Chemically optimized antimyosin Fab conjugates with chelating polymers: importance of the nature of the protein-polymer single site covalent bond for biodistribution and infarction localization.
Murine antimyosin Fab fragment was conjugated with 111In-labeled N-terminal-modified DTPA-polylysine using three bifunctional reagents: N-hydroxysuccinimide esters of 3-(2-pyridyldithio)propionic acid (SPDP conjugate), 4-(maleimidomethyl)cyclohexanecarboxylic acid (SMCC conjugate) and bromoacetic acid (BrAc conjugate) for potential localization of experimental myocardial infarction. Using various antibody preparations and a rabbit acute myocardial infarction model the following parameters were observed: (1) an in vitro antigen binding activity of SPDP conjugate = SMCC conjugate > BrAc conjugate, (2) a blood clearance rate of SPDP conjugate > BrAc conjugate > SMCC conjugate, (3) a liver and splenic accumulation of SPDP conjugate > BrAc conjugate > SMCC conjugate, and (4) the infarcted tissue activity showed an accumulation of SMCC conjugate > SPDP conjugate > BrAc conjugate. This study exemplifies the importance of rational chemical design of antimyosin Fab-chelating polymer conjugate for improved target tissue localization in vivo.
Trubetskoy
V S
VS
Center for Imaging and Pharmaceutical Research, Massachusetts General Hospital, Charlestown 02129.
Narula
J
J
Khaw
B A
BA
Torchilin
V P
VP
D000818:Animals; D000911:Antibodies, Monoclonal / Q000097:blood / Q000737:chemistry*; D000918:Antibody Specificity; D000937:Antigen-Antibody Reactions; D002614:Chelating Agents / Q000737:chemistry; D003432:Cross-Linking Reagents / Q000737:chemistry; D007140:Immunoglobulin Fab Fragments / Q000097:blood / Q000737:chemistry*; D007205:Indium Radioisotopes / Q000097:blood; D008657:Metabolic Clearance Rate; D051379:Mice; D009203:Myocardial Infarction / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism; D009218:Myosins / Q000276:immunology*; D004369:Pentetic Acid / Q000737:chemistry; D011107:Polylysine / Q000097:blood / Q000737:chemistry; D011817:Rabbits; D014018:Tissue Distribution
D000911:Antibodies, Monoclonal; D002614:Chelating Agents; D003432:Cross-Linking Reagents; D007140:Immunoglobulin Fab Fragments; D007205:Indium Radioisotopes; D011107:Polylysine; D004369:Pentetic Acid; D009218:Myosins