First-in-human study of the safety and efficacy of TOL101 induction to prevent kidney transplant rejection.

TOL101 is a murine IgM mAb targeting the αß TCR. Unlike other T cell targets, the αß TCR has no known intracellular signaling domains and may provide a nonmitogenic target for T cell inactivation. We report the 6-month Phase 2 trial data testing TOL101 in kidney transplantation. The study was designed to identify a dose that resulted in significant CD3 T cell modulation (<25 T cell/mm(3) ), to examine the safety and tolerability of TOL101 and to obtain preliminary efficacy information. Thirty-six patients were enrolled and given 5-10 daily doses of TOL101; 33 patients completed dosing, while three discontinued after two doses due to a self-limiting urticarial rash. Infusion adjustments, antihistamines, steroids and dose escalation of TOL101 reduced the incidence of the rash. Doses of TOL101 above 28 mg resulted in prolonged CD3 modulation, with rapid recovery observed 7 days after therapy cessation. There were no cases of patient or graft loss. Few significant adverse events were reported, with one nosocomial pneumonia. There were five biopsy-confirmed acute cellular rejections (13.9%); however, no donor-specific antibodies were detected. Overall TOL101 was well-tolerated, supporting continued clinical development using the dose escalating 21-28-42-42-42 mg regimen.

99th Dahlem conference on infection, inflammation and chronic inflammatory disorders: triggering of autoimmune diseases by infections.

Human autoimmune diseases, such as multiple sclerosis, type 1 diabetes, rheumatoid arthritis and systemic lupus erythematosus (SLE), are linked genetically to distinct major histocompatibility complex (MHC) class II molecules and other immune modulators. However, genetic predisposition is only one risk factor for the development of these diseases, and low concordance rates in monozygotic twins as well as geographical distribution of disease risk suggest a critical role for environmental factors in the triggering of these autoimmune diseases. Among potential environmental factors, infections have been implicated in the onset and/or promotion of autoimmunity. This review will discuss human autoimmune diseases with a potential viral cause, and outline potential mechanisms by which pathogens can trigger autoimmune disease as discerned from various animal models of infection-induced autoimmune disease.