title: Novel human single chain antibody fragments that are rapidly internalizing effectively target epithelioid and sarcomatoid mesotheliomas.
abstract: Human antibodies targeting all subtypes of mesothelioma could be useful to image and treat this deadly disease. Here we report tumor targeting of a novel internalizing human single chain antibody fragment (scFv) labeled with (⁹⁹m)Tc ((⁹⁹m)Tc-M40) in murine models of mesothelioma of both epithelioid (M28) and sarcomatoid (VAMT-1) origins. (⁹⁹m)Tc-M40 was taken up rapidly and specifically by both subtype tumor cells in vitro, with 68% to 92% internalized within 1 hour. The specificity of binding was evidenced by blocking (up to 95%) with 10-fold excess of unlabeled M40. In animal studies, tumors of both subtypes were clearly visualized by SPECT/CT as early as 1 hour postinjection of (⁹⁹m)Tc-M40. Tumor uptake measured as percent of injected dose per gram tissue (%ID/g) at 3 hours was 4.38 and 5.84 for M28 and VAMT-1 tumors, respectively, significantly greater than all organs or tissues studied (liver, 2.62%ID/g; other organs or tissues <1.7%ID/g), except the kidneys (130.7%ID/g), giving tumor-to-blood ratios of 5:1 and 7:1 and tumor-to-muscle ratios of 45:1 and 60:1, for M28 and VAMT-1, respectively. The target-mediated uptake was confirmed by a nearly 70% reduction in tumor activity following administration of 10-fold excess of unlabeled scFv. Taken together, these results indicate that M40 can rapidly and specifically target epithelioid and sarcomatoid tumor cells, demonstrating the potential of this agent as a versatile targeting ligand for imaging and therapy of all subtypes of mesothelioma.
authors: Center for Molecular and Functional Imaging, Department of Radiology and Biomedical Imaging, University of California, San Francisco, California, USA.
authors: Arun K
authors: AK
authors: Iyer
authors: Xiaoli
authors: X
authors: Lan
authors: Xiaodong
authors: X
authors: Zhu
authors: Yang
authors: Y
authors: Su
authors: Jinjin
authors: J
authors: Feng
authors: Xiaoju
authors: X
authors: Zhang
authors: Dongwei
authors: D
authors: Gao
authors: Youngho
authors: Y
authors: Seo
authors: Henry F
authors: HF
authors: Vanbrocklin
authors: V Courtney
authors: VC
authors: Broaddus
authors: Bin
authors: B
authors: Liu
authors: Jiang
authors: J
authors: He
mesh_terms: D000818:Animals; D019788:Fluorodeoxyglucose F18; D006801:Humans; D000922:Immunotoxins / Q000737:chemistry / Q000276:immunology* / Q000493:pharmacokinetics; D007553:Isotope Labeling; D008297:Male; D008654:Mesothelioma / Q000000981:diagnostic imaging / Q000276:immunology* / Q000532:radiotherapy; D051379:Mice; D008819:Mice, Nude; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000737:chemistry / Q000276:immunology* / Q000493:pharmacokinetics; D012509:Sarcoma / Q000000981:diagnostic imaging / Q000276:immunology* / Q000532:radiotherapy; D057127:Single-Chain Antibodies / Q000276:immunology* / Q000493:pharmacokinetics; D013667:Technetium / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D014018:Tissue Distribution; D015899:Tomography, Emission-Computed, Single-Photon
chemical_list: D000922:Immunotoxins; D019275:Radiopharmaceuticals; D057127:Single-Chain Antibodies; D019788:Fluorodeoxyglucose F18; D013667:Technetium