title: New strategy for the extension of the serum half-life of antibody fragments.
abstract: Antibody fragments can recognize their cognate antigen with high affinity and can be produced at high yields, but generally display rapid blood clearance profiles. For pharmaceutical applications, the serum half-life of antibody fragments is often extended by chemical modification with polymers or by genetic fusion to albumin or albumin-binding polypeptides. Here, we report that the site-specific chemical modification of a C-terminal cysteine residue in scFv antibody fragments with a small organic molecule capable of high-affinity binding to serum albumin substantially extends serum half-life in rodents. The strategy was implemented using the antibody fragment F8, specific to the alternatively spliced EDA domain of fibronectin, a tumor-associated antigen. The unmodified and chemically modified scFv-F8 antibody fragments were studied by biodistribution analysis in tumor-bearing mice, exhibiting a dramatic increase in tumor uptake for the albumin-binding antibody derivative. The data presented in this paper indicate that the chemical modification of the antibody fragment with the 2-(3-maleimidopropanamido)-6-(4-(4-iodophenyl)butanamido)hexanoate albumin-binding moiety may represent a general strategy for the extension of the serum half-life of antibody fragments and for the improvement of their in vivo targeting performance.
authors.affiliation: Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, and Philochem AG, ETH Zurich, Wolfgang-Pauli-Str. 10, CH-8093 Zurich, Switzerland.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Trüssel
authors.forename: Christoph
authors.initials: C
authors.lastname: Dumelin
authors.forename: Katharina
authors.initials: K
authors.lastname: Frey
authors.forename: Alessandra
authors.initials: A
authors.lastname: Villa
authors.forename: Fabian
authors.initials: F
authors.lastname: Buller
authors.forename: Dario
authors.initials: D
authors.lastname: Neri
mesh_terms: D000818:Animals; D000915:Antibody Affinity; D003001:Cloning, Molecular; D005260:Female; D006207:Half-Life; D007128:Immunoglobulin Fragments / Q000737:chemistry* / Q000302:isolation & purification / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D009374:Neoplasms, Experimental; D012709:Serum Albumin / Q000737:chemistry*; D014018:Tissue Distribution
chemical_list: D007128:Immunoglobulin Fragments; D012709:Serum Albumin