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Rapid Infarct Imaging with a Technetium-99m-Labeled Antimyosin Recombinant Single-Chain Fv: Evaluation in a Canine Model of Acute Myocardial Infarction

Research and Development Division of Centocor, Inc., Malvern, Pennsylvania
Creative Biomolecules, Hopkinton, Massachusetts

Correspondence: For reprints or correspondence contact: Mark A. Nedelman, MS, Centocor, Inc., 200 Great Valley Parkway, Malvern, PA 19355.

ABSTRACT

Studies of monoclonal antibody-based imaging agents show that blood clearance is inversely proportional to molecular size, i.e., Fab or Fab' > F(ab')₂ > IgG. Indium-111-antimyosin Fab-DTPA is a highly specific and sensitive marker for myocardial necrosis. An improvement on current antibody diagnostic imaging may result from the use of smaller labeled fragments. We report the first in vivo targeting of acute myocardial infarction with a novel recombinant single-chain Fv (sFv) antimyosin protein. The sFv (MW = 27,594) is approximately one-half the size of the Fab and is comprised of the heavy and light chain variable regions from the myosin-specific murine monoclonal antibody R11D10 which were joined by a 15-amino-add linker and expressed as a fusion protein (sFv) in E. coli. The binding affinity of the sFv for cardiac myosin was similar to the affinity observed for the Fab fragment. Technetium-99m labeling of the sFv was accomplished by the attachment of a cleavable, ester-linked bifunctional chelator (RP-1). Comparative studies in mice showed ^99mTc-sFv-RP-1 cleared significantly faster (p < 0.001) than ^99mTc-Fab'-RP-1 and ¹¹¹In-Fab-DTPA antimyosin fragments. Furthermore, measurement of ^99mTc-sFv-RP-1 blood clearance in a canine model of acute myocardial infarction gave a mean T_1/2 of 0.54 ± 0.13 hr versus 2.80 ± 0.57 and 2.58 ± 0.64 hr for Fab-DTPA and Fab'-RP-1 (p < 0.05), respectively. Despite its comparatively rapid clearance, ^99mTc sFv-RP-1 had similar uptake in the infarct compared to the Fab'-RP-1. In addition, infarct visualization was more rapid with the sFv. Thus, these data demonstrate antimyosin sFv possesses characteristics necessary for rapid imaging of myocardial necrosis.