PO.ET01.03 · 实验与分子治疗
BC602:一种处于IND申报支持阶段的LGR5x EGFR双特异性抗体,在小鼠CDX和PDX模型中具有卓越的抗肿瘤疗效
BC602: An IND-enabling stage LGR5x EGFR bispecific antibody with superior anti-tumor efficacy in mouse CDX and PDX models
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作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
表皮生长因子受体(EGFR)是许多癌症类型肿瘤发生中的关键驱动癌基因。EGFR靶向抗体主要被批准用于EGFR过表达的癌症,包括结直肠癌(CRC)、头颈部鳞状细胞癌(HNSCC)和鳞状非小细胞肺癌(NSCLC)。这些抗体通过结合细胞外结构域以阻断配体结合并诱导受体内化和降解来发挥其功能。为进一步增强EGFR的内化和降解,我们开发了一种不对称的LGR5*EGFR双特异性抗体(BsAb)BC602,其一个臂为靶向富含亮氨酸重复序列的G蛋白偶联受体5(LGR5)的VHH,另一个臂为靶向EGFR的Fab。为进一步增强抗肿瘤活性,BC602的Fc经工程改造以增强FcgammaRIII结合和ADCC活性。在ELISA和BLI实验中,BC602分别以高亲和力结合LGR5蛋白和EGFR蛋白。在表达LGR5和EGFR的细胞系中,BC602以个位数nM的水平对细胞表面受体表现出高结合亲和力,而同型对照抗体无结合。在pH-rodo内化实验中,BC602在两种细胞系中均诱导出显著高于单独EGFR抗体或LGR5抗体的内化程度。在使用患者来源类器官(PDO)的生长抑制实验中,BC602表现出强效的抑制活性,远强于EGFR抗体。在多个小鼠CDX和PDX模型中研究了BC602的抗肿瘤疗效。BC602表现出剂量依赖性抗肿瘤疗效,其抗肿瘤疗效强于EGFR抗体,优于或相当于处于临床开发阶段的竞品。在AGS小鼠异种移植肿瘤模型中,BC602以5 mg/kg显示出72%的TGI,而EGFR抗体的TGI为50%。在A431-LGR5小鼠异种移植肿瘤模型中,BC602以1/3/10 mg/kg分别显示出42%、67%和83%的TGI。BC602在这些小鼠模型中对小鼠体重无影响,也未显示任何其他安全性问题。BC602表现出良好的CMC理化性质,生产产量高。BC602的非临床GLP PK和毒性研究以及200L规模的临床批次生产正在进行中。预计将于2026年第三季度递交IND申报,计划适应症包括同时过表达EGFR和LGR5的癌症类型,包括HNSCC和CRC。
查看英文原文 English abstract
Epidermal growth factor receptor (EGFR) is a key driver oncogene in the tumorigenesis of many cancer types. EGFR targeting antibodies are approved mainly in EGFR overexpression cancers including colorectal cancer (CRC), head and neck squamous carcinoma (HNSCC), and squamous non-small cell lung cancer (NSCLC). These antibodies exert their function by binding to the extracellular domain(s) to block ligand binding and to induce receptor internalization and degradation. To further enhance EGFR internalization and degradation, we developed an asymmetric LGR5*EGFR bispecific antibody (BsAb) BC602, with one arm as VHH targeting leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5), and the other arm as Fab targeting EGFR. To further increase the anti-tumor activity, BC602 Fc is engineered for enhanced FcgammaRIII binding and ADCC activity. In ELISA and BLI assays, BC602 binds to the LGR5 protein and EGFR protein with high affinity, respectively. In LGR5 and EGFR expressing cell lines,BC602 showed high binding affinity to cell surface receptors at single digit nM, while isotype control antibody showed no binding. In the pH-rodo internalization assay, BC602 induced significantly higher internalization magnitude than EGFR antibody or LGR5 antibody alone in both cell lines. In growth inhibition assay using the patient-derived organoids (PDO), BC602 showed potent inhibitory activity, much stronger than EGFR antibody. The antitumor efficacy of BC602 was studied in several mouse CDX and PDX models. BC602 demonstrated dose-dependent anti-tumor efficacy, with the antitumor efficacy stronger than EGFR antibody, superior or comparable to its competitor in clinical development stage. In AGS mouse xenograft tumor model, BC602 at 5 mg/kg showed a TGI of 72% while EGFR antibody had a TGI of 50%. In A431-LGR5 mouse xenograft tumor model, BC602 at 1/3/10 mg/kg showed TGI of 42%, 67%, and 83% respectively. BC602 showed no effect on mouse body weight or showed any other safety concerns in these mouse models. BC602 demonstrated good physicochemical properties for CMC, with a high production yield. Non-clinical GLP PK and toxicity studies of BC602 and 200L scale clinical batch production are ongoing. IND filing is expected in 2026 Q3, and the planned indications include cancer types that overexpress both EGFR and LGR5 including HNSCC and CRC.
利益披露 Disclosure
Z. Shao, None..
T. Wang, None..
W. Jia, None..
K. Lok, None..
Z. Pan, None.