212P - BRGSF-HIS mice as a predictive tool for safety assessment of biologics

Background

Immunotherapies are efficacious, but are often associated to immune-related adverse events, such as the cytokine release syndrome (CRS). Safety assessment of therapeutics in preclinical models remains challenging, as they should be relevant and translational. Models exhibiting a human immune system are widely used, but the composition of the human immune system developed remains a concern. Here we report the use of a model exhibiting functional human lymphoid and myeloid compartments as a predictive tool to investigate safety.

Methods

BRGSF mice reconstituted with human umbilical cord blood CD34⁺ cells were injected with anti-CD3 antibody (OKT3), anti-CD3/CD19 bispecific T-cell engager Blinatumomab, or VISTA-targeting antibody. Human myeloid and dendritic cells’ contribution was investigated in hFlt3L-boosted in CD34-reconstituted BRGSF-HIS mice. OKT3 treatment was also tested in human PBMC-reconstituted BRGSF mice. Cytokine release, immune cell distribution, and clinical signs were followed.

Results

We report here the key contribution of myeloid and dendritic cells in the development of CRS-associated features in BRGSF-HIS mice. OKT3 administration induced the release of a larger panel of cytokines in CD34⁺-reconstituted BRGSF mice in presence of myeloid cells, than in PBMC-reconstituted BRGSF mice, which display mainly T and B cells. The clinical signs of cytokine release (body weight loss, temperature drop) were also correlated to the presence of the myeloid compartment. OKT3-induced cytokine release and body weight loss were prevented by Infliximab in CD34⁺-reconstituted BRGSF mice, suggesting that this model also enables assessment of clinical management therapies. Treatment with Blinatumomab and a “first-in-class” anti-VISTA, SNS-101 showed the induction of CRS features in CD34⁺-reconstituted BRGSF mice, confirming observations from their respective use in the clinic. Preliminary phase I clinical data previously reported demonstrated that SNS-101 displays an acceptable risk/benefit profile, corroborating the preclinical safety findings in BRGSF-HIS mice.

Conclusions

Altogether, the data suggest that CD34-reconstituted BRGSF-HIS mice could be used as a predictive tool to investigate immunotherapies' safety.

Clinical trial identification

NCT05864144.

Editorial acknowledgement

Legal entity responsible for the study

genOway.

Funding

genOway.

Disclosure

K. Thiam, G. Martin, A. Gonon, P. Martin-Jeantet, A. Rezza: Financial Interests, Institutional, Full or part-time Employment, Stock: genOway. E. van der Horst: Financial Interests, Institutional, Full or part-time Employment, Stock: Sensei Biotherapeutics.