This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Dennis, M. S. Articles by Schwall, R. Search for Related Content PubMed PubMed Citation Articles by Dennis, M. S. Articles by Schwall, R.

Imaging Tumors with an Albumin-Binding Fab, a Novel Tumor-Targeting Agent

Departments of ¹ Antibody Engineering, ² Translational Oncology, and ³ Biomedical Imaging, Genentech, Inc., South San Francisco, California

Requests for reprints: Mark S. Dennis, Antibody Engineering Department, Genentech, Inc., 1 DNA Way, MS27, South San Francisco, CA 94080. Phone: 650-225-1162; Fax: 650-225-3734; E-mail: msd{at}gene.com.

Association with albumin as a means to improve biodistribution and tumor deposition of a Fab was investigated using AB.Fab4D5, a bifunctional molecule derived from trastuzumab (HERCEPTIN) capable of binding albumin and tumor antigen HER2 (erbB2) simultaneously. AB.Fab4D5 was compared with trastuzumab and a trastuzumab-derived Fab (Fab4D5) for the ability to target tumors overexpressing HER2 in mouse mammary tumor virus/HER2 allograft models. Biodistribution was monitored using intravital microscopy, histology, and integrated single-photon emission computed tomography/computed tomography analysis. Fab4D5 tumor deposition was characterized by rapid but transient appearance in tumor at 2 h with little retention, followed by rapid accumulation in kidney by 6 h. Trastuzumab was slow to accumulate in tumors and slow to clear from normal tissues, although significant tumor deposition was achieved by 24 h. In contrast, AB.Fab4D5 was observed at 2 h in tumor and its presence was sustained beyond 24 h similar to trastuzumab. Intravital microscopy revealed that at peak tumor accumulation, tumor cell staining by AB.Fab4D5 was more uniform than for Fab4D5 or trastuzumab. Similar tumor deposition was achieved for both AB.Fab4D5 and trastuzumab at 48 h (35.9 ± 1.8% and 38.2 ± 3.1% injected dose/g); however, AB.Fab4D5 targeted tumors more rapidly and quickly cleared from blood, leading to a lower overall normal tissue exposure. Importantly, unlike Fab4D5, AB.Fab4D5 did not accumulate in kidney, suggesting that association with albumin leads to an altered route of clearance and metabolism. Rapid targeting, excellent tumor deposition and retention, coupled with high tumor to blood ratios may make AB.Fab an exceptional molecule for imaging and cancer therapy. [Cancer Res 2007;67(1):254–61]

This article has been cited by other articles:

				A. Jonsson, J. Dogan, N. Herne, L. Abrahmsen, and P.-A. Nygren Engineering of a femtomolar affinity binding protein to human serum albumin Protein Eng. Des. Sel., August 1, 2008; 21(8): 515 - 527. [Abstract] [Full Text] [PDF]

				B. M. Tijink, T. Laeremans, M. Budde, M. S.-v. Walsum, T. Dreier, H. J. de Haard, C. R. Leemans, and G. A.M.S. van Dongen Improved tumor targeting of anti-epidermal growth factor receptor Nanobodies through albumin binding: taking advantage of modular Nanobody technology Mol. Cancer Ther., August 1, 2008; 7(8): 2288 - 2297. [Abstract] [Full Text] [PDF]

				M. E. Ackerman, D. Pawlowski, and K. D. Wittrup Effect of antigen turnover rate and expression level on antibody penetration into tumor spheroids Mol. Cancer Ther., July 1, 2008; 7(7): 2233 - 2240. [Abstract] [Full Text] [PDF]

				S. B. Lee, M. Hassan, R. Fisher, O. Chertov, V. Chernomordik, G. Kramer-Marek, A. Gandjbakhche, and J. Capala Affibody Molecules for In vivo Characterization of HER2-Positive Tumors by Near-Infrared Imaging Clin. Cancer Res., June 15, 2008; 14(12): 3840 - 3849. [Abstract] [Full Text] [PDF]

				H. Jin, R. Yang, Z. Zheng, M. Romero, J. Ross, H. Bou-Reslan, R. A.D. Carano, I. Kasman, E. Mai, J. Young, et al. MetMAb, the One-Armed 5D5 Anti-c-Met Antibody, Inhibits Orthotopic Pancreatic Tumor Growth and Improves Survival Cancer Res., June 1, 2008; 68(11): 4360 - 4368. [Abstract] [Full Text] [PDF]

				J. H.E. Baker, K. E. Lindquist, L. A. Huxham, A. H. Kyle, J. T. Sy, and A. I. Minchinton Direct Visualization of Heterogeneous Extravascular Distribution of Trastuzumab in Human Epidermal Growth Factor Receptor Type 2 Overexpressing Xenografts Clin. Cancer Res., April 1, 2008; 14(7): 2171 - 2179. [Abstract] [Full Text] [PDF]

				R. Stork, K. A. Zettlitz, D. Muller, M. Rether, F.-G. Hanisch, and R. E. Kontermann N-Glycosylation as Novel Strategy to Improve Pharmacokinetic Properties of Bispecific Single-chain Diabodies J. Biol. Chem., March 21, 2008; 283(12): 7804 - 7812. [Abstract] [Full Text] [PDF]

				R. Stork, D. Muller, and R. E. Kontermann A novel tri-functional antibody fusion protein with improved pharmacokinetic properties generated by fusing a bispecific single-chain diabody with an albumin-binding domain from streptococcal protein G Protein Eng. Des. Sel., November 3, 2007; (2007) gzm061v1. [Abstract] [Full Text] [PDF]

				L. Sampath, S. Kwon, S. Ke, W. Wang, R. Schiff, M. E. Mawad, and E. M. Sevick-Muraca Dual-Labeled Trastuzumab-Based Imaging Agent for the Detection of Human Epidermal Growth Factor Receptor 2 Overexpression in Breast Cancer J. Nucl. Med., September 1, 2007; 48(9): 1501 - 1510. [Abstract] [Full Text] [PDF]