Differential tumor-targeting abilities of three single-domain antibody formats.
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.
Bell
Andrea
A
Institute for Biological Sciences, National Research Council of Canada, 100 Sussex Drive, Ottawa, ON, Canada K1A 0R6.
Wang
Zheng J
ZJ
Arbabi-Ghahroudi
Mehdi
M
Chang
Tingtung A
TA
Durocher
Yves
Y
Trojahn
Ulrike
U
Baardsnes
Jason
J
Jaramillo
Maria L
ML
Li
Shenghua
S
Baral
Toya N
TN
O'Connor-McCourt
Maureen
M
Mackenzie
Roger
R
Zhang
Jianbing
J
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
D007128:Immunoglobulin Fragments; D066246:ErbB Receptors