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Title: | In vitro and in vivo evaluation of human tumor necrosis factor-alpha (hTNFalpha) chemically conjugated to monoclonal antibody. | Austin Authors: | Pietersz, Geoffrey A;Toohey, B;McKenzie, Ian F C | Affiliation: | The Austin Research Institute, Austin Hospital, Heidelberg Victoria, Australia | Issue Date: | 16-May-1998 | Publication information: | Journal of Drug Targeting; 5(2): 109-20 | Abstract: | Human tumor necrosis-alpha (hTNF-alpha) was chemically conjugated to the murine anti-Ly-2.1 T cell antibody using heterobifunctional crosslinking agents SAMSA and SPDP. SDS-PAGE analysis of the affinity purified conjugate consisted mainly of 1:1 and 1:2 (Ly-2.1:TNF) complexes. Conjugated hTNF retained 50% of its cytotoxic activity by the L929 cytolytic assay, with an IC50 = 0.12 ng/ml. hTNF-Ly-2.1 was also cytotoxic to E3 cells (Ly-2.1+ve) with an IC50 = 1.7 microg/ml - 3 times more cytotoxic to these cells than non-conjugated hTNF in vitro. However in vivo hTNF-Ly-2.1 conjugates were more toxic to mice than hTNF. In vivo blood clearance studies in E3 tumor bearing CBF1 mice demonstrated that the half life of the conjugate was 2 hr, compared to 20 min for hTNF. In biodistribution studies, tumor accumulation of 3% was seen for hTNF-Ly-2.1 while for unconjugated hTNF no activity in tumor was detected 24hr post injection. A single dose of hTNF-Ly-2.1 increased the accumulation of 125I-anti-Ly-2.1 by 3 fold compared to controls. However, the antitumor effect of hTNF-Ly-2.1 on E3 cells in vivo was marginal with some tumor growth retardation at day 1-3. The results of these in vitro and in vivo studies on chemically conjugated h-TNF-MoAb will be helpful in the design of novel recombinant fusion proteins for targeting the biologic activity of TNF to tumours. | Gov't Doc #: | 9588867 | URI: | http://ahro.austin.org.au/austinjspui/handle/1/13598 | DOI: | 10.3109/10611869808995864 | Journal: | Journal of drug targeting | URL: | https://pubmed.ncbi.nlm.nih.gov/9588867 | Type: | Journal Article | Subjects: | Animals Antibodies, Monoclonal.chemistry Cell Line Drug Evaluation Half-Life Humans Immunoconjugates.administration & dosage.isolation & purification.pharmacokinetics Mice Recombinant Proteins.administration & dosage.pharmacokinetics Thymoma.metabolism Thymus Neoplasms.metabolism Tissue Distribution Tumor Necrosis Factor-alpha.chemistry.pharmacokinetics |
Appears in Collections: | Journal articles |
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