TY - JOUR
T1 - VISTA checkpoint inhibition by pH-selective antibody SNS-101 with optimized safety and pharmacokinetic profiles enhances PD-1 response
AU - Thisted, Thomas
AU - Smith, F. Donelson
AU - Mukherjee, Arnab
AU - Kleschenko, Yuliya
AU - Feng, Feng
AU - Jiang, Zhi Gang
AU - Eitas, Timothy
AU - Malhotra, Kanam
AU - Biesova, Zuzana
AU - Onumajuru, Adejumoke
AU - Finley, Faith
AU - Cifuentes, Anokhi
AU - Zhang, Guolin
AU - Martin, Gaëlle H.
AU - Takeuchi, Yoshiko
AU - Thiam, Kader
AU - Schreiber, Robert D.
AU - van der Horst, Edward H.
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024/12
Y1 - 2024/12
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85189631006&partnerID=8YFLogxK
U2 - 10.1038/s41467-024-47256-x
DO - 10.1038/s41467-024-47256-x
M3 - Article
C2 - 38575562
AN - SCOPUS:85189631006
SN - 2041-1723
VL - 15
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 2917
ER -