Gotistobart (ONC-392/BNT-316): A Comprehensive Clinical and Scientific Review of a Next-Generation Anti-CTLA-4 Antibody

Executive Summary

Gotistobart (also known as ONC-392 and BNT-316) is an investigational, humanized IgG1 monoclonal antibody representing a next-generation approach to immune checkpoint inhibition by targeting the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). Its development is predicated on a novel, pH-sensitive mechanism of action designed to overcome the significant toxicity limitations of first-generation anti-CTLA-4 therapies. By binding to CTLA-4 at neutral pH and dissociating in the acidic tumor microenvironment (TME), gotistobart aims to preserve the CTLA-4 receptor, allowing it to be recycled to the T-cell surface. This mechanism is hypothesized to selectively deplete immunosuppressive regulatory T-cells (Tregs) within the tumor while maintaining systemic immune tolerance, thereby improving the therapeutic index.

The clinical development program, designated PRESERVE, has explored gotistobart as both a monotherapy and in combination regimens across a range of advanced, treatment-refractory solid tumors. Early data from the Phase 1/2 PRESERVE-001 trial demonstrated encouraging single-agent activity in patients with metastatic non-small cell lung cancer (NSCLC) that had progressed on prior PD-(L)1 inhibitors, with an objective response rate of 29.6%. Further studies have shown promising efficacy signals in combination with pembrolizumab for platinum-resistant ovarian cancer (PRESERVE-004) and with lutetium Lu 177 vipivotide tetraxetan for metastatic castration-resistant prostate cancer (PRESERVE-006).