      Document 0154
 DOCN  DRG0154
 UNIQUE IDENTIFIER        DRG-0093
 NAME OF SUBSTANCE        Polyethylene Glycolated IL-2 [AmFAR Tx Dir
                          1995;7(4)]
 SYNONYMS                 PEG IL-2 [AmFAR Tx Dir 1995;7(4)]
 SYNONYMS                 PEG-Interleukin-2 [Facts and Comparisons
                          1995]
 SYNONYMS                 Interleukin-2 PEG [Facts and Comparisons
                          1995]
 SYNONYMS                 Proleukin-PEG [ImmunoFacts 1993]
 PROTOCOL ID NUMBERS      NIAID ACTG 141
 PROTOCOL ID NUMBERS      FDA 072A
 PROTOCOL ID NUMBERS      FDA 072B
 PROTOCOL ID NUMBERS      NIAID ACTG 236
 SECONDARY SOURCE ID      CS-PG89-36 [NIAID ACTG 141]
 PHARMACOLOGICAL ACTION   MODE OF ACTION: Interleukin-2 (IL-2) is a
                          lymphokine which stimulates the proliferation
                          of T-lymphocytes and thus amplifies immune
                          response to an antigen; it also has action on
                          B-lymphocytes and induces the proliferation
                          of interferon-gamma and activation of natural
                          killer cells.  However, recombinant IL-2
                          (rIL-2) when expressed in Escherichia coli is
                          un-glycosylated, has limited solubility,
                          requires high dose and long term regimens for
                          tumor regression and antibodies to rIL-2 have
                          been found in patients undergoing clinical
                          trials with rIL-2.  These antibodies could
                          potentially interfere with the effectiveness
                          of the drug. Covalent attachment of
                          polyethylene glycol (PEGylation) enhances
                          solubility, increases circulatory life and
                          eliminates the possi bility of potential
                          aggregates of rIL-2 which may elicit an
                          immune response. In one clinical trial of PEG
                          IL-2, all patients demonstrated high levels
                          of lymphokine-activated killer cell activity
                          by cells freshly removed from the circulation
                          and in the absence of in vitro exposure to
                          IL-2. Natural killer cell activity was also
                          enhanced. Limiting dilution analysis revealed
                          an increase in the frequency of
                          IL-2-responsive cells from abnormally low to
                          levels above normal during the course of
                          injections. In a subgroup of four patients
                          with greater than or equal to 400 CD4+ T
                          cells/microliter at entry, there was a trend
                          to sustained increases in CD4+ T cell
                          numbers. However, this increase did not reach
                          statistical significance. This subset of
                          patients also exhibited higher proliferative
                          responses to phytohemagglutinin as mitogen.
                          Several of these effects persisted for 3-6
                          months after cessation of therapy. In
                          conclusion, the study reports low-dose IL-2
                          regimens lead to sustained immune enhancement
                          in the absence of toxicity. [J Exp Med 1993
                          Feb 1;177(2)] [The Extra Pharmacopoeia 1993]
                          [J of Immunology 1990 Jan 1;144]
 DISEASES STUDIED/TREATED Investigated to determine effects on the
                          immune system, HIV virus, and antibody titers
                          [J Exp Med 1993 Feb 1;177(2)] [NIAID ACTG
                          141]
 CLASSIFICATION CODE      Immunomodulator [AmFAR Tx Dir 1993;6(3)]
 OTHER MAJOR USES         Immunotherapy of various malignant neoplasms;
                          treatment of a number of viral infections and
                          mitogens [The Extra Pharmacopoeia 1993]
                          [NIAID ACTG 042]
 SUBSTANCE INTERACTIONS   Interacts with drugs used in chemotherapy,
                          hormonal therapy or other immunotherapy, and
                          with antihypertensives.  [NIAID ACTG 141]
 ADVERSE EFFECTS          Side effects to interleukin-2 may include
                          encephalopathy, fever, malaise, diarrhea and
                          mild anorexia. Other side effects to
                          interleukin-2 may also include adverse
                          pulmonary, cardiovascular and hepatic
                          reactions. Thrombocytopenia, proteinuria,
                          hemoglobinuria, granulocytopenia,
                          eosinophilia, lymphopenia, rash, exacerbation
                          of polymositis and dermatomyositis,
                          dose-related fatigue, arthralgia, myalgia,
                          nausea, vomiting, anuria, and creatinine
                          elevation have been reported. [J Infect Dis
                          1993 Mar;167(3)] [NIAID ACTG 042]
 CONTRAINDICATIONS        Contraindicated in the presence of major
                          organ allograft, significant cardiac disease,
                          central nervous system lesions, pregnancy or
                          lactation.  [NIAID ACTG 141] [NIAID ACTG 042]
 CHEMICAL/PHYSICAL DATA   DRUG DESCRIPTION:  Human recombinant
                          interleukin-2 expressed in E. coli [J of
                          Immunology 1990 Jan 1;144]
 CHEMICAL/PHYSICAL DATA   DRUG DESCRIPTION: It is purified and
                          chemically modified with a water soluble
                          polymer, monomethoxy polyethylene glycol
                          (PEG) to enhance solubility and extend in
                          vivo circulation [J of Immunology 1990 Jan
                          1;144]
 CHEMICAL/PHYSICAL DATA   SOLUBILITY: Covalent attachment of PEG to
                          recombinant interleukin-2 (rIL-2) makes the
                          molecule very hydrophilic, have a longer
                          circulation life and completely soluble at
                          any pH [J of Immunology Jan 1, 1990, 144]
 SUBSTANCE DELIVERY DATA  MODE OF DELIVERY: Intraveneous infusion;
                          intradermal. [J Exp Med 1993 Feb 1;177(2)]
                          [NIAID ACTG 141]
 MANUFACTURERS            Cetus
 REFERENCES               Ramachandran RV, Katzenstein D, Merigan TC.
                          Long-term effects of interleukin-2 on CD4
                          cell counts in human immunodeficiency
                          virus-infected patients [letter]. J Infect
                          Dis. 1994 Oct;170(4):1044-6.
 REFERENCES               Wood R, Montoya JG, Kundu SK, Schwartz DH,
                          Merigan TC. Safety and efficacy of
                          polyethylene glycol-modified interleukin-2
                          and zidovudine in human immunodeficiency
                          virus type 1 infection: a phase I/II study. J
                          Infect Dis. 1993 Mar;167(3):519-25.
 REFERENCES               Teppler H, Kaplan G, Smith KA, Montana Al,
                          Meyn P, Cohn ZA. Prolonged immunostimulatory
                          effect of low-dose polyethylene glycol
                          interleukin 2 in patients with human
                          immunodeficiency virus type 1 infection. J
                          Exp Med. 1993 Feb 1;177(2):483-92.
 REFERENCES               Teppler H, Kaplan G, Smith K, Cameron P,
                          Montana A, Meyn P, Cohn Z. Efficacy of low
                          doses of the polyethylene glycol derivative
                          of interleukin-2 in modulating the immune
                          response of patients with human
                          immunodeficiency virus type 1 infection. J
                          Infect Dis. 1993 Feb;167(2):291-8.
 REFERENCES               Waites L, Fyfe G, Senechek D, Husemann C,
                          Santiago F, Lamborn K, Vollmer C.
                          Polyethylene glycol modified interleukin-2
                          (PEG IL-2) therapy in HIV seropositive
                          individuals. Int Conf AIDS. 1992 Jul
                          19-24;8(3):145 (abstract no. PuB 7580).
 REFERENCES               Teppler H, Montana A, Meyn P, Kaplan G, Cohn
                          ZA. Prolonged immunostimulatory effect of low
                          dose PEG interleukin-2 in HIV-infected
                          individuals. Int Conf AIDS. 1992 Jul
                          19-24;8(2):B162 (abstract no. PoB 3453.
 REFERENCES               Wood R, Montoya J, Kundu S, Merigan TC.
                          Safety and efficacy of Peg IL-2 and ZDV in
                          HIV infection. Int Conf AIDS. 1992 Jul
                          19-24;8(3):147 (abstract no. PuB 7589).
 REFERENCES               Shih Y, Konrad MW, Warren MK, Childs A,
                          Paradise C, Meyers FJ, Groves ES. Suppression
                          and transient induction of lymphokines in
                          cancer patients after administration of
                          polyethylene glycolated interleukin-2. Eur J
                          Immunol. 1992 Mar;22(3):727-33.
 ENTRY MONTH              9007
 LAST REVISION DATE       950928
 

SOURCE: National Library of Medicine, Bethesda, MD.  Distributed by AEGIS.
