New therapeutic candidate enters the lupus pipeline - CD30 indications to spread from oncology to autoimmune disease?

Seattle Genetics to open clinical study of CD30 targeting brentuximab in lupus [link]


From UpdatesPlus-Lupus is our regular report analyzing breaking development across the field of lupus research and development - for further information and sample copies  please contact Dr Jon Goldhill

• Seattle Genetics has successfully developed and launched Brentuximab (SGN-35) as Adcetris for the treatment of  relapsed or refractory CD30+ Hodgkin lymphoma
• Brentuximab consists of an anti-CD30 mAb (SGN-30) conjugated to a cytotoxic agent monomethyl auristatin E
• This allows selective internalization of the cytotoxic by CD30 expressing tumor cells leading to their destruction
  
• CD30 has also been implicated in autoimmune disease
• CD30 and its ligand CD30L are members of the TNF super-family expressed on activated lymphocytes
  
• CD30 over-expression has been reported in lupus.  As long ago as 1995 it was reported that sCD30 levels were increased 10-fold in lupus patients correlating with disease activity 
  
• Over-expression was later confirmed and shown to include SLE and lupus nephritis patients
• More recently SLE patients have been shown to express a high rate of CD30 T cells.  Moreover expression was on CD8 T cells rather than CD4 T cells which preferentially express CD30 under healthy conditions
• Seattle Genetics retrospectively reviewed data from lymphoma patients and concluded that concomitant autoimmune disease was improved in some patients treated with brentuximab
• Seattle Genetics has now announced the initiation of a phase 2 study of brentuximab in SLE
  
• The new study will administer brentuximab to 40 patients (q3w)

Comments:  Given the limited lupus pipeline new candidates entering the clinic are particularly welcome.  This is especially the case when candidates are first in class.  By word of caution however, the brentuximab product label carries a boxed warning of PML and lists a large number of toxicities although it should be noted that trials were in an oncology setting and causality is difficult to conclude.  From a mechanistic perspective we would expect brentuximab to impact both CD4 and CD8 CD30 positive cells although previous data suggest CD8 T cells may be a more relevant target.  Moving forward we also ask if strategies aimed at more selective targeting of CD8 cells could improve the therapeutic index.  For example, OX40 and CD30 reportedly act synergistically to regulate CD8 cells, opening options for bispecific approaches.  Finally, we note that sCD30 has been related to lupus disease activity.  We presume that this is an indirect measure of membrane bound CD30, and that cleavage in turn increases sCD30.  It would be useful to verify however whether sCD30 carries a pathophysiologic role