Anti-tumor effect of CT-322 as an Adnectin inhibitor of vascular endothelial growth factor receptor-2

Mamluk, Roni; Carvajal, Irvith M.; Morse, Brent; Wong, Henry K.; Abramowitz, Janette; Aslanian, Sharon; Lim, Ai-Ching; Gokemeijer, Jochem; Storek, Michael; Lee, Joonsoo; Gosselin, Michael; Wright, Martin C.; Camphausen, Raymond T.; Wang, Jack; Chen, Yan; Miller, Kathy D.; Sanders, Kerry L.; Short, Sarah M.; Sperinde, Jeff; Prasad, G.; Williams, Stephen J.; Kerbel, Robert S.; Ebos, John M.L.; Mutsaers, Anthony J.; Mendlein, John; Harris, Alice C.; Furfine, Eric S.

doi:10.4161/mabs.2.2.11304

Cited by 68 publications

(69 citation statements)

References 38 publications

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“…Adnectins are genetically engineered variants of human fibronectin designed by redirecting the binding characteristics of fibronectin to specific disease targets, such as receptors, ligands, or proteins, while leaving the fibronectin backbone intact. CT-322 selectively binds and inhibits human, monkey, and rodent VEGFR-2 and has preclinical antitumor activity (1). The fibronectin-based protein moiety of CT-322 is linked to a 40-kDa branched polyethylene glycol (PEG) moiety to enhance drug exposure.…”

Section: Introductionmentioning

confidence: 99%

Phase I and Pharmacokinetic Study of CT-322 (BMS-844203), a Targeted Adnectin Inhibitor of VEGFR-2 Based on a Domain of Human Fibronectin

Tolcher

Sweeney

Papadopoulos

et al. 2011

Clinical Cancer Research

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Purpose: To determine the maximum tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics, immunogenicity, and preliminary antitumor activity of CT-322 (BMS-844203), a VEGFR-2 inhibitor and the first human fibronectin domain-based targeted biologic (Adnectin) to enter clinical studies.Experimental Design: Patients with advanced solid malignancies were treated with escalating doses of CT-322 intravenously (i.v.) weekly (qw), or biweekly (q2w). Plasma samples were assayed for CT-322 concentrations, plasma VEGF-A concentrations, and antidrug antibodies.Results: Thirty-nine patients completed 105 cycles of 0.1 to 3.0 mg/kg CT-322 i.v. either qw or q2w. The most common treatment-emergent grade 1/2 toxicities were fatigue, nausea, proteinuria, vomiting, anorexia, and hypertension. Grade 3/4 toxicities were rare. Reversible proteinuria, retinal artery, and vein thrombosis, left ventricular dysfunction, and reversible posterior leukoencephalopathy syndrome were dose limiting at 3.0 mg/kg. The MTD was 2 mg/kg qw or q2w. CT-322 plasma concentrations increased dose proportionally. Plasma VEGF-A levels increased with dose and plateaued at 2 mg/kg qw. Anti-CT-322 antibodies developed without effects on pharmacokinetics, VEGF-A levels, or safety. Minor decreases in tumor measurements occurred in 4 of 34 evaluable patients and 24 patients had stable disease.Conclusions: CT-322 can be safely administered at 2 mg/kg i.v. qw or q2w and exhibits promising antitumor activity in patients with advanced solid tumors. The absence of severe toxicities at the MTD, demonstration of plasma drug concentrations active in preclinical models, and clinical pharmacodynamic evidence of VEGFR-2 inhibition warrant further development of CT-322 and suggest strong potential for Adnectin-based targeted biologics.

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Section: Introductionmentioning

confidence: 99%

Phase I and Pharmacokinetic Study of CT-322 (BMS-844203), a Targeted Adnectin Inhibitor of VEGFR-2 Based on a Domain of Human Fibronectin

Tolcher

Sweeney

Papadopoulos

et al. 2011

Clinical Cancer Research

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“…10,11 The first Adnectin tested in a clinical trial, CT-322, targets vascular endothelial growth factor-2 (VEGFR-2). 12 Phase I studies on CT-322 showed that it was well tolerated and produced pharmacological effects expected from the inhibition of the VEGFR-2 pathway. 13 The first example of a bispecific Adnectin, which targets cell signaling through EGFR and IGF-IR, is described here.…”

Section: Introductionmentioning

confidence: 99%

A fibronectin scaffold approach to bispecific inhibitors of epidermal growth factor receptor and insulin-like growth factor-I receptor

Emanuel

Engle

Chao

et al. 2011

mAbs

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“…Adnectins are pharmaceutically highly-suited to their therapeutic disease target and can be designed for receptors, ligands or proteins with a high nanomolar or picomolar affinity, potency and specificity by varying the amino acid sequence of three clustered targeting loops (14). The PEGylated Adnectin CT-322 binds and blocks the activity of VEGFR-2, a key player in tumor angiogenesis, resulting in reduced endothelial cell function, as determined preclinically in vitro and in vivo (15)(16)(17)(18). This therapeutic approach differs from that of other antiangiogenic drugs (e.g., sorafenib and sunitinib) in terms of its selectivity on this specific VEGFR2-pathway (17,18).…”

Section: Introductionmentioning

confidence: 99%

“…The PEGylated Adnectin CT-322 binds and blocks the activity of VEGFR-2, a key player in tumor angiogenesis, resulting in reduced endothelial cell function, as determined preclinically in vitro and in vivo (15)(16)(17)(18). This therapeutic approach differs from that of other antiangiogenic drugs (e.g., sorafenib and sunitinib) in terms of its selectivity on this specific VEGFR2-pathway (17,18).…”

Section: Introductionmentioning

confidence: 99%

Adnectin CT-322 inhibits tumor growth and affects microvascular architecture and function in Colo205 tumor xenografts

Ackermann

Carvajal²,

Morse³

et al. 2010

Int J Oncol

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Abstract. Antiangiogenesis has become a promising pillar in modern cancer therapy. This study investigates the antiangiogenic effects of the PEGylated Adnectin™, CT-322, in a murine Colo-205 xenograft tumor model. CT-322 specifically binds to and blocks vascular endothelial growth factor receptor (VEGFR-2). Adnectins are a novel class of targeted biologics engineered from the 10th domain of human fibronectin. CT-322 treated tumors exhibited a significant reduction in tumor growth of 69%, a 2.8 times lower tumor surface area and fewer necrotic areas. Control tumors showed a 2.36-fold higher microvessel density (MVD) and a 2.42 times higher vessel volume in corrosion casts. The vascular architecture in CT-322-treated tumors was characterized by a strong normalization of vasculature. This was quantified in corrosion casts of CT-322 treated tumors in which the intervascular distance (a reciprocal parameter indicative of vessel density) and the distance between two consecutive branchings were assessed, with these distances being 2.21 times and 2.37 times greater than in controls, respectively. Fluorescence molecular tomography (FMT) equally affirmed the inhibitory effects of CT-322 on tumor vasculature as indicated by a 60% reduction of the vascular probe, AngioSense, accumulating in tumor tissue, as a measurement of vascular permeability. Moreover, AngioSense accumulation was reduced as early as 24 h after starting treatment. The sum of these effects on tumor vasculature illustrates the anti-angiogenic mechanism underlying the antitumor activity of CT-322 and provides support for further evaluation of this Adnectin in combinatorial strategies with standard of care therapies. IntroductionAngiogenesis is one of the growth-influencing steps for numerous pathologic processes, in particular for tumor growth (1). Tumorigenesis and tumor progression depend on an 'angiogenic switch' whereby the tumor initiates recruitment of its own blood supply, a process which occurs at different stages of tumor progression pathways, depending on the tumor type and tumor microenvironment (2).Tumor blood vessels differ both in architecture and structure from their normal physiological counterparts. Tumor vessel systems are characterized by a lack of normal hierarchy, poor vessel wall construction without medial layers, missing differentiation into structurally established arteries and veins, tortuous courses with dead ends, and irregular, dilated sinusoidal vessel diameters (3,4). These differences in morphological features of tumor vasculature may be related to a deficiency in pericyte function and an abnormal expression of angiogenic molecules (5,6).The importance of the inhibition of angiogenesis as a component of therapeutic oncology concepts is increasing. Antiangiogenic agents may be used not only for the treatment, but also for the prevention of tumor recurrence or metastasis (7). Currently, numerous VEGF pathways blocker groups such as antibodies, small molecules, siRNAs and traps are in clinical development or already commercially...

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Anti-tumor effect of CT-322 as an Adnectin inhibitor of vascular endothelial growth factor receptor-2

Cited by 68 publications

References 38 publications

Phase I and Pharmacokinetic Study of CT-322 (BMS-844203), a Targeted Adnectin Inhibitor of VEGFR-2 Based on a Domain of Human Fibronectin

Phase I and Pharmacokinetic Study of CT-322 (BMS-844203), a Targeted Adnectin Inhibitor of VEGFR-2 Based on a Domain of Human Fibronectin

A fibronectin scaffold approach to bispecific inhibitors of epidermal growth factor receptor and insulin-like growth factor-I receptor

Adnectin CT-322 inhibits tumor growth and affects microvascular architecture and function in Colo205 tumor xenografts

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