Ex vivo efficacy of C1s antibody as Complement inhibitor in cold agglutinin disease

C1s antibody prevents Complement-mediated destruction of red blood cells exposed to patient autoantibodies

2014-04-14

(Press-News.org) SOUTH SAN FRANCISCO, Calif.--True North Therapeutics, Inc., announced today a publication demonstrating that the company's C1s antibody prevents the destruction of human red blood cells exposed to plasma samples of patients with a type of autoimmune hemolytic anemia (AIHA). The article entitled "TNT003, an inhibitor of the serine protease C1s, prevents complement activation induced by cold agglutinin disease patient autoantibodies" was published on-line in the journal Blood earlier this month. TNT003 is the murine analog of True North's lead humanized monoclonal antibody drug candidate, TNT009, for which the company plans to initiate the first clinical program in 2015.

In ex vivo studies using plasma samples from patients with a type of AIHA known as cold agglutinin disease (CAD), True North demonstrated that red blood cells exposed to patient samples contained high levels of Complement proteins deposited on the cell surface. True North showed that by inhibiting Complement deposition on the red blood cell membrane, TNT003 prevented the red blood cells from being engulfed by macrophages, immune cells responsible for clearing Complement-coated cells and debris from the blood. TNT003 also prevented direct red blood cell lysis driven by a CAD sample that contained unusually high levels of autoantibodies, suggesting that a Complement inhibitor like TNT003 could be efficacious in severe cases of CAD.

"By selectively shutting down the Classical Complement pathway with an antibody, the main drivers of anemia in CAD have been reduced in this preclinical study. Using TNT003 and a large number of 40 patient samples, we were able to deepen the field's understanding of the Complement system's role in this rare disease. The study strengthens the hypothesis that such an approach could be beneficial in this rare patient population," stated Sandip Panicker, PhD, C1s Program Lead and senior author on the journal article in Blood.

TNT003 inhibits C1s, a member of the Complement family of plasma proteins, which, upon activation, trigger a powerful enzymatic cascade that destroys and removes pathogens from the circulation. However, aberrant Complement system activation has been described in numerous autoimmune settings in which antibodies that attack self, known as autoantibodies, play a role in disease pathogenesis. Like other forms of AIHA, CAD is a disorder in which anti-red blood cell antibodies bind to and lead to the destruction of patient red blood cells through Complement system activation.

Dr. Panicker further stated, "As Complement system activity is the only known driver of red blood cell destruction in patients with CAD, the results in the study published in Blood provide compelling evidence for the development of TNT009, the company's lead humanized monoclonal antibody, for the treatment of CAD and potentially other forms of AIHA, for which no approved therapies exist."

INFORMATION: About TNT009

TNT009 is a first-in-class molecule developed to selectively inhibit C1s, a serine protease specific to the Classical Complement pathway of the immune system. By precisely targeting the Classical Complement pathway, TNT009 offers a novel approach for treating Complement-mediated diseases with significant unmet medical needs in the hematologic, renal, and neurological therapeutic areas. With a unique mechanism of action and high target specificity, TNT009 selectively inhibits disease processes in the Classical Complement pathway cascade while maintaining the important immune surveillance provided by the Alternative Complement Pathway and Lectin Complement Pathway. With preclinical and ex vivo data demonstrating TNT009's efficacy, True North Therapeutics anticipates initiating the first clinical program with TNT009 in 2015.

About True North Therapeutics

True North Therapeutics is a biotechnology company developing novel therapies that selectively target the Complement pathway of the immune system to address fundamental mechanisms in diseases with high unmet need, including rare diseases. The company's lead monoclonal antibody drug candidate, TNT009, selectively inhibits a target in the Classical Complement pathway, thereby preventing downstream disease processes involving phagocytosis, inflammation, and cell lysis. True North's drug development programs are focused on Complement-mediated diseases in the hematologic, renal, and neurological therapeutic areas. True North Therapeutics is located in South San Francisco, California. For more information, please visit http://www.truenorthrx.com.

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