A Phase II Clinical Trial of TRC105 (Anti-Endoglin Antibody) in Adults With Advanced/Metastatic Urothelial Carcinoma

Apolo, Andrea B.; Karzai, Fatima; Trepel, Jane B.; Alarcon, Sylvia V.; Lee, Sunmin; Lee, Min-Jung; Tomita, Yusuke; Cao, Liang; Yu, Yunkai; Merino, María J.; Madan, Ravi A.; Parnes, Howard L.; Steinberg, Seth M.; Rodriguez, Beatriz Walter; Seon, Ben K.; Gulley, James L.; Arlen, Philip M.; Dawson, Nancy A.; Figg, William D.; Dahut, William L.

doi:10.1016/j.clgc.2016.05.010

Cited by 43 publications

(41 citation statements)

References 60 publications

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“…TRC105 is a chimeric IgG1 antibody that binds human endoglin and murine endoglin, albeit with lower affinity, and is in development as an antiangiogenic therapy (37–40). Because we have determined that endoglin promotes VEGF signaling and VEGF‐induced sprouting and angiogenesis, we asked whether TRC105 cooperates with anti–VEGF therapy to inhibit angiogenesis.…”

Section: Resultsmentioning

confidence: 99%

Endoglin interacts with VEGFR2 to promote angiogenesis

et al. 2018

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Endoglin, a TGF-β coreceptor predominantly expressed in endothelial cells, plays an important role in vascular development and tumor-associated angiogenesis. However, the mechanism by which endoglin regulates angiogenesis, especially during tip cell formation, remains largely unknown. In this study, we report that endoglin promoted VEGF-induced tip cell formation. Mechanistically, endoglin interacted with VEGF receptor (VEGFR)-2 in a VEGF-dependent manner, which sustained VEGFR2 on the cell surface and prevented its degradation. Endoglin mutants deficient in the ability to interact with VEGFR2 failed to sustain VEGFR2 on the cell surface and to promote VEGF-induced tip cell formation. Further, an endoglin-targeting monoclonal antibody (mAb), TRC105, cooperated with a VEGF-A targeting mAb, bevacizumab, to inhibit VEGF signaling and tip cell formation in vitro and to inhibit tumor growth, metastasis, and tumor-associated angiogenesis in a murine tumor model. This study demonstrate a novel mechanism by which endoglin initiates and regulates VEGF-driven angiogenesis while providing a rationale for combining anti-VEGF and anti-endoglin therapy in patients with cancer.-Tian, H., Huang, J. J., Golzio, C., Gao, X., Hector-Greene, M., Katsanis, N., Blobe, G. C. Endoglin interacts with VEGFR2 to promote angiogenesis.

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Section: Resultsmentioning

confidence: 99%

Endoglin interacts with VEGFR2 to promote angiogenesis

et al. 2018

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“…This is underscored by the fact that phase 1 and 2 trials of TRC105 in solid tumors have shown it to be well tolerated at clinically relevant doses. [8][9][10] When the maximum tolerated dose was exceeded, at 15 mg/kg every week, hypoproliferative anemia has been reported. 9 This side effect was easily monitorable, reversible, and treatable without adverse sequelae, 9 however, this would be important to monitor closely in leukemia patients receiving TRC105.…”

Section: Discussionmentioning

confidence: 99%

“…[5][6][7] This receptor is a therapeutic target and TRC105, an endoglinneutralizing antibody, is currently in phase 2 and 3 trials as an antiangiogenic agent for the treatment of solid tumors. [8][9][10] In addition to the endothelial lineage, endoglin also plays a key role in hematopoiesis. We have reported an important function for endoglin in cell fate specification and early hematopoiesis, [11][12][13][14][15] and a potential role beyond the embryonic stage is suggested by the expression of this receptor on the hematopoietic stem cell (HSC) isolated from every hematopoietic site, including the aorta-gonad-mesonephros, 16,17 the fetal liver, 18 and the bone marrow (BM), 19,20 in which endoglin has been reported to identify the long-term repopulating HSC.…”

Section: Introductionmentioning

confidence: 99%

Endoglin: a novel target for therapeutic intervention in acute leukemias revealed in xenograft mouse models

Dourado

Baik

Oliveira

et al. 2017

Blood

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• Leukemia-forming activity is enriched in endoglinexpressing AML and B-ALL blasts using a mouse xenograft model. • Inhibition of endoglin function with TRC105 reduces leukemia development and progression.Endoglin (CD105), a receptor of the transforming growth factor-b superfamily, has been reported to identify functional long-term repopulating hematopoietic stem cells, and has been detected in certain subtypes of acute leukemias. Whether this receptor plays a functional role in leukemogenesis remains unknown. We identified endoglin expression on the majority of blasts from patients with acute myeloid leukemia (AML) and acute B-lymphoblastic leukemia (B-ALL). Using a xenograft model, we find that CD105 1 blasts are endowed with superior leukemogenic activity compared with the CD105 2 population.We test the effect of targeting this receptor using the monoclonal antibody TRC105, and find that in AML, TRC105 prevented the engraftment of primary AML blasts and inhibited leukemia progression following disease establishment, but in B-ALL, TRC105 alone was ineffective due to the shedding of soluble CD105. However, in both B-ALL and AML, TRC105 synergized with reduced intensity myeloablation to inhibit leukemogenesis, indicating that TRC105 may represent a novel therapeutic option for B-ALL and AML. (Blood. 2017;129(18):2526-2536

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“…32–34 More importantly, various studies have confirmed that, in more than ten solid tumor types, high expression of CD105 is correlated with poor patient outcomes, which makes it a widely-applicable target in cancer. 35–38 Using TRC105 (a chimeric IgG1 monoclonal antibody which binds to both human and murine CD105 39,40 ) as the targeting ligand, our group has monitored CD105 expression using both antibody and nanoplatforms, demonstrating the great potential of CD105-targeted agents for future extensive applications in cancer diagnosis and therapy. 41–47 Inspired by this previous success, we set out to develop our first PET/MRI probe targeted to CD105.…”

Section: Introductionmentioning

confidence: 99%

Radiolabeled, Antibody-Conjugated Manganese Oxide Nanoparticles for Tumor Vasculature Targeted Positron Emission Tomography and Magnetic Resonance Imaging

Zhan

Shi

Ehlerding

et al. 2017

ACS Appl. Mater. Interfaces

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Manganese oxide nanoparticles (Mn3O4 NPs) have attracted a great deal of attention in the field of biomedical imaging because of their ability to create an enhanced imaging signal in MRI as novel potent T1 contrast agents. In this study, we present tumor vasculature-targeted imaging in mice using Mn3O4 NPs through conjugation to the anti-CD105 antibody TRC105 and radionuclide copper-64 (64Cu, t1/2: 12.7 h). The Mn3O4 conjugated NPs, 64Cu-NOTA-Mn3O4@PEG-TRC105, exhibited sufficient stability in vitro and in vivo. Serial positron emission tomography (PET) and magnetic resonance imaging (MRI) studies evaluated the pharmacokinetics and demonstrated targeting of 64Cu-NOTA-Mn3O4@PEG-TRC105 to 4T1 murine breast tumors in vivo, compared to 64Cu-NOTA-Mn3O4@PEG. The specificity of 64Cu-NOTA-Mn3O4@PEG-TRC105 for the vascular marker CD105 was confirmed through in vivo, in vitro, and ex vivo experiments. Since Mn3O4 conjugated NPs exhibited desirable properties for T1 enhanced imaging and low toxicity, the tumor-specific Mn3O4 conjugated NPs reported in this study may serve as promising multifunctional nanoplatforms for precise cancer imaging and diagnosis.

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A Phase II Clinical Trial of TRC105 (Anti-Endoglin Antibody) in Adults With Advanced/Metastatic Urothelial Carcinoma

Cited by 43 publications

References 60 publications

Endoglin interacts with VEGFR2 to promote angiogenesis

Endoglin interacts with VEGFR2 to promote angiogenesis

Endoglin: a novel target for therapeutic intervention in acute leukemias revealed in xenograft mouse models

Radiolabeled, Antibody-Conjugated Manganese Oxide Nanoparticles for Tumor Vasculature Targeted Positron Emission Tomography and Magnetic Resonance Imaging

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