In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. 1826-1826
Abstract:
Introduction: GI-101 was designed to address the significant unmet needs in immunotherapy for noninflamed tumor. The harmonized mechanisms of action consist of the extracellular domain of CD80 acting as a CTLA-4 inhibitor, together with a long-acting IL-2 variant that preferentially binds to the IL2Rβ. Therefore, GI-101 can play a role in the activation of cytotoxic immune cells and inhibition of CTLA-4-B7.1 axis-based immune suppression. Methods: The binding affinity of GI-101 to IL-2Rs, CTLA-4, and CD28 was performed by SPR and immune cell proliferation was analyzed by CFSE assay in vitro. GI-101 induced dose-dependent pharmacodynamics effects with consistent magnitude following repeat administration in monkeys. Direct anti-tumor effect of GI-101 was tested by single or combination treatment manner in multiple syngeneic and humanized models. Immune profiling in TME was analyzed by flow cytometry, IHC and IFN-γ ELISPOT assay. To mimic the standard care (SOC) in clinic, TC1 lung cancer model was involved in evaluating the efficacy of both 1st line and maintenance therapy of GI-101 with or without immuno-chemotherapy (Cisplatin, Pemetrexed, and anti-PD-1). Results: CD80 of GI-101 highly binds to CTLA-4 (Kd, 2.9nM), acting as a decoy ligand. IL-2 variant induces CD8+ T and NK cell proliferation. However, GI-101 had no evidence of toxicity related to IL-2 activity in the non-GLP monkey study, including vascular leakage syndrome and cytokine storm. GI-101 elicits improved restoration of immune functions in human PBMCs co-cultured setting with PD-L1/CTLA-4 co-expressed tumor cells. A dose-dependent (3 to 12 mg/kg) single inhibition of tumor growth was observed in CT26 syngeneic model. Immune profiling revealed a robust increase of M1 macrophages, CD8+ central memory T (Tcm) and NK cells but not Tregs in TME. Splenocyte tumor-specific immune cells were strongly proliferated when stimulated with CT26 neoantigens (gp70). IFN-γ+ T cells were significantly increased in draining lymph nodes from GI-101 treated mice. Furthermore, GI-101 was superior at inhibiting tumor growth when co-treated with anti-PD-1 in syngeneic (MC38, TC1, and B16F10) and MDA-MB-231 humanized mice models. Finally, the combination of GI-101 and immuno-chemotherapy showed not only suppressed tumor growth but also improved survival compared to immuno-chemotherapy alone. Conclusion: The complementary modes of action of GI-101 via checkpoint blockade and IL-2 activity to enhance the proliferation and activation of Tcm and NK cells are projected to translate into superior clinical efficacy and safety as indicated even in ‘cold tumor' models. GI-101 has promising potential to replace the first-generation ICBs as a monotherapy or in combination with other immunotherapies. Our findings provide a rationale for further clinical investigations. Citation Format: Kyoung-Ho Pyo, Young Jun Koh, Chun-Bong Synn, Jae Hwan Kim, Youngseon Byeon, Ha Ni Jo, Young Seob Kim, Wongeun Lee, Do Hee Kim, Seul Lee, Dong Kwon Kim, Eun ji Lee, Beung-Chul Ahn, Min Hee Hong, Myoung Ho Jang, Sun Min Lim, Hye Ryun Kim, Su Youn Nam, Byoung Chul Cho. Comprehensive preclinical study on GI-101, a novel CD80-IgG4-IL2 variant protein, as a therapeutic antibody candidate with bispecific immuno-oncology target [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1826.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2021-1826
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2021
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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