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

Abstract

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...

Sphingosine-1-Phosphate as Lung and Cardiac Vasculature Protecting Agent in SARS-CoV-2 Infection

“…The following supporting information can be downloaded at: https:// www.mdpi.com/article/10.3390/ijms241713088/s1. Reference [115] is cited in the supplementary file.…”