Novel immunosuppressant agents targeting activated lymphocytes by biocompatible MPC polymer conjugated with interleukin-2.
The immunopharmacological profile of novel biocompatible water-soluble interleukin-2 (IL-2)-conjugated 2-methacryloyloxyethyl phosphorylcholine (MPC) polymer immunosuppressive agents was established. MPC-co-n- butyl methacrylate (BMA)-co-p-nitrophenylcarbonyloxyethyl methacrylate (NPMA) (PMBN) was prepared as a backbone for these novel agents. PMBN contained MPC as a biocompatible unit, BMA as a hydrophobic domain in water, and NPMA as an immobilizable unit with IL-2. This research showed that proliferation of cell lines with high-affinity IL-2 receptors derived from T cell malignancies were suppressed by the PMBN conjugated with IL-2 (PMBN-IL2 conjugate) incorporating paclitaxel (PTX) and cyclosporin A at lower concentrations than used conventionally. PMBN-IL2 conjugates incorporating PTX also inhibited the proliferation of responder cells in a human mixed lymphocyte culture at a lower concentration than unconjugated drug. However, PMBN-IL2 conjugates incorporating FK506 inhibited proliferation no more than FK506 alone. The PMBN-IL2 conjugate with PTX may therefore be useful for selectively eliminating activated lymphocytes that hyperproduce high-affinity IL-2 receptors. As an entirely human 'immunotoxin analogue' it may not be associated with the dose-limiting toxicity and immunogenicity of conventional immunotoxins.
Chiba
N
N
Department of Surgery, Keio University School of Medicine, Tokyo, Japan.
Ueda
M
M
Shimada
T
T
Jinno
H
H
Watanabe
J
J
Ishihara
K
K
Kitajima
M
M
D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics; D001672:Biocompatible Materials / Q000138:chemical synthesis / Q000493:pharmacokinetics; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D016572:Cyclosporine / Q000493:pharmacokinetics*; D016503:Drug Delivery Systems / Q000379:methods; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics*; D007376:Interleukin-2 / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D008213:Lymphocyte Activation / Q000187:drug effects*; D007959:Lymphocyte Culture Test, Mixed; D008689:Methacrylates / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D017239:Paclitaxel / Q000493:pharmacokinetics; D011092:Polyethylene Glycols / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D012995:Solubility; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D016559:Tacrolimus / Q000493:pharmacokinetics
D000972:Antineoplastic Agents, Phytogenic; D001672:Biocompatible Materials; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D008689:Methacrylates; C513779:poly(2-methacryloyloxyethyl phosphorylcholine-co-n-butyl methacrylate-co-p-nitrophenyloxycarbonyl polyethyleneglycol methacrylate); D011092:Polyethylene Glycols; D016572:Cyclosporine; D017239:Paclitaxel; D016559:Tacrolimus