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398 AGEN1181, an Fc engineered anti-CTLA-4 antibody, demonstrates clinical activity, alone or in combination with balstilimab (anti-PD-1), and broadens the therapeutic potential of CTLA-4 therapy
  1. Steven O’Day1,
  2. Anthony El khoueiry2,
  3. Chethan Ramamurthy3,
  4. Andrea Bullock4,
  5. Irina Shapiro5,
  6. Serina6,
  7. Haiyong Han7,
  8. Lernik Ohanjanian Namagerdi5,
  9. Remigiusz Kaleta5,
  10. Anna Wijatyk5,
  11. Olivia Wijatyk5,
  12. Waldo Ortuzar5,
  13. Marek Ancukiewicz5,
  14. Jennifer Buell5,
  15. Dhan Chand5 and
  16. Michael Gordon8
  1. 1John Wayne Cancer Institute, Santa Monica, CA, USA
  2. 2University of Southern California, Los Angeles, CA, USA
  3. 3University of Texas at San Antonio, San Antonio, TX, USA
  4. 4Beth Israel Deaconess Medical Center, Boston, MA, USA
  5. 5Agenusbio, Lexington, MA, USA
  6. 6Translational Genomics Research, Phoenix, AK, USA
  7. 7Translational Genomics Research Institut, Phoenix, AZ, USA
  8. 8honorhealth, Scottsdale, AZ, USA


Background Immune checkpoint therapies targeting CTLA-4, alone, or in combination with anti-PD-1 have shown durable responses in cancer patients. However, responses are limited to a small subset of patients in the most common immunogenic cancers. Here we describe, a novel anti-CTLA-4 antibody, AGEN1181, with enhanced FcyR-dependent functionality that harnesses a novel mechanism of action to promote superior T cell activation and anti-cancer immunity. Concordant with preclinical findings, we report preliminary safety, pharmacodynamic and efficacy data from a phase 1 study of AGEN1181 (NCT03860272), alone or in combination with balstilimab (anti-PD-1 antibody) in a range of immunogenic and non-immunogenic tumors.

Methods The functional activity of AGEN1181 or AGEN1181-like mouse surrogate were assessed in primary cell-based assays or in PD-1 refractory syngeneic tumor-bearing mouse models (B16F10 or KPC pancreatic tumor). Efficacy was evaluated as monotherapy, or in combination with anti-PD-1, focal radiation or chemotherapy. In an ongoing phase I study, AGEN1181 is administered intravenously once every 3- or 6-weeks as monotherapy (0.1–4 mg/kg), or every 6-weeks (1–4 mg/kg) in combination with balstilimab (3 mg/kg) dosed every 2 weeks. Dose-limiting toxicities were evaluated in the first 28 days of treatment. Neoantigen burden was assessed from pre-treatment tumor biopsy, as available, by next-generation sequencing. Fcγ receptor genotyping was assessed by real-time PCR. Immunophenotyping of peripheral blood mononuclear cells collected pre- and post-treatment were analyzed by flow cytometry.

Results Preclinically, AGEN1181 demonstrated superior T cell activation than a standard IgG1 anti-CTLA-4 analogue in donors expressing either the low or high affinity FcγRIIIA. In poorly immunogenic tumor-bearing mouse models, AGEN1181-like surrogate demonstrated robust tumor control in combination with anti-PD-1 and focal radiation or chemotherapy. As of August 25th, 2020, we observed a clinical benefit rate of 63–53% at 6 and 12 weeks respectively among evaluable treated patients. We observed two durable responses in patients with endometrial cancer that were BRCA-, microsatellite stable and PD-L1 negative. These patients progressed on prior PD-1 therapy or chemoradiation respectively. Notably, responders expressed either the low or high affinity FcγRIIIA. AGEN1181 showed potent dose-dependent increases in peripheral CD4+Ki67+, CD4+ICOS+ and CD4+HLA-DR+ T-cells. Treatment was well tolerated through the highest dose tested. Grade 3 or greater immune-related adverse events occurred in 28.5% patients and were consistent with CTLA-4 therapies.

Conclusions AGEN1181 is designed to expand the benefit of anti-CTLA-4 therapy to a broader patient population. AGEN1181, alone or in combination with balstilimab, demonstrates clinical activity in heavily pretreated patients.

Trial Registration NCT03860272

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