Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Monoclonal antibody or fragment thereof
Reexamination Certificate
1994-06-02
2001-11-13
Carlson, Karen Cochrane (Department: 1653)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Monoclonal antibody or fragment thereof
C424S158100, C424S164100, C424S169100, C530S351000
Reexamination Certificate
active
06315999
ABSTRACT:
TECHNICAL FIELD
The present invention relates to pharmaceutical products for the treatment of sepsis and, in particular to products including an antibody to TNF-&agr; (tumour necrosis factor alpha). As used herein the term sepsis encompasses Gram negative and Gram positive bacteremia, septicemia and endotoxemia, as well as septic (or endotoxic) shock.
BACKGROUND ART
Septic shock is a condition which may be associated with Gram positive infections, such as those due to pneumococci and streptococci, or with Gram negative infections, such as those due to
Escherichia coli,
Klebsiella-Enterobacter, Pseudomonas, and Serratia. In the case of the Gram-negative organisms the shock syndrome is not due to bloodstream invasion with bacteria per se but is related to release of endotoxin, the lipopolysaccharide (LPS) moiety of the organisims' cell walls, into the circulation.
Septic shock is characterized by inadequate tissue perfusion and circulatory insufficiency due to diffuse cell and tissue injury and the pooling of blood in the microcirculation. Hypotension, oliguria, tachycardia, tachypnea and fever are observed in most patients.
The mortality rate associated with septic shock from gram negative bacteremia remains unacceptably high despite the availability of a wide variety of potent antimicrobial agents. The failure of antimicrobial agents to improve the outlook in septic shock is related to large part to the intrinsic toxicity of endotoxin (LPS) produced by gram negative bacteria. Antibiotics have no immediate effect on endotoxin and may transiently elevate circulating endotoxin levels following the initiation of therapy during Gram negative bacteremia.
Alternative measures have been sought to prevent the deleterious effects of endotoxemia. An attractive strategy has been the development of active or passive immunotherapy against endotoxin itself. Serotype specific immunity to LPS and polyclonal and monoclonal antibody immunotherapy directed against the core glycolipid of gram negative bacterial LPS have been at least partially successful in a number of experimental and clinical studies of septic shock.
Recent evidence indicated that the monocyte/macrophage derived cytokine, tumour necrosis factor-alpha, is a principal mediator of the hemodynamic and pathophysiologic effects of endotoxin. Polyclonal and monoclonal antibodies directed against tumor necrosis factor have demonstrated protective efficacy against potentially lethal doses of endotoxin as well as large intravenous doses of
Escherichia coli.
DISCLOSURE OF THE INVENTION
The present inventors have now established that by using a combination of antibody to the cytokine TNF-&agr; and antibody to LPS for the treatment of septic shock significant additional decreases in mortality relative to either antibody used alone, may be produced.
Thus, according to the present invention there is provided a pharmaceutical product containing an antibody to endotoxin (hereinafter referred to as anti-LPS) and an antibody to TNF-&agr; (hereinafter referred to as an anti-TNF) as a combined preparation for simultaneous mixed, simultaneous separate, or sequential, use in therapy of sepsis.
In one embodiment of the invention the pharmaceutical product may take the form of a pharmaceutical composition comprising anti-LPS and an anti-TNF and, optionally, a pharmaceutically acceptable, excipient diluent or carrier. The pharmaceutical composition is suitably for use in therapy of sepsis.
A further aspect of the invention provides for the use of an anti-LPS and an anti-TNF, in the manufacture of a pharmaceutical product for the treatment of sepsis. The invention also provides for the treatment of sepsis in animals, and in particular in man, by the combined administration of an anti-TNF and an anti-LPS. The pharmaceutical product of the present invention is particularly suitable for the treatment of septic shock associated with Gram negative endotoxemia. In addition, it is particularly suitable for the treatment of patients who are neutropenic for example because they are receiving chemotherapy for cancer.
The anti-TNF and anti-LPS antibodies for use according to the present invention may in general belong to any immunoglobulin class. Thus, for example anti-TNF or anti-LPS antibodies of immunoglobulin class G and/or immunoglobulin class M may be employed.
Each antibody may be of animal, for example mammalian origin and may be for example of murine, rat or human origin. Each may be a whole immunoglobulin, or a fragment thereof, for example a F(ab′)
2
, Fab′ or Fab fragment, or a fragment obtained by recombinant DNA techniques, for example Fv fragments (as described in International Patent Application WO89/02465).
The anti-TNF antibody may be polyspecific but is preferably monospecific and, particularly preferably is monospecific for human TNF-&agr;. The anti-LPS antibody may, likewise, be polyspecific or monospecific for LPS. The LPS molecule consists of a heteropolysaccharide chain covalently linked to a glycolipid (lipid A or core glycolipid). Part of the heteropolysaccharide chain, known as the core polysaccharide, has a structure which appears to be similar, or identical in closely-related strains of bacteria. The remainder of the chain is called the O-specific chain and is highly variable in composition. The anti-LPS antibody may be monospecific for the O-specific chain but is preferably monospecific for the core polysaccharide and particularly preferably for the core glycolipid. For example, it may be specific for the core glycolipid of LPS from the J5 mutant of
E. coli.
The antibodies may be polyclonal or monoclonal antibodies but are preferably monoclonal. Particularly useful antibodies for use according to the invention include recombinant anti-TNF and anti-LPS antibodies i.e. antibodies which have been produced using recombinant DNA techniques.
Especially useful recombinant antibodies include, (1) those having an antigen binding site at least part of which is derived from a different antibody, for example those in which the hypervariable or complementarity determining regions of one antibody have been grafted into the variable framework regions of a second, different, and preferably human, antibody (as described in European Patent Application EP-A-239400); (2) recombinant antibodies or fragments wherein non-Fv sequences have been substituted by non-Fv sequences from other, different antibodies (as described in European Patent Application EP-A-171496, EP-A-173494 and EP-A-194276); and (3) recombinant antibodies or fragments possessing substantially the structure of a natural immunoglobulin but wherein the hinge region has a different number of cysteine residues from that found in the natural immunoglobulin, or wherein one or more cysteine residues in a surface pocket of the recombinant antibody or fragment is in the place of another amino acid residue present in the natural immunoglobulin (as described in International Patent Application Nos. WO89/01974 and WO89/01782 respectively).
Each antibody (anti-TNF, anti-LPS) may be prepared using well-known immunological techniques employing the TNF-&agr; or LPS as antigen. Thus, in the case of anti-TNF for example, any suitable host may be injected with TNF-&agr; and the serum collected to yield the desired polyclonal anti-TNF antibody after appropriate purification and/or concentration, (for example by affinity medium). Alternatively, splenocytes or lymphocytes may be recovered from the TNF injected host and immortalised using for example the method of Kohler et al. Eur. J. Immunol. 6, 511, (1976), the resulting cells being diluted and cloned to obtain a single genetic line producing monoclonal anti-TNF&agr; antibodies in accordance with conventional practice. Antibody fragments may be produced using conventional techniques for example by enzymatic digestion e.g. with pepsin [Parham, J. Immunol. 131, 1985, (1983)] or papain [Lamoyi and Nisonoff, J. Immunol. 56, 235, (1983)]. Where it is desired to produce recombinant anti-TNF&agr; antibodies, these may be pro
Bodmer Mark William
Cross Alan S.
Opal Steven Michael
Sadoff Jerald C.
Carlson Karen Cochrane
Schneller Marina V.
Solvay S.A.
Venable
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