title: 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 = 14) by the administration of Lipofundin 20% using PBS-receiving animals as control (n = 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.
authors.affiliation: a Research and Development Direction, Center of Molecular Immunology , Havana , Cuba.
authors.forename: Yosdel
authors.initials: Y
authors.lastname: Soto
authors.forename: Niurka
authors.initials: N
authors.lastname: Mesa
authors.forename: Yumisley
authors.initials: Y
authors.lastname: Alfonso
authors.forename: Arlenis
authors.initials: A
authors.lastname: Pérez
authors.forename: Fernando
authors.initials: F
authors.lastname: Batlle
authors.forename: Tania
authors.initials: T
authors.lastname: Griñán
authors.forename: Adonis
authors.initials: A
authors.lastname: Pino
authors.forename: Justo
authors.initials: J
authors.lastname: Viera
authors.forename: Milagros
authors.initials: M
authors.lastname: Frómeta
authors.forename: Victor
authors.initials: V
authors.lastname: Brito
authors.forename: Armando
authors.initials: A
authors.lastname: Olivera
authors.forename: Francisco
authors.initials: F
authors.lastname: Zayas
authors.forename: Ana M
authors.initials: AM
authors.lastname: Vázquez
mesh_terms: D061605:Administration, Intravenous; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D050197:Atherosclerosis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D004338:Drug Combinations; D005455:Fluorescent Antibody Technique; D006025:Glycosaminoglycans / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D015609:Organotechnetium Compounds; D010743:Phospholipids; D011817:Rabbits; D016719:Radioimmunodetection / Q000379:methods; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D013012:Sorbitol; D013431:Sulfates / Q000378:metabolism; D013667:Technetium; D013997:Time Factors; D014018:Tissue Distribution
chemical_list: D000911:Antibodies, Monoclonal; D004338:Drug Combinations; D006025:Glycosaminoglycans; D015609:Organotechnetium Compounds; D010743:Phospholipids; D011993:Recombinant Fusion Proteins; D013431:Sulfates; C008288:Lipofundin; D013012:Sorbitol; D013667:Technetium
keywords: % ID/g, percentage of injected dose per gram of tissue; At-R, Atherosclerotic rabbits; CS, chondroitin sulfate; CSPG, chondroitin sulfate proteoglycans; DS, dermatan sulfate; ELISA, enzyme-linked immunoadsorbent assay; GAG, glycosaminoglycan; LDL, low density lipoprotein; NZW rabbits, New Zealand White rabbits; Non At-R, Non atherosclerotic rabbit; PG, proteoglycans; atherosclerosis; glycosaminoglycans; imaging; mAb, monoclonal antibody; monoclonal antibodies; technetium-99m