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Tumour necrosis factor increases tumour uptake of Co-administered antibody-carboxypeptidase G2 conjugate

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Increased tumour uptake of antibodies and antibody-drug conjugates has been demonstrated following pretreatment of animals with recombinant human tumour necrosis factor-α (rTNF-α) and interleukin 2 immunoconjugates. The experiments reported here were performed to determine whether improved tumour localisation of antibody-carboxypeptidase G2 conjugates could be achieved, with a view to applying this technology to antibody-directed enzyme-prodrug therapy (ADEPT). B6CF1 mice bearing the Ly-2.1+ murine thymoma E3 were simultaneously injected with 2.0 μgrTNF-α and 3.5 μg (74 kBq) 125I-labelled murine anti-Ly-2.1-CPG2 conjugate. Mice in control groups received phosphate buffered saline in place of rTNF-α. The conjugate corresponded in molecular weight to a mixture of 1:1 and 2:1 (CPG2:IgG) conjugate and retained its antigen binding specificity and enzymic activity in vitro. A significant increase in tumour uptake was observed 24 h after administration when rTNF-α-treated animals were compared to controls (28.1 ± 9.7% / g and 11.6 ± 2.3% / g, respectively). Other tissues, most notably gut, skin and kidney also showed an increased localisation of conjugate. By 48 h, analysis of tissue:blood ratios demonstrated that although tumour:blood ratios were significantly higher in rTNF-α-treated animals (P < 0.05), all the other tissue:blood ratios were not significantly different between the two groups.

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