Abstract 5655: Efficacy of antibodies targeting TfR1 in xenograft mouse models of AIDS-related non-Hodgkin lymphoma

Abstract

Abstract Infection with the human immunodeficiency virus (HIV) and the development of acquired immunodeficiency syndrome (AIDS) increases the risk of developing B-cell lymphomas. AIDS-related B-cell non-Hodgkin lymphoma (AIDS-NHL) remains a significant clinical problem in the era of effective combination anti-retroviral therapy. In fact, AIDS-NHL is currently the most common AIDS-related malignancy in developed countries, where NHL accounts for 23-30% of all AIDS-related deaths. Transferrin receptor 1 (TfR1), also known as CD71, is a type II transmembrane homodimeric protein involved in the cellular uptake of iron and the regulation of cell growth. It is expressed on normal B cells at low levels and is upregulated upon activation. HIV infection leads to the chronic activation of B cells, which results in high expression of TfR1 on these cells, B-cell dysfunction, and ultimately the development of AIDS-NHL. Importantly, TfR1 expression is correlated with stage and prognosis of NHL including AIDS-NHL. Thus, it is a meaningful target for antibody-based NHL therapy. We previously developed a mouse/human chimeric IgG3 specific for human TfR1 (ch128.1/IgG3) and have shown that this antibody administered intraperitoneally exhibits antitumor activity in an in vivo model of AIDS-NHL where NOD-SCID mice were challenged intraperitoneally with 2F7 human Burkitt lymphoma (BL) cells that are positive for the Epstein-Barr Virus (EBV). More recently, we have developed a mouse/human chimeric IgG1 version of ch128.1 that shows significant antitumor activity in various disseminated mouse models of human multiple myeloma (MM), another B-cell malignancy. In the present studies, we sought to further explore in two novel mouse models of human AIDS-NHL the utility of targeting the TfR1 with ch128.1/IgG1 and its recently developed humanized version (hu128.1). To accomplish this goal, we used the 2F7 cell line variant 2F7-BR44, which forms metastases in the brain of mice upon intravenous (i.v.) injection. We also used human JB cells, which are of particular relevance since they are human BL cells that are EBV negative. We found that systemic (i.v.) treatment with ch128.1/IgG1 or hu128.1 of SCID-Beige mice challenged locally (subcutaneously) with 2F7-BR44 or JB tumor cells results in significant antitumor activity against different stages of the disease. Treatment of mice challenged systemically (i.v.) with 2F7-BR44 or JB tumor cells also showed antitumor activity, including long-term survival in some cases. Taken together, our results suggest that targeting TfR1 with antibodies such as ch128.1/IgG1 and hu128.1 has potential as an effective therapy for B-cell malignancies, including MM and AIDS-NHL. Citation Format: Tracy R. Daniels-Wells, Pierre V. Candelaria, Emiko Kranz, Jing Wen, Lan Weng, Masakazu Kamata, Juan Carlos Almagro, Otoniel Martinez-Maza, Manuel L. Penichet. Efficacy of antibodies targeting TfR1 in xenograft mouse models of AIDS-related non-Hodgkin lymphoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5655.