Identification of an antilaminin-1 scFv that preferentially homes to vascular solid tumors.
The tumor vasculature and extracellular matrix make attractive targets for distinguishing solid tumors from normal cells. In solid tumors, the processes of angiogenesis and metastasis potentially give rise to unique epitopes not usually accessible in homeostatic organs. Specific targeting of solid tumors for radioimmunotherapy requires that the targeting agent accumulate rapidly and at high levels at the tumor site. This study involved the selection of scFvs that recognize laminin-1 in vitro from the Tomlinson I and J phage display libraries. Selected, purified scFvs were radioiodinated and injected in tumor-bearing mice. One of these, scFv 15-9, exhibited preferential accumulation at subcutaneous tumors when compared to other antilaminin scFvs or to a control scFv. Autoradiographic analysis indicated that scFv15- 9 also displayed a higher vessel:parenchyma ratio than did two other antilaminin scFvs, scFv 15-6 and scFv 15-1, indicating a preferential accumulation of scFv 15-9 around vessel structures. Immunohistochemistry confirmed that scFv 15-9 accumulated at sites of endothelial cells lining vessel structures where significant levels of laminin were present. These data demonstrate that scFv 15-9 binds to a specific epitope on laminin and has potential for tumor endoradiotherapy in subcutaneous tumors.
Davern
Sandra M
SM
Oak Ridge National Laboratory, Building 45005, Bethel Valley Road, Oak Ridge, TN 37831, USA.
Foote
Linda J
LJ
Lankford
Trish K
TK
Macy
Sallie D
SD
Wall
Melissa D
MD
Kennel
Stephen J
SJ
D000818:Animals; D000918:Antibody Specificity; D001485:Basement Membrane; D004730:Endothelium, Vascular / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes; D005109:Extracellular Matrix / Q000378:metabolism; D007128:Immunoglobulin Fragments / Q000737:chemistry; D007135:Immunoglobulin Variable Region / Q000737:chemistry; D007150:Immunohistochemistry; D007167:Immunotherapy / Q000379:methods; D007797:Laminin / Q000737:chemistry* / Q000276:immunology; D051379:Mice; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000276:immunology*; D009389:Neovascularization, Pathologic; D019151:Peptide Library; D011485:Protein Binding; D016499:Radioimmunotherapy / Q000379:methods*; D014018:Tissue Distribution
D000939:Epitopes; D007128:Immunoglobulin Fragments; D007135:Immunoglobulin Variable Region; D007797:Laminin; D019151:Peptide Library; C121346:laminin 1