Live imaging experiment visualising the pharmacological effect of CT-013 on NET formation as compared to human neutrophils treated with a control human IgG and triggered with a calcium ionophore to form NETs

 

Preclinical data 

Citryll develops a first in class therapeutic antibody that targets Neutrophil Extracellular Traps (NET) formation for the treatment of a range of human diseases with potential for SLE, RA, vasculitis, IPF and other indications.

The initial therapeutic antibodies designated therapeutic Anti- Citrullinated Protein Antibodies or tACPAs, prior to optimisation were identified among ACPAs cloned from RA patient B lymphocytes. We have since demonstrated tACPA’s cellular MoA to be interfering with NET biology, using primary human neutrophils from healthy donors as well as RA and SLE patients and numerous in vivo pharmacology studies.

– Therapeutic use of tACPAs in an RA mouse model resulted in the arrest of inflammation and prevents a further increase of the inflammatory response, and significantly decreased joint damage, close to normal (Chirivi et al., J Clin Cell Immunol 2013, S6, 1-13).

– Prophylactic administration in 2 different mouse RA models (CAIA and CIA) significantly prevented the onset of inflammation. Histological analysis of inflamed joints treated mice revealed a significant decrease in neutrophil influx and joint damage, as compared to control animals to near normal tissue. tACPA also strongly inhibits the formation of NETs in the affected joints of these mice.

– The tACPA development candidate CIT-013 recognises the citrullinated N-terminus of histone-2A and histone-4 which are present in human NETs and are essential for NET formation. Neutrophils and aberrant NET formation contribute to the induction and propagation of inflammation. NETs are believed to be central for developing autoimmunity in human RA, SLE and other indications and are present in RA joints. NETs also play a central role in sepsis induced organ failure. NETs are found in large numbers of lungs of chronically infected lungs of Cystic fibrosis, lungs of COPD patients and in lungs of virally induced exacerbation of Asthma, inhibiting lung function.

– tACPAs are active in preclinical models for Idiopathic Pulmonary Fibrosis (IPF) and colitis. In the IPF animal model we find that tACPA protects against tissue damage in the lung. Furthermore, strongly decreased circulating neutrophil levels were observed in tACPA treated mice compared to mice that received a control antibody in both animal models.


Development candidate CIT-013

– Near human lead antibodies were generated with appropriate potencies and favourable characteristics for development including low aggregation, good stability and good production in CHO based stable cell lines. CMC including cell line generation, bioreactor scaling, process and formulation development are ongoing at Lonza for the development candidate CIT-013.

In summary, the current status is: preclinical proof of concept using SLE and RA patient neutrophils, animal models for RA, early data in IPF and colitis; NETosis inhibition is expected to decrease auto-antigen release with the potential to disrupt the autoimmunity cycle and NET mediated tissue damage due to release of histone and other toxic NET components.

Clinical development towards PoC in SLE, a phase 1b study

CIT-013 has a number of life cycle opportunities and after careful analysis we have chosen SLE as the first indication for which Citryll intends to obtain clinical Proof of Concept that tACPA can inhibit NETosis  through NET and SLE biomarkers as well as exploratory clinical efficacy readouts.