      Document 0061
 DOCN  DRG0061
 UNIQUE IDENTIFIER        DRG-0186
 NAME OF SUBSTANCE        Chimeric anti-TNF monoclonal antibody [NIAID
                          93 I-182]
 SYNONYMS                 Chimeric A2 [NIAID 93 I-182]
 SYNONYMS                 cA2 [NIAID 93 I-182]
 PROTOCOL ID NUMBERS      NIAID 93 I-182
 PROTOCOL ID NUMBERS      NIAID IL-2/TNF ANTAG.
 SECONDARY SOURCE ID      DRG
 PHARMACOLOGICAL ACTION   MODE OF ACTION: A high-affinity neutralizing
                          murine anti-human TNF IgG monoclonal antibody
                          designated A2 has been produced. Murine IgG
                          antibodies may have properties that are
                          undesirable for human therapeutic use, such
                          as stimulation of a human anti-murine
                          antibody (HAMA) response. Therefore, a
                          murine-human chimeric monoclonal antibody was
                          constructed by cloning the heavy and light
                          chain variable region genomic domains of A2
                          and joining them to the respective heavy and
                          light chain domains of human gamma1 constant
                          regions. The resulting mouse-human chimeric
                          IgG monoclonal antibody, designated cA2, was
                          expressed from a stably transfected SP2/0
                          murine hybridoma cell line. Incorporating
                          human constant region structure into the
                          chimeric construct might also be expected to
                          improve allogenic antibody effector function
                          and increase serum circulating half-life in
                          human subjects. To date, experience with cA2
                          has been gained in two phase I/II studies. In
                          a phase I/II trial in healthy human
                          volunteers, 9 volunteers received cA2 alone
                          in ascending doses of 0.1, 1, 5, or 10
                          milligrams per kilogram bodyweight. cA2 was
                          well tolerated by all volunteers. Tumor
                          necrosis factor-alpha (TNF-alpha) is a
                          monocyte-derived cytokine shown to be
                          important in killing both tumor cells and
                          target cells infected with certain viruses.
                          Sustained blood levels of TNF have been found
                          in studies of patients with sepsis, and TNF
                          levels above 540 pg/ml have been associated
                          with a fatal outcome. Elevated serum TNF
                          levels increase with the advancing stage of
                          infection. TNF-alpha has also been
                          demonstrated to enhance HIV replication in
                          chronically infected T lymphocytic and
                          promonocytic cell lines when administered
                          alone. A recent study has shown that
                          treatment of primary blood monocyte-derived
                          macrophages with recombinant TNF-alpha
                          enhanced HIV replication fivefold or more
                          above control. Thus TNF-alpha appears to be
                          one of multiple inflammatory cytokines that
                          may serve to upregulate HIV expression and
                          thereby accelerate clinical progression of
                          HIV disease. TNF-alpha also functions
                          biologically in the control of nutritional
                          homeostasis and indeed derives its other
                          name, cachetin, from the dysregulation that
                          may be associated with excessive levels or
                          activity of this cytokine. The desire to
                          block the actions of TNF-alpha in producing
                          enhanced HIV expression and cachexia thus
                          serves as an important rationale for the
                          development and clinical testing of an
                          anti-TNF antibody. [NIAID 93 I-182]
 DISEASES STUDIED/TREATED Inhibition of tumor necrosis factor
                          production in HIV infection [NIAID 93 I-182]
 CLASSIFICATION CODE      Immunomodulator [NIAID 93 I-182]
 ADVERSE EFFECTS          Chimeric A2 has been well tolerated in phase
                          I/II clinical trials. [NIAID 93 I-182]
 CHEMICAL/PHYSICAL DATA   DRUG DESCRIPTION: Chimeric A2 (cA2) is an
                          anti-TNF (tumor necrosis factor) mouse-human
                          monoclonal antibody [NIAID 93 1-182]
 SUBSTANCE DELIVERY DATA  DOSAGE FORM: 10 mg/kg in 150 ml of saline
                          from original glass vial containing 300 mg of
                          cA2 in a buffer solution (pH 7.2). [NIAID 93
                          I-182]
 SUBSTANCE DELIVERY DATA  MODE OF DELIVERY: Intravenous infusion.
                          [NIAID 93 I-182]
 SUBSTANCE DELIVERY DATA  STORAGE: The vials must be stored
                          refrigerated at 2 to 8 C. [NIAID 93 I-182]
 REFERENCES               Maini RN, Elliott MJ, Brennan FM, Williams
                          RO, Chu CQ, Paleolog E, Charles PJ, Taylor
                          PC, Feldmann M. Monoclonal anti-TNF alpha
                          antibody as a probe of pathogenesis and
                          therapy of rheumatoid disease. Immunol Rev
                          1995 Apr;144:195-223.
 REFERENCES               Dessi S, Batetta B, Spano O, Bagby GJ,
                          Tessitore L, Costelli P, Baccino FM, Pani P,
                          Argiles JM. Perturbations of triglycerides
                          but not of cholesterol metabolism are
                          prevented by anti-tumor necrosis factor
                          treatment in rats bearing an ascites hepatoma
                          (Yoshida AH-130). Br J Cancer 1995
                          Nov;72(5):1138-43.
 REFERENCES               Elliott MJ, Feldmann M, Maini RN. TNF alpha
                          blockade in rheumatoid arthritis: rationale,
                          clinical outcomes and mechanisms of action.
                          Int J Immunopharmacol 1995 Feb;17(2)141-5.
 REFERENCES               Walker RE, Kelly GG, Kilgariff CE, Woody JN,
                          Falloon J, Polis MA, Davey RT, Kovacs JA,
                          Masur H, Lane HC. A pilot study of the safety
                          and antiviral activity of a chimeric anti-TNF
                          antibody in HIV infected patients. Program
                          Abstr Intersci Conf Antimicrob Agents
                          Chemother. 1994 Oct 4-7;:58.
 REFERENCES               Vyakarnam A, Matear P, Meager A, Shultz T,
                          Loveday C, Beverley P. Inhibition of HIV-1
                          replication in CD4+ T cell subsets with
                          anti-TNF neutralising antibodies. Int Conf
                          AIDS. 1990 Jun 20-23;6(3):161 (abstract no.
                          S.A.317).
 ENTRY MONTH              9308
 LAST REVISION DATE       960417
 

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