title: Imaging tumors with an albumin-binding Fab, a novel tumor-targeting agent.
abstract: 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.
authors.affiliation: Department of Antibody Engineering, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080, USA. msd@gene.com
authors.forename: Mark S
authors.initials: MS
authors.lastname: Dennis
authors.forename: Hongkui
authors.initials: H
authors.lastname: Jin
authors.forename: Debra
authors.initials: D
authors.lastname: Dugger
authors.forename: Renhui
authors.initials: R
authors.lastname: Yang
authors.forename: Leanne
authors.initials: L
authors.lastname: McFarland
authors.forename: Annie
authors.initials: A
authors.lastname: Ogasawara
authors.forename: Simon
authors.initials: S
authors.lastname: Williams
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Cole
authors.forename: Sarajane
authors.initials: S
authors.lastname: Ross
authors.forename: Ralph
authors.initials: R
authors.lastname: Schwall
mesh_terms: D000418:Albumins / Q000737:chemistry / Q000493:pharmacokinetics*; D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000493:pharmacokinetics*; D061067:Antibodies, Monoclonal, Humanized; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted; D018796:Immunoconjugates / Q000737:chemistry / Q000493:pharmacokinetics*; D007128:Immunoglobulin Fragments / Q000737:chemistry / Q000378:metabolism*; D008325:Mammary Neoplasms, Experimental / Q000000981:diagnostic imaging / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D011877:Radionuclide Imaging; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis / Q000378:metabolism; D000068878:Trastuzumab
chemical_list: D000418:Albumins; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018796:Immunoconjugates; D007128:Immunoglobulin Fragments; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab