On November 12, 2021 Sensei Biotherapeutics, Inc. (NASDAQ: SNSE), an immunotherapy company focused on the discovery and development of next generation therapeutics for cancer, reported the first preclinical data for SNS-101, its anti-VISTA (V-domain Ig suppressor of T cell activation) product candidate (Press release, Sensei Biotherapeutics, NOV 12, 2021, View Source [SID1234595410]). The data will be presented during a poster session on November 13, 2021, at the Society for Immunotherapy of Cancer (SITC) (Free SITC Whitepaper)’s (SITC 2021) 36th Annual Meeting in Washington, D.C. and virtually .
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"VISTA has been recognized for years as an important immune checkpoint but has been difficult to drug due to its unique pH-dependent biology," said Robert Pierce, M.D. chief scientific officer of Sensei Biotherapeutics. "VISTA is primarily expressed on myeloid cells, a hub of immunosuppressive activity, and functions as a checkpoint exclusively under acidic conditions where it binds to its receptor, PSGL-1. Our scientific team has been evaluating VISTA for several years. Accordingly, we believe, the key to unlocking the power of this checkpoint lies with the development of an antibody that selectively binds the active form of VISTA that is only present within the low pH of the tumor microenvironment. At SITC (Free SITC Whitepaper), we are excited to share the preclinical data demonstrating that SNS-101 binds active VISTA with high affinity and significant selectivity (~600-fold increase at pH 6.0 versus 7.4)."
Dr. Pierce continued, "We are also encouraged by early in vivo evidence from a human VISTA knock-in mouse model showing improved immune responses, including the anticipated combination effect with anti-PD1 in a PD1 blockade responsive tumor model. We continue to expand on this research and are looking forward to sharing more in vivo data at a future medical conference. IND-enabling studies are already underway to evaluate the potential of SNS-101 to become a novel treatment for solid cancers, as both a monotherapy and in combination, that overcomes on-target/off-tumor toxicities seen today with other I/O approaches."
Preclinical data for SNS-101 are being presented in a poster (#228) titled: "Antagonistic pH-selective VISTA antibody SNS-101 potentiates anti-PD-1/PD-L1-induced anti-tumor immunity." A summary of data in the poster include:
Preclinical data demonstrated that SNS-101 successfully blocked the interaction of VISTA with its PSGL-1 receptor, demonstrating high-affinity binding to low pH-VISTA sub-nanomolar affinity with exemplary (>600-fold) pH-selectivity vs. physiologic pH-VISTA.
SNS-101, in combination with an anti-PD-1 inhibitor, led to superior anti-tumor activity compared to PD-1 alone.
SNS-101 is a fully human IgG1 and has entered IND-enabling studies.
Sensei will host a virtual science symposium on Tuesday, November 16, 2021, at 4:00 p.m. Eastern Time to discuss the potential of the VISTA checkpoint inhibitor to address current limitations of immune checkpoint therapy. The event will be hosted by Sensei’s management team and will include a presentation on VISTA biology by Robert Schreiber, Ph.D., the Andrew M. Bursky and Jane M. Bursky Distinguished Professor of Pathology and Immunology, Professor of Molecular Microbiology and co-leader of the tumor immunology program at the Siteman Comprehensive Cancer Center and Founding Director of the Center for Human Immunology and Immunotherapy Programs at the Washington University School of Medicine.
A live webcast of the symposium will be available under "Events & Presentations" in the Investors section of the company’s website at www.senseibio.com. An archived replay will be available for approximately 90 days following the event.
About VISTA (V-domain Ig suppressor of T cell activation)
VISTA (B7-H5) is recognized as an important immune checkpoint regulator that is expressed primarily on myeloid cells, a hub of immunosuppressive activity, and acts via binding to its receptor on T-cells (PSGL-1) at sub physiologic pH. Disrupting the interaction of VISTA and its receptor on T-cells has been shown to enhance T-cell activation and tumor cell death. The VISTA-PSGL-1 T-cell checkpoint is activated under low pH conditions such as the tumor microenvironment. VISTA is found to be expressed in numerous cancer types and appears to be associated with PD-1 resistance.
The therapeutic hypothesis that Sensei believes differentiates its VISTA program is that an effective and safe inhibitory anti-VISTA antibody must demonstrate: (1) selective binding to the active form of VISTA (protonated/low pH) in order to avoid target mediated drug disposition and on-target/off-tumor effects; (2) effective inhibition of active VISTA’s interaction with PSGL-1; and (3) Fc-mediated activation of tumor resident myeloid cells to facilitate conversion from an immunosuppressive to an immune-activating phenotype.
About SNS-101
SNS-101 is a potent, pH-dependent fully human monoclonal antibody designed to block the interaction of VISTA, a novel immune checkpoint that is expressed primarily on myeloid cells, with its receptor, PSGL-1. Selectivity is achieved because SNS-101 targets the active (i.e., protonated) VISTA present in the low pH tumor microenvironment. SNS-101 was selected based on 1) the lack of significant binding to VISTA at physiologic pH (i.e., deprotonated VISTA in the blood), and 2) its high-affinity binding to active VISTA (pH 6.0), which yielded a > 600-fold selectivity. Based on the biochemical properties of SNS-101, Sensei anticipates tumor microenvironment selective activity for this preclinical product candidate. VISTA has been shown to be expressed in numerous tumor types, including non-small cell lung cancer (NSCLC).