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A novel 5T4-targeting antibody-drug conjugate H6-DM4 exhibits potent therapeutic efficacy in gastrointestinal tumor xenograft models.

ABSTRACT: 5T4, also named as trophoblast glycoprotein, is often upregulated in some cancer cells. Here, we demonstrated that 5T4 was highly expressed in gastric, colorectal, and pancreatic cancer, associated with significantly poor prognosis of gastrointestinal (GI) cancer patients. To search for new targeting drugs for GI cancer, we developed a novel anti-5T4 monoclonal antibody with high affinity and robust internalization ability and conjugated it to the potent microtubule inhibitor DM4 to produce conjugate H6-DM4. This antibody-drug conjugate (ADC) displayed significant cytotoxicity in a panel of GI cancer cell lines with IC50 values in the nanomolar range. H6-DM4 eradicated established GI tumor xenograft models at 2.5 mg/kg or 10 mg/kg without observable toxicity. Further, 5T4 was highly expressed in cancer-initiating cells (CICs) compared with non-CICs in colorectal cancer. In vitro and in vivo, treatment with H6-DM4 exhibited a powerful efficacy on colorectal CICs. Additionally, colorectal cancer cells resistant to platinum were effectively eliminated by H6-DM4. Taken together, our results showed 5T4-positive GI cancer cells, colorectal cancer-initiating cells, and platinum-resistant colorectal cancer cells were potently eliminated by H6-DM4, indicating H6-DM4 may be a potential candidate drug for GI cancer treatment.

SUBMITTER: Wang R

PROVIDER: S-EPMC5934552 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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A novel 5T4-targeting antibody-drug conjugate H6-DM4 exhibits potent therapeutic efficacy in gastrointestinal tumor xenograft models.

Wang Ruixue R Lai Qinhuai Q Tang Liangze L Tao Yiran Y Yao Yuqin Y Liu Yu Y Lu Ying Y Shen Chaoyong C Lu Ran R Fan Chuanwen C Zhang Ruirui R Wang Yuxi Y Yu Lin L Yang Tinghan T Wu Yangping Y Peng Yujia Y Wei Xian X Fu Yuyin Y Lai Weirong W Gou Lantu L Yang Jinliang J

American journal of cancer research 20180401 4

5T4, also named as trophoblast glycoprotein, is often upregulated in some cancer cells. Here, we demonstrated that 5T4 was highly expressed in gastric, colorectal, and pancreatic cancer, associated with significantly poor prognosis of gastrointestinal (GI) cancer patients. To search for new targeting drugs for GI cancer, we developed a novel anti-5T4 monoclonal antibody with high affinity and robust internalization ability and conjugated it to the potent microtubule inhibitor DM4 to produce conj ...[more]

PMID: 29736307

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Project description:BackgroundThe 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.MethodsIn 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.ResultsITC-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.ConclusionsOur 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.

Dataset Information

A novel 5T4-targeting antibody-drug conjugate H6-DM4 exhibits potent therapeutic efficacy in gastrointestinal tumor xenograft models.

Publications

A novel 5T4-targeting antibody-drug conjugate H6-DM4 exhibits potent therapeutic efficacy in gastrointestinal tumor xenograft models.

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