Anti-carcinoembryonic antigen (CEA) diabody for rapid tumor targeting and imaging

Wu, AM Williams, LE Zieran, L Padma, A Sherman, M Bebb, GG Odom-Maryon, T Wong, JYC Shively, JE Raubitschek, AA

Am. Wu et al., Anti-carcinoembryonic antigen (CEA) diabody for rapid tumor targeting and imaging, TUMOR TARG, 4(1), 1999, pp. 47-58

49

INGLESE

Article

Medical Research Diagnosis & Treatment

TUMOR TARGETING

1351-8488 → ACNP

4

1

1999

47 - 58

ISI

1351-8488(199904)4:1<47:AA(DFR>2.0.ZU;2-W

Single-chain antibody (scFv) dimers (also known as diabodies) provide a fac ile route for production of engineered fragments with favorable tumor targe ting and biodistribution properties in vivo, A scFv was constructed from th e variable regions of the anti-carcinoembryonic antigen (CEA) monoclonal an tibody T84.66 using a peptide linker of only eight amino acid residues in o rder to prevent formation of scFv monomers and produce dimers (diabodies) e xclusively, The anti-CEA diabody was secreted at high level from E. coil an d was purified by affinity chromatography, The T84.66/GS8 diabody bound ant igen bivalently and retained a high apparent affinity for CEA (K-A = 8.19 x 10(10) M-1) as determined by surface plasmon resonance. Targeting properti es of I-123-labeled T84.66 diabody were evaluated in vivo using athymic mic e bearing LS174T human colorectal carcinoma xenografts. I-123-labeled anti- CPA diabodies exhibited rapid targeting of CPA-positive xenografts, reachin g a maximum uptake level of 13.68 +/- 1.49% injected dose per gram 2 h afte r administration. Rapid blood clearance resulted in high tumor/blood uptake ratios; for example, 9.37 at 6 h and 48.69 at 24 h. Using a gamma camera e quipped with a pinhole collimator, LS174T xenografts of masses 0.12 to 0.48 gm were readily imaged 6 h after injection, Performance of the anti-CPA di abody (bivalent, 55 kDa) was compared with previously described cognate fra gments of T84.66, namely the scFv (28 kDa, monovalent) and minibody (scFv-C (H)3 dimer; bivalent, 80 kDa) by calculation of imaging figures of merit, R esults show that diabodies labeled with short-lived radionuclides such as I -123 Or F-18 Should provide useful rapid clinical imaging agents.