Monodispersed DOTA-PEG–Conjugated Anti-TAG-72 Diabody Has Low Kidney Uptake and High Tumor-to-Blood Ratios Resulting in Improved 64Cu PET

Journal of Nuclear Medicine

David Leong¹  Fabio Turatti¹  Paul Sanders¹  Andrew Raubitschek¹  Anne-Line Anderson¹  Lin Li¹  James R. Bading¹  Peter J. Hudson¹  Desiree Crow¹  David Colcher¹  Paul J. Yazaki¹  Lawrence E. Williams¹  Erasmus Poku¹  John E. Shively¹  Debra Tamvakis¹ 

关键词: diabody;    CC49;    TAG-72;    DOTA;    ⁶⁴Cu;    polyethylene glycol;    PET;   

DOI  :  10.2967/jnumed.109.074153

学科分类：医学（综合）

来源: Society of Nuclear Medicine

【 摘 要 】

Diabodies are noncovalent dimers of single-chain antibody fragments that retain the avidity of intact IgG but have more favorable blood clearance than intact IgG. Radiometals offer a wide range of half-lives and emissions for matching imaging and therapy requirements and provide facile labeling of chelate-antibody conjugates. However, because of their high retention and metabolism in the kidney, the use of radiometal-labeled diabodies can be problematic for both imaging and therapy. Methods: Having previously shown that 111In-DOTA-polyethylene glycol (PEG)3400-anti–carcinoembryonic antigen diabody has less than half the kidney uptake and retention of non-PEGylated diabody and that the two have similarly high tumor uptake and retention, we synthesized a similar derivative for an anti–tumor-associated glycoprotein 72 diabody. We also reduced the molecular size of the polydispersed PEG3400 to monodispersed PEG27 and PEG12 (nominal masses of 1,321 and 617, respectively). We performed biodistributions of their DOTA conjugates radiolabeled with 125I, 111In, or 64Cu in tumor-bearing athymic mice. Results: The addition of PEG3400 to the diabody reduced kidney uptake to a level (≈10 percentage injected dose/g) comparable to that obtained with radiometal-labeled intact IgG. The PEG27 and PEG12 diabody conjugates also demonstrated low kidney uptake without reduction of tumor uptake or tumor-to-blood ratios. When radiolabeled with 64Cu, the DOTA-PEG12 and -PEG27 diabody conjugates gave high-contrast PET images of colon cancer xenografts in athymic mice. Conclusion: PEGylated diabodies may be a valuable platform for delivery of radionuclides and other agents to tumors.

【 授权许可】

Unknown