Cationized hyperimmune immunoglobulins: pharmacokinetics, toxicity evaluation and treatment of human immunodeficiency virus-infected human-peripheral blood lymphocytes-severe combined immune deficiency mice.
The in vivo pharmacokinetics and efficacy of cationized human immunoglobulins in the human-peripheral blood lymphocytes-severe combined immune deficiency mouse model were evaluated in the present studies using the severe combined immunodeficient mouse transplanted with human lymphocytes and infected with human immunodeficiency virus (HIV)-1. Immunoglobulins from noninfected humans and from HIV-infected individuals were cationized. The pharmacokinetic analysis showed that the cationized immunoglobulins have a markedly reduced mean residence time and a marked increase in organ uptake compared to the native immunoglobulins. The toxicity studies performed with homologous immunoglobulins in BALB/c mice demonstrated cationized homologous immunoglobulins have no tissue toxicity at a daily dose of 7.5 mg/kg. Treatment of HIV-infected severe combined immune deficiency mice that were transplanted with human lymphocytes demonstrated therapeutic efficacy for a 2-week treatment at a dose of 5 mg/kg cationized HIV immune globulin. In conclusion, cationized immunoglobulins are potential antibody-based therapeutics for the treatment of acquired immune deficiency syndrome; cationized antibodies undergo enhanced transport into lymphocytes and when homologous cationized immunoglobulins are administered there is no measurable tissue toxicity.
Pardridge
W M
WM
Department of Medicine, University of California at Los Angeles School of Medicine, USA.
Kang
Y S
YS
Diagne
A
A
Zack
J A
JA
D000818:Animals; D000998:Antiviral Agents / Q000097:blood* / Q000494:pharmacology* / Q000633:toxicity; D002412:Cations; D002478:Cells, Cultured; D005260:Female; D015658:HIV Infections / Q000097:blood* / Q000188:drug therapy* / Q000276:immunology; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D016756:Immunoglobulins, Intravenous / Q000097:blood* / Q000494:pharmacology* / Q000633:toxicity; D017710:Lymphocyte Transfusion; D008214:Lymphocytes / Q000187:drug effects / Q000821:virology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D002412:Cations; C084715:HIV hyperimmune globulin; D016756:Immunoglobulins, Intravenous