      Document 0218
 DOCN  DRG0218
 UNIQUE IDENTIFIER        DRG-0029
 NAME OF SUBSTANCE        Antigens, CD4 [Lancet 1990 May 12; Vol 335 No
                          8698]
 SYNONYMS                 Recombinant Soluble T4 [NIAID ACTG 066]
 SYNONYMS                 rsT4 [NIAID ACTG 066]
 SYNONYMS                 CD4 Antigens [Lancet 1990 May 12; Vol 335 No
                          8698]
 SYNONYMS                 rCD4 [NIAID ACTG 133]
 SYNONYMS                 Soluble CD4 [Lancet 1990 May 12; Vol 335 No
                          8698]
 SYNONYMS                 Recombinant soluble CD4 [MeSH]
 SYNONYMS                 CD4 Surface antigen [Lancet 1990 May 12; Vol
                          335 No 8698]
 SYNONYMS                 SK&F-106528 [MeSH]
 SYNONYMS                 sT4 [MeSH]
 SYNONYMS                 sCD4 [Am J Med Apr 10;90(4A)]
 SYNONYMS                 rsCD4 [Ann Int Med 1990 Feb 15;112(4)]
 PROTOCOL ID NUMBERS      NIAID ACTG 066
 PROTOCOL ID NUMBERS      NIAID ACTG 101
 PROTOCOL ID NUMBERS      NIAID ACTG 133
 PROTOCOL ID NUMBERS      NCI 88 C-146A
 PROTOCOL ID NUMBERS      NCI 89 C-121
 PROTOCOL ID NUMBERS      NIAID 89 I-139
 PROTOCOL ID NUMBERS      FDA 064A
 PROTOCOL ID NUMBERS      FDA 064B
 IND NUMBER               BB3034
 SECONDARY SOURCE ID      DRG
 PHARMACOLOGICAL ACTION   Recombinant soluble CD4 is capable of binding
                          to HIV envelope gp120 with affinity similar
                          to that of native CD4 and blocks entry of
                          HIV-1 into CD4-bearing cells. Antiviral
                          activity of soluble CD4 has been demonstrated
                          in vitro by measurement of decreases in both
                          reverse transcriptase activity and
                          HIV-induced cell fusion. However,
                          quantitative virologic studies performed to
                          date on blood of patients receiving
                          recombinant soluble CD4 (sCD4) demonstrated
                          no efficacy in vivo despite good drug levels
                          in serum. These results led to an examination
                          of the neutralizing activity of sCD4 against
                          multiple primary HIV-1 isolates from infected
                          patients. The findings demonstrated that
                          primary isolates were significantly more
                          resistant to sCD4 than were laboratory
                          strains. Serum half-life of recombinant sCD4
                          after intravenous administration is 45
                          minutes. After intramuscular injection of
                          CD4, however, peak serum levels are not
                          reached until 4 to 6 hours. During repeated
                          intramuscular administration serum
                          concentrations of the drug were relatively
                          stable and rose in a dose-related fashion to
                          steady-state levels of 15 to 30, 20 to 80,
                          and 50 to 300 ng/mL for the patient cohorts
                          receiving 3, 9, and 30 mg/d, respectively.
                          High dose IV rsCD4 was safely administered to
                          3 patients and produced a subjective
                          improvement in clinical symptoms. rsCD4
                          exhibited linear pharmacokinetics over the
                          dose range studied (1-10 mg/kg). [J Acquir
                          Immune Defic Syndr 1995;9(2)] [Am J Med Apr
                          10;90(4A)] [Ann Int Med 1990 Feb 15;112(4)]
 DISEASES STUDIED/TREATED Primary HIV infection [J Acquir Immune Defic
                          Syndr 1995;9(2)]
 CLASSIFICATION CODE      Antiretroviral [Drug Evaluations Annual 1995]
 ADVERSE EFFECTS          In a phase I study no patient developed
                          severe or life threatening toxicities related
                          to rsCD4 therapy. Nine patients developed
                          local, mild, or moderate reactions at
                          injection sites at least once during the
                          study consisting of mild transient erythema.
                          One patient developed a maculopapular
                          eruption which resolved upon withdrawal of
                          sCD4. [Ann Int Med 1990 Feb 15;112(4)]
 CHEMICAL/PHYSICAL DATA   DRUG DESCRIPTION: A truncated version of the
                          complete CD4 polypeptide that includes most
                          of the extracellular domain, but with the
                          transmembrane and C-terminal regions deleted
                          [Ann Int Med 1990 Feb 15;112(4)] [MeSH]
 CHEMICAL/PHYSICAL DATA   DRUG DESCRIPTION: This molecule is produced
                          using recombinant technology and is soluble
                          in serum unlike the complete CD4 polypeptide
                          [Ann Int Med 1990 Feb 15;112(4)] [MeSH]
 CHEMICAL/PHYSICAL DATA   SOLUBILITY: Soluble in water [NIAID ACTG 066]
 SUBSTANCE DELIVERY DATA  DOSAGE FORMS: Vials containing frozen
                          solution (containing 5 mg/ml of rsT4). [NIAID
                          ACTG 066]
 SUBSTANCE DELIVERY DATA  MODE OF DELIVERY: Soluble CD4 can be given
                          intramuscularly, subcutaneously, or by IV
                          infusion [Lancet 1990 May 12; Vol 335 No
                          8698]
 SUBSTANCE DELIVERY DATA  STORAGE: Store frozen at -20 C to -25 C (-4 F
                          to -13 F) until thawed for use (thaw slowly
                          by placing at room temperature). [NIAID ACTG
                          066]
 MANUFACTURERS            Biogen
 MANUFACTURERS            Dana Farber Cancer Institute
 MANUFACTURERS            Genentech
 MANUFACTURERS            Smith Kline and French Laboratories
 REFERENCES               Schacker T, Coombs RW, Collier AC, Zeh EJ,
                          Fox I, Alam J, Nelson K, Eggert E, Corey L.
                          The effects of high-dose recombinant soluble
                          CD4 on human immunodeficiency virus type 1
                          viremia. J Infect Dis. 1994 Jan;169(1):37-40.
 REFERENCES               Sachs M, Fong KL, Blanchard L, Wikler M.
                          High-dose recombinant soluble CD4 (rsCD4) in
                          patients with HIV-1 infection. Abstr Gen Meet
                          Am Soc Microbiol. 1993;93:437 (abstract no.
                          T-33).
 REFERENCES               Husson RN, Chung Y, Mordenti J, Butler KM,
                          Chen S, Duliege AM, Brouwers P, Jarosinski P,
                          Mueller BU, Ammann A, et al. Phase I study of
                          continuous-infusion soluble CD4 as a single
                          agent and in combination with oral
                          dideoxyinosine therapy in children with
                          symptomatic human immunodeficiency virus
                          infection. J Pediatr. 1992 Oct;121(4):627-33.
 REFERENCES               Watanabe M, Boyson HE, Lord CI, Letvin NL.
                          Chimpanzees immunized with recombinant
                          soluble CD4 develop anti-self CD4 antibody
                          responses with anti-human immunodeficiency
                          virus activity. Proc Natl Acad Sci U S A.
                          1992 Jun 1;89(11):5103-7.
 REFERENCES               McHardy S, Leen CL. Brettle RP, Bird AG, Bell
                          J, Eisner J. Tolerance of continuous
                          subcutaneous infusion (CSCI) of recombinant
                          soluble CD4 (rsCD4). Int Conf AIDS. 1991 Jun
                          16-21;7(2):200 (abstract no. W.B.2075).
 REFERENCES               Bugelski PJ, Thiem PA, Truneh A, Morgan DG.
                          Recombinant human soluble CD4 does not
                          inhibit immune function in cynomolgus
                          monkeys. Toxicol Pathol. 1991;19(4 Pt
                          2):580-8.
 REFERENCES               Sun W, Virani N, Hawkes C, Wagner K, Oster C,
                          Tramont E, Burke D, Redfield R. High dose
                          continuos IV infusions of soluble CD4 (sCD4).
                          Inf Conf AIDS. 1990 Jun 20-23;6(2):398
                          (abstract no. 2177).
 REFERENCES               Rosenberg M, Bugelski PJ, Fong KL, Drutz DJ,
                          Sweet RW, Webb DD. Soluble recombinant CD4--a
                          potential therapeutic agent for HIV
                          infection. Biotherapy. 1990;2(2):107-18.
 REFERENCES               Allan JD, Kahn J, Hodges T, Sherwin S,
                          Volberding P, Groopman J. A phase I study of
                          the safety and phamacokinetics of soluble
                          recombinant CD4 (rCD4) in patients with AIDS
                          and ARC. Int Conf AIDS. 1989 Jun 4-9;5:337
                          (abstract no. T.B.P.303).
 REFERENCES               Schooley R, Ho D, Gaut P, Tierney M,
                          Schindler J, Henochowicz S. Escalating dose
                          tolerance trial of recombinant soluble CD4 in
                          humans. Int Conf AIDs. 1989 Jun 4-9;5:212
                          (abstract no. Th.B.O.6).
 ENTRY MONTH              8906
 LAST REVISION DATE       960310
 

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