TolerRX, Inc, of Cambridge, Massachusetts, announced the initiation of a phase Ib study of the monoclonal antibody TRX4 in patients with moderate-to-severe chronic plaque psoriasis, as well as a phase Ib study of TRX1, a humanized antibody that is being developed in collaboration with Genentech, Inc, for the treatment of refractory cutaneous lupus erythematosus (CLE).

TRX4, which binds to the T-cell receptor CD3, is believed to inhibit the function of autoreactive T cells while inducing regulatory T cell pathways. The phase Ib US study will evaluate the safety and efficacy of escalating multiple doses of TRX4. The impending launch of this phase 1b study follows on the heels of a phase 1a clinical trial of escalating single intravenous doses of TRX4 in patients with moderate-to-severe psoriasis that uncovered clinically meaningful improvements in the skin of several patients.

TolerRX has also been enrolling subjects in a phase 1b escalating-dose trial to determine the safety and efficacy of TRX1 in patients with refractory CLE. A humanized, nondepleting anti-CD4 monoclonal antibody, TRX1 binds to the CD4 receptor found on both T-effector cells and T-regulatory cells. The compound is expected to block the activation and function of T-effector cells and to favor the dominance of T-regulatory cells. 

The company has completed a phase Ia single-dose, placebo-controlled, double-blind safety and pharmacokinetic study of TRX1 in healthy volunteers. The trial results showed that TRX1 appeared to be well tolerated and did not deplete T cells, and first-dose side effects, such as fevers, chills, and hypotension, were not observed. 

In preclinical studies, TRX1 has demonstrated the ability to induce long-term, antigen-specific tolerance to a normally immunogenic protein without compromising normal immune function. 

In November 2005, TolerRX announced that Abbott Laboratories will handle scale-up and GMP manufacturing of TRX4 for use in clinical trials, as well as supply commercial-grade material to support regulatory submissions and potential commercial launch. The financial terms of the agreement were not disclosed. 

Earlier in the year, TolerRX obtained certain intellectual property and material assets from Diabetogen Biosciences Inc, relating to the therapeutic use of anti-CD3 antibodies in autoimmune diseases. TolerRx acquired access to the technology under an original patent application and a licensing agreement between Diabetogen of London, Ontario, Canada, and the Institut National de La Santé et de La Recherche Médicale (INSERM) in France.
 
TolerRx has also acquired the rights to technology and material relating to a panel of fully human anti-CD3 antibodies under a licensing agreement between Diabetogen and Abgenix, Inc (soon to be acquired by Amgen). Financial terms were not disclosed. 

Another party interested in anti-CD3 antibodies is MacroGenics, Inc, of Rockville, Maryland, which announced in mid-2005 the signing of an agreement with Tolerance Therapeutics, Inc, in which MacroGenics will acquire the intellectual property, materials, and expertise related to a promising anti-CD3 monoclonal antibody for the treatment of Type 1 diabetes and other autoimmune diseases. MacroGenics is seeking a strategic partner to fund and codevelop anti-CD3 antibodies for these disorders. 

MacroGenics is also developing a humanized anti-CD3 monoclonal antibody with a modified Fc component called hOKT3 (ala-ala) in partnership with the National Institutes of Health-funded Immune Tolerance Network. This antibody may have potential therapeutic benefits in a wide range of immunologic diseases including systemic lupus erythematosus, ulcerative colitis, and psoriasis, and is being considered for studies in these and other indications.

—A. Techman