Research & Development

Discovery of lead molecule

The discovery of ACHAs with therapeutic effect

First generation therapeutic anti-citrullinated histone antibodies (tACHAs) were isolated from the B cell antibody repertoire of RA patients and affinity selected for binding to cyclic citrullinated filaggrin peptide.

From RA-derived ACHA to the lead candidate CIT-013

tACHAs were tested in collagen antibody-induced arthritis (CAIA) mouse model to identify one which prevented development of arthritis. The epitope of this progenitor antibody was identified as the citrullinated N-terminus of Histones H2A and H4, which enabled generation of a mouse mAb against the same epitope, with anti-inflammatory effects in vivo. This mAb was humanized and further modified to generate Citryll’s clinical asset, CIT-013.

CIT-013’s dual mode of action

CIT-013 has a dual mode of action which results from its picomolar binding affinity for the citrullinated N-terminal sequence of histone H2A and H4.

Firstly, CIT-013 acts upon the final stage of NETosis when the cell membrane becomes permeable at a discrete site to allow CIT-013 to bind its epitope on the decondensing chromatin. It is this binding which inhibits rupture and release of the extracellular traps.

CIT-013 binding to NETs after the NETosis pathway of Neutrophil is activated

Secondly, CIT-013 binding to NETs and netting neutrophils forms an immune complex which, because CIT-013 has a function Fc region, engages macrophages to phagocytose the NETs.

As a consequence, CIT-013 binds both tissue NETs to enhance their clearance and also bind netting neutrophils to block the production of more NETs at source.

Peer reviewed scientific publications from Citryll that support these findings can be found at Publications

CIT-013 binding to NET fragments induces phagocytosis by a macrophage