Novel approach to psoriasis as GSK takes first in class anti-LAG-3 mAb, GSK2831781 into the clinic

The alert below is from our UpdatesPlus-Psoriasis service. UpdatesPlus is a service comprising alerts and monthly reports including pipeline and trial updates plus analysis of key information.  The service is designed for industry and academics across the Immunology and Inflammation spectrum.  To register for UpdatesPlus or to get further information please contact fiona.watts@leaddiscovery.co.uk

• LAG-3 (CD223) is a protein specifically expressed by recently activated T cells.  LAG-3 binds MHC class II and plays a central role in the activation of antigen presenting cells 
  
• Selective depletion of cells expressing LAG-3 has been suggested as a therapeutic approach to autoimmune disease and cytotoxic anti-LAG-3 antibodies have been shown to prevent experimental allograft rejection
• GSK has developed GSK2831781, a humanized cytotoxic mAb molecule that targets LAG-3.  This mAb is also able to support antibody dependent cell cytotoxicity and is therefore expected to depleted activated T cells
  
• A healthy volunteer/psoriasis patient trial has now opened, initially testing single ascending doses in healthy volunteers to investigate safety, tolerability and PK/PD of iv GSK2831781
• LAG-3 has been previously shown to  down-regulate tuberculin reactivation of T cells in the skin of BCG inoculated primates.  The study will also determine the effect of GSK2831781 on skin inflammation in healthy subjects previously vaccinated with BCG and challenged topically with tuberculin (Note that this is the Mantoux tuberculin skin test, a standard clinical test of immune response to tuberculosis)
• The second part of the study will enroll psoriasis patients
• Skin biopsies, systemic biomarkers and clinical response endpoints will allow both MOA investigation (including depletion of T cells).  Moreover the identification of systemic biomarkers will drive future studies in indications where biopsies are more challenging to collect
• The study is indicated as running from July 2014 to August 2016

Comments:  The development of this target represents an exciting advance potentially depleting T cells in a targeted fashion.  We expect that GSK2831781 will be targeted to multiple therapy areas in addition to psoriasis if safe.  Antibodies which support antibody dependent cell cytotoxicity have previously been developed successfully (eg Rituxan and Herceptin).  Of note the GSK mAb is de-fucosylated.  This is expected to both enhance cytotoxicity and reduce the risk of anti-drug antibody formation.  We congratulate GSK on its novel translational approach through the use of the Mantoux test.  This represents an ingenious approach to better understanding the potential of GSK2831781.  This also however raises concerns over the safety of GSK2831781 - specifically, if GSK2831781 reduces the response to tuberculin, we ask whether it may also limit the protective role of BCG vaccination and raise the risk of tuberculosis infection.  Given that GSK2831781 is advancing into the clinic, we assume that GSK has preclinical data to suggest that this is not the case