which can be explained by the different mechanisms of action of the fusion protein alone (iron starvation) and that of the immunotoxin (protein synthesis inhibition). We have previously reported ch128.1Av alone, or complexed to b-SO6, are not toxic to normal human hematopoietic stem cells, which can be explained by the lack of TfR1 expression on such cells. Our results suggest the potential use of anti-TfR1 antibody-mediated approaches as therapeutic interventions against AIDS-NHL. Citation Format: Tracy R. Daniels-Wells, Lai Sum Leoh, Daniel Widney, Dharma R. Thapa, Jose Leon Merino, Larry Magpantay, Otoniel Martinez-Maza, Manuel L. Penichet. A flexible antibody-based strategy targeting CD71 for the treatment of AIDS-related non-Hodgkin9s lymphoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1240. doi:10.1158/1538-7445.AM2013-1240