Anti-human Activin Receptor-like Kinase 1 (ALK1) Antibody Attenuates Bone Morphogenetic Protein 9 (BMP9)-induced ALK1 Signaling and Interferes with Endothelial Cell Sprouting

Meeteren, Laurens A. van; Thorikay, Midory; Bergqvist, Simon; Pardali, Evangelia; Stampino, Corrado Gallo; Hu-Lowe, Dana D.; Goumans, Marie–José; Dijke, Peter ten

doi:10.1074/jbc.m111.338103

Cited by 90 publications

(89 citation statements)

References 38 publications

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“…BMP9 expression in tumors has been proposed as a potential biomarker for selecting patients who might benefit most from such therapy (43). Besides dalantercept, an anti-ALK1 antibody (Pfizer) is undergoing development as a potential antitumor agent (18,44). Also, in clinical development as an antitumor agent is a chimeric antibody (TRACON) capable of neutralizing endoglin (CD105; ref.…”

Section: Discussionmentioning

confidence: 99%

Safety, Pharmacokinetics, Pharmacodynamics, and Antitumor Activity of Dalantercept, an Activin Receptor–like Kinase-1 Ligand Trap, in Patients with Advanced Cancer

Bendell

Gordon

Hurwitz

et al. 2014

Clinical Cancer Research

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Section: Discussionmentioning

confidence: 99%

Safety, Pharmacokinetics, Pharmacodynamics, and Antitumor Activity of Dalantercept, an Activin Receptor–like Kinase-1 Ligand Trap, in Patients with Advanced Cancer

Bendell

Gordon

Hurwitz

et al. 2014

Clinical Cancer Research

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“…Telangiectasia, which is associated with mutations in the ALK-1 gene in patients affected by HHT type 2, was observed in approximately 9% of patients, and considered to be treatment-related in approximately 7%, suggesting target engagement and in vivo inhibition of ALK-1 by PF-03446962 (9)(10)(11). A similar finding of treatment-related telangiectasia has been reported in clinical studies of an ALK-1 receptor fusion protein (dalantercept) and an endoglin-neutralizing antibody (TRC105) in patients with advanced cancer (13)(14)(15)(16).…”

Section: Discussionmentioning

confidence: 99%

“…Blood samples were collected for PK assessments on days 1, 3,5,8,11,15, and 22 of the first cycle, and on day 1 of the following cycles, until cycle 12. Patient samples were assayed for PF-03446962 serum concentrations (QPS LLC) using a validated chemiluminescence enzyme-linked immunosorbent assay.…”

Section: Assessmentsmentioning

confidence: 99%

“…PF-03446962 demonstrated antiangiogenic activity in human xenograft tumor models (12). It inhibited ALK-1 signaling and endothelial cell sprouting induced by proangiogenic factors, but did not affect VEGF signaling and VEGF-induced proliferation or migration of endothelial cells, thus providing evidence of a novel mechanism to inhibit angiogenesis (11).…”

Section: Introductionmentioning

confidence: 98%

“…It has been shown in preclinical studies to selectively block binding of the ALK-1 ligands BMP-9 and TGFb to ALK-1, and to inhibit recruitment of the coreceptor endoglin into the ALK-1 angiogenesis-signaling complex (10)(11)(12). PF-03446962 demonstrated antiangiogenic activity in human xenograft tumor models (12).…”

Section: Introductionmentioning

confidence: 99%

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A Phase I Study of the Anti-Activin Receptor-Like Kinase 1 (ALK-1) Monoclonal Antibody PF-03446962 in Patients with Advanced Solid Tumors

Goff

Cohen

Berlin

et al. 2016

Clinical Cancer Research

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Purpose: Objectives of this dose-finding study were to determine the MTD and recommended phase II dose (RP2D) of the first-in-class anti-activin receptor-like kinase 1 (ALK-1) monoclonal antibody PF-03446962, and assess safety and antitumor activity in patients with advanced solid tumors.Experimental Design: This open-label, multicenter study was based on a 3þ3 design. PF-03446962 was administered biweekly by intravenous infusion, at doses ranging from 0.5 to 15 mg/kg.Results: Forty-four patients received treatment with PF-03446962. Dose-limiting toxicities observed during dose escalation included grade 3 increased amylase, grade 3/4 increased lipase, and grade 3/4 thrombocytopenia. The MTD was determined to be 10 mg/kg. The RP2D was set at 7 mg/kg for patients with advanced solid tumors, based on the observed safety, pharmacokinetics, and antitumor activity. The most-frequent treatment-related, all-grade adverse events included thrombocytopenia (20.5%), fatigue (15.9%), and nausea, increased amylase, and increased lipase (each 11.4%). Treatment-related telangiectasia was noted in 7% of patients, suggesting in vivo inhibition of the ALK-1 pathway.

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A phase I study of the human anti‐activin receptor‐like kinase 1 antibody PF‐03446962 in Asian patients with advanced solid tumors

et al. 2016

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Preclinical studies suggest that ALK‐1 signaling mediates a complementary angiogenesis pathway activated upon development of resistance to vascular endothelial growth factor (VEGF)‐targeted therapies. Inhibition of ALK‐1 signaling may lead to disruption of tumor angiogenesis and growth. We report findings from a multicenter, open‐label, phase I study of the fully human anti‐ALK‐1 mAb PF‐03446962 conducted in Japan and South Korea, in Asian patients with advanced solid tumors. The dose escalation Part 1 of the study was based on a standard 3 + 3 design (n = 16). In Part 2, patients were treated with PF‐03446962 at 7 and 10 mg/kg (10/cohort), including patients with disease progression following prior VEGF receptor (R)‐targeted therapy. Primary objectives were determination of the maximum tolerated dose (MTD) and recommended phase II dose (RP2D). Secondary objectives included safety, pharmacokinetics, pharmacodynamics, and antitumor activity of PF‐03446962. No dose‐limiting toxicity (DLT) was noted in the 12 DLT‐evaluable patients. Treatment was well tolerated. The MTD for biweekly intravenous administration was estimated to be 10 mg/kg and the RP2D 7 mg/kg. Treatment‐related grades 1–3 thrombocytopenia was experienced by 27.8% patients. The most frequent nonhematologic treatment‐related AEs were grades 1–2 pyrexia and epistaxis. Four patients (3/4 with hepatocellular carcinoma) developed telangiectasia suggesting vascular targeting and in vivo ALK‐1 inhibition by PF‐03446962. Stable disease for 12 weeks or more was observed in 25.7% of patients and in 44.4% of those with hepatocellular carcinoma. ALK‐1 inhibition by PF‐03446962 may represent a novel antiangiogenic strategy for patients with advanced solid malignancies complementary to current treatment with VEGF(R)‐targeted inhibitors or chemotherapy.

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Anti-human Activin Receptor-like Kinase 1 (ALK1) Antibody Attenuates Bone Morphogenetic Protein 9 (BMP9)-induced ALK1 Signaling and Interferes with Endothelial Cell Sprouting

Cited by 90 publications

References 38 publications

Safety, Pharmacokinetics, Pharmacodynamics, and Antitumor Activity of Dalantercept, an Activin Receptor–like Kinase-1 Ligand Trap, in Patients with Advanced Cancer

Safety, Pharmacokinetics, Pharmacodynamics, and Antitumor Activity of Dalantercept, an Activin Receptor–like Kinase-1 Ligand Trap, in Patients with Advanced Cancer

A Phase I Study of the Anti-Activin Receptor-Like Kinase 1 (ALK-1) Monoclonal Antibody PF-03446962 in Patients with Advanced Solid Tumors

A phase I study of the human anti‐activin receptor‐like kinase 1 antibody PF‐03446962 in Asian patients with advanced solid tumors

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