Author: Collins, B H ; Leopardi, F V ; Lu, C ; Song, M ; MacDonald, A L ; Lo, D J ; Mulvihill, M S ; Farris, A B ; Kachlany, S C ; Springer, T A ; Parker, B S ; Anderson, D J ; Reimann, K A ; Samy, K P ; How, T ; Kirk, A D ; Franke, K S ; Williams, K D

Costimulation blockade (CoB) via belatacept is a lower-morbidity alternative to calcineurin inhibitor (CNI)-based immunosuppression. However, it has higher rates of early acute rejection. These early rejections are mediated in part by memory T cells, which have reduced dependence on the pathway targeted by belatacept and increased adhesion molecule expression. One such molecule is leukocyte function antigen (LFA)-1. LFA-1 exists in two forms: a commonly expressed, low-affinity form and a transient, high-affinity form, expressed only during activation. We have shown that antibodies reactive with LFA-1 regardless of its configuration are effective in eliminating memory T cells but at the cost of impaired protective immunity. Here we test two novel agents, leukotoxin A and AL-579, each of which targets the high-affinity form of LFA-1, to determine whether this more precise targeting prevents belatacept-resistant rejection. Despite evidence of ex vivo and in vivo ligand-specific activity, neither agent when combined with belatacept proved superior to belatacept monotherapy. Leukotoxin A approached a ceiling of toxicity before efficacy, while AL-579 failed to significantly alter the peripheral immune response. These data, and prior studies, suggest that LFA-1 blockade may not be a suitable adjuvant agent for CoB-resistant rejection.

01 Nov 2015·Journal of Investigative Dermatology Symposium Proceedings

Mechanisms of LtxA (Leukotoxin), a Potent New Anti-Inflammatory Agent for the Treatment of Alopecia Areata

Review

Author: Kachlany, Scott C

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.

01 Jun 2015·Leukemia ResearchQ4 · MEDICINE

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

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.

News (Medical) associated with Actinobac Biomed, Inc.

28 Jun 2011

·www.biospace.com

Actinobac Biomed, Inc. Release: Recent Study Shows Leukothera™ Combined with Other Agents Has Enhanced Anti-Leukemia Effects

NEW BRUNSWICK, N.J., June 27, 2011 /PRNewswire/ -- Recent findings published in the scientific journal Leukemia Research ( ), showed that when combined with standard anti-leukemia agents, the biological activity of LeukotheraTM, a drug candidate under development by Actinobac Biomed, Inc., showed synergistic anti-leukemia effects. The outcome of these in vitro experimentsdemonstrated that combining LeukotheraTM with such widely employed drugs as etoposide, mitoxantrone, daunorubicin, busulfan and imatinib killed leukemia cells much more effectively than when the agents were used alone. LeukotheraTM is a natural biologic agent that specifically targets malignant and/or inflammatory white blood cells involved in disease. Dr. Scott Kachlany, founder of Actinobac Biomed, explained. "Drug combination therapies for cancer are now frequently considered by oncologists due to their many advantages, which include the possibility of reducing doses of toxic chemotherapeutic agents and a lower chance of developing drug resistance," he said. "The biological mechanism of LeukotheraTM differs from that of other cancer drugs so including it to blood cancer treatment protocols may be a highly effective strategy." Actinobac Biomed, Inc. was founded in 2009 with financial backing from Foundation Venture Capital Group, LLC, to develop commercial products based upon technology developed at the University of Medicine and Dentistry of New Jersey. The company has exclusively licensed the rights to develop LeukotheraTM as a therapeutic agent for the treatment of hematologic malignancies, autoimmune and inflammatory diseases and HIV infection. "We provided early seed funding to Actinobac because we are convinced that they are working on breakthrough research that can make a huge difference for people suffering with leukemia and other diseases," said James M. Golubieski, president of Foundation Venture Capital Group ( ), an affiliate of New Jersey Health Foundation. For more information about Foundation Venture Capital Group, contact Jim Golubieski at (908) 731-6601 or jgolubieski@njhf.org. For more information or to explore ways in which to partner with Actinobac, contact them at (732) 371-2694, info@actinobac.com or visit . SOURCE Foundation Venture Capital Group, LLC

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Leukocyte function antigen-1 (LFA-1) antagonist(Actinobac Biomed, Inc.) ( CD11a )	Hematologic Diseases More	Pending
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