Factors modulating the delivery and effect of enzymatic cargo conjugated with antibodies targeted to the pulmonary endothelium.
Vascular drug targeting may improve therapies, yet a thorough understanding of the factors that regulate effects of drugs directed to the endothelium is needed to translate this approach into the clinical domain. To define factors modulating the efficacy and effects of endothelial targeting, we used a model enzyme (glucose oxidase, GOX) coupled with monoclonal antibodies (anti-TM(34) or anti-TM(201)) to distinct epitopes of thrombomodulin, a surface determinant enriched in the pulmonary endothelium. GOX delivery results in conversion of glucose and oxygen into H(2)O(2) leading to lung damage, a clear physiologic endpoint. Results of in vivo studies in mice showed that the efficiency of cargo delivery and its effect are influenced by a number of factors including: 1) The level of pulmonary uptake of the targeting antibody (anti-TM(201) was more efficient than anti-TM(34)); 2) The amount of an active drug delivered to the target; 3) The amount of target antigen on the endothelium (animals with suppressed TM levels showed less targeting); and, 4) The substrate availability for the enzyme cargo in the target tissue (hyperoxia augmented GOX-induced injury). Therefore, both activities of the conjugates and biological factors control targeting and effects of enzymatic cargo. Understanding the nature of such "modulating biological factors" will hopefully allow optimization and ultimately applications of drug targeting for "individualized" pharmacotherapy.
Shuvaev
Vladimir V
VV
Institute for Environmental Medicine, School of Medicine, University of Pennsylvania Medical Center, 36th Street and Hamilron Walk, Philadelphia, PA 19104, USA.
Christofidou-Solomidou
Melpo
M
Scherpereel
Arnaud
A
Simone
Eric
E
Arguiri
Evguenia
E
Tliba
Samira
S
Pick
Jeremy
J
Kennel
Stephen
S
Albelda
Steven M
SM
Muzykantov
Vladimir R
VR
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism*; D000915:Antibody Affinity; D002626:Chemistry, Pharmaceutical; D004305:Dose-Response Relationship, Drug; D004337:Drug Carriers; D016503:Drug Delivery Systems; D004730:Endothelium, Vascular / Q000276:immunology / Q000378:metabolism*; D004798:Enzymes / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D005947:Glucose / Q000378:metabolism; D005949:Glucose Oxidase / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism; D018496:Hyperoxia / Q000378:metabolism; D007275:Injections, Intravenous; D008168:Lung / Q000098:blood supply* / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008863:Microspheres; D010100:Oxygen / Q000378:metabolism; D011137:Polystyrenes / Q000737:chemistry; D018180:Thrombomodulin / Q000276:immunology / Q000378:metabolism*; D013997:Time Factors
D000911:Antibodies, Monoclonal; D004337:Drug Carriers; D004798:Enzymes; D011137:Polystyrenes; D018180:Thrombomodulin; D006861:Hydrogen Peroxide; D005949:Glucose Oxidase; D005947:Glucose; D010100:Oxygen