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Johnson-Farley N.,Rutgers Cancer Institute of New Jersey | Bertino J.R.,Rutgers Cancer Institute of New Jersey | Belinka B.A.,Actinobac Biomed, Inc. | Kachlany S.C.,Actinobac Biomed, Inc.
Leukemia Research | Year: 2015

Leukotoxin (LtxA) is a protein secreted from the oral bacterium Aggregatibacter actinomycetemcomitans. LtxA binds to the β2 integrin lymphocyte-associated function antigen-1 (LFA-1) on human white blood cells (WBCs), resulting in cell death. LtxA is currently under investigation as a novel therapy (Leukothera®) for treating hematologic malignancies and autoimmune diseases. We show here that LtxA has potent in vivo anti-lymphoma activity in mice. LtxA caused complete regression of B-cell tumors and promoted long-term survival of mice. The mechanism of LtxA-mediated killing of malignant lymphocytes was further examined. We found that LtxA kills malignant lymphocytes by a novel mechanism requiring the death receptor Fas and caspase-8, but not Fas ligand (FasL) or caspase-9. We also determined that LFA-1 and Fas are closely associated on the cell surface and this proximity of LFA-1 and Fas could explain how signaling through an integrin can lead to cell death. In addition to LFA-1, this work reveals a second surface protein, Fas, that is critical for LtxA-mediated cell death. Knowledge of the mechanism of cell death induced by LtxA will facilitate the development and understanding of this potent experimental therapeutic agent. © 2015 Elsevier Ltd. Source

Gupta A.,The New School | Le A.,The New School | Belinka B.A.,Actinobac Biomed, Inc. | Kachlany S.C.,The New School
Leukemia Research | Year: 2011

Leukotoxin (Leukothera™; LtxA) is a bacterial protein and experimental therapeutic that binds leukocyte function antigen (LFA-1) on white blood cells (WBCs) and induces cell death via apoptosis or necrosis. We previously found that LtxA preferentially targets WBCs with high levels of activated LFA-1, which is characteristic of many leukemias and lymphomas, and showed that LtxA exhibits significant anti-leukemia activity in vivo using the humanized SCID mouse model. In this report, we demonstrate that LtxA induces very rapid (1 h) apoptosis in acute monocytic leukemia THP-1 cells characterized by binding of annexin V to cells, loss of mitochondrial membrane potential, depletion of cellular ATP, and fragmentation of chromosomal DNA. We tested the activity of LtxA in combination with the standard chemotherapeutic agents, etoposide, mitoxantrone, daunorubicin, busulfan, and imatinib against several leukemia cell lines, including THP-1, GDM-1, HL-60, and KU-812 cells. LtxA exhibited synergism with all the drugs, and the levels of synergy were dependent on the doses used and cell lines examined. In general, the greatest level of synergy was observed with LtxA and etoposide or imatinib. Combination index (CI) values were less than 0.1 for many of the combinations, indicating very strong synergism. In addition, LtxA alone was cytotoxic to primary cells from newly diagnosed, relapsed, and refractory patients with different hematological malignancies. Thus, LtxA is highly effective at inducing rapid apoptosis both as a single agent and in combination with approved leukemia therapies. © 2011 Elsevier Ltd. Source

Kachlany S.C.,Rutgers University | Kachlany S.C.,Actinobac Biomed, Inc.
Journal of Investigative Dermatology Symposium Proceedings | Year: 2015

Alopecia areata is an autoimmune condition where activated, pro-inflammatory white blood cells (WBCs) attack the hair follicles, resulting in hair loss. Migration of these activated WBCs from the blood stream and into the follicle tissue requires interaction between the integrin, lymphocyte function-associated antigen-1 (LFA-1) on WBCs, and ICAM-1 on vascular endothelial cells. High levels of active LFA-1 are uniquely expressed on WBCs that are involved in autoimmune and inflammatory conditions. The natural biologic agent LtxA (Leukothera) preferentially targets and depletes disease activated and malignant WBCs by binding to active LFA-1. The experimental drug has demonstrated significant therapeutic efficacy against autoimmune/inflammatory conditions such as psoriasis and allergic asthma in mouse models for these diseases. In addition, when injected into rodents, rhesus macaques, and dogs, LtxA was demonstrated to be physiologically active, biologically specific, and extremely well-tolerated. LFA-1 is an attractive target for therapy because it is only normally present on WBCs and has been shown to be activated and overexpressed on WBCs that are responsible for autoimmune/inflammatory conditions. © 2015 The Society for Investigative Dermatology. Source

Espinosa V.,Center for Immunity and Inflammation | Rivera-Medina A.,Center for Immunity and Inflammation | Aguila H.A.,The New School | Kachlany S.C.,Actinobac Biomed, Inc.
Journal of Leukocyte Biology | Year: 2015

Allergic asthma is a chronic respiratory disease that results from an exaggerated inflammatory response in the airways. Environment stimuli, such as pollen and HDM, cause activation and migration of inflammatory WBCs into the respiratory tract, where they cause lung damage. Migration of these WBCs is dependent on the active configuration of the β2 integrin LFA-1. The experimental therapeutic agent LtxA specifically targets active LFA-1 and causes cell death. We investigated the association between LFA-1 and allergic asthma and hypothesized that targeting LFA-1 with LtxA could be an attractive strategy for treatment of the condition. We examined LFA-1 (CD11a) levels on PBMCs from patients with allergic asthma compared with healthy controls. Patients exhibited a significantly higher percentage of PBMCs expressing LFA-1 than healthy controls. Furthermore, the level of LFA-1 expression on patient PBMCs was greater than on healthy PBMCs. We identified a unique cellular population in patients that consisted of CD4– CD11ahi cells. We also evaluated LtxA in a HDM extract-induced mouse model for allergic asthma. LtxA caused resolution of disease in mice, as demonstrated by a decrease in BALF WBCs, a reduction in pulmonary inflammation and tissue remodeling, and a decrease in proinflammatory cytokines IL-4, IL-5, IL-9, IL-17F, and IL-23α in lung tissue. LFA-1 may serve as an important marker in allergic asthma, and the elimination of activated WBCs by use of LtxA could be a viable therapeutic strategy for treating patients with this condition. © Society for Leukocyte Biology. Source

Hioe C.E.,New York University | Tuen M.,New York University | Vasiliver-Shamis G.,New York University | Alvarez Y.,New York University | And 7 more authors.
PLoS ONE | Year: 2011

The cellular adhesion molecule LFA-1 and its ICAM-1 ligand play an important role in promoting HIV-1 infectivity and transmission. These molecules are present on the envelope of HIV-1 virions and are integral components of the HIV virological synapse. However, cellular activation is required to convert LFA-1 to the active conformation that has high affinity binding for ICAM-1. This study evaluates whether such activation can be induced by HIV itself. The data show that HIV-1 gp120 was sufficient to trigger LFA-1 activation in fully quiescent naïve CD4 T cells in a CD4-dependent manner, and these CD4 T cells became more susceptible to killing by LtxA, a bacterial leukotoxin that preferentially targets leukocytes expressing high levels of the active LFA-1. Moreover, virus p24-expressing CD4 T cells in the peripheral blood of HIV-infected subjects were found to have higher levels of surface LFA-1, and LtxA treatment led to significant reduction of the viral DNA burden. These results demonstrate for the first time the ability of HIV to directly induce LFA-1 activation on CD4 T cells. Although LFA-1 activation may enhance HIV infectivity and transmission, it also renders the cells more susceptible to an LFA-1-targeting bacterial toxin, which may be harnessed as a novel therapeutic strategy to deplete virus reservoir in HIV-infected individuals. Source

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