Targeting endosialin/CD248 through antibody-mediated internalization results in impaired pericyte maturation and dysfunctional tumor microvasculature

Rybiński, K; Imtiyaz, Hongxia Z.; Mittica, Barrie; Drozdowski, Brian; Fulmer, James; Furuuchi, Keiji; Fernando, Shawn; Henry, Marianne; Chao, Qimin; Kline, Brad; Albone, Earl F.; Wustner, Jason; Lin, Jianbo; Nicolaides, Nicholas C.; Grasso, Luigi; Zhou, Yuhong

doi:10.18632/oncotarget.4559

Cited by 33 publications

(41 citation statements)

References 18 publications

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“…Preclinical studies with ontuxizumab have shown that treatment of tumor-bearing mice resulted in small, dysfunctional vessels in the tumors and that endosialin/TEM-1 expression on neovascular pericytes was decreased due to antibody-mediated internalization [28]. These results are consistent with a report by Naylor et.al.…”

Section: Introductionsupporting

confidence: 91%

Novel antibody probes for the characterization of endosialin/TEM-1

et al. 2016

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Endosialin (Tumor Endothelial Marker-1 (TEM-1), CD248) is primarily expressed on pericytes of tumor-associated microvasculature, tumor-associated stromal cells and directly on tumors of mesenchymal origin, including sarcoma and melanoma. While the function of endosialin/TEM-1 is incompletely understood, studies have suggested a role in supporting tumor growth and invasion thus making it an attractive therapeutic target. In an effort to further understand its role in cancer, we previously developed a humanized anti-endosialin/TEM-1 monoclonal antibody (mAb), called ontuxizumab (MORAb-004) for testing in preclinical and clinical studies. We herein report on the generation of an extensive panel of recombinant endosialin/TEM-1 protein extracellular domain (ECD) fragments and novel mAbs against ECD motifs. The domain-specific epitopes were mapped against ECD sub-domains to identify those that can detect distinct structural motifs and can be potentially formatted as probes suitable for diagnostic and functional studies. A number of mAbS were shown to cross-react with the murine and human protein, potentially allowing their use in human animal models and corresponding clinical trials. In addition, pairing of several mAbs supported their use in immunoassays that can detect soluble endosialin/TEM-1 (sEND) in the serum of healthy subjects and cancer patients.

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Section: Introductionsupporting

confidence: 91%

Novel antibody probes for the characterization of endosialin/TEM-1

et al. 2016

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“…Consistent with this concept, unlike targeting PDGFRb or ablating pericytes, treatment of syngeneic tumor bearing human CD248 knock-in mice with the anti-human endosialin antibody MORAb-004 did not result in a reduction in vessel number or destabilization of the vasculature, as monitored by endothelial cell viability, pericyte coverage, and integrity of the basement membrane, but significantly impaired the growth of B16-F10 tumors following subcutaneous or intravenous inoculation (36). Importantly, in the study reported here, the impairment in metastatic dissemination in the EN KO mice was not associated with gross alterations in the tumor vasculature.…”

Section: Discussionmentioning

confidence: 75%

“…Although endosialin was originally named TEM1 (tumor endothelial marker 1; refs. 6,8), this was later shown to be a misleading nomenclature when different laboratories reported endosialin expression being restricted to stromal pericytes and myofibroblasts and absent from endothelial cells of various human and mouse tumors (9,11,12,25,36). The downregulated expression in the adult in combination with the striking upregulation in tumors makes endosialin an oncofetal protein that is, in principle, strictly based on its unique pathology-associated expression pattern, an attractive therapeutic target.…”

Section: Discussionmentioning

confidence: 99%

Endosialin-Expressing Pericytes Promote Metastatic Dissemination

et al. 2016

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Metastasis is a multistep process that is critically dependent on the interaction of metastasizing tumor cells with cells in the local microenvironment. Within this tumor stroma, vesselassociated pericytes and myofibroblasts share a number of traits, including the upregulated expression of the transmembrane receptor endosialin (CD248). Comparative experiments in wild-type and endosialin-deficient mice revealed that stromal endosialin does not affect primary tumor growth but strongly promotes spontaneous metastasis. Mechanistically, endosialin-expressing pericytes in the primary tumor facilitate distant site metastasis by promoting tumor cell intravasation in a cell contact-dependent manner, resulting in elevated numbers of circulating tumor cells. Corresponding to these preclinical experiments, in independent cohorts of primary human breast cancers, upregulated endosialin expression significantly correlates with increased metastasis and poorer patient survival. Together, the data demonstrate a critical role for endosialin-expressing primary tumor pericytes in mediating metastatic dissemination and identify endosialin as a promising therapeutic target in breast cancer. Cancer Res; 76(18); 5313-25. Ó2016 AACR.

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“…Inhibiting endosialin by monoclonal Ab can decrease tumor growth and tumor metastasis [135]. As such, clinical trials aimed to determine safety profiles and the optimal dose for endosialin-targeted drugs are underway in RR pediatric HL patients (NCT01748721).…”

Section: Treatmentmentioning

confidence: 99%

Pediatric Hodgkin lymphoma- biomarkers, drugs, and clinical trials for translational science and medicine

et al. 2016

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Hodgkin lymphoma (HL) is a lymphoid malignancy that is typically derived from germinal-center B cells. EBV infection, mutations in NF-κB pathway genes, and genetic susceptibility are known risk factors for developing HL. CD30 and NF-κB have been identified as potential biomarkers in pediatric HL patients, and these molecules may represent therapeutic targets. Although current risk adapted and response based treatment approaches yield overall survival rates of >95%, treatment of relapse or refractory patients remains challenging. Targeted HL therapy with the antibody-drug conjugate Brentuximab vedotin (Bv) has proven to be superior to conventional salvage chemotherapy and clinical trials are being conducted to incorporate Bv into frontline therapy that substitutes Bv for alkylating agents to minimize secondary malignancies. The appearance of secondary malignancies has been a concern in pediatric HL, as these patients are at highest risk among all childhood cancer survivors. The risk of developing secondary leukemia following childhood HL treatment is 10.4 to 174.8 times greater than the risk in the general pediatric population and the prognosis is significantly poorer than the other hematological malignancies with a mortality rate of nearly 100%. Therefore, identifying clinically valuable biomarkers is of utmost importance to stratify and select patients who may or may not need intensive regimens to maintain optimal balance between maximal survival rates and averting late effects. Here we discuss epidemiology, risk factors, staging, molecular and genetic prognostic biomarkers, treatment for low and high-risk patients, and the late occurrence of secondary malignancies in pediatric HL.

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Targeting endosialin/CD248 through antibody-mediated internalization results in impaired pericyte maturation and dysfunctional tumor microvasculature

Cited by 33 publications

References 18 publications

Novel antibody probes for the characterization of endosialin/TEM-1

Novel antibody probes for the characterization of endosialin/TEM-1

Endosialin-Expressing Pericytes Promote Metastatic Dissemination

Pediatric Hodgkin lymphoma- biomarkers, drugs, and clinical trials for translational science and medicine

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