TUMOR-NECROSIS-FACTOR INCREASES TUMOR UPTAKE OF CO-ADMINISTERED ANTIBODY-CARBOXYPEPTIDASE-G2 CONJUGATE

Increased tumour uptake of antibodies and antibody-drug conjugates has been demonstrated following pretreatment of animals with recombinant human tumour necrosis factor-alpha (rTNF-alpha) and interleukin 2 immu noconjugates. The experiments reported here were performed to determin e 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 beari ng the Ly-2.1+ murine thymoma E3 were simultaneously injected with 2.0 mug rTNF-alpha and 3.5 mug (74 kBq) I-125-labelled murine anti-Ly-2.1 -CPG2 conjugate. Mice in control groups received phosphate buffered sa line in place of rTNF-alpha. The conjugate corresponded in molecular w eight to a mixture of 1:1 and 2:1 (CPG2:IgG) conjugate and retained it s antigen binding specificity and enzymic activity in vitro. A signifi cant increase in tumour uptake was observed 24 h after administration when rTNF-alpha-treated animals were compared to controls (28.1 +/- 9. 7% / g and 11.6 +/- 2.3% / g, respectively). Other tissues, most notab ly gut, skin and kidney also showed an increased localisation of conju gate. By 48 h, analysis of tissue:blood ratios demonstrated that altho ugh tumour:blood ratios were significantly higher in rTNF-alpha-treate d animals (P < 0.05), all the other tissue:blood ratios were not signi ficantly different between the two groups.