作者: Tuhin, Israth Jahan ; Lou, Xiaoyan ; Yan, Zhiqiang ; Ye, Jing ; Zhou, Meixia ; Shao, Jiaqi ; Xu, Nan ; Monty, Masuma Akter ; Zhu, Hongjia ; Fang, Xiaoyan ; Jia, Yujie ; Li, Minghao ; Kang, Liqing ; Yu, Lei ; Tan, Jingwen

Although chimeric antigen receptor (CAR) T cell immunotherapy has shown promising significance in B cell malignancies, success against T cell malignancies remains unsatisfactory because of shared antigenicity between normal and malignant T cells, resulting in fratricide and hindering CAR production for clinical treatment. Here, we report a new strategy of blocking the CD7 antigen on the T cell surface with a recombinant anti-CD7 antibody to obtain a sufficient amount of CD7-targeting CAR-T cells for T cell acute lymphoblastic leukemia (T-ALL) treatment. Feasibility was evaluated systematically, revealing that blocking the CD7 antigen with an antibody effectively blocked CD7-derived fratricide, increased the expansion rate, reduced the proportion of regulatory T (Treg) cells, maintained the stem cell-like characteristics of T cells, and restored the proportion of the CD8⁺ T cell population. Ultimately, we obtained anti-CD7 CAR-T cells that were specifically and effectively able to kill CD7 antigen-positive target cells, obviating the need for complex T cell modifications. This approach is safer than previous methods and provides a new, simple, and feasible strategy for clinical immunotherapies targeting CD7-positive malignant tumors.

2021-09-01·Leukemia research4区 · 医学

An antibody-drug conjugate with intracellular drug release properties showing specific cytotoxicity against CD7-positive cells

4区 · 医学

Article

作者: Milhas, Sabine ; Miller, Ami ; Lodge, Adam ; Rabbitts, Terry H ; Mysliwy, Justyna ; Jain, Arvind ; Al Nakeeb, Majid ; Zhang, Jing ; Williamson, Daniel J ; Thirlway, Jenny

Refractory T cell acute leukaemias that no longer respond to treatment would benefit from new modalities that target T cell-specific surface proteins. T cell associated surface proteins (the surfaceome) offer possible therapy targets to reduce tumour burden but also target the leukaemia-initiating cells from which tumours recur. Recent studies of the T cell leukaemia surfaceome confirmed that CD7 is highly expressed in overt disease. We have used an anti-CD7 antibody drug conjugate (ADC) to show that the binding of antibody to surface CD7 protein results in rapid internalization of the antigen together with the ADC. As a consequence, cell killing was observed via induction of apoptosis and was dependent on cell surface CD7. The in vitro cytotoxic activity (EC₅₀) of the anti-CD7 ADC on T cell acute leukaemia (T-ALL) cells Jurkat and KOPT-K1 was found to be in the range of 5-8 ng/mL. In a pre-clinical xenograft model of human tumour growth expressing CD7 antigen, growth was curtailed by a single dose of ADC. The data indicate that CD7 targeting ADCs may be developed into an important second stage therapy for T cell acute leukaemia, for refractory CD7-positive leukaemias and for subsets of acute myeloid leukaemia (AML) expressing CD7.

2016-02-01·Head & neck2区 · 医学

Epidermal growth factor receptor inhibition by anti-CD147 therapy in cutaneous squamous cell carcinoma

2区 · 医学

Article

作者: Sweeny, Larissa ; Frederick, John W. ; Zhou, Tong ; Hartman, Yolanda ; Rosenthal, Eben L.

BACKGROUND:

Advanced cutaneous squamous cell carcinoma (SCC) is an uncommon and aggressive malignancy. As a result, there is limited understanding of its biology and pathogenesis. CD147 and epidermal growth factor receptor (EGFR) have been identified as oncologically important targets, but their relationship remains undefined in cutaneous SCC.

METHODS:

Multiple cutaneous SCC cell lines (Colo-16, SRB-1, and SRB-12), were treated in vitro with a range of chimeric anti-CD147 monoclonal antibody (mAb) (0, 50, 100, and 200 µg/mL) or transfected with a small interfering RNA against CD147 (SiCD147). Cell proliferation, migration (scratch wound healing assay), and protein expression was then assessed. In vivo, Colo-16 flank xenografts were treated anti-CD147 mAb (150 µg i.p. triweekly).

RESULTS:

After treatment with anti-CD147 (200 µg/mL), there was a significant decrease in proliferation for all cell lines relative to controls (p < .005). In addition, treatment with anti-CD147 (200 µg/mL) resulted in decreased cell migration for all cell lines, with an average of 43% reduction in closure compared to controls (p < .001). Colo-16 SiCD147 expression demonstrated similar reduction in proliferation and wound closure. Anti-CD147 antibody therapy and siRNA mediated reduction in CD147 expression were both found to decrease protein expression of EGFR, which correlated with a reduction in downstream total and phosphorylated protein kinase B (pAKT). Tumor growth in vivo was reduced for both the anti-CD147 treatment group and the SiCD147 group relative to controls.

CONCLUSION:

Inhibition and downregulation of CD147 in cutaneous SCC resulted in suppression of the malignant phenotype in vitro and in vivo, which may be mediated in part by an alteration in EGFR expression. As a result, CD147 may serve as a potential therapeutic target for advanced cutaneous SCC.

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适应症	最高研发状态	国家/地区	公司	日期
器官移植排斥	临床3期	加拿大	-	-
器官移植排斥	临床3期	英国	-	-
器官移植排斥	临床3期	-	Celltech Oy	-
器官移植排斥	临床3期	-	Novartis Pharma AG	-
类风湿关节炎	临床3期	-	Novartis Pharma AG	-
类风湿关节炎	临床3期	-	Celltech Oy	-