Evidence for enhanced tissue factor expression in age-related macular degeneration

Cho, Youngeun; Cao, Xiaoguang; Shen, Defen; Tuo, Jingsheng; Parver, Leonard M.; Rickles, Frederick R.; Chan, Chi Chao

doi:10.1038/labinvest.2010.184

Cited by 33 publications

(22 citation statements)

References 38 publications

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“…The incidence of ocular events, including conjunctivitis, was reduced in the patients enrolled after implementation of mitigation measures. Although the mechanism of the ocular events is not known, TF expression has been demonstrated in the ocular epithelium (32,33), which may result in treatmentemergent toxicity in these cells. The understanding of TF-related epistaxis and ocular events is continuing to evolve, and further studies are needed to optimize mitigation strategies, as well as to assess the long-term effects of tisotumab vedotin, the duration of these AESIs, and the mechanisms by which they occur.…”

Section: Discussionmentioning

confidence: 99%

Tisotumab Vedotin in Previously Treated Recurrent or Metastatic Cervical Cancer

Hong

Concin

Vergote

et al. 2020

Clinical Cancer Research

101

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◥Purpose: Tissue factor (TF) is a potential target in cervical cancer, as it is frequently highly expressed and associated with poor prognosis. Tisotumab vedotin, a first-in-class investigational antibody-drug conjugate targeting TF, has demonstrated encouraging activity in solid tumors. Here we report data from the cervical cancer cohort of innovaTV 201 phase I/II study (NCT02001623).Patients and Methods: Patients with recurrent or metastatic cervical cancer received tisotumab vedotin 2.0 mg/kg every 3 weeks until progressive disease, unacceptable toxicity, or consent withdrawal. The primary objective was safety and tolerability. Secondary objectives included antitumor activity.Results: Of the 55 patients, 51% had received !2 prior lines of treatment in the recurrent or metastatic setting; 67% had prior bevacizumab þ doublet chemotherapy. Fifty-one percent of patients had squamous cell carcinoma. The most common grade 3/4 treatment-emergent adverse events (AEs) were anemia (11%), fatigue (9%), and vomiting (7%). No grade 5 treatment-related AEs occurred. Investigator-assessed confirmed objective response rate (ORR) was 24% [95% confidence interval (CI): 13%À37%]. Median duration of response (DOR) was 4.2 months (range: 1.0 þ À9.7); four patients responded for >8 months. The 6-month progression-free survival (PFS) rate was 29% (95% CI: 17%À43%). Independent review outcomes were comparable, with confirmed ORR of 22% (95% CI: 12%À35%), median DOR of 6.0 months (range: 1.0 þ À9.7), and 6-month PFS rate of 40% (95% CI: 24%À55%). Tissue factor expression was confirmed in most patients; no significant association with response was observed.Conclusions: Tisotumab vedotin demonstrated a manageable safety profile and encouraging antitumor activity in patients with previously treated recurrent or metastatic cervical cancer.Cervical cancer is a common cancer in women, with an estimated 570,000 new cases globally in 2018, and represents the third leading cause of cancer-related death in women worldwide (1). Approximately 15,500 and 61,000 new cases of cervical cancer were estimated in North America and in Europe in 2018, respectively, resulting in approximately 5,800 and 25,800 deaths (2). Recurrent or metastatic cervical cancer has a poor prognosis, with a 5-year survival rate of 17% (3). Bevacizumab and doublet chemotherapy (paclitaxel and cisplatin or paclitaxel and topotecan) were adopted as first-line (1L) standard-ofcare therapy for recurrent or metastatic cervical cancer in the past 5 years (4-6). However, nearly all patients relapse after 1L treatment, and single-institution experiences indicate that the percentage of patients who receive a second-line (2L) therapy varies (30%-70%) as many patients die before receiving treatment (7,8).Available 2Lþ therapies for recurrent or metastatic cervical cancer are characterized by low response rates (5,6). Before adoption of bevacizumab plus doublet chemotherapy in 1L, therapies administered in the 2Lþ setting reported response rates in the range of 4.5% to 15%, with median s...

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Section: Discussionmentioning

confidence: 99%

Tisotumab Vedotin in Previously Treated Recurrent or Metastatic Cervical Cancer

Hong

Concin

Vergote

et al. 2020

Clinical Cancer Research

101

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“…Thus, stimulation mimicking inflammatory and oxidative stress was used to challenge RPE cells and verify the FasL-mediated pathway in RPE apoptosis. LPS and H 2 O 2 have been successfully used to induce inflammatory and oxidative stress, respectively, in RPE cells [36-37]. Meanwhile, TCDD, a member of the polychlorinated dibenzo- p -dioxin family, was first used in RPE cells to induce oxidative stress.…”

Section: Discussionmentioning

confidence: 99%

Enhanced apoptosis in retinal pigment epithelium under inflammatory stimuli and oxidative stress

et al. 2012

Self Cite

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Age-related macular degeneration (AMD) is a neurodegenerative disease that causes irreversible central vision loss in the elderly. Retinal pigment epithelium (RPE) has been found to be a key component in AMD pathogenesis. The Ccl2−/−/Cx3cr1−/− (DKO) mouse on Crb1rd8 background is created as an AMD model, developing AMD-like retinal lesions. Our study aimed to examine RPE apoptosis in DKO mouse and human ARPE-19 cell line. DKO RPE expressed higher apoptotic proteins when compared with age-matched wild type (WT) RPE in physiological conditions. Apoptosis of primary cultured mouse RPE was evaluated under stimulation with lipopolysaccharide for inflammatory stimulation and 2,3,7,8-tetrachlorodibenzo-p-dioxin or H2O2 for oxidative stress. Compared with WT RPE, DKO RPE was more susceptible to Fas ligand (FasL)-mediated apoptosis under both inflammatory and oxidative stress, with less cell viability and higher expression of apoptotic transcripts and proteins. Decreased cell viability was also observed in ARPE-19 cells under each stimulus. Furthermore, we also investigated the anti-apoptotic effects of decoy receptor 3 (DcR3), a decoy receptor for FasL, on ARPE-19 cells under inflammatory and oxidative stress. DcR3 pre-incubated ARPE-19 cells showed decreased apoptosis, with increased cell viability and decreased expression of apoptotic transcripts and proteins under the stimuli. On the contrary, knockdown of DcR3 in ARPE-19 cells showed totally opposite results. Our study demonstrates that FasL-mediated RPE apoptosis may play a pivotal role in AMD pathogenesis.

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“…With the advent of safer linker-payloads such as XMT-1267 (48), we anticipate lack of MMAE-associated toxicities for the clinical-stage group 25 ADC. Finally, the antibodies described herein could also be prioritized for the treatment of other diseases associated with upregulation of membranous TF expression, such as macular degeneration (49). A FVII-Fc fusion protein that binds TF reduces the size of choroid neovascular (CNV) lesions in various animal models (50,51).…”

Section: Discussionmentioning

confidence: 99%

Treating Tissue Factor–Positive Cancers with Antibody–Drug Conjugates That Do Not Affect Blood Clotting

Theunissen

Cai

Bhatti

et al. 2018

Molecular Cancer Therapeutics

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The primary function of tissue factor (TF) resides in the vasculature as a cofactor of blood clotting; however, multiple solid tumors aberrantly express this transmembrane receptor on the cell surface. Here, we developed anti-TF antibody-drug conjugates (ADC) that did not interfere with the coagulation cascade and benchmarked them against previously developed anti-TF ADCs. After screening an affinity-matured antibody panel of diverse paratopes and affinities, we identified one primary paratope family that did not inhibit conversion of Factor X (FX) to activated Factor X (FXa) and did not affect conversion of prothrombin to thrombin. The rest of the antibody panel and previously developed anti-TF antibodies were found to perturb coagulation to varying degrees. To compare the anticancer activity of coagulation-inert and -inhibitory antibodies as ADCs, a selection of antibodies was conjugated to the prototypic cytotoxic agent monomethyl auristatin E (MMAE) through a protease-cleavable linker. The coagulation-inert and -inhibitory anti-TF ADCs both killed cancer cells effectively. Importantly, the coagulation-inert ADCs were as efficacious as tisotumab vedotin, a clinical stage ADC that affected blood clotting, including in patient-derived xenografts from three solid tumor indications with a need for new therapeutic treatments-squamous cell carcinoma of the head and neck (SCCHN), ovarian, and gastric adenocarcinoma. Furthermore, a subset of the anti-TF antibodies could also be considered for the treatment of other diseases associated with upregulation of membranous TF expression, such as macular degeneration. .

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Evidence for enhanced tissue factor expression in age-related macular degeneration

Cited by 33 publications

References 38 publications

Tisotumab Vedotin in Previously Treated Recurrent or Metastatic Cervical Cancer

Tisotumab Vedotin in Previously Treated Recurrent or Metastatic Cervical Cancer

Enhanced apoptosis in retinal pigment epithelium under inflammatory stimuli and oxidative stress

Treating Tissue Factor–Positive Cancers with Antibody–Drug Conjugates That Do Not Affect Blood Clotting

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