title: Antibody-directed affinity therapy applied to the immune system: in vivo effectiveness and limited toxicity of daunomycin conjugated to HPMA copolymers and targeting antibody.
abstract: 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.
mesh_terms: 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
chemical_list: D000179:Acrylates; D000911:Antibodies, Monoclonal; D000954:Antigens, Surface; D000949:Histocompatibility Antigens Class II; D008689:Methacrylates; D018800:Thy-1 Antigens; C032802:hydroxypropyl methacrylate; D003630:Daunorubicin