GI Innovation (South Korea)

BackgroundGI-101 (CD80-IL2v) is a novel immunocytokine, designed to direct IL-2v to tumor and immune cells. IL-2v of GI-101 is engineered to maximize the expansion of cytotoxic T and NK cells but not Treg cells, and CD80 further inhibits Treg cell function. GI-101 demonstrated single agent activity in an anti-PD-L1 experienced patient (ORR 5.9% in heavily-treated population).1 Here we report clinical outcomes from dose escalation of Part B of the study.MethodsKeynote-B59 is an ongoing, phase 1/2 study of GI-101 monotherapy and in combination with various agents in patients (pts) with advanced solid tumors. In dose escalation of Part B, pts received intravenous GI-101 (0.002~0.15 mg/kg) and pembrolizumab (200 mg) on day 1 of each 21-day cycle. The primary objective is to assess safety, tolerability and maximum tolerated dose (MTD) and/or combination RP2D (cRP2D).ResultsAs of 20 Apr 2023, 25 pts with any solid tumors who failed on standard of care received GI-101 plus pembrolizumab. The median number of prior therapies were 3 [1–9], and 64% were previously treated with immune checkpoint blockade (ICI) therapy. Treatment-related adverse events occurred in 23 pts (92%), with the most common events (≥ 20%) being pyrexia (48%), AST/AST increased (28%, 24%). One case of dose-limiting toxicity was observed; MTD was not reached. 0.15 mg/kg GI-101 Q3W was established as the cRP2D based on the desirable expansion of peripheral immune cells and anti-cancer activities. Objective responses were observed in 4 of 24 evaluable pts (ORR 16.7%) regardless of prior anti-PD(L)1 therapy; 2 confirmed PR in pts with NSCLC and clear cell RCC (ccRCC), both failed on previous anti-PD(L)1 therapy, and 2 unconfirmed PR in pts with metastatic carcinoma of unknown origin (MUO) and ccRCC. The ORR in pts who failed on previous ICI therapy was 13.3% while that of ICI-naïve population was 22.2%. Overall disease control rate was 66.7% including 4 pts of SD > 6 months. Pts who had objective response showed significantly higher level of central memory T and CD8+ T cell expansion in peripheral blood. In a patient achieved PR, significant infiltration of CD8+ T and NK cells were observed in tumor microenvironment with minimal impact on Treg cells.ConclusionsGI-101 was well tolerated when combined with pembrolizumab in pts with advanced solid tumors. GI-101 plus pembrolizumab demonstrated anti-tumor activity in a heavily pre-treated patient population, with prior anti-PD(L)1 therapies. The dose expansion phase of the study is currently ongoing.Trial RegistrationClinical trial identification: NCT04977453ReferenceCho BC, Shin S, Lee JL, et al. Preliminary results of GII-101-P101 (Keynote-B59): GI-101 (CD80-IgG4 Fc-IL2v) as a single agent and in combination with pembrolizumab in patients with advanced and/or metastatic solid tumors. Journal for ImmunoTherapy of Cancer 2022;10:doi: 10.1136/jitc-2022-SITC2022.0718

BackgroundCD73, a pivotal ectoenzyme responsible for the conversion of adenosine monophosphate (AMP) to adenosine, exhibits widespread expression on tumor cells and promotes accumulation of adenosine within the tumor microenvironment (TME). Adenosine acts as a potent immunomodulatory factor, effectively attenuating anti-tumor immune responses in the TME by binding to adenosine receptors expressed on diverse immune cell populations. Consequently, the elevated levels of adenosine pose significant barriers to the efficacy of various anti-cancer therapies, including chemotherapy, targeted therapy, and immunotherapy. Despite the considerable potential of interleukin-2 (IL-2) as an immunocytokine for stimulating cytotoxic lymphocytes, IL-2 demonstrates limited efficacy in overcoming immunosuppression induced by high levels of adenosine.MethodsWe generated GI-108, a novel bifunctional fusion protein. The anti-CD73 antibody was selected from clones screened in the single-chain variable fragment (scFv) phage library based on its CD73 blocking efficacy. The IL-2 variant which lacks binding affinity to the IL-2Rα to minimize selectivity to regulatory T cells, was then fused to the anti-CD73 antibody.ResultsGI-108 showed comparable binding affinity to human CD73 (hCD73) as Oleclumab, despite targeting different binding epitopes. Compared to Oleclumab, GI-108 demonstrated superior maximum efficacy in blocking both membrane-bound and soluble CD73 without inducing any hook effects. By attenuating its affinity to IL-2Rα, GI-108 selectively increased CD8+ T cells while minimizing its impact on regulatory T cells. In non-human primates, the administration of GI-108 led to a significant increase in cytotoxic lymphocytes. Similarly, a greater activation of the IL-2-STAT5 signaling axis by GI-108 was observed in CD8+ T cells than regulatory T cells. Importantly, the phosphorylation of STAT5 in CD8+ T cells by GI-108 was greater than that by wild-type IL-2, Proleukin. This observation was attributed to the binding of GI-108 to CD73-high CD8+ T cells in cis-binding manner, facilitating the transmission of a stronger signal to IL-2Rβγ. GI-108 effectively restored the proliferation or activity of CD8+ T cells in the presence of high levels of AMP. The reinvigorated cytolytic CD8+ T cells demonstrated sufficient cytotoxicity against CD73high tumor cells (MDA-MB-231). Administration of GI-108 to a humanized mouse bearing MDA-MB-231 induced significant inhibition of tumor growth.ConclusionsGI-108 is a potent bifunctional fusion protein with the ability to selectively target to the tumor site to reinvigorate immunosuppressed immune cells in the TME. As such, this innovative IL-2-based bifunctional agent provides a promising therapeutic strategy for the treatment of cancer.

Angiogenesis should be precisely regulated because disordered neovascularization is involved in the aggravation of multiple diseases. The vascular endothelial growth factor (VEGF)-A/VEGF receptor 2 (VEGFR-2) axis is crucial for controlling angiogenic responses in vascular endothelial cells (ECs). Therefore, inactivating VEGFR-2 signaling may effectively suppress aberrant angiogenesis and alleviate related symptoms. In this study, we performed virtual screening, identified the synthetic disaccharide 6′-sialylgalactose (6SG) as a potent VEGFR-2-binding compound and verified its high binding affinity by Biacore assay. 6SG effectively suppressed VEGF-A-induced VEGFR-2 phosphorylation and subsequent in vitro angiogenesis in HUVECs without inducing cytotoxicity. 6SG also inhibited VEGF-A-induced extracellular-regulated kinase (ERK)/Akt activation and actin stress fiber formation in HUVECs. We demonstrated that 6SG inhibited retinal angiogenesis in a mouse model of retinopathy of prematurity and tumor angiogenesis in a xenograft mouse model. Our results suggest a potential therapeutic benefit of 6SG in inhibiting angiogenesis in proangiogenic diseases, such as retinopathy and cancer.