LFA-1-targeting Leukotoxin (LtxA; Leukothera®) causes lymphoma tumor regression in a humanized mouse model and requires caspase-8 and Fas to kill malignant lymphocytes

Q4 · MEDICINE

Article

Author: DiFranco, Kristina M ; Belinka, Benjamin A ; Kachlany, Scott C ; Elson, David ; Bertino, Joseph R ; Johnson-Farley, Nadine ; Vega, Brian A

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.

01 May 2012·Journal of Biological ChemistryQ2 · BIOLOGY

Leukotoxin (Leukothera®) Targets Active Leukocyte Function Antigen-1 (LFA-1) Protein and Triggers a Lysosomal Mediated Cell Death Pathway

Q2 · BIOLOGY

Article

Author: DiFranco, Kristina M ; Perez, Jarelys ; Galusha, Lindsey E ; Fineza, Camille D ; Nguyen, To-Vy K ; Gupta, Anukriti ; Kachlany, Scott C

Leukotoxin (LtxA) is a protein toxin that is secreted from the oral bacterium, Aggregatibacter actinomycetemcomitans. LtxA targets specifically the β(2) integrin, leukocyte function antigen-1 (LFA-1) on white blood cells (WBCs) and causes cell death. LtxA preferentially targets activated WBCs and is being developed as a therapeutic agent for the treatment of WBC diseases such as hematologic malignancies and autoimmune/inflammatory diseases. However, the mechanism by which interaction between LtxA and LFA-1 results in cell death is not well understood. Furthermore, how LtxA preferentially recognizes activated WBCs is not known. We show here that LtxA interacts specifically with LFA-1 in the active (exposed) conformation. In THP-1 monocytes, LtxA caused rapid activation of caspases, but LtxA could overcome the inhibition of caspases and still intoxicate. In contrast, inhibiting the vesicular trafficking pathway or cathepsin D release from the lysosome resulted in significant inhibition of LtxA-mediated cytotoxicity, indicating a more potent, lysosomal mediated cell death pathway. LtxA caused rapid disruption of the lysosomal membrane and release of lysosomal contents into the cytosol. Binding of LtxA to LFA-1 resulted in the internalization of both LtxA and LFA-1, with LtxA localizing specifically to the lysosomal compartment. To our knowledge, LtxA represents the first bacterial toxin shown to localize to the lysosome where it induces rapid cell death.

01 Nov 2011·Leukemia ResearchQ4 · MEDICINE

Synergistic targeting of leukemia with leukotoxin and chemotherapy

Q4 · MEDICINE

Communications

Author: Robert J. Kreitman

A review.The research of Gupta et al. (2011) entitled, 'In vitro synergism between LFA-1 targeting leukotoxin (Leukothera) and standard chemotherapeutic agents in leukemia cells' is reviewed with commentary and referencesGupta et al. showed that synergism between leukotoxin (LtxA) and chemotherapy is promising for the development of this toxin for the treatment of leukemias.They discussed the important next steps in this development, namely administration of LtxA in vivo with or without chemotherapy agents, and point out that in non-human primates, the tolerated concentration of LtxA is 0.4 μg/mL.

100 Deals associated with Leukothera

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Indication	Highest Phase	Country/Location	Organization	Date
Autoimmune Diseases	Phase 1	US	Actinobac Biomed, Inc.	31 Jan 2021
Hematologic Neoplasms	Phase 1	US	Actinobac Biomed, Inc.	31 Jan 2021
HIV Infections	Phase 1	US	Actinobac Biomed, Inc.	31 Jan 2021

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