Thisted et al. VISTA checkpoint inhibition by pH-selective antibody SNS-101 with optimized safetyand pharmacokinetic profiles enhances PD-1 response, Nature Communications, 2024
genOway’s human VISTA KI and BRGSF-HIS mouse models were used to assess efficacy and safety of the pH-selective antibody SNS-101 against human VISTA and demonstrate enhanced combo therapy efficacy with anti-PD-1 in different tumor cell lines
Despite the therapeutic potential of blocking VISTA, clinical development of anti-VISTA antibodies has been challenging due to high compound clearance via target mediated drug disposition (TMDD) in VISTA+ cells at physiologic pH, and systemic cellular activation and cytokine release syndrome (CRS) at sub-therapeutic doses, reducing the likelihood of reaching efficient levels in tumors.
The study conducted by BMS published in Nature (2019) has described the activity of VISTA at low pH, as found in tumor microenvironment (TME), due to protonation of surface-exposed histidines residues. This allowed the identification of PSGL1 ligand of VISTA at selective acidic pH. SenseiBio has developed SNS-101, a fully human monoclonal IgG1 antibody specifically targeting the protonated and active form of VISTA. The objective was to mitigate the rapid clearance of the VISTA targeting antibodies happening at physiologic pH and keep a safety profile without CRS development in vista to move to clinical phases.
The recently published paper in Nature Communications (April 2024) resulting from the collaboration between Sensei Biotherapeutics, genOway and Washington Univ. School of Medicine compares the SNS-101 antibody to other anti-VISTA antibodies regarding VISTA binding and inhibition. SNS-101 targets a novel epitope, compared to other anti-VISTA identified through published literature and patents, which confers a higher affinity at low pH and improved inhibition through its binding to VISTA.
CRS response was evaluated as a critical factor for a potential entry into the clinical. SNS-101 did not induce any of the tested pro-inflammatory cytokines when co-cultured in vitro with human umbilical vein endothelial cells or human PBMCs, and neither ex vivo on fresh human blood cells. To mimic a more physiological response, the human CD34+ reconstituted BRGSF-HIS mouse model was used to evaluate the safety of SNS-101 antibody. As shown in the figure below, SNS-101, independent of the tested dose, did not induce a pro-inflammatory response, contrary to the OKT3 positive control.
The team used the humanized VISTA KI model (hVISTA-KI) to assess the pharmacokinetics of SNS-101, due to the lack of cross-reactivity with mouse VISTA. In the figure below, serum clearance in hVISTA-KI was similar to WT; however, it increased in the hVISTA-KI-bearing tumor. This implies a specific localization of SNS-101 at the tumor site, as evaluated by the blood mean residence time (MRT).
Non-human primates were used to evaluate toxicity of the compound. SNS-101 demonstrated an absence of clinical signs after dose-proportional exposure, and displayed linear disposition characteristics (absence of TMDD), as SNS-101 binds to VISTA only when the latter becomes protonated.
Using the hVISTA-KI mouse model, the combination therapy with anti-mouse PD-1 displayed a significant tumor growth inhibition compared to the SNS-101 monotherapy. The figure below shows the results on the MC38 (colon adenocarcinoma) cell line; similar findings and increased survival rate were observed on MB49 (bladder cancer) and MCA/1956 (sarcoma tumor cell line) as well.
A phenotype shift in macrophages from M2 to M1 profile was observed in the combination therapy, as well as an increase in tumor-infiltrated lymphocytes. The suggested mechanism of action would be a modulation on the immune suppressive function of the M2-like macrophages at the tumor site using the combination of VISTA and PD1 blockers.
The gathered data published by Van der Horst’s team, using genOway’s humanized VISTA-KI and BRGSF-HIS mouse models, allowed SNS-101 compound to enter phase I of clinical trials in solid tumors.
The humanized VISTA KI and BRGSF-HIS mouse models are available at genOway, designer and provider of preclinical models in several therapeutic areas, including immuno-oncology, metabolism, cardiovascular diseases, and neuroscience.
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