Application of monoclonal antibodies against cytosine deaminase for the in vivo clearance of a cytosine deaminase immunoconjugate.
The selective delivery of anticancer drugs to tumors vs normal tissue using targeted antibody-enzyme conjugates for prodrug activation is limited by the amount of drug generated by blood-borne enzyme. Clearance of non-tumor-associated conjugate would increase the tumor/blood conjugate ratio, and enable larger amounts of prodrugs to be administered. A method for clearing the monoclonal antibody (mAb) conjugate L6-cytosine deaminase (L6-CD) was established by using an antibody raised against CD. The mAb 102-26 was obtained by immunizing BALB/C mice with CD conjugated to keyhole limpet hemocyanin. 102-26 was able to precipitate purified CD from solution as assessed by radioimmune precipitation and recognized CD in Western blot analyses. Similar studies were used to establish that 102-26 also recognized CD when conjugated to the L6 and 1F5 mAbs. Selective removal of L6-CD from the circulation of nude mice bearing H2981 human lung adenocarcinoma (L6-antigen positive) was achieved by injecting 102-26 24 h after L6-CD administration. High T/B ratios were obtained by clearance of a L6-CD (38:1 compared to 1.3:1 without clearance).
Kerr
D E
DE
Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, Washington 98121.
Garrigues
U S
US
Wallace
P M
PM
Hellström
K E
KE
Hellström
I
I
Senter
P D
PD
D000230:Adenocarcinoma / Q000276:immunology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000276:immunology; D000941:Antigens / Q000276:immunology; D001710:Biotin; D015153:Blotting, Western; D043525:Cytosine Deaminase; D004337:Drug Carriers; D004797:Enzyme-Linked Immunosorbent Assay; D006433:Hemocyanins / Q000276:immunology; D008168:Lung / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009700:Nucleoside Deaminases / Q000008:administration & dosage / Q000276:immunology*; D011863:Radioimmunoassay
D000911:Antibodies, Monoclonal; D000941:Antigens; D004337:Drug Carriers; D001710:Biotin; D006433:Hemocyanins; D009700:Nucleoside Deaminases; D043525:Cytosine Deaminase; C032808:keyhole-limpet hemocyanin