Tumour necrosis factor increases tumour 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 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 micrograms rTNF-alpha and 3.5 micrograms (74kBq) 125I-labelled murine anti-Ly-2.1-CPG2 conjugate. Mice in control groups received phosphate buffered saline in place of rTNF-alpha. 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-alpha-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-alpha-treated animals (P < 0.05), all the other tissue:blood ratios were not significantly different between the two groups.
Melton
R G
RG
Division of Biotechnology, PHLS Centre for Applied Microbiology & Research, Salisbury, Wilts, U.K.
Rowland
J A
JA
Pietersz
G A
GA
Sherwood
R F
RF
McKenzie
I F
IF
D000818:Animals; D002268:Carboxypeptidases / Q000378:metabolism*; D004591:Electrophoresis, Polyacrylamide Gel; D007074:Immunoglobulin G / Q000378:metabolism*; D000922:Immunotoxins / Q000378:metabolism*; D007376:Interleukin-2 / Q000494:pharmacology*; D051379:Mice; D008815:Mice, Inbred Strains; D011993:Recombinant Fusion Proteins / Q000378:metabolism*; D013945:Thymoma / Q000378:metabolism / Q000628:therapy; D013953:Thymus Neoplasms / Q000378:metabolism / Q000628:therapy; D013997:Time Factors; D014018:Tissue Distribution; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D007074:Immunoglobulin G; D000922:Immunotoxins; D007376:Interleukin-2; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; D002268:Carboxypeptidases