title: Differential tumor-targeting abilities of three single-domain antibody formats.
abstract: The large molecular size of antibody drugs is considered one major factor preventing them from becoming more efficient therapeutics. Variable regions of heavy chain antibodies (HCAbs), or single-domain antibodies (sdAbs), are ideal building blocks for smaller antibodies due to their molecular size and enhanced stability. In the search for better antibody formats for in vivo imaging and/or therapy of cancer, three types of sdAb-based molecules directed against epidermal growth factor receptor (EGFR) were constructed, characterized and tested. Eleven sdAbs were isolated from a phage display library constructed from the sdAb repertoire of a llama immunized with a variant of EGFR. A pentameric sdAb, or pentabody, V2C-EG2 was constructed by fusing one of the sdAbs, EG2, to a pentamerization protein domain. A chimeric HCAb (cHCAb), EG2-hFc, was constructed by fusing EG2 to the fragment crystallizable (Fc) of human IgG1. Whereas EG2 and V2C-EG2 localized mainly in the kidneys after i.v. injection, EG2-hFc exhibited excellent tumor accumulation, and this was largely attributed to its long serum half life, which is comparable to that of IgGs. The moderate size (approximately 80 kDa) and intact human Fc make HCAbs a unique antibody format which may outperform whole IgGs as imaging and therapeutic reagents.
authors.affiliation: Institute for Biological Sciences, National Research Council of Canada, 100 Sussex Drive, Ottawa, ON, Canada K1A 0R6.
authors.forename: Andrea
authors.initials: A
authors.lastname: Bell
authors.forename: Zheng J
authors.initials: ZJ
authors.lastname: Wang
authors.forename: Mehdi
authors.initials: M
authors.lastname: Arbabi-Ghahroudi
authors.forename: Tingtung A
authors.initials: TA
authors.lastname: Chang
authors.forename: Yves
authors.initials: Y
authors.lastname: Durocher
authors.forename: Ulrike
authors.initials: U
authors.lastname: Trojahn
authors.forename: Jason
authors.initials: J
authors.lastname: Baardsnes
authors.forename: Maria L
authors.initials: ML
authors.lastname: Jaramillo
authors.forename: Shenghua
authors.initials: S
authors.lastname: Li
authors.forename: Toya N
authors.initials: TN
authors.lastname: Baral
authors.forename: Maureen
authors.initials: M
authors.lastname: O'Connor-McCourt
authors.forename: Roger
authors.initials: R
authors.lastname: Mackenzie
authors.forename: Jianbing
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002161:Camelids, New World; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D066246:ErbB Receptors / Q000187:drug effects* / Q000235:genetics; D005260:Female; D006801:Humans; D007128:Immunoglobulin Fragments / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D010190:Pancreatic Neoplasms / Q000188:drug therapy; D015202:Protein Engineering; D016415:Sequence Alignment
chemical_list: D007128:Immunoglobulin Fragments; D066246:ErbB Receptors