Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Structurally-modified antibody – immunoglobulin – or fragment...
Reexamination Certificate
2002-02-07
2004-12-14
Helms, Larry R. (Department: 1642)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Structurally-modified antibody, immunoglobulin, or fragment...
C424S130100, C530S388850
Reexamination Certificate
active
06830752
ABSTRACT:
FIELD OF THE INVENTION
The present invention concerns molecules which bind and neutralize the cytokine interferon-gamma. More specifically, the present invention relates to sheep-derived antibodies and engineered antibody constructs, such as humanized single-chain Fv fragments, chimeric antibodies, diabodies, triabodies, tetravalent antibodies and peptabodies which can be used to treat diseases wherein interferon-gamma activity is pathogenic. Examples of such diseases are: septic shock, cachexia, multiple sclerosis and psoriasis.
BACKGROUND OF THE INVENTION
Interferon-gamma (IFN&ggr;) is a member of the interferon family of immunomodulatory proteins and is produced by activated T helper type-1 cells (Th1 cells) and natural killer cells (NK cells). Apart from its potent antiviral activity, IFN&ggr; is known to be involved in a variety of immune functions (for a review, see Billiau, 1996) and inflammatory responses. Indeed, IFN&ggr; is the primary inducer of the expression of the major histocompatibility complex (MHC) class-II molecules (Steinman et al., 1980) by macrophages and other cell types and stimulates the production of inflammatory mediators such as tumor necrosis factor-alpha (TNF&agr;), interleukin-1 (IL-1) and nitric oxide (NO) (Lorsbach et al., 1993). In this respect, IFN&ggr; is shown to be important in the macrophage-mediated defence to various bacterial pathogens. Furthermore, IFN&ggr; is also shown to be a potent inducer of the expression of adhesion molecules, such as the intercellular adhesion molecule-1 (ICAM-1, Dustin et al., 1988), and of important costimulators such as the B7 molecules on professional antigen presenting cells (Freedman et al., 1991). Moreover, IFN&ggr; induces macrophages to become tumoricidal (Pace et al., 1983) and provokes Ig isotype switching (Snapper and Paul, 1987).
The anti-viral, tumoricidal, inflammatory- and immunomodulatory activity of IFN&ggr; clearly has beneficial effects in a number of clinical conditions. However, there are a number of clinical situations in which IFN&ggr;-activity has deleterious effects. These include cancer cachexia (Denz et al., 1993; Iwagaki et al., 1995), septic shock (Doherty et al., 1992), skin disorders such as psoriasis and bullous dermatoses (Van den Oord et al., 1995), allograft rejection (Landolfo et al., 1985; Gorczynski, 1995), chronic inflammations such as ulcerative colitis and Crohn's disease (WO 94/14467 to Ashkenazi & Ward), and autoimmune diseases such as multiple sclerosis (M S, Panitch et al., 1986), experimental lupus (Ozmen et al., 1995), arthritis (Jacob et al., 1989; Boissier et al., 1995) and autoimmune encephalomyelitis (Waisman et al., 1996).
Cachexia is a phenomenon often seen in cancer patients and is associated with losses of lean body mass, and altered carbohydrate and lipid metabolism. This so called ‘chronic wasting syndrom’ is often the immediate cause of death. In recent years, interest has focused on the role of proinflammatory cytokines in cancer related cachexia. Current data support the concept that cachexia is linked to the presence of certain cytokines among which IFN&ggr; seems to play a central role. Denz et al. (1993) reported that increased neopterin and decreased tryptophan concentrations—which are closely related to IFN&ggr;-activity—are detected in cachectic patients suffering from hematological disorders. Neopterin is synthesized and secreted by monocytes/macrophages upon stimulation by IFN&ggr; from activated T cells. Tryptophan is an indispensable amino acid which can be catabolized by indoleamine 2,3-dioxygenase, an enzyme induced by IFN's, and which absence initiates mechanisms responsible for cachexia (Brown et al., 1991). The correlation between high neopterin levels, decreased tryptophan levels and weight loss was confirmed by Iwagaki et al. (1995). In experimental models, cancer-induced cachexia can be altered by the administration of IFN&ggr; neutralizing antibodies (Matthys et al., 1991; Langstein et al., 1991) Septic shock is the result of a severe bacterial infection, and remains a common cause of death among critically ill, hospitalized patients despite improvements in supportive care (Bone et al., 1992). Although septic shock may be associated with gram-positive infections, attention has focused on the more common pathogenesis of gram-negative sepsis and the toxic role of endotoxin (=lipopolysaccharide or LPS), a component of the outer membrane of gram-negative and some gram-positive bacteria. Many of the effects of LPS are mediated through the release of cytokines such as TNF&agr; (Tracey, 1991), IL-1 (Wakabayashi et al., 1991) and IFN&ggr; (Bucklin et al., 1994). Much of the evidence supporting the role of these cytokines as mediators of septic shock comes from lethality studies involving the blockade of individual cytokines, resulting in protection of experimental animals from otherwise lethal doses of endotoxin or gram-negative bacteria. One of the first events in septic shock is the activation of T cells by antigen presenting cells onto which bacterial superantigen is bound (Miethke et al., 1993). Upon activation, for which co-stimulation of CD28 is essential (Saha et al., 1996), these T cells proliferate and produce a surge of proinflammatory cytokines such as IL-2, TNF&agr; and IFN&ggr; eventuating in the clinical syndrome. Also, it is hypothesized that LPS induces the expression of the &agr;1/&bgr;1 integrin (VLA-1) heterodimer on activated monocytes which then display an increased capacity to adhere to the endothelial basement membrane. Similar effects can be induced by incubation of monocytes with IFN&ggr; (Rubio et al., 1995). VLA-1 might also contribute to further monocyte activation and potentiation of the production of monocyte-derived pro-inflammatory cytokines during sepsis (Rubio et al., 1995). Although very promising results were obtained with antibodies neutralising TNF&agr; in experimental animal models, clinical trials with anti-TNF&agr; antibodies revealed only a slight reduction or even no reduction in mortality rate of patients with septic shock (Wherry et al., 1993; Reinhart et al., 1996). A fusion protein containing the extracellular portion of the TNF receptor and the Fc portion of IgG1 also did not affect mortality (Fisher et al., 1996). Pentoxifylline (PTX), a methyl xanthine derivative, is currently being tested for its effect on the outcome of septic shock. PTX is known to lower the serum concentrations of at least TNF&agr;, IL-1 and IFN&ggr; (Bienvenu et al., 1995; Zeni et al., 1996). Initial data reveal that PTX leads to an improvement of the clinical status of septic patients (Mandi et al., 1995). There is evidence that IFN&ggr; is a mediator of lethality during sepsis. Antibodies that either neutralize IFN&ggr; or block the IFN&ggr;-receptor are protecting against lethality (Bucklin et al., 1994; Doherty et al., 1992). A synergistic effect between IFN&ggr; and TNF&agr; has also been suggested (Doherty et al., 1992; Ozmen et al., 1994). Although not in itself lethal, IFN&ggr; has been shown to be essential for the manifestation of TNF-induced lethality in the generalized Shwartzman reaction (Ozmen et al., 1994).
Bullous, inflammatory and neoplastic dermatoses are a heterogenous group of skin disorders during which IFN&ggr; may play a pathogenic role. Bullous dermatoses encompass epidermolysis bullosa acquisita, bullous penihigoid, dermatitis herpetiformes Duhring, linear IgA disease, herpes gestationis, cicatricial pemhigoid, bullous systemic lupus erythematosis, epidermolysis bullosa junctionalis, epidermolysis bullosa dystrophicans, porphyria cutanea tarda and Lyell-Syndrome (Megahed, 1996). Also erythema exsudativum multiform major (Kreutzer et al., 1996), IgG-mediated subepidermal bullous dermatosis (Chan & Cooper, 1994), bullous lichen planus (Willsteed et al., 1991) and paraneoplastic bullous dermatosis (Pantaleeva, 1990) can be classified among the bullous dermatoses. A pathogenic role of IFN&ggr; during bullous dermatoses has been suggested by Van den Oord et al. (1995). The role of
Buyse Marie-Ange
Sablon Erwin
Helms Larry R.
Howrey Simon Arnold & White , LLP
Innogenetics N. V.
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