•     THE PIPELINE
•        Otelixizumab
•     > TRX1
•        TRX518 (GITR)
•        TRX385 (ILT3)
•        TRX585 (ILT5)

TRX1 (including its modified version) is a targeted T cell immunomodulator.  It is designed to halt the generation of neutralizing antibodies that inactivate protein-based therapies which are used to treat a number of serious conditions.  Additionally, it is designed to halt the generation of pathogenic autoantibodies that may cause many autoimmune diseases.

TRX1 is a unique, humanized monoclonal antibody that targets the CD4 receptor found on T cells.  It is thought to work by preventing the activation of T effector cells that drive the differentiation and proliferation of specific B cells that generate pathogenic autoantibodies or drug-neutralizing antibodies.  CD4-targeting monoclonal antibodies have also been shown to up-regulate T regulatory cells that inhibit the generation of additional copies of these specific B cells.

Development Background:

TRX1 has been evaluated in a single-dose, placebo-controlled, double-blind Phase 1 clinical trial to assess the safety and biological activity in 9 healthy volunteers. In this study, TRX1 was well tolerated, did not deplete T cells, and had no observed first-dose side effects (such as fevers, chills, and hypotension). Subsequently, we completed a Phase 1b clinical trial evaluating three different dose levels of TRX1 in 17 patients with cutaneous lupus erythematosus. Results were consistent with those in the first study.  Additionally, a modified version of TRX1 has been evaluated in a Phase 1 study in rheumatoid arthritis including more than 50 patients dosed. 

TRX1 has not been tested in patients with SLE or MS, but preclinical laboratory studies suggest that it may be effective.

In an article published in the Journal of Immunology in 2004, we demonstrated that in nonhuman primates, a short course of TRX1 can induce a long-term, antigen-specific tolerance to a normally immunogenic protein without compromising normal immune function.  Comparable results have been demonstrated in human patients with cutaneous lupus.  Thus, TRX1 may have utility in enzyme replacement therapy (ERT), particularly in those patients who do not make any (or very little) endogenous enzyme (CRIM-negative).  Those patients typically develop robust immune responses to administered enzyme, making ERT difficult or ineffective. 

About Lupus

The Lupus Foundation of America estimates that approximately 1.5 million Americans have a form of lupus. Lupus erythematosus (LE) is a multifaceted disease with a wide spectrum of manifestations ranging from solitary, chronic skin lesions in chronic discoid LE to multiple organ involvement in SLE. CLE is a chronic, recurrent autoimmune disorder that can occur at any age and is part of the spectrum of presentations of LE. CLE primarily affects the skin, but may also involve the hair and mucous membranes.

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About Rheumatoid Arthritis

The Arthritis Foundation estimates that RA affects more than one million Americans. RA is a chronic, debilitating disease that occurs when the immune system inappropriately attacks joint tissue, causing chronic inflammation and irreversible destruction of cartilage, tendons, and bone. This destruction often results in chronic pain, loss of function, and disability. There is no cure for RA and current treatments focus on treating pain and relieving inflammation.

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About CRIM-Negative Pompe Disease

Pompe disease is a progressive, debilitating, multisystemic, neuromuscular disease. It is caused by an inherited mutation that results in a deficiency in or absence of the enzyme acid alpha-glucosidase (GAA), which metabolizes glycogen. Without normal levels of functioning GAA, glycogen builds up in skeletal and cardiac muscle cells, resulting in progressive tissue damage, loss of function, and ultimately death. Pompe disease is a rare disease, with an incidence of 1 in 40,000 births; many of those affected are infants or young children. The only treatment for Pompe disease is enzyme-replacement therapy (ERT) with alglucosidase, a bioengineered version of naturally occurring human GAA. Patients with cross-reactive immunologic material (CRIM)-negative Pompe disease generate neutralizing antibodies that inactivate alglucosidase. Tolerx is currently evaluating whether TRX1 can halt the generation of these antibodies, thereby restoring the efficacy of ERT.

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