Anti-VISTA agents profiling: complementarity of BRGSF-HIS and hVISTA Knock-in as preclinical models for immunotherapies

The selection of relevant preclinical models which most closely resemble human tumor biology has considerable potential to ensure better prediction in preclinical studies.

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LATEST UPDATE, June 2023: The strategy of using both the humanized ICP Vista model and genOway's immunodeficient BRGSF-HIS model enabled the Sensei Biotherapeutics team to effectively validate the therapeutic interest of the SNS-101 molecule and obtain FDA IND (Investigational New Drug Applications) approval in just 2 years. Following this approval in April 2023, Sensei Biotherapeutics announced in June that a first patient had received his first dose of treatment.

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During the preclinical tests for the assessment of its drug candidate, Sensei Bio used genOway’s preclinical models. These models allowed it to better qualify its anti-VISTA antibody SNS-101, in terms of pharmacology, pharmacokinetics and toxicology. Please take a look at this article to see how our models helped it advance its pre-clinical testing.

Previous anti-VISTA therapeutics showed early stop in clinics and were associated to side effects such as cytokine release syndrome (CRS). Johnston et al., 2019¹ report that VISTA binds PSGL-1 and suppresses T cells selectively at acidic pH such as that found in tumor microenvironments. Therefore, VISTA targeting may represent a promising therapeutic approach for cancer. Researchers found that antibodies engineered to selectively bind and block PSGL-1-VISTA interaction in acidic environments were effective to reverse VISTA-mediated immune suppression in vivo.

The SNS-101, a pH selective anti-VISTA antibody developed by Sensei Bio

In summary, Sensei Bio’ study attests to the relevance of genOway’s preclinical models to:

• Test the efficacy of anti-VISTA antibodies
• Assess the toxicity of anti-VISTA antibodies and to minimize cytokine release syndrome in clinical testing
• Benchmark new antibodies and select those that are interesting to test in the clinical phase

On the basis of these different data, Sensei Bio developed a new human monoclonal IgG1 pH-sensitive antibody (named SNS-101), specific for the protonated, active form of VISTA.

After checking the inhibitory potential of SNS-101 on the binding of VISTA with its partners (PSGL-1, VSIG-3 and LRIG-1) at low pH, Edward van der Horst et al. tested the probability that their compound would induce a CRS, what was observed with first generation of anti-VISTA. CRS risk was first evaluated using circulating fresh human whole blood. The toxicity of SNS-101 was also evaluated in a preclinical model expressing human myeloid and lymphoid cells, BRGFS-HIS mouse, to enable a more translatable investigation. While OKT3, an anti-CD3 antibody, and JNJ, a pH non-selective anti-VISTA antibody, induced cytokine release in BRGSF-HIS mice, dose-dependent injections of SNS-101 antibody did not cause any significant induction of cytokines.

In a second step, the researchers assessed the efficacy of their immuno-oncology compound in the immunocompetent humanized VISTA mouse. These preclinical models represent a powerful model system for studying how compounds modulate immune cell response in a physiological microenvironment, because interaction of tumors with their microenvironment and with immune cells is fully functional.

Through PK studies in non-human primates, Edward von der Horst et al. also demonstrated that the pH-sensitive binding of SNS-101 avoids the rapid clearance by target mediated drug disposition (TMDD) that has been observed with non-pH-sensitive VISTA antibodies.

In MN49 tumor-bearing VISTA-KI mice, SNS-101 treatment induced a significant tumor growth inhibition 21 days after injection. This inhibitory effect was enhanced when anti-VISTA SNS-101 antibody was combined with the anti-PD-1 antibody.

Taken together, all these results from Sensei Bio demonstrate that anti-VISTA SNS-101 can abrogate TMDD and lower cytokine releasing syndrome (CRS) risk, while significantly enhancing the anti-tumor effects of PD-1 blockade. Interestingly, the work performed by Sensei Bio illustrates the complementarity of different preclinical models in answering specific scientific questions.

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⇒ To learn more about our preclinical models, please feel free to contact us

⇒ To know more about SNS-101, please click here

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References

1. Robert J Johnston, Linhui Julie Su, Jason Pinckney, David Critton, Eric Boyer, Arathi Krishnakumar, Martin Corbett, Rose Dibella, Lynne Campbell, Gaelle H Martin, Hadia Lemar, Thomas Cayton, Richard Y-C Huang, Xiaodi Deng, Akbar Nayeem, Haibin Chen, Burce Ergel, Joseph M Rizzo, Aaron P Yamniuk, Sanjib Dutta, Justine Ngo, Andrea Olga Shorts, Radha Ramakrishnan, Alexander Kozhich, Jim Holloway, Hua Fang, Ying-Kai Wang, Zheng Yang, Kader Thiam, Ginger Rakestraw, Arvind Rajpal, Paul Sheppard, Michael Quigley, Keith S Bahjat, Alan J Korman. (2019). VISTA is an acidic pH-selective ligand for PSGL-1. Nature, 574(7779):565-570