Shin Seol Hwa, Ju Eun Jin, Park Jin, Ko Eun Jung, Kwon Mi Ri, Lee Hye Won, Son Ga Won, Park Yun-Yong, Kim Yeon Joo, Song Si Yeol, Lee Sangkwang, Seo Beom Seok, Song Jin-A, Lim Sangbin, Jung Doohwan, Kim Sunyoung, Lee Hyangsook, Park Seok Soon, Jeong Seong-Yun, Choi Eun Kyung
Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea.
Asan Institute for Life Sciences, ASAN Medical Center, Seoul, 05505, Republic of Korea.
Cancer Cell Int. 2023 Aug 18;23(1):172. doi: 10.1186/s12935-023-02991-x.
The B7-H3 protein, encoded by the CD276 gene, is a member of the B7 family of proteins and a transmembrane glycoprotein. It is highly expressed in various solid tumors, such as lung and breast cancer, and has been associated with limited expression in normal tissues and poor clinical outcomes across different malignancies. Additionally, B7-H3 plays a crucial role in anticancer immune responses. Antibody-drug conjugates (ADCs) are a promising therapeutic modality, utilizing antibodies targeting tumor antigens to selectively and effectively deliver potent cytotoxic agents to tumors.
In this study, we demonstrate the potential of a novel B7-H3-targeting ADC, ITC-6102RO, for B7-H3-targeted therapy. ITC-6102RO was developed and conjugated with dHBD, a soluble derivative of pyrrolobenzodiazepine (PBD), using Ortho Hydroxy-Protected Aryl Sulfate (OHPAS) linkers with high biostability. We assessed the cytotoxicity and internalization of ITC-6102RO in B7-H3 overexpressing cell lines in vitro and evaluated its anticancer efficacy and mode of action in B7-H3 overexpressing cell-derived and patient-derived xenograft models in vivo.
ITC-6102RO inhibited cell viability in B7-H3-positive lung and breast cancer cell lines, inducing cell cycle arrest in the S phase, DNA damage, and apoptosis in vitro. The binding activity and selectivity of ITC-6102RO with B7-H3 were comparable to those of the unconjugated anti-B7-H3 antibody. Furthermore, ITC-6102RO proved effective in B7-H3-positive JIMT-1 subcutaneously xenografted mice and exhibited a potent antitumor effect on B7-H3-positive lung cancer patient-derived xenograft (PDX) models. The mode of action, including S phase arrest and DNA damage induced by dHBD, was confirmed in JIMT-1 tumor tissues.
Our preclinical data indicate that ITC-6102RO is a promising therapeutic agent for B7-H3-targeted therapy. Moreover, we anticipate that OHPAS linkers will serve as a valuable platform for developing novel ADCs targeting a wide range of targets.
由CD276基因编码的B7-H3蛋白是B7蛋白家族的成员，是一种跨膜糖蛋白。它在多种实体瘤中高表达，如肺癌和乳腺癌，并且与正常组织中的有限表达以及不同恶性肿瘤的不良临床结果相关。此外，B7-H3在抗癌免疫反应中起关键作用。抗体药物偶联物（ADC）是一种有前景的治疗方式，利用靶向肿瘤抗原的抗体将强效细胞毒性药物选择性且有效地递送至肿瘤。
在本研究中，我们展示了一种新型靶向B7-H3的ADC（ITC-6102RO）用于B7-H3靶向治疗的潜力。ITC-6102RO通过使用具有高生物稳定性的邻羟基保护芳基硫酸盐（OHPAS）接头，与吡咯并苯二氮卓（PBD）的可溶性衍生物dHBD进行开发和偶联。我们在体外评估了ITC-6102RO在过表达B7-H3的细胞系中的细胞毒性和内化作用，并在体内过表达B7-H3的细胞衍生和患者衍生的异种移植模型中评估了其抗癌疗效和作用模式。
ITC-6102RO抑制了B7-H3阳性肺癌和乳腺癌细胞系中的细胞活力，在体外诱导细胞周期停滞于S期、DNA损伤和细胞凋亡。ITC-6102RO与B7-H3的结合活性和选择性与未偶联的抗B7-H3抗体相当。此外，ITC-6102RO在B7-H3阳性的JIMT-1皮下异种移植小鼠中证明有效，并对B7-H3阳性肺癌患者衍生的异种移植（PDX）模型表现出强效抗肿瘤作用。在JIMT-1肿瘤组织中证实了包括dHBD诱导的S期停滞和DNA损伤在内的作用模式。
我们的临床前数据表明ITC-6102RO是一种有前景的用于B7-H3靶向治疗的治疗剂。此外，我们预计OHPAS接头将成为开发针对广泛靶点的新型ADC的有价值平台。
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