VISTA checkpoint inhibition by pH-selective antibody SNS-101 with optimized safety and pharmacokinetic profiles enhances PD-1 response

Thomas Thisted, F. Donelson Smith, Arnab Mukherjee, Yuliya Kleschenko, Feng Feng, Zhi-Gang Jiang, Timothy Eitas, Kanam Malhotra, Zuzana Biesova, Adejumoke Onumajuru, Faith Finley, Anokhi Cifuentes, Guolin Zhang, Gaëlle H. Martin, Yoshiko Takeuchi, Kader Thiam, Robert D. Schreiber and Edward H. Horst ()
Additional contact information
Thomas Thisted: Sensei Biotherapeutics Inc.
F. Donelson Smith: Sensei Biotherapeutics Inc.
Arnab Mukherjee: Sensei Biotherapeutics Inc.
Yuliya Kleschenko: Sensei Biotherapeutics Inc.
Feng Feng: Sensei Biotherapeutics Inc.
Zhi-Gang Jiang: Sensei Biotherapeutics Inc.
Timothy Eitas: Sensei Biotherapeutics Inc.
Kanam Malhotra: Sensei Biotherapeutics Inc.
Zuzana Biesova: Sensei Biotherapeutics Inc.
Adejumoke Onumajuru: Sensei Biotherapeutics Inc.
Faith Finley: Sensei Biotherapeutics Inc.
Anokhi Cifuentes: Sensei Biotherapeutics Inc.
Guolin Zhang: Sensei Biotherapeutics Inc.
Gaëlle H. Martin: genOway
Yoshiko Takeuchi: Washington Univ. School of Medicine
Kader Thiam: genOway
Robert D. Schreiber: Washington Univ. School of Medicine
Edward H. Horst: Sensei Biotherapeutics Inc.

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract VISTA, an inhibitory myeloid-T-cell checkpoint, holds promise as a target for cancer immunotherapy. However, its effective targeting has been impeded by issues such as rapid clearance and cytokine release syndrome observed with previous VISTA antibodies. Here we demonstrate that SNS-101, a newly developed pH-selective VISTA antibody, addresses these challenges. Structural and biochemical analyses confirmed the pH-selectivity and unique epitope targeted by SNS-101. These properties confer favorable pharmacokinetic and safety profiles on SNS-101. In syngeneic tumor models utilizing human VISTA knock-in mice, SNS-101 shows in vivo efficacy when combined with a PD-1 inhibitor, modulates cytokine and chemokine signaling, and alters the tumor microenvironment. In summary, SNS-101, currently in Phase I clinical trials, emerges as a promising therapeutic biologic for a wide range of patients whose cancer is refractory to current immunotherapy regimens.

Date: 2024
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DOI: 10.1038/s41467-024-47256-x

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