Targeting arterial wall sulfated glycosaminoglycans in rabbit atherosclerosis with a mouse/human chimeric antibody

Abstract

The progression of atherosclerosis is favored by increasing amounts of chondroitin sulfate proteoglycans in the artery wall. We previously reported the reactivity of chP3R99 monoclonal antibody (mAb) with sulfated glycosaminoglycans and its association with the anti-atherogenic properties displayed. Now, we evaluated the accumulation of this mAb in atherosclerotic lesions and its potential use as a probe for specific in vivo detection of the disease. Atherosclerosis was induced in NZW rabbits (n D 14) by the administration of Lipofundin 20% using PBSreceiving animals as control (n D 8). Accumulation of chP3R99 mAb in atherosclerotic lesions was assessed either by immunofluorescence detection of human IgG in fresh-frozen sections of aorta, or by immunoscintigraphy followed by biodistribution of the radiotracer upon administration of 99m Tc-chP3R99 mAb. Immunofluorescence studies revealed the presence of chP3R99 mAb in atherosclerotic lesions 24 h after intravenous administration, whereas planar images showed an evident accumulation of 99m Tc-chP3R99 mAb in atherosclerotic rabbit carotids. Accordingly, 99m Tc-chP3R99 mAb uptake by lesioned aortic arch and thoracic segment was increased 5.6-fold over controls and it was 3.9-folds higher in carotids, in agreement with immunoscintigrams. Moreover, the deposition of 99m Tc-chP3R99 mAb in the artery wall was associated both with the presence and size of the lesions in the different portions of evaluated arteries and was greater than in non-targeted organs. In conclusion, chP3R99 mAb preferentially accumulates in arterial atherosclerotic lesions supporting the potential use of this anti-glycosaminoglycans antibody for diagnosis and treatment of atherosclerosis.

Phase I trial of anti-GD2 monoclonal antibody hu3F8 plus GM-CSF: Impact of body weight, immunogenicity and anti-GD2 response on pharmacokinetics and survival

“…28 In a rabbit and an apoE ¡/¡ mouse model, an affinity enhanced P3 antibody with the ability to inhibit LDL-chondrotin sulfate association, induced an active anti-chondroitin sulfate antibody response, preventing the formation of, and arresting the progression of atherosclerosis. [29][30][31] In our patients, the ability to mount a spontaneous anti-GD2 response was negatively influenced by the HAHA response but not by hu3F8 dosage level. Patients with positive HAHA (resulting in fewer treatment cycles received) had anti-GD2 response below the median.…”

Recent Advances of Radionuclide-Based Molecular Imaging of Atherosclerosis

“…Thus, an antibody-based tracer of 99m Tc-chP3R99 mAb targeting chondroitin sulfate was developed for atherosclerosis imaging in a lipofundin-induced New Zealand White (NZW) rabbit atherosclerotic model using immunoscintigram planar imaging (fig. 2C) [42]. Compared to non-atherosclerotic rabbits, the uptake of 99m Tc-chP3R99 mAb at the atherosclerotic lesion was 3.9 fold higher.…”

“…(C) Noninvasive planar images with injection of 99m Tc-chP3R99 mAb by atherosclerotic (left image) and healthy (center image) rabbits, demonstrating the accumulation in the carotid indicated by arrowheads, compared to the injection of control radiotracer 99m Tc-chT3 mAb (right image). Modified with permission [39, 41, 42]. …”

Endothelial Glycocalyx as Biomarker for Cardiovascular Diseases: Mechanistic and Clinical Implications

“…The concentration of hyaluronic acid, a minor constituent, showed a negative gradient from normal areas to atheromatous areas in the human aorta, with its biological function being a negative regulator on vascular smooth muscle cell (VSMC) proliferation and a positive regulator of the migration [39]. One study reported that the progression of atherosclerosis was favored by an increase in chondroitin sulfate in the arterial walls [40], while another reported that serum soluble sdc1 was significantly elevated in patients with acute coronary syndrome, suggesting a contributory effect of eGC damage to atherosclerotic plaque vulnerability [41]. …”