29 A First-in-Human Phase I Monotherapy Study of RG7212 (R), a Novel Monoclonal Antibody Targeting TWEAK Signaling in Patients with Advanced Solid Tumors

Lassen, U.; Schellens, Jan H.M.; Siu, L.L.; Jonker, Derek J.; Sørensen, Morten; Jarutat, Tiantom; Wang, K.; Geho, David; DeMario, Mark; Goss, Glenwood D.

doi:10.1016/s0959-8049(12)71828-2

Cited by 5 publications

(7 citation statements)

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“…5B). Consistent with the expected changes in immune cell recruitment from the cytokine changes in mice, a decrease in tumor macrophages was observed the melanoma tumor (36).…”

Section: Rg7212 Efficacy Is Dependent On Immune Cell Functionsupporting

confidence: 83%

“…Tumor shrinkage and decreases in pERK (Fig. 5B) and Ki67 were also observed in a patient with melanoma after RG7212 treatment (36), supporting that proliferation is decreased in tumors with RG7212 treatment. Levels of Ã , all mRNA changes in ACHN cells or xenografts except PDL1 induced in MDA-MB-436 in vitro with TWEAK stimulation and CXCL3 mRNA decreased in Caki-1 xenografts after RG7212 treatment.…”

Section: Tweak-induced Effects Are Reversed In Rg7212-treated Micesupporting

confidence: 63%

“…RG7212 acts as a TWEAK antagonist, blocking TWEAK-induced signaling and cytokine production, promoting apoptosis, altering immune cell distribution, and inhibiting tumor growth without toxicity in mice. In phase I testing, evidence of tumor regression, with pharmacodynamic changes consistent with those observed in mice and without toxicity, was observed in patients (36).…”

Section: Translational Relevancementioning

confidence: 64%

“…5A) were decreased in tumors from RG7212-treated mice. By quantitative immunohistochemistry (IHC), TRAF1 protein was decreased more than 50% in tumors in mice and in patient tumor biopsies in the phase I study following RG7212 dosing (36).…”

Section: Tweak-induced Effects Are Reversed In Rg7212-treated Micementioning

confidence: 99%

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RG7212 Anti-TWEAK mAb Inhibits Tumor Growth through Inhibition of Tumor Cell Proliferation and Survival Signaling and by Enhancing the Host Antitumor Immune Response

Yin

Luistro

Zhong

et al. 2013

Clinical Cancer Research

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Purpose: To explore the role of TWEAK in tumor growth and antitumor immune response and the activity and mechanism of RG7212, an antagonistic anti-TWEAK antibody, in tumor models.Experimental Design: TWEAK-induced signaling and gene expression were explored in tumor cell lines and inhibition of these effects and antitumor efficacy with RG7212 treatment was assessed in human tumor xenograft-, patient-derived xenograft, and syngeneic tumor models and phase I patients. Genetic features correlated with antitumor activity were characterized.Results: In tumor cell lines, TWEAK induces proliferation, survival, and NF-kB signaling and gene expression that promote tumor growth and suppress antitumor immune responses. TWEAK-inducible CD274, CCL2, CXCL-10 and -11 modulate T-cell and monocyte recruitment, T-cell activation, and macrophage differentiation. These factors and TWEAK-induced signaling were decreased, and tumor, blood, and spleen immune cell composition was altered with RG7212 treatment in mice. RG7212 inhibits tumor growth in vivo in models with TWEAK receptor, Fn14, expression, and markers of pathway activation. In phase I testing, signs of tumor shrinkage and stable disease were observed without dose-limiting toxicity. In a patient with advanced, Fn14-positive, malignant melanoma with evidence of tumor regression, proliferation markers were dramatically reduced, tumor T-cell infiltration increased, and tumor macrophage content decreased. Antitumor activity, a lack of toxicity in humans and animals and no evidence of antagonism with standard of care or targeted agents in mice, suggests that RG7212 is a promising agent for use in combination therapies in patients with Fn14-positive tumors.

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“…5B). Consistent with the expected changes in immune cell recruitment from the cytokine changes in mice, a decrease in tumor macrophages was observed the melanoma tumor (36).…”

Section: Rg7212 Efficacy Is Dependent On Immune Cell Functionsupporting

confidence: 83%

Section: Tweak-induced Effects Are Reversed In Rg7212-treated Micesupporting

confidence: 63%

Section: Translational Relevancementioning

confidence: 64%

Section: Tweak-induced Effects Are Reversed In Rg7212-treated Micementioning

confidence: 99%

See 2 more Smart Citations

RG7212 Anti-TWEAK mAb Inhibits Tumor Growth through Inhibition of Tumor Cell Proliferation and Survival Signaling and by Enhancing the Host Antitumor Immune Response

Yin

Luistro

Zhong

et al. 2013

Clinical Cancer Research

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“…Moreover, Fn14 expression is considered a negative prognostic factor in glioblastoma multiforme (6), breast cancer (19), gastric cancer (20), and NSCLC (21). Therefore, targeting TWEAK:Fn14 signaling has led to the development of several anticancer therapeutic strategies, including the antibodies enavatuzumab, BIIB036, and RG7212 (22)(23)(24).…”

Section: Introductionmentioning

confidence: 99%

A Phase I Monotherapy Study of RG7212, a First-in-Class Monoclonal Antibody Targeting TWEAK Signaling in Patients with Advanced Cancers

Lassen

Meulendijks

Siu

et al. 2015

Clinical Cancer Research

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Purpose: Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) and fibroblast growth factor-inducible molecule 14 (Fn14) are a ligand-receptor pair frequently overexpressed in solid tumors. TWEAK:Fn14 signaling regulates multiple oncogenic processes through MAPK, AKT, and NFkB pathway activation. A phase I study of RG7212, a humanized anti-TWEAK IgG1k monoclonal antibody, was conducted in patients with advanced solid tumors expressing Fn14.Experimental Design: Dose escalations, over a 200-to 7,200-mg range, were performed with patients enrolled in weekly (QW), bi-weekly (Q2W), or every-three-week (Q3W) schedules. Primary objectives included determination of dose and safety profile. Secondary endpoints included assessments related to inhibition of TWEAK:Fn14 signaling, tumor proliferation, tumor immune cell infiltration, and pharmacokinetics.Results: In 192 treatment cycles administered to 54 patients, RG7212 was well-tolerated with no dose-limiting toxicities observed. More than 95% of related adverse events were limited to grade 1/2. Pharmacokinetics were dose proportional for all cohorts, with a t 1/2 of 11 to 12 days. Pharmacodynamic changes included clearance of free and total TWEAK ligand and reductions in tumor Ki-67 and TRAF1. A patient with BRAF wild-type melanoma who received 36 weeks of RG7212 therapy had tumor regression and pharmacodynamic changes consistent with antitumor effects. Fifteen patients (28%) received 16 or more weeks of RG7212 treatment.Conclusion: RG7212 demonstrated excellent tolerability and favorable pharmacokinetics. Pharmacodynamic endpoints were consistent with reduced TWEAK:Fn14 signaling. Tumor regression was observed and prolonged stable disease was demonstrated in multiple heavily pretreated patients with solid tumors. These encouraging results support further study of RG7212. Clin Cancer Res; 21(2); 258-66. Ó2014 AACR.

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TWEAK/Fn14 Activation Participates in Skin Inflammation

Liu

Xiao

Xia

2017

Mediators of Inflammation

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Tumor necrosis factor- (TNF-) like weak inducer of apoptosis (TWEAK) participates in multiple biological activities via binding to its sole receptor—fibroblast growth factor-inducible 14 (Fn14). The TWEAK/Fn14 signaling pathway is activated in skin inflammation and modulates the inflammatory responses of keratinocytes by activating nuclear factor-κB signals and enhancing the production of several cytokines, including interleukins, monocyte chemotactic protein-1, RANTES (regulated on activation, normal T cell expressed and secreted), and interferon gamma-induced protein 10. Mild or transient TWEAK/Fn14 activation contributes to tissular repair and regeneration while excessive or persistent TWEAK/Fn14 signals may lead to severe inflammatory infiltration and tissue damage. TWEAK also regulates cell fate of keratinocytes, involving the function of Fn14-TNF receptor-associated factor-TNF receptor axis. By recruiting inflammatory cells, promoting cytokine production, and regulating cell fate, TWEAK/Fn14 activation plays a pivotal role in the pathogenesis of various skin disorders, such as psoriasis, atopic dermatitis, cutaneous vasculitis, human papillomavirus infection and related skin tumors, and cutaneous autoimmune diseases. Therefore, the TWEAK/Fn14 pathway may be a potential target for the development of novel therapeutics for skin inflammatory diseases.

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29 A First-in-Human Phase I Monotherapy Study of RG7212 (R), a Novel Monoclonal Antibody Targeting TWEAK Signaling in Patients with Advanced Solid Tumors

Cited by 5 publications

References 0 publications

RG7212 Anti-TWEAK mAb Inhibits Tumor Growth through Inhibition of Tumor Cell Proliferation and Survival Signaling and by Enhancing the Host Antitumor Immune Response

RG7212 Anti-TWEAK mAb Inhibits Tumor Growth through Inhibition of Tumor Cell Proliferation and Survival Signaling and by Enhancing the Host Antitumor Immune Response

A Phase I Monotherapy Study of RG7212, a First-in-Class Monoclonal Antibody Targeting TWEAK Signaling in Patients with Advanced Cancers

TWEAK/Fn14 Activation Participates in Skin Inflammation

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