NARILIS lunch seminar | Prof. Mireille DUMOULIN, ULiège

We are pleased to invite you to a seminar given by

Prof. Mireille DUMOULIN

Centre for Protein Engineering (CIP), InBios, Departement of Life Sciences, Faculty of Sciences, ULiège

NEPTUNS : Nano-Antibodies to Explore Protein Structure and Functions

Her seminar is entitled:

NbE201: a Camelid Single-Domain Antibody Fragment to Inhibit Neutrophil Elastase and reduce lung inflammation

Muco-obstructive lung diseases are characterized by chronic neutrophilic inflammation and an imbalance between proteolytic enzymes and their inhibitors, thereby causing lung matrix destruction and perpetuating inflammation. Elastase is one of the major serine proteases secreted by neutrophils and it therefore constitutes a promising therapeutic target. From a llama immune library of VHH genes, we selected, by phage display, a camelid single-domain antibody fragment (also referred to as VHH or Nanobody) named NbE201, which is able to inhibit tightly, specifically, and competitively both human (hNE) and murine (mNE) elastase. Its in vitro inhibitory activity is similar to that of alpha-1 antitrypsin (i.e., AAT, the main endogenous inhibitor of hNE) and superior to that of Sivelestat (i.e., the only clinically approved hNE inhibitor beside AAT). The X-ray crystal structure of the VHH-hNE complex shows that the CDR1 and CDR3 of NbE201 bind into the active site of the enzyme, obstructing its access to both small and macromolecular substrates. However, they do not bind deeply enough into the substrate binding pocket to be hydrolyzed. NbE201 is highly stable against chemical and thermal denaturation, oxidation, and deamidation. Moreover, NbE201 is able to inhibit NE in sputa from patients with muco-obstructive diseases and it prevents the development of acute respiratory distress syndrome induced by the instillation of NE into the lungs of mice. Altogether, these results highlight the high therapeutic potential of NbE201 to treat pulmonary inflammatory diseases.

I will also take the opportunity of this seminar to introduce AlpaNano, a platform developed at CIP to generate and select VHHs.

Invited by Prof. Catherine Michaux, UNamur, Laboratory of Physical Chemistry of Biomolecules (CPB)