Tumor targeting of radiometal labeled anti-CEA recombinant T84.66 diabody and T84.66 minibody: Comparison to radioiodinated fragments

Citation
Pj. Yazaki et al., Tumor targeting of radiometal labeled anti-CEA recombinant T84.66 diabody and T84.66 minibody: Comparison to radioiodinated fragments, BIOCONJ CHE, 12(2), 2001, pp. 220-228
Citations number
30
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Chemistry & Analysis
Journal title
BIOCONJUGATE CHEMISTRY
ISSN journal
1043-1802 → ACNP
Volume
12
Issue
2
Year of publication
2001
Pages
220 - 228
Database
ISI
SICI code
1043-1802(200103/04)12:2<220:TTORLA>2.0.ZU;2-6
Abstract
Recombinant antibody fragments offer potential advantages over intact monoc lonal antibodies in the radioimmunoscintigraphy (RIS) of solid tumors. Due to their smaller molecular size, antibody fragments have shown rapid tumor targeting and blood clearance, a more uniform tumor distribution and a lowe r potential to elicit a human immune response. Previously, we have expresse d two genetically engineered antibody fragments, the T84.66 diabody (scFv d imer) and the T84.66 minibody (scFv-C(H)3 dimer), specific to carcinoembryo nic antigen (CEA). When radioiodinated, both antibody fragments exhibited r apid tumor targeting and rapid blood clearance in xenografted mice. To exte nd and optimize their future clinical RIS utility with radiometals, these a ntibody fragments were conjugated with the macrocycle 1,4,7,10-tetraazacycl ododecane N,N',N",N"'-tetraacetic acid (DOTA) and labeled with In-111. Tumo r targeting and biodistribution studies were carried out in athymic mice xe nografted with a human colorectal tumor cell line, LS174T. The [In-111]T84. 66 diabody (55 kDa) exhibited very rapid tumor targeting with 12.5 +/- 0.4% injected dose per gram (% ID g(-1) +/- standard error) at 2 h and reached a maximum of 13.3 +/- 0.9% ID g(-1) at 6 h. However, kidney uptake was obse rved to reached a peak of 183.5 +/- 21.0% ID g(-1) at 6 h, a result similar to that reported by others for other low molecular weight fragments labele d with radiometals. Preadministration of an oral dose of D-lysine resulted in a 59% lowering of the renal accumulation at 6 h, but was accompanied by a 31% reduction of tumor uptake to 9.2 +/- 1.2% ID g(-1). The second recomb inant antibody fragment, the [In-111]T84.66 minibody (80 MDa), displayed ra pid tumor targeting of 14.2 +/- 6.1% ID g(-1) at 2 h, and reached a maximum activity of 24.5 +/- 6.1% ID g(-1) by 12 h. Renal uptake achieved a platea u of 12-13% ID g(-1) which cleared to 7.2% ID g(-1) at 72 h. However, hepat ic uptake was elevated and reached a maximum of 26.0 +/- 1.0% ID g(-1) at 1 2 h in these xenograft-bearing mice. Experiments in nontumor bearing mice s howed a reduction of hepatic activity at 12 h to 16.6 +/- 1.5% ID g(-1), in dicative of an intrinsic hepatic accumulation of the [In-111]DOTA-T84.66 mi nibody or metabolites. While the anti-CEA [In-111]DOTA-T84.66 diabody and T 84.66 minibody retain the rapid tumor targeting properties of the radioiodi nated form, the normal organ accumulation (kidneys and liver, respectively) of the [In-111]DOTA forms appeared problematic for RIS and RIT application s. Development of alternative blocking strategies or new metabolizable chel ates are under investigation to enhance the utility of the radiometal form of these and other promising recombinant antibody fragments.