Background Anti-CTLA-4 antibodies, such as ipilimumab, were among the first immuno-oncology agents to provide significantly improved outcomes for patients. However, existing anti-CTLA-4 therapies fail to induce a response in a majority of patients, and can induce severe immune-related adverse events. It has been assumed that checkpoint inhibition, i.e., blocking the interaction between CTLA-4 and its B7 ligands (CD80 and CD86), is the primary mechanism of action for ipilimumab. Here we present non-clinical evidence of antitumor activity and reduced liver and gastro-intestinal toxicity with a CTLA-4 targeted agent, GIGA-564, designed to work solely by FcR-mediated Treg depletion in the tumor microenvironment.
Methods The pharmacology of GIGA-564 was characterized in vitro with ELISAs and cell-based assays and in vivo using human CTLA-4 knock-in (hCTLA-4 KI mice). The toxicology of GIGA-564 in comparison to commercial ipilimumab was evaluated using hCTLA-4 KI mice. The PK and tolerability of GIGA-564 was investigated in cynomolgus monkeys.
The non-clinical studies described were approved by the appropriate committees of Crown BioSciences, WuXi Apptec, or Primate Products.
Results We identified a monoclonal antibody, GIGA-564, that binds to CTLA-4 at an epitope that differs from ipilimumab’s by only a few amino acids but has limited checkpoint inhibitor activity. GIGA-564 has enhanced anti-tumor activity compared to commercial ipilimumab in hCTLA-4 KI mice bearing MC38 tumors (N= 8 or 13 per a group, p = 0.004 for tumor growth inhibition). GIGA-564 also has increased ability to induce in vitro FcR signaling and induces more depletion of intratumoral Tregs (p = 0.026 for CTLA-4 MFI on intratumoral Tregs 1 Day after a single dose of the respective antibody) and less Treg proliferation (p = 9.7e-4) in a hCTLA-4 KI mice bearing MC38 tumors (N = 6 to 12 per a group). In a four-week toxicology study in hCTLA-4 KI mice, GIGA-564 induced less toxicity than commercial ipilimumab in the gastro-intestinal tract and liver and the STD10 was the highest dose tested (30 mg/kg/dose, n= 3 to 12 per a group). PK data from a PK and tolerability study in cynomolgus monkeys (n = 3 per a group) was used to estimate human PK parameters. Clearance of GIGA-564 in humans was projected to be 4.40 mL/day/kg and t1/2 was projected to be 17.2 days (consistent with a human IgG1 antibody).
Conclusions The first-in-human Phase 1a/b clinical study has been designed based on the totality of the data and will be presented.
Ethics Approval The non-clinical studies described were approved by the appropriate committees of Crown BioSciences, WuXi Apptec, or Primate Products.
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