425 KVA12.1: an anti-VISTA monoclonal antibody with strong single agent anti-tumor activity and no evidence of cytokine mediated toxicity

Guillaudeux, Thierry; Lustig, Kurt; Frazier, Emily; Kabi, Neda; Katz, Chen; Peckham, D. W.; Xu, Mingkai; Iadonato, Shawn P.

doi:10.1136/jitc-2022-sitc2022.0425

Cited by 2 publications

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“…The anti-VISTA antibody KVA12123 (Kineta, Inc.) is a fully human-engineered IgG1 mAb designed to bind to VISTA through a unique epitope in the extracellular domain, blocking interactions with putative VISTA binding partners, and blocking VISTA function ( 58 ). It has been engineered to provide strong single-agent tumor growth inhibition with no demonstrated CRS-associated cytokine release observed in preclinical models ( 59 ). Additionally, the effects of KVA12123 have been shown to reverse immunosuppression in the TME by increasing infiltrating T effector cells (CD4+ and CD8+), increasing the ratio of M1 macrophages, and enhancing the activation of NK cells ( 60 ).…”

Section: Antibodies Targeting Vista Are Currently In Developmentmentioning

confidence: 99%

Section: Antibodies Targeting Vista Are Currently In Developmentmentioning

confidence: 99%

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Clinical and research updates on the VISTA immune checkpoint: immuno-oncology themes and highlights

Noelle,

Lines,

Lewis

et al. 2023

Front. Oncol.

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Immune checkpoints limit the activation of the immune system and serve an important homeostatic function but can also restrict immune responses against tumors. Inhibition of specific immune checkpoint proteins such as the B7:CD28 family members programmed cell death protein-1 (PD-1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) has transformed the treatment of various cancers by promoting the anti-tumor activation of immune cells. In contrast to these effects, the V-domain immunoglobulin suppressor of T-cell activation (VISTA) regulates the steady state of the resting immune system and promotes homeostasis by mechanisms distinct from PD-1 and CTLA-4. The effects of VISTA blockade have been shown to include a decrease in myeloid suppression coupled with proinflammatory changes by mechanisms that are separate and distinct from other immune checkpoint proteins; in some preclinical studies these immune effects appear synergistic. Given the potential benefits of VISTA blockade in the context of cancer therapy, the second Annual VISTA Symposium was convened virtually on September 23, 2022, to review new research from investigators and immuno-oncology experts. Discussions in the meeting extended the knowledge of VISTA biology and the effects of VISTA inhibition, particularly on cells of the myeloid lineage and resting T cells, as three candidate anti-VISTA antibodies are in, or nearing, clinical development.

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Section: Antibodies Targeting Vista Are Currently In Developmentmentioning

confidence: 99%

Section: Antibodies Targeting Vista Are Currently In Developmentmentioning

confidence: 99%

Clinical and research updates on the VISTA immune checkpoint: immuno-oncology themes and highlights

Noelle,

Lines,

Lewis

et al. 2023

Front. Oncol.

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“…Target-mediated drug disposition and the resultant low free drug concentration in plasma can severely limit biodistribution into the tumor, leading to inadequate target coverage in the TME. To date, all anti-VISTA antibodies that bind VISTA at physiologic pH in the blood have demonstrated non-linear drug elimination, indicating significant TMDD [14][15][16][17].…”

Section: Vista and Ctla-4: Two Immune Checkpoints That Illustrate Dis...mentioning

confidence: 99%

“…In support of this hypothesis, Kineta is developing an anti-VISTA IgG1 antibody engineered to reduce binding to FcRs and has demonstrated significant diminution of cytokine secretion in a preclinical CRS model [15]. Although decreased affinity for Fc receptors appears to have mitigated CRS risk, binding of KVA12123 to VISTA on blood cells at physiologic pH fails to eliminate significant TMDD [15], as this is a consequence of CDR-dependent, target-mediated internalization and clearance.…”

Section: Vista and Ctla-4: Two Immune Checkpoints That Illustrate Dis...mentioning

confidence: 99%

Conditionally Active, pH-Sensitive Immunoregulatory Antibodies Targeting VISTA and CTLA-4 Lead an Emerging Class of Cancer Therapeutics

Smith,

Pierce,

Thisted

et al. 2023

Antibodies

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Immune checkpoints and other immunoregulatory targets can be difficult to precisely target due to expression on non-tumor immune cells critical to maintaining immune homeostasis in healthy tissues. On-target/off-tumor binding of therapeutics results in significant pharmacokinetic and pharmacodynamic problems. Target-mediated drug disposition (TMDD) significantly limits effective intratumoral drug levels and adversely affects anti-tumor efficacy. Target engagement outside the tumor environment may lead to severe immune-related adverse events (irAEs), resulting in a narrowing of the therapeutic window, sub-optimal dosing, or cessation of drug development altogether. Overcoming these challenges has become tractable through recent advances in antibody engineering and screening approaches. Here, we review the discovery and development of conditionally active antibodies with minimal binding to target at physiologic pH but high-affinity target binding at the low pH of the tumor microenvironment by focusing on the discovery and improved properties of pH-dependent mAbs targeting two T cell checkpoints, VISTA and CTLA-4.

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425 KVA12.1: an anti-VISTA monoclonal antibody with strong single agent anti-tumor activity and no evidence of cytokine mediated toxicity

Cited by 2 publications

References 0 publications

Clinical and research updates on the VISTA immune checkpoint: immuno-oncology themes and highlights

Clinical and research updates on the VISTA immune checkpoint: immuno-oncology themes and highlights

Conditionally Active, pH-Sensitive Immunoregulatory Antibodies Targeting VISTA and CTLA-4 Lead an Emerging Class of Cancer Therapeutics

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