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1380 Non-clinical results and design of first-in-human study for GIGA-564, a third-generation anti-CTLA-4 monoclonal antibody
  1. Jason M Redman1,
  2. Vincent Poon1,
  3. Ariel Niedecken2,
  4. Yao Chiang2,
  5. Rong Deng3,
  6. Kacy Stadtmiller2,
  7. Michael A Asensio2,
  8. Janice Lansita4,
  9. Kyle P Carter2,
  10. Ellen K Wagner2,
  11. Edward Garmey5,
  12. Carl Millward6,
  13. James L Gulley1 and
  14. Erica L Stone2
  1. 1National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
  2. 2GigaGen, San Carlos, CA, USA
  3. 3RandD Q-Pharm Consulting, LLC, Pleasanton, CA, USA
  4. 4Alira Health, San Francisco, CA, USA
  5. 5CMO Consulting, Concord, CA, USA
  6. 6Grifols, San Carlos, CA, USA
  • Journal for ImmunoTherapy of Cancer (JITC) preprint. The copyright holder for this preprint are the authors/funders, who have granted JITC permission to display the preprint. All rights reserved. No reuse allowed without permission.


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.

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See

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