Tuesday, July 5, 2016

Selective elimination of autoimmune B cells using novel CAR-T technology based on antigen decoy

Few days ago journal Science published very interesting study describing a novel approach of treating autoimmune [auto-antibody]-dependent diseases. Called chimeric auto-antibody receptor (CAAR) T cell technology, this method can selectively eliminate autoantigen specific B cells in autoimmune diseases such as Pemphigus vulgaris, lupus, Myasthenia Gravis, Graves diseases and so on.

This new technology is based on a simple idea: antigen decoy. For example, during pemphigus vulgaris autoimmune B cells secrete autoantibodies to the keratinocyte adhesion protein desmoglein (Dsg3) that causes severe skin inflammation. Short-term management of diseases is achieved by total B cell depletion, but disease returns. The authors reasoned that if engineered T cells would express Dsg3 as a CARs, such antigen decoy CAAR T cells would selectively engage disease-causing anti-Dsg3-specific auto-antibody producing B cells. Such interaction should eliminate only Dsg3 specific B cells, sparing normal, infectious-specific B cells.

Indeed, the authors showed that CAAR-T cells expressing Dsg3 as a CAR construct (EC1-4 CAAR) can selectively interact with Dsg3-specific autoimmune B cells in vitro.  

More importantly in vivo NSG mice experiments confirmed that Dsg3 CAAR T cells could selectively eliminate human Nalm6 CD19+ B cell line expressing autoimmune Dsg3-specific receptors (PVB28/F779). In addition the authors claim that Dsg3 CAAR-T cells did not interfere with normal human skin epithelial functioning expressing Dsg3's natural ligand desmocollins.

In summary, if the results of this study is confirmed by other groups it would open up a new path for treating auto-antibody dependent autoimmune diseases.

David Usharauli


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