Homogeneous immunoconjugates for boron neutron-capture therapy: design, synthesis, and preliminary characterization.
The application of immunoprotein-based targeting strategies to the boron neutron-capture therapy of cancer poses an exceptional challenge, because viable boron neutron-capture therapy by this method will require the efficient delivery of 10(3) boron-10 atoms by each antigen-binding protein. Our recent investigations in this area have been focused on the development of efficient methods for the assembly of homogeneous immunoprotein conjugates containing the requisite boron load. In this regard, engineered immunoproteins fitted with unique, exposed cysteine residues provide attractive vehicles for site-specific modification. Additionally, homogeneous oligomeric boron-rich phosphodiesters (oligophosphates) have been identified as promising conjugation reagents. The coupling of two such boron-rich oligophosphates to sulfhydryls introduced to the CH2 domain of a chimeric IgG3 has been demonstrated. The resulting boron-rich immunoconjugates are formed efficiently, are readily purified, and have promising in vitro and in vivo characteristics. Encouragingly, these studies showed subtle differences in the properties of the conjugates derived from the two oligophosphate molecules studied, providing a basis for the application of rational design to future work. Such subtle details would not have been as readily discernible in heterogeneous conjugates, thus validating the rigorous experimental design employed here.
Guan
L
L
Department of Chemistry and Biochemistry, University of California, Los Angeles, CA 90095, USA.
Wims
L A
LA
Kane
R R
RR
Smuckler
M B
MB
Morrison
S L
SL
Hawthorne
M F
MF
D000818:Animals; D001666:Binding Sites, Antibody; D001895:Boron; D016754:Boron Neutron Capture Therapy / Q000379:methods*; D015195:Drug Design; D004912:Erythrocytes; D006461:Hemolysis; D006801:Humans; D007128:Immunoglobulin Fragments / Q000737:chemistry; D007074:Immunoglobulin G / Q000737:chemistry* / Q000378:metabolism; D007162:Immunoproteins / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000627:therapeutic use; D007554:Isotopes; D051379:Mice; D008958:Models, Molecular; D011487:Protein Conformation; D017452:Receptors, IgG / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000493:pharmacokinetics / Q000627:therapeutic use; D012756:Sheep; D014018:Tissue Distribution
D007128:Immunoglobulin Fragments; D007074:Immunoglobulin G; D007162:Immunoproteins; D007554:Isotopes; D017452:Receptors, IgG; D011993:Recombinant Fusion Proteins; D001895:Boron