[Translation] Phase I/II clinical study to evaluate the safety, tolerability, pharmacokinetic characteristics and preliminary efficacy of IBB0979 in subjects with locally advanced/metastatic solid tumors

剂量递增阶段：评估 IBB0979 在局部晚期/转移性实体瘤受试者中的安全性和耐受性，确定 MTD、DRDE 和/或 DLT；剂量扩展阶段：评估 IBB0979 在局部晚期/转移性实体瘤受试者中的安全性和耐受性，确定 II 期临床研究推荐剂量（RP2D）；临床探索阶段：评估 IBB0979 在特定瘤种受试者中的初步有效性。

[Translation]

Dose escalation phase: evaluate the safety and tolerability of IBB0979 in subjects with locally advanced/metastatic solid tumors, and determine the MTD, DRDE and/or DLT; Dose expansion phase: evaluate the safety and tolerability of IBB0979 in subjects with locally advanced/metastatic solid tumors, and determine the recommended dose (RP2D) for Phase II clinical studies; Clinical exploration phase: evaluate the preliminary efficacy of IBB0979 in subjects with specific tumor types.

Start Date03 Jul 2023

Sponsor / Collaborator

Sunho (China) Biopharmaceutical Co., Ltd.

NCT05991583 / RecruitingPhase 1/2

A Phase I/II Open-Label Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of IBB0979 in Patients With Locally Advanced or Metastatic Solid Tumors

This is a Phase 1/2, open-label, dose escalation and dose expansion study designed to characterize the safety, tolerability, PK, immunogenicity, and preliminary antitumor activity of IBB0979 in previously treated patients with locally advanced or metastatic solid tumors.

Start Date28 Jun 2023

Sponsor / Collaborator

Sunho (China) Biopharmaceutical Co., Ltd.

100 Clinical Results associated with IL-10R x CD276

100 Translational Medicine associated with IL-10R x CD276

0 Patents (Medical) associated with IL-10R x CD276

Literatures (Medical) associated with IL-10R x CD276

01 Jul 2023·Cancer communications (London, England)

Enhancement of CAR-T cell activity against cholangiocarcinoma by simultaneous knockdown of six inhibitory membrane proteins.

Article

Author: Xia, Baijin ; Qiao, Yidan ; Tan, Jizhou ; Chen, Jie ; Liu, Bingfeng ; Zou, Fan ; Wu, Xiangyuan ; Yan, Shumei ; Zhang, Hui ; Lin, Keming ; Zhang, Xu ; Chen, Yongjian ; Wang, Xuemei ; Zhang, Yiwen ; He, Xin ; Lu, Lijuan

BACKGROUNDExisting treatments for cholangiocarcinoma have poor efficacy. However, chimeric antigen receptor-T (CAR-T) cells are emerging as a potential therapeutic strategy. Solid tumors possess multiple adverse factors in an immunosuppressive microenvironment that impair CAR-T cell infiltration and function. This study aimed to improve the function of CAR-T cells through knock down immune checkpoints and immunosuppressive molecular receptors.METHODSWe evaluated the expression of epidermal growth factor receptor (EGFR) and B7 homolog 3 protein (B7H3) antigens in cholangiocarcinoma tissues using immunohistochemistry and screened specific immune checkpoints in the cholangiocarcinoma microenvironment via flow cytometry. Subsequently, we engineered CAR-T cells targeting EGFR and B7H3 antigens. We simultaneously knocked down immune checkpoints and immunosuppressive molecular receptors in CAR-T cells by constructing two clusters of small hairpin RNAs and evaluated the engineered CAR-T cells for antitumor activity both in vitro, using tumor cell lines and cholangiocarcinoma organoid models, and in vivo, using humanized mouse models.RESULTSWe observed high expression of EGFR and B7H3 antigens in cholangiocarcinoma tissues. EGFR-CAR-T and B7H3-CAR-T cells demonstrated specific anti-tumor activity. We found an abundance of programmed cell death protein 1 (PD-1), T cell immunoglobulin and mucin domain-containing protein 3 (Tim-3), and T cell immunoglobulin and ITIM domain (Tigit) on infiltrated CD8⁺ T cells in the cholangiocarcinoma microenvironment. We then decreased the expression of these 3 proteins on the surface of CAR-T cells, named PTG-scFV-CAR-T cells. Furthermore, we knocked-down the expression of transforming growth factor beta receptor (TGFβR), interleukin-10 receptor (IL-10R), and interleukin-6 receptor (IL-6R) of PTG-scFV-CAR-T cells. Those cells, named PTG-T16R-scFV-CAR-T cells, potently killed tumor cells in vitro and promoted apoptosis of tumor cells in a cholangiocarcinoma organoid model. Finally, the PTG-T16R-scFv-CAR-T cells showed greater inhibitory effect on tumor growth in vivo, and were superior in prolonging the survival of mice.CONCLUSIONSOur results revealed that PTG-T16R-scFV-CAR-T cells with knockdown of sextuplet inhibitory molecules exhibited strong immunity against cholangiocarcinoma and long-term efficacy both in vitro and in vivo. This strategy provides an effective and personalized immune cell therapy against cholangiocarcinoma.

01 Oct 2018·Experimental Cell ResearchQ3 · MEDICINE

Negative roles of B7-H3 and B7-H4 in the microenvironment of cervical cancer

Q3 · MEDICINE

Article

Author: Shi, Xuejiao ; Qian, Qiuhong ; Han, Sai ; Wang, Ying ; Yang, Xingsheng ; Zhang, Juan ; Zong, Liju ; Cui, Baoxia ; Kong, Beihua ; Zhang, Youzhong ; Ma, Yana ; Jin, Jing ; Liu, Lu

Although persistent human papilloma virus (HPV) infection exerts a crucial influence on cervical carcinogenesis, other factors are also involved in its development, such as intraepithelial lesions and cervical cancer. B7-H3 and B7-H4, which have been reported to be co-regulatory ligands in the B7 family, had been found to be overexpressed in cervical cancer and correlated with adverse clinicopathological features and poor prognosis in our previous studies. In this study, we sought to explore the effects of B7-H3 and B7-H4 on the cervical microenvironment. Among several immune cytokines, interleukin-10 (IL-10) and transforming growth factor (TGF) β1 stand out as important immunosuppressive factors. Our studies found that IL-10 expression increased with pathological change levels and significantly correlated with cervical cancer differentiation (P < 0.05). TGF-β1 correlated with lymph node metastasis (LNM) (P < 0.01). Expression of B7-H3 and B7-H4 positively correlated with the expression of IL-10 and TGF-β1. After co-culture, we found that overexpression of B7-H3 and B7-H4 in cervical cancer cell lines resulted in activation of the cell cycle and decreased apoptosis of U-937 cells. In addition, the contents of IL-10 and TGF-β1, as well as their protein expression levels, increased in co-culture supernatants in U-937 cells, suggesting regulation by the p-JAK2/STAT3 pathway. The in vivo results demonstrated that with the increasing expression of B7-H3/B7-H4, the expression of IL-10 and TGF-β1 also increased significantly. Overall, the expression of B7-H3 and B7-H4 favored an immunosuppressive microenvironment by promoting the production of IL-10 and TGF-β1, thereby resulting in progression of cervical carcinogenesis.

01 Nov 2013·Oncology LettersQ4 · MEDICINE

Clinical significance of the induction of macrophage differentiation by the costimulatory molecule B7-H3 in human non-small cell lung cancer

Q4 · MEDICINE

Article

Author: Yang‑Qin Zhang ; Jing Sun ; Yong Mao ; Xue‑Guang Zhang ; Chuan‑Yong Mu ; Feng‑Qing Fu ; Yun‑Di Guo

B7-H3, a member of the B7 family of molecules, is expressed in certain types of human cancer and is important in tumor development and progression. Although several studies have reported that the expression of B7-H3 is correlated with poor outcomes in patients with cancer, its exact role in cancer remains unknown. In the present study, the expression levels of B7-H3 in the pathological specimens of 105 patients treated for non-small cell lung cancer (NSCLC) were examined by immunohistochemistry. A high expression level of B7-H3 was observed in 46.9% of the 105 NSCLC tissue specimens. These patients demonstrated a more advanced tumor grade and a shorter survival time. In addition, we also examined the levels of tumor-associated macrophages (TAMs) in NSCLC tissues and observed that the levels were positively correlated with the expression of B7-H3, and that higher levels of macrophages were associated with lower levels of infiltrating T cells and a shorter survival time. These results demonstrated that TAMs are important in the evasion of tumor immune surveillance in NSCLC. Furthermore, through knockdown of B7-H3 by RNA interference, we observed that soluble B7-H3 was capable of inducing macrophages to express higher levels of macrophage mannose receptor (MMR) and lower levels of human leukocyte antigen (HLA)-DR, as well as higher levels of interleukin-10 (IL-10) and lower levels of IL-1β in vitro. These observations are characteristic of an anti-inflammatory/reparatory (alternative/M2) phenotype. Therefore, our data suggests that B7-H3 proteins are involved in the progression of NSCLC by inducing the development of monocytes into anti-inflammatory cells.

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