Single-chain Fv radioimmunotargeting.
The availability of engineered antibody species has catalyzed new developments in radioimmunotargeting. This chapter summarized recent studies of single-chain Fv (sFv) proteins, which are minimal antibody binding sites engineered as single polypeptide chains. The single-chain Fv can be as small as 26 kDa monomers or may be engineered as larger fusion proteins designed to self-associate into dimeric or multimeric species. They typically exhibit rapid clearance that results in high targeting specificity within a matter of hours. We have compared different modes of administration to allow further manipulation of their biodistribution and targeting properties. Results of the present study comparing intravenous (i.v.) and intraperitoneal (i.p.) administration show comparable long-term retention in circulation, but the i.v. route showed an initially high peak blood level while i.p. injection did not. As with a single sFv dose, repeated bolus injections of sFv attained high target-to-background ratios, whereas continuous sFv infusion reached a steady state level of free sFv in blood and kidney that exceeded that in tumor xenografts. We observed improved localization of radioiodinated sFv in tumor xenografts if the radioiodine label resisted dehalogenation from the protein, which was accomplished, for example, through conjugation of a para-131I-benzoyl group to Iysyl epsilon-amino groups of the protein. Modification of the sFv by genetic incorporation of a cysteinyl peptide (to form sFv') provided a chelation site for radiometals that simplified incorporation of 99mTc with the opportunity for improved diagnostic imaging in cancer and other diseases. Therapeutic applications of sFv radioimmunotargeting could rely on sFv' complexed to 186Re or 188Re. Engineering sFv of sFv' with increased antigen-binding affinity and appropriately manipulating their mode of administration should promote sustained tumor retention conducive to clinically useful therapeutic indices.
Huston
J S
JS
Creative BioMolecules, Inc., Department of Immunology, Royal Postgraduate Medical School, Hammersmith Hospital, London, United Kingdom.
George
A J
AJ
Adams
G P
GP
Stafford
W F
WF
Jamar
F
F
Tai
M S
MS
McCartney
J E
JE
Oppermann
H
H
Heelan
B T
BT
Peters
A M
AM
Houston
L L
LL
Bookman
M A
MA
Wolf
E J
EJ
Weiner
L M
LM
D000818:Animals; D006801:Humans; D009369:Neoplasms / Q000000981:diagnostic imaging*; D016719:Radioimmunodetection; D013667:Technetium; D014018:Tissue Distribution
D013667:Technetium