Targeting of liver metastases of colorectal cancer with IgG, F(ab')2, and Fab' anti-carcinoembryonic antigen antibodies labeled with 99mTc: the role of metabolism and kinetics.

Department of Nuclear Medicine, Friedrich-Alexander-University of Erlangen-Nuremberg, Germany.
Cancer Research (Impact Factor: 9.28). 12/1995; 55(23 Suppl):5777s-5785s.
Source: PubMed

ABSTRACT The aim of this study was to investigate targeting of the liver metastases by directly 99mTc-labeled complete (IgG) and fragmented antibodies [F(ab')2 and Fab'] in relation to their kinetics and metabolic fate. A total of 127 patients with metastatic colorectal cancer were examined [IgG1, BW 431/26 (Behringwerke, Marburg, Germany) n = 50; F(ab')2, F023C5 (Sorin Biomedica, Saluggia, Italy) n = 58; Fab', IMMU-4 (Immunomedics, Morris Plains, NJ) n = 19]. Native monoclonal antibodies (MAbs), serum samples from 10 min to 24 h postinjection (p.i.), and urine were analyzed by gel filtration chromatography. Kinetic data were deduced from whole-body and single-photon emission computed tomographic scans, performed 10 min to 24 h p.i. (region-of-interest technique). In BW 431/26, 96% of injected activity was labeled IgG1; in F023C5, 29% was F(ab')2, and 71% was Fab'; and in IMMU-4, 92% was Fab', and 8% was F(ab')2. Serum half-lives were: IgG1, 36 h (liver uptake predominant); F(ab')2, 16 h; and Fab', 4 h (renal uptake predominant). All MAbs were metabolized, fragments more rapidly than IgG, to low-molecular-weight products and excreted into the urine (e.g., Tc-cystine). In targeting liver metastases, sensitivities were found to be higher for fragments (44.1, 72.5, and 80% for BW 431/26, F023C5, and IMMU-4, respectively) but at significantly lower tumor:background ratios than with IgG (1.78 +/- 0.29 versus 1.29 +/- 0.11 and 1.43 +/- 0.53; P < 0.01). With IgG, there was a continuous tumor uptake over 24 h, whereas with fragments, the maximal uptake occurred mostly within 1 h, with subsequent clearance being slower for antigen-bound activity than for nonspecific background. Hence, diagnosis was possible mostly after 4 h with fragments but often not before 24 h with IgG. These results show that the higher sensitivity of fragments in liver lesion targeting at earlier p.i. times does not rely on an increased antibody uptake but on a more rapid clearance of nonspecific background activity due to faster metabolism and excretion. Intact MAbs show a slow, continuous uptake, leading to higher tumor:background ratios at later p.i. times, often beyond the imaging possibilities of 99mTc.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Published correlations for the principal aspects of hydraulic fracturing were combined into a digital computer program to facilitate the study of inter-related variables. The computer program includes individual relationships for fracture width during pumping, fracture area generated, propping agent embedment, flow capacities of propped fractures, and transport of propping agents in horizontal fractures. The effects of more than 20 treatment and formation parameters on the predicted results of hydraulic fracturing treatments were studied. The effects of propping agent, formation, and fracturing fluid parameters on well productivity are discussed. The parameters that were found to have the most pronounced effects on hydraulic fracturing treatments are injection rate, treatment volume, fracturing fluid coefficient, size and amount of propping agent, spearhead volume, well drainage radius, and formation capacity.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Radioimmunopharmaceutical agents enabling rapid high-reso- lution imaging, high tumor-to-background ratios, and minimal immunogenicity are being sought for cancer diagnosis and im- aging. Genetic engineering techniques have allowed the design of single-chain Fv's (scFv's) of monoclonal antibodies (mAbs) recognizing tumor-associated antigens. These scFv's show good tumor targeting and biodistribution properties in vivo, indicating their potential as imaging agents when labeled with a suitable radionuclide. Methods: Divalent (sc(Fv)2) and tetrava- lent ((sc(Fv)2)2) scFv's of mAb CC49 were evaluated for radio- immunolocalization of LS-174T colon carcinoma xenografts in athymic mice. scFv's were radiolabeled with 99mTc by way of the bifunctional chelator succinimidyl-6-hydrazinonicotinate hydro- chloride using tricine as the transchelator. The immunoreactivity and in vitro stability of the scFv's were analyzed after radiola- beling. Biodistribution and pharmacokinetic studies were per- formed to determine the tumor-targeting potential of the radio- labeled scFv's. Whole-mouse autoradiography illustrated the possible application of these 99mTc-labeled multivalent scFv's for imaging. Results: The radiolabeling procedure gave $95% radiometal incorporation, with a specific activity of .74 MBq/mg scFv. In solid-phase radioimmunoassay, both sc(Fv)2 and (sc(Fv)2)2 exhibited 75%- 85% immunoreactivity, with non- specific binding between 0.8% and 1.2%. Size-exclusion high- performance liquid chromatography showed sc(Fv)2 as a 60- kDa protein and (sc(Fv)2)2 as a 120-kDa protein. Blood clearance studies showed the elimination half-life of 99mTc-labeled sc(Fv)2 as 144 min and that of (sc(Fv)2)2 as 307 min. Whole-body clear- ance studies confirmed the rapid elimination of scFv's, with half-lives of 184 6 19 min for sc(Fv)2 and 265 6 39 min for (sc(Fv)2)2 (P , 0.001). At 6 h after administration, the tumor localization was 7.2 6 0.7 percentage injected dose per gram of tumor (%ID/g) for 99mTc-sc(Fv)2. 99mTc-(sc(Fv)2)2 showed a tumor uptake of 19.1 6 1.1 %ID/g at the same time; the amount of radioactivity in the tumors was 4-fold higher than in the spleen and kidneys and 2-fold higher than in the liver. Macroautora- diography performed at 6 and 16 h after administration clearly detected the tumor with both scFv's. Conclusion: 99mTc- labeled multivalent scFv's show good tumor-targeting charac- teristics and high radiolocalization indices (tumor-to-back- ground ratio). These reagents, therefore, have the potential for use in clinical imaging studies of cancer in the field of nuclear medicine.
  • [Show abstract] [Hide abstract]
    ABSTRACT: The development of monoclonal antibodies (mAbs) using the hybridoma technology has led to new approaches for imaging cancer patients. mAbs against carcinoembryonic antigen (CEA) or TAG-72, two tumour-associated antigens expressed by the vast majority of colorectal adenocarcinomas, have been successfully conjugated with various radionuclides such as I-131, I-123, Tc-99m and In-111. Clinical trials have demonstrated the relative safety of these molecules as well as their unique ability to identify lesions not detected by conventional radiographic imaging modalities. In-111 satumomab pendetide was the first clinically approved murine mAb conjugate for imaging colorectal and ovarian carcinomas. Clinical experience suggests a useful role for In-111 satumomab pendetide in the post-operative evaluation of patients with suspected recurrent colorectal cancer, as well as the potential for altering patient management and possibly a reduction in the costs associated with the work-up and evaluation of patients with occult recurrent colorectal carcinomas. The routine clinical application of these murine-based mAbs is limited by the induction of host immune responses, notably the formation of human anti-mouse antibodies. These have been shown to significantly alter the biodistribution and pharmacokinetics of In-111 satumomab pendetide, leading to a reduction in tumour targeting effectiveness. Alternatives such as the development of chimaeric antibodies or entirely human mAbs, or the use of the nonimmunogenic portion of the mAb, i.e. Fab’ fragments, have been proposed and are currently under investigation. Tc-99m arcitumomab, an Fab’ fragment of IMMU-4, an anti-CEA monoclonal antibody, has recently been approved for imaging in colorectal cancer.
    09/1996; 6(3). DOI:10.1007/BF03259519

Preview (2 Sources)

Available from