Ligand size and valency strongly influence the receptor uptake and clearance of tumor angiogenesis imaging agents. The structures of successful imaging agents exhibit a high degree of variability, encompassing small mono-valent arginine-glycine-aspartic acid (RGD)-containing peptides, multivalent RGD-oligomers, and a monoclonal antibody against integrin alpha-v-beta-3 (α v β 3 ). We have pursued a nano-scale approach to imaging of angiogenesis using rationally designed polyamidoamine (PAMAM) dendrimers covalently adorned with RGD-cyclopeptides. An orthogonal oxime-ligation strategy was applied to chemoselectively effect conjugation of the PAMAM dendrimers with RGD-cyclopeptides for targeting α v β 3 . Fluorescent dyes for optical imaging and chelates for gadolinium-based magnetic resonance (MR) imaging were subsequently appended to create robust multimodal macromolecular imaging agents. Fluorescence microscopy revealed selective binding of the resulting RGD peptide-bearing dendrimer with empty chelates to α v β 3 -expressing cells, but somewhat reduced selectivity was observed following Gd(III) complexation. The expected incomplete saturation of chelates with Gd(III) ions permitted radiometal complexation, and an in vivo tissue distribution of the resulting agent in M21 melanoma tumorbearing mice showed mostly renal and reticuloendothelial accumulation, with the tumor:blood ratio peaking (3.30 ± .03) at 2 hr post-injection.
Background and purpose:The studies described here are the first to evaluate the in vitro and in vivo properties of In with high labelling yields. Based on the efficiency in tumour targeting and low normal tissue uptake, panitumumab may be an effective targeting component for radioimmunodiagnostic and radioimmunotherapeutic applications.
Monoclonal antibodies (MAbs) labeled with radiometallonuclides via metal chelators are being investigated in the laboratory for use in clinical trials. The biodistribution of 111In- and 88Y-labeled antibody (MAb B72.3) using two isomeric forms (CHX-A and CHX-B) of the 2-(p-isothiocyanatobenzyl)-cyclohexyl-DTPA was compared in athymic mice bearing LS-174T tumors, human colon carcinoma xenografts. CHX-(A or B)-125I-DTPA-B72.3 was co-injected in all athymic mice to assess if the chelate conjugation altered the properties of MAb B72.3. In vitro studies demonstrated maintenance of integrity and immunoreactivity for both radioimmunoconjugates. The in vivo analysis, however, indicated major differences between the two isomer forms. In fact, the 88Y-CHX-A-DTPA radioimmunoconjugate demonstrated over the 7-day study period, a more efficient and stable tumor localization as well as a slower blood clearance rate than the CHX-B-DTPA chelate conjugate, suggesting a greater in vivo stability. Differences were also evident in critical normal organ uptake: no significant increase in liver- and spleen- or bone-to-blood ratios was observed when the CHX-A-DTPA chelate was labeled with indium or yttrium. The results described here demonstrate that the CHX-A-DTPA chelate conjugate can be considered more suitable than the CHX-B-DTPA isomer form when radiometallonuclides are coupled to an MAb.
The administration of murine monoclonal antibodies (MAbs) induces, in many patients, an immunological response represented by the development of human anti-mouse antibodies (HAMA). HAMA have been previously shown to interfere in some assays for the detection of CEA, as well as other non tumor related analytes. The present study was performed to determine whether the CA 72-4 assay is affected by the presence of HAMA, and to establish conditions capable of overcoming this artifact. Serum samples obtained from 8/9 patients entered into a therapeutic protocol using 131I-labeled MAb B72.3 showed the development of apparently high levels of TAG-72 during the clinical follow-up concurrent with the appearance of elevated titers of HAMA. Heat treatment at 90 degrees C at pH 5.0 sodium acetate, previously reported as a method of abolishing HAMA interference without affecting CEA levels, resulted in a considerable loss of detectable TAG-72. However, treatment of these samples at 90 degrees C in pH 6.5 Bis Tris abolished the artifact due to HAMA and resulted in the reversion of reported TAG-72 levels to those observed prior to any MAb administration. As the use of murine MAbs, for both diagnostic and therapeutic applications continues to expand, the identification of this artifactual increase in reported antigen levels due to the development of HAMA has become an important factor in the use of tumor markers, e.g. TAG-72 and CEA, in the follow-up of carcinoma patients.
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