Sylviane Muller
University of Strasbourg, France
Title: Autophagy pathway as a target of therapeutic P140 peptide used in lupus
Biography
Biography: Sylviane Muller
Abstract
P140 is a 21-mer peptide (sequence 131-151, phosphorylated at position 140) that is derived from the spliceosomal protein
U1-70K. In a multicenter, randomized, placebo-controlled phase IIb study, P140/Lupuzor™ had no adverse safety signals
and met its primary efficacy end points in lupus patients. These results confirm data generated in MRL/lpr lupus-prone mice in
which the preclinical studies were performed. We found previously that P140 reduces autophagic flux in MRL/lpr B cells and
that macroautophagy (the best characterized type of autophagy) is abnormally enhanced in T-lymphocytes from lupus mice and
patients. More recently, we discovered that in MRL/lpr mice, P140 more precisely targets a selective form of autophagy, called
chaperone-mediated autophagy. We deciphered the successive steps of P140 action leading in fine to a decay of endogenous
antigen processing and loading to MHCII molecules and as a consequence, to a lower activation of auto-reactive T cells. Here,
the mechanism of action of P140 was further studied in the peripheral cells from normal and lupus individuals. As in MRL/
lpr mice, P140 enters human B cells via a clathrin-dependent endo-lysosomal pathway and induces a decrease of MHCII cell
surface expression. It affected autophagy processes in human B cells but did not induce apoptosis of B cells from healthy or
lupus patients. These findings and others provide strong arguments to conclude that the mechanism of action of P140 peptide
is similar in MRL/lpr mice and lupus patients. These results shed light on mechanisms by which P140/Lupuzor modulates
lupus disease in humans affected by this disorder.