Antibody-directed affinity therapy applied to the immune system: in vivo effectiveness and limited toxicity of daunomycin conjugated to HPMA copolymers and targeting antibody.
The applicability of targeting therapy intervention in lymphatic tissue was studied. The effect was measured as the inhibition of anti-sheep red blood cell antibody response expressed in plaque-forming cells. Daunomycin was used as the effective drug and polyclonal and monoclonal anti-Thy 1.2 or anti-Iak antibody served for targeting. Both components were coupled to a soluble N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer with oligopeptidic side sequences which permitted a controlled release of the drug in the target tissue. HPMA copolymer conjugates with side sequences Gly-Phe-Leu-Gly cleavable by lysosomal enzymes decreased in vivo the antibody reaction by 60-85%. A comparable amount of free targeting antibody was without a significant effect. Injection of targeted daunomycin decreased the toxicity of the drug against hematopoietic precursors in bone marrow colony-forming unit-spleen 80 times compared to the same amount of free drug. The in vivo effectiveness of targeted daunomycin was confirmed morphologically. Application of free daunomycin lead to a significant irritation of Kupffer cells in liver while none of the daunomycin-antibody-copolymer conjugate had such an effect.
D000179:Acrylates / Q000008:administration & dosage*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D000954:Antigens, Surface / Q000276:immunology; D003114:Colony-Forming Units Assay; D003630:Daunorubicin / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity; D005260:Female; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D008689:Methacrylates / Q000008:administration & dosage*; D051379:Mice; D008805:Mice, Inbred A; D013154:Spleen / Q000166:cytology; D018800:Thy-1 Antigens; D014018:Tissue Distribution
D000179:Acrylates; D000911:Antibodies, Monoclonal; D000954:Antigens, Surface; D000949:Histocompatibility Antigens Class II; D008689:Methacrylates; D018800:Thy-1 Antigens; C032802:hydroxypropyl methacrylate; D003630:Daunorubicin