title: Synthesis and evaluation of multivalent branched HPMA copolymer-Fab' conjugates targeted to the B-cell antigen CD20.
abstract: Several drug delivery designs combine synthetic drug carriers with covalently conjugated targeting moieties. Such modifications of monoclonal antibodies (mAb), or their Fab' fragments, inevitably result in diminished affinity for their targeted tissue. In an attempt to overcome this limitation, high molecular weight, branched N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers were synthesized and conjugated with Fab' fragments of the anti-CD20 antibody, 1F5. This produced multivalent conjugates with varying valency (amount of Fab' per macromolecule) targeted to the B-cell antigen CD20. Evaluation of a multivalent effect was done by determining the apparent K(D) at low concentrations of conjugates, the Sips heterogeneity factor, a, and the binding enhancement factors of each construct. The results clearly indicated that multivalency could improve the affinity of the HPMA copolymer-Fab' conjugates to that of unconjugated mAb.
authors.affiliation: Departments of Bioengineering, and Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, Utah 84112, USA.
authors.forename: Russell N
authors.initials: RN
authors.lastname: Johnson
authors.forename: Pavla
authors.initials: P
authors.lastname: Kopecková
authors.forename: Jindrich
authors.initials: J
authors.lastname: Kopecek
mesh_terms: D000178:Acrylamides / Q000737:chemistry*; D000911:Antibodies, Monoclonal / Q000737:chemistry; D018951:Antigens, CD20 / Q000378:metabolism*; D016503:Drug Delivery Systems / Q000379:methods*; D015195:Drug Design; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry*; D011485:Protein Binding
chemical_list: D000178:Acrylamides; D000911:Antibodies, Monoclonal; D018951:Antigens, CD20; D007140:Immunoglobulin Fab Fragments; C032976:N-(2-hydroxypropyl)methacrylamide