LIPOPOLYSACCHARIDE BINDING OPSONIN AND METHODS OF USE THEREOF

Abstract: An opsonin is disclosed which has been isolated from human serum and which is present at high levels in normal serum in distinction to the acute phase protein LBP. The opsonin comprises a protein in purified form that is capable of binding to lipopolysaccharide to form a complex that is recognized by a receptor on monocytes, macrophage cells and polymorphonuclear cells, and that possesses an apparent molecular weight of about 90 kD as determined by SDS-PAGE analysis. The opsonin has been further characterized and appears to be a complex of a protease and a substrate for such protease. The substrate appears to possess some structural similarity to protein C inhibitor, and the opsonin is believed to be derived from a protease cascade leading to its availability for interaction with LPS. Diagnostic and therapeutic utilities are proposed, and testing procedures, materials in kit form, recombinant materials and procedures, and pharmaceutical compositions are likewise set forth.

Description: LIPOPOLYSACCHARIDE BINDING OPSONIN AND METHODS OF USE THEREOF TECHNICAL FIELD OF THE INVENTION The present invention relates to newly discovered and isolated proteins and to methods and compositions including such proteins for preventing or treating sepsis. More particularly, the- present invention relates to a molecule that binds to lipopolysaccharide (LPS) and to the CD14 monocyte differentiation antigen, and to antibodies thereto that may thereby inhibit the binding of LPS complexes by CD14-expressing cells. BACKGROUND OF THE INVENTION Sepsis is morbid condition induced by a toxin, the introduction or accumulation of which is most commonly caused by infection or trauma. The initial symptoms of sepsis typically include chills, profuse sweat, irregularly remittent fever, prostration and the like, followed by persistent fever, hypotension leading to shock, neutropenia, leukopenia, disseminated intravascular coagula.tion, adult respiratory distress syndrome and multiple or **,g ,an failure. Sepsis-inducing toxins have been found associated with pathogenic bacteria, viruses, plants and venoms. Among the well described bacterial toxins are the endotoxins or lipopolysaccharides(LPS) of the gram-negative bacteria. These molecules are glycolipids that are ubiquitous in the outer membrane of all " gram-negative bacteria. While the chemical structure of most of the LPS molecule is complex and diverse, a common feature is the lipid A region of LPS [E. Th. Rietschel et al., in Handbook of Endotoxins, 1:187-214 eds., R.A. Proctor and E. Th. Rietschel, Elsevier, Amsterdam (1984)]; recognition of lipid A in biologic systems initiates many, if not all, of the pathophysiologic changes of sepsis. Because lipid A structure is highly conserved among all types of gram- negative organisms, common pathophysiologic changes characterize gram-negative sepsis. LPS is believed to be a primary cause of death in humans during gram-negative sepsis, particularly when the symptoms include adult respiratory distress syndrome (ARDS) [van Deventer et al. , Lancet, 1:605 (1988); Ziegler et al., J. Infect. Pis.. 136:19-28 (1987)]. For instance, one particular cytokine, tumor necrosis factor alpha/cachectin (TNF) , has recently been reported to be a primary mediator of septic shock [Beutler et al., N. Enq. J. Med. f 316:379 (1987)]. Intravenous injection of LPS endotoxin from bacteria into experimental animals and man produces a rapid, transient release of TNF [Beutler et al., J. Immunol. , 135:3972 (1985); Mathiεon et al., J. ' Clin. Invest. . 81:1925 (1988)]. Evidence that TNF is a critical mediator of septic shock comes primarily from experiments in which pretreatment of animals with anti- TNF antibodies reduces lethality [Beutler et al., Science. 229:869, (1985); Mathison et al., J. Clin. Invest. 8JL:1925 (1988)]. These reports suggest that interruption of the secretion of TNF caused by LPS or other factors would ameliorate the often lethal symptoms of sepsis. Current concepts support the contention that the primary response of the host to LPS (including man) involves the recognition of LPS by cells of the monocyte/macrophage lineage, followed by the rapid elaboration of a variety of cell products including the general group known as cytokines. Other cell types believed to participate in sepsis and in particular in the response to LPS are polymorphonuclear leukocytes (PMN) and endothelial cells; each of these cell types are also capable of responding to LPS with the elaboration of potent inflammatory substances, and in the case of polymorphonuclear leukocytes, the elaboration of cytotoxic molecules. Upon introduction of LPS into the blood, it may bind to a protein termed lipopolysaccharide binding protein (LBP) . LBP is a 60 kD glycoprotein present at concentrations of less than 100 ng/ml in the serum of healthy animals and man. During the acute phase, LBP is synthesized by hepatocytes, " and reaches concentrations of 30-50 ug/ml in serum. LBP can be purified from acute phase human and rabbit serum [Tobias et al. J. Exp. Med.. 164:777-793 (1986) ] . LBP recognizes the lipid A region of LPS and forms high affinity, 1:1 stoichiometric complexes with both rough and smooth form LPS [Tobias et al., J. Biol. Chem.. 264:10867-10871 (1989)]. LBP bears N-terminal sequence hemology with the LPS-binding protein known as bactericidal permeability-increasing factor, (BPI) [Tobias et al., J. Biol. Chem., 263 . :13479-13481, (1988)]. BPI is stored in the specific granules of PMN [Weiss et al., Blood, 69.:652-659, (1987)] and kills gram-negative bacteria by binding LPS and disrupting the permeability barrier [Weiss et al., J. Immunol.. 132:3109-3115, (1984)]. In contrast to BPI, LBP is not directly cytotoxic for gram-negative bacteria [Tobias et al., J\_ Biol. Chem.. 161:13479-13481, (1988)] and its precise biological function has been obscure. By way of further background, the cells of the monocyte/macrophage lineage perform diverse immune function including the phagocytosis of micro-organisms, the uptake of antigenic material and its presentation in a form which is stimulatory to helper T cells. They are probably also involved in the immune surveillance against tumors and they secrete some complement components and cytokines. Surface membrane antigens play a critical role in regulating these activities. Several monocyte/macrophage surface antigens have been identified and their molecular weight has been determined. One such antigen, CD14, is a 55-kD glycoprotein expressed by monocytes, macrophages, and activated granulocytes. It is recognized by a number of monoclonal antibodies (mAbs) including M02, MY4, 3C10 and LEUM3. Although no biological function has yet been ascribed to CD14, its restricted expression on mature cells suggests an important effector function. The nucleotide sequence of the gene encoding the monocyte cell surface differentiation antigen CD14 has been determined and the amino acid residue sequence of CD14 has been deduced therefrom [Ferrero et al., Nucleic Acids Research, 16:4173 (1988)]. Human serum contains trace quantities of the protein lipopolysaccharide binding protein (LBP) , and it has recently been shown that this protein interacts first with LPS (endotoxin) and then with CD14 on the surface of phagocytes to provoke cellular responses that underlie the phenomenon of septic shock [Wright et al.. Science, 249:1431-1433 (1990)]. However, several observations suggested that, while LBP can participate in the binding of LPS and CD14, it may not be the only protein involved. Three observations have been noted that commend this conclusion: (1) the addition of purified LBP to human mononuclear cells did not restore the ability of these cells to synthesize TNF in response to physiological doses of LPS as observed in the presence of serum; (2) LBP is an acute phase reactant that is present in satisfactory quantities during the acute phase response, but sufficient quantities may not be present in healthy individuals to explain their responses to LPS; and (3) "LPB-like" activity has been assayed by measuring the ability of solutions to mediate the binding of LPS to macrophages, and very high levels in serum from healthy individuals have been found, which levels are far too high to be explained by the content of LBP in the serum. These observations were the incentive for seeking a novel molecule in human serum that had the properties of binding LPS and CD14. In copending United States Application Serial No. 07/473,609, a molecule named •• septin" by the Applicant was identified that was found to function as an opsonin, and that exhibited the following profile of characteristics: (a) the opsonin is^ capable of binding to lipopolysaccharide (LPS) to form a complex that is recognized by a receptor or monocytes, macrophage cells and polymorphonuclear cells (PMNs) ; (b) the opsonin possess an apparent molecular weight of about 90 kD as determined by SDS-PAGE; (c) the opsonin is present in high levels in normal serum, and enhances the elaboration of TNF by monocytes in response to LPS; (d) a complex of the opsonin and LPS stimulates PMN activity, promotes increased PMN adhesion to endotheliu , causes PMN degranulation and upregulateε the expression of the adhesion molecule CR3? and (e) the opsonin is unable to bind to the receptor CD14 when first bound in a complex with Lipid IVa, the biosynthetic precursor of LPS. The apparent involvement of the molecule with host response to invasion and other traumatic events forecast an active role for the molecule in both diagnostic and therapeutic applications related to infection and trauma. Subsequent study of the molecule has revealed additional structural and functional characteristics that enhance the understanding of the molecule and, in turn, are believed to broaden its utility. It is therefore toward the increased understanding and application of the molecule that the present Application is directed. SUMMARY OF THE INVENTION In accordance with the present invention, a molecule named by the applicant herein "septin" has been discovered that functions as an opsonin. The opsonin comprises a protein in purified form that as its primary affirmative characteristics, is capable of binding to lipopolysaccharide to form a complex recognized by a receptor on monocytes, macrophage cells and polymorphonuclear cells; and that possesses an apparent molecular weight of about ' 90 kD as determined by SDS-PAGE analysis. The present opsonin possesses additional affirmative characteristics, among them that it is present in high levels in normal serum, and enhances the elaboration of TNF by monocytes in response to lipopolysaccharide. Also, when the opsonin is in a complex with lipopolysaccharide, it stimulates polymorphonuclear cell activity, promotes the increased adhesion of polymorphonuclear cells to endothelium, upregulates the expression of the adhesion molecule CR3, and causes the degranulation of said polymorphonuclear cells. Further properties of the present opsonin include its inability to bind to the receptor CD14 when first bound in a complex with the biosynthetic precursor of lipopolysaccharide known as Lipid IVa. While the complete role that the present isolate plays in the cascade of reactions to host invasion is as yet undefined, its participation in the elicitation of certain of the activities and conditions associated with mobilization against host invasion is clear. Accordingly, the opsonin possesses the potential for use as a diagnostic tool to identify and perhaps differentiate between various stimuli whether invasive or idiopathic, by the activation of" the present opsonin that such stimuli may promote. The present opsonin possesses certain characteristics in common with lipopolysaccharide binding protein (LBP) . Like LBP, the present opsonin H-s serum-derived and binds LPS-coated particles and'mediates their attachment to macrophages in a CD14-dependent fashion. Unlike LBP, however, the present opsonin has a different molecular weight from LBP, is present in normal serum in high levels, and, for example, may be present in amounts ranging up to on the order of about 4 μg/ml. This is significantly greater than the known opsonin LBP, which as indicated earlier, is present in a maximal concentration of less than 100 ng/ l in healthy individuals. The present opsonin is also significantly more potent than LBP, and for example, exhibits as much as 20-fold greater activity in the mediation of the binding of complexes with LPS-coated erythrocytes with macrophage cells. Particularly, maximal binding of lipopolysaccharide to monocytes, macrophage cells and polymorphonuclear cells as measured by the binding activity of LPS-coated erythrocytes to human macrophage cells may be achieved by the presence and binding with such erythrocytes of a concentration of no more than about 0.05 μg/ml of the opsonin. The present opsonin is also distinct from LBP by the peak of activity that it exhibited in elution with NaCl, as described in Example 1 infra. f and as shown in FIGURE 1. Particularly, the present opsonin was eluted with BioRex resin with an NaCl gradient and displayed a prominent peak at about 200 mM NaCl, in contrast to a far smaller peak for LBP that appeared at >500 mM NaCl. Further discussion of these data appears in Example 1. Further study and characterization of the opsonin of the present invention reveals that it comprises a complex of a protease and a substrate for the protease. More particularly, the substrate appears to bear some structural similarity to human protein C inhibitor (PCI) . The opsonin is now theorized to participate in a protease cascade in conjunction with its interaction with LPS, thereafter is believed to form a complex and interact with CD14. As such, the exact molecular weight and structure of the perceived components of the opsonin are yet to be determined, and it is theorized that the opsonin may be derived from several proteases and proteins which interact. The opsonin of the invention has been studied by exposure to protease inhibitors, and antibodies to the opsonin have likewise been raised. The data presented hereinafter reveal that the activity of the opsonin is substantially diminished by contact with protease inhibitors. Particular protease inhibitors that have been found to exert this activity are selected from the group consisting of antipain, leupeptin, benzamidine, chymostatin, pepstatin A, aprotinin and mixtures of these. The present invention likewise extends to antibodies developed to the opsonin, including antibodies that may be raised against a component of the protease cascade that appears to give rise to the opsonin. An exemplary antibody to the opsonin was raised in rabbits and has been determined to completely block the binding of LPS to monocytes (MO) . Both monoclonal and polyclonal antibodies to the opsonin are contemplated and includeable herein. The present opsonin was initially identified and characterized and found to comprise a 90 kilodalton (kD) protein on sodium dodecyl sulfate polyacrylamide gel 9 electrophoresis (SDS-PAGE) . As set out above, the opsonin may be prepared by isolation and purification from body fluid and particularly serum. The serum or other fluid may be subjected to a series of known isolation techniques, whereupon the opsonin may be recovered. The present invention naturally contemplates alternate means for preparation of the opsonin, including where applicable known genetic replicative techniques, and the invention is accordingly intended to cover such synthetic preparations within its scope. The isolation of the cDNA amino acid sequence will facilitate the reproduction of the opsonin by recombinant genetic techniques as discussed in detail hereinafter. Thus, the DNA sequence encoding the present opsonin or analogs thereof can be used to construct vectors for expression in host systems by recombinant DNA techniques. The invention further includes a method for detecting idiopathic or invasive stimuli on the basis of their ability to elicit the activities affected by the present opsonin. In particular, invasive stimuli could be identified and detected by their ability to bind with the present opsonin and to form a complex recognized by a receptor on monocytes, macrophage cells and polymorphonuclear cells. In this method, macrophage cells derived for example, from the THP1 cell line could be treated with/exposed to a number of known stimulator materials such as endotoxin, trypanosomes or the like, as a control, while parallel ' cellular samples could be treated with or exposed to an extract of material from the presumed situs of the infective stimulus. All samples could thereafter be incubated in accordance with the methods described above, and thereafter subjected to the sequence of separation techniques also defined, whereupon testing of the resulting isolates derived from the control and unknown Samples could be compared to determine whether a macrophage activating binding complex involving the opsonin, if any, is developed and is identical or even similar either structurally or functionally. In similar fashion, an assay system for screening of potential drugs effective to counteract the opsonin may be prepared. In one instance, the test drug could be administered to a macrophage sample with the opsonin and a quantity of lipopolysaccharide present, to determine its effect upon the binding activity of the opsonin to either the LPS or the macrophage. In an alternate procedure, the opsonin may be introduced into a cellular test system in which the opsonin is known to be active, and the prospective drug may also be introduced to the same cell culture and the culture may thereafter be examined to observe any changes in the activity of the opsonin in comparison with the addition of the prospective drug alone, or the effect of added quantities of the known opsonin. The present invention also relates to a method for detecting the presence of stimulated, spontaneous, or idiopathic pathological states in mammals, by measuring the activity and presence of the opsonin of the present invention. More particularly, the activity of the opsonin may be followed directly by the assay techniques discussed later on, through the use of an appropriately labeled quantity of the opsonin. Alternately, the opsonin can be used to raise binding partners or antibodies that could in turn, be labeled and introduced into a medium such as serum, to test for the presence of opsonin therein, and to thereby assess the state of the host from which the medium was drawn. Thus, both the opsonin and any antibodies that may be raised thereto, are capable of use in connection with various diagnostic techniques, including immunoassayε, such as a radioimmunoassay, using for example, an 11 antibody to the opsonin that has been labeled by either radioactive addition, reduction with sodium borohydride, or radioiodination. In an immunoassay, a control quantity of the opsonin, its antibody, or the like may be prepared and labeled with an enzyme, a specific binding partner and/or a radioactive element, and may then b^ introduced into a blood sample of a mammal believed offee undergoing invasion. After the labeled material or„,its binding partner(s) has had an opportunity to react with sites- within the sample, the resulting mass may be examined by known techniques, which may vary with the nature of the label attached. In the instance where a radioactive label, such as the isotopes U C, 131 I, 3 H, I and S are used, known currently available counting procedures may be utilized. In the instance where the label is an enzyme, detection may be accomplished by any of the presently utilized colorimetric, spectrophotometric, fluorospectro- photometric or gasometric techniques known in the art. The present invention includes an assay system which may be prepared in the form o€ a test kit for the • quantitative analysis of the extent of the presence of the opsonin. The system or test kit may comprise a labeled component prepared by one of the radioactive and/or enzymatic techniques discussed here'in, coupling a label to the opsonin; and one or more additional immunochemical reagents, at least one of which is a free or immobilized ligand, capable either of binding with the labeled component, • its binding partner, one of the components to be determined or their binding partner(s) . In a further embodiment, the present invention relates to certain therapeutic methods which would be based upon the activity of the opsonin, antibodies to the opsonin, or upon agents or other drugs determined to possess the same or an antagonistic activity. A first therapeutic method is associated with the prevention of the manifestations of conditions following from the binding activity of the opsonin, such as inflammation and fever, and comprises administering either an antibody to the opsonin, an agent capable of modulating the production and/or activity of the opsonin, or an agent not an antibody to the opsonin that is capable of acting as an antagonist to the opsonin, either individually or in mixture with each other in an amount effective to prevent the development of those conditions in the host. More specifically, the therapeutic method generally referred to herein could include the method for the treatment of sepsis, inflammation and/or fever by the administration of pharmaceutical compositions that may comprise effective quantities of antibodies to the opsonin, or other equally effective drugs developed for instance by a drug screening assay prepared and used in accordance with a further aspect of the present invention. A variant embodiment of this therapeutic method could include initially detecting the presence and activity of the opsonin and thereafter administering the appropriate pharmaceutical composition. Accordingly, it is a principal object of the present invention to provide an opsonin in purified form that exhibits certain characteristics and activities associated with the host response to invasive stimuli in mammals. It is a further object of the present invention to provide methods for the preparation of the opsonin, including recombinant means. It is a further object of the present invention to provide a method for detecting the presence of the opsonin in mammals in which invasive, spontaneous, or idiopathic pathological states such as infection are suspected to be present. It is a further object of the present invention to provide a method and associated assay system for screening substances such as drugs, agents and the like, potentially effective in either mimicking the activity or combating the adverse effects of the opsonin in mammals. It is a still further object of the present invention to provide a method for ' the treatment of mammals to control the amount or activity of the opsonin, so as to alter the adverse consequences of''such presence or activity. It is a still further object of the present invention to provide a method for the treatment of mammals to promote the amount or activity of the opsonin, so as to treat or avert the adverse consequences of invasive, spontaneous or idiopathic pathological states. It is a still further object of the present invention to provide pharmaceutical compositions for use in therapeutic methods which comprise or are based upon the opsonin or its binding p'artner(s) , or upon agents or drugs that control the production, or that mimic or antagonize the activities of the opsonin. Other objects and advantages will become apparent to those skilled in the art from a review of the ensuing description which proceeds with reference to the following illustrative drawings. BRIEF DESCRIPTION OF THE DRAWINGS FIGURE 1 is a graph depicting the purification of the present opsonin septin. Human plasma was exposed to BioRex in batch fashion, then poured into a column and eluted with the NaCl gradient illustrated. OD 280 and activity of fractions are illustrated. Septin-rich fractions, pooled as shown, possessed a dominant 90 kD band and >10 lower molecular weight bands. Subsequent purification on Mono Q yielded a homogeneous preparation shown in the inset. FIGURE 2 is a graph depicting how septin-LPS complexes cause increased expression of CR3 on PMN. Suspensions of PMN were incubated for 30 minutes at 37 β C with doses of LPS (Re) in the presence and absence of the opsonin septin, and expression of CR3 on the cell surface was determined by FACS, as described in Lo et al, J. Immunol. , 143(10) :3325-3329 (1989). Expression of FcRIII was unchanged in this period. FIGURE 3 is a graph depicting how septin-LPS complexes cause increased binding activity of CR3 on PMN. PMN were incubated in assay plates for 45 minutes at 37"C with doses of LPS (Re) in the presence and absence of septin. The resulting monolayers were washed and incubated for 30 minutes with C3bi-coated erythrocytes, and the attachment index was enumerated as the number of erythrocytes bound per 100 phagocytes, as described in Wright et al., 3___ Immunol.. 136(5) :1759-1764 (1986). DETAILED DESCRIPTION In accordance with the present invention there may be employed conventional molecular biology, microbiology, and recombinant DNA techniques within the skill of the art. Such techniques are explained fully in the literature. See, e.g., Maniatis, Fritsch & Sambrook, 15 "Molecular Cloning: A Laboratory Manual" (1982) ; "DNA Cloning: A Practical Approach," Volumes I and II (D.N. Glover ed. 1985) ; "Oligonucleotide Synthesis" (M.J. Gait ed. 1984) ; "Nucleic Acid Hybridization 11 [B.D. Ha eε & S.J. Higgins edε. (1985)]; "Transcription And Translation" [B.D. Hames & S.J. Higgins, eds. (1984)]; "Animal Cell Culture" [R.I. Freshney, ed. (1986)]; "Immobilized Cells And Enzymes" [IRL Press, (1986)]; B. Perbal, "A Practical Guide To Molecular Cloning" (1984). Therefore, if appearing herein, the following terms shall have the definitions set out below. The term "stimulus" and its plural as used herein are * intended to apply to invasive events such as infection, as well as conditions caused by wounding, and to idiopathic or spontaneous states that may for example, originate from cellular or metabolic derangements or other causes. The term "opsonin" as used throughout the present application and claims refers to protein material having the profile of activities set forth herein and in the Claims. Accordingly, proteins displaying substantially equivalent or altered activity are likewise contemplated. These modificationε may'be deliberate, for example, such as modifications obtained through site-directed mutagenesis, or may be accidental, such as those obtained through mutations in hosts that are producers of the opsonin. Also, the term 1 "opsonin" is intended to include within its scope proteins specifically recited herein as well aε all εubstantially homologous analogs and allelic variations. A "replicon" is any genetic element (e.g., plasmid, chromosome, virus) that functions as an autonomous unit of DNA replication in vivo; i.e. , capable of replication under its own control. A "vector" is a replicon, such as plasmid, phage or cosmid, to which another DNA segment may be attached so as to bring about the replication of the attached segment. A "DNA molecule" refers to the polymeric form of deoxyribonucleotides (adenine, guanine, thymine, or cytosine) in its either single stranded form, or a double-stranded helix. This term refers only to the primary and secondary structure of the molecule, and does not limit it to any particular tertiary forms. Thus, thiε term includes double-stranded DNA found, inter alia, in linear DNA molecules (e.g., restriction fragments) ' , viruses, plasmids, and chromosomes. In discussing the structure of particular double-stranded DNA molecules, sequences may be described herein according to the normal convention of giving only the sequence in the 5* to 3 1 direction along the nontranscribed εtrand of DNA (i.e. , the strand having a sequence homologous to the mRNA) . A DNA "coding sequence" is a double-stranded DNA sequence which is transcribed and translated into a polypeptide in vivo when placed under the control of appropriate regulatory sequences. The boundaries of the coding sequence are determined by a start codon at the 5' (amino) terminus and a translation stop codon at the 3 ' (carboxyl) terminus. A coding sequence can include, but iε not limited to, prokaryotic εequences, cDNA from eukaryotic mRNA, genomic DNA sequences from eukaryotic (e.g., mammalian) DNA, and even synthetic DNA sequences. A polyadenylation signal and transcription termination sequence will usually be located 3 1 to the coding sequence. 17 Transcriptional and translational control sequences are DNA regulatory sequences, such as promoters, enhancerε, polyadenylation signals, terminators, and the like, that provide for the expresεion of a coding sequence in a host cell. A "promoter sequence" is"a DNA regulatory region capable of binding RNA polymerase in a cell and initiating transcription of a downstream (3' direction) coding sequence. For purposes of defining the present invention, the promoter sequence is bounded at its 3 1 terminus by the transcription " initiation site and extends upstream (5' direction) to include the minimum number of baseε or elementε necessary to initiate transcription at levels detectable above background. Within the promoter sequence will be found a transcription initiation site (conveniently defined by mapping vith nuclease SI) , as well as protein binding domains (consensus sequences) responsible for the bind ng of * RN " olymerase. Eukaryotic promoters will 6 " ften, but not always, contain "TATA" boxes and "CAT" boxes. Prokaryotic promoterε contain Shine-Daigarno sequences in addition to the -10 and -35 consenεus sequences. A coding εequence iε ""under the control" of transcriptional and translational control sequences in a cell when RNA polymerase transcribes the coding sequence into mRNA, which is then 'translated into the protein encoded by the coding sequence. * ■ A "signal sequence" can^be included before the coding εequence. Thiε εequence encodeε a έignal peptide, N- terminal to the polypeptide, that communicates to the host cell to direct the polypeptide to the cell surface or secrete the polypeptide into the media, and this signal peptide iε clipped off by the hoεt cell before the protein leaves the cell^ * Signal sequences can be found associated with a variety of proteins native to prokaryotes and eukaryotes. For instance, alpha-factor, a native yeast protein, is secreted from yeast, and its signal εequence can be attached to heterologous proteins to be secreted into the media (See U.S. Patent 4,546,082, EPO 0 116 201, publication date 12 January 1983; U.S. Patent Application Serial No. 522,909, filed 12 August 1983) . Further, the alpha-factor leader and its analogs have been found to secrete heterologous proteins from a variety of yeaεt, εuch aε Saccharomyceε and Kluyverom ceε, (EPO 88312306.9 filed 23 December 1988; U.S. Patent Application Serial No. 139,682, filed 30 December 1987, and EPO Publication No. 0 301 669, publication date 1 February 1989) . A cell haε been "tranεformed" by exogenouε or heterologous DNA when such DNA has been introduced inside the cell. The transforming DNA may or may not be integrated (covalently linked) into chromosomal DNA making up the genome of the cell. In prokaryotes, yeast, and mammalian cells for example, the tranεforming DNA may be maintained on an epiεo al element such as a plasmid. With reεpect to eukaryotic cellε, a εtably tranεformed cell iε one in which the transforming DNA haε become integrated into a chromosome so that it is inherited by daughter cells through chromosome replication. This stability is demonstrated by the ability of the eukaryotic cell to establish cell lines or clones comprised of a population of daughter cells containing the transforming DNA. A "clone" is a population of cells derived from a single cell or common ancestor by mitosis. A "cell line" is a clone of a primary cell that iε capable of εtable growth in vitro for many generationε. Two DNA εeguenceε are "substantially homologous" when at least about 75% (preferably at least about 80%, and most preferably at least about 90 or 95%) of the nucleotides match over the defined length of the DNA sequenceε. Sequenceε that are substantially homologous can be 19 identified by comparing the sequences using standard software available in sequence data banks, or in a Southern hybridization experiment under, for example, stringent conditions as defined for that particular syεtem. Defining appropriate hybridization conditions is within the skill of the art. See, e.g., Maniatis et al., supra; DNA Cloning, Vols. I & II, supra; Nucleic Acid Hybridization, supra. A "heterologous" region of the DNA construct is an identifiable segment of DNA within a larger DNA molecule that is not found in association with the larger molecule in nature. Thus, when the heterologous region encodes a mammalian gene, the gene will usually be flanked by DNA that does not flank the mammalian genomic DNA in the genome of the source organism. Another example of a heterologous coding sequence iε a construct where the coding sequence itself is not found in nature (e.g., a cDNA where the genomic coding sequence contains intronε, or synthetic sequences having codons different than the native gene) . Allelic variations or naturally-occurring mutational events do not give rise to a heterologous region of DNA as defined herein. A composition comprising "A" (where "A" is a single protein, DNA molecule, vector, etc.) is subεtantially free of "B" (where "B" comprises one or more contaminating proteins, DNA molecules, vectors, etc.) when at least about 75% by weight of the proteins, DNA, vectors (depending on the category of species to which A and B belong) in the composition iε "A". Preferably, "A" comprises at least about 90% by weight of the A+B species in the composition, most preferably at least about 99% by weight. It is also preferred that a composition, which is subεtantially free of contamination, contain only a εingle molecular weight species having the activity or characteristic of the species of interest. An "antibody" is any immunoglobulin, including antibodies and fragments thereof, that bindε a specific epitope. The term encompasεeε, inter alia, polyclonal, monoclonal, and chimeric antibodieε, the laεt mentioned deεcribed in further detail in U.S. Patent Nos. 4,816,397 and 4,816,567. An "antibody combining site" is that structural portion of an antibody molecule comprised of heavy and light chain variable and hypervariable regions that specifically binds antigen. The phrase "antibody molecule" in itε various grammatical forms as used herein contemplates both an intact immunoglobulin molecule and an immunologically active portion of an immunoglobulin molecule. Exemplary antibody moleculeε are intact immunoglobulin moleculeε, εubstantially intact immunoglobulin molecules and those portions of an immunoglobulin molecule that containε the paratope, including thoεe portions known in the art as Fab, Fab 1 , F(ab') 2 and F(V), which portions are preferred for use in the therapeutic methods described herein. Fab and F(ab') 2 portions of antibody molecules are prepared by the proteolytic reaction of papain and pepεin, respectively, on substantially intact antibody molecules by methodε that are well-known. See for example, U.S. Patent No. 4,342,566 to Theofilopolouε et al. (The disclosures of the art cited herein are hereby incorporated by reference.). Fab* antibody molecule portions are also well-known and are produced from F(ab*) 2 portionε followed by reduction of the disulfide bonds linking the two heavy chain portions aε with mercaptoethanol, and followed by alkylation of the resulting protein mercaptan with a reagent such as 21 iodoacetamide. An antibody containing intact antibody moleculeε is preferred herein. The phrase "monoclonal antibody" in its variouε grammatical formε refers to an antibody having only one species of antibody combining site capable of immunoreacting with a particular antigen. A monoclonal antibody thus typically displays a single binding affinity for any antigen with which it immunoreacts. A monoclonal antibody may therefore contain an antibody molecule having a plurality of antibody combining sites, each immunospecific for ,a different antigen; e.g., a bispecific (chimeric) monoclonal antibody. The phrase "εubεtantially simultaneously" is used herein to mean within a time period sufficient to produce concurrent results; e.g..,, bacterial lysis as a result of antibiotic administration,and amelioration or prevention of symptomε of sepsiε that may occur as a result of that lysis by administration of an anti-opsonin antibody, peptide analog, or a εubcombination or combination thereof, aε deεcribed herein. The phraεe "pharmaceutically acceptable" referε to molecular entitieε and cσmpoεitions that are physiologically tolerable and do not typically produce an allergic or similar untoward reaction, such as gastric upset, dizziness and the like, when administered to a human. The phrase "therapeutically effective amount" iε uεed herein to mean an amount sufficient to prevent, and preferably reduce by at leaεt about 3 t 0 percent, more preferably by at least 50 percent, most preferably by at least 90 percent, a clinically significant change in the plasma level of TNF, or other feature of septic shock such aε elevated blood pressure, fever or white cell count. In its primary aεpect, the present invention concerns the isolation and identification of a newly discovered particular factor hereinafter referred to as the opsonin, that has been found to be present in serum or plasma, and that participates in the binding of εtimulator materialε that characteristically accompany an invaεive εtimulus such as lipopolyεaccharide (LPS),. to monocyteε, macrophage cells and polymorphonuclear leukocytes such as bacteria, virus, certain tumors, protozoa and other toxins such as endotoxin, or an idiopathic state. Previous studies by the applicant have shown that the serum protein, LBP, binds to LPS-coated erythrocytes and mediates their binding to the antigen CD14 on human macrophageε, and that the macrophage-LPS complex εo formed, in turn, activateε the elaboration of certain factorε such as TNF, that appear to mediate and mobilize the host against the invasive stimulus. To determine if additional serum proteins with the ability to bind LPS and CD14 and thereby initiate this catabolic responεe exist, human serum was fractionated and each fraction assayed for its capacity to mediate interaction of LPS- coated erythrocytes with macrophages. The result of this investigation aε set forth herein iε the discovery of the LPS-binding opsonin that has been named herein "septin". As stated earlier, the opsonin comprises a protein in purified form that as its primary affirmative characteristicε, iε capable of binding to lipopolysaccharide to form a complex recognized by a receptor on monocytes, macrophage cellε and polymorphonuclear cells; and that posseεεeε an apparent molecular weight of about 90 kD aε determined by SDS-PAGE analysis. More particularly, the opsonin of the invention haε now been determined to comprise a complex of a protease and a substrate for such protease. This determination is consistent with the present characterization of the opsonin aε participating in a proteaεe cascade that includes interaction of the opεonin with LPS and the formation of a complex capable of binding with CD14. While the opεonin appears to possess an apparent molecular weight of about 93 kilodaltons (kD) , the exact attribution of the molecular weight to the respective components believed to comprise the opsonin is as yet not fully determined. It is theorized that the substrate for the protease, which appears to possess some structural similarity to protein C inhibitor (PCI) , a plasma protein of the serpin family; however, experimentation with a sample of protein C inhibitor has revealed no such similarity in activity. Further investigation of the interaction of the protease or proteaseε with the substrate will follow in an effort to elucidate the originε of the activity of the complex molecule from its putative precursor components. Aε a reεult of the determination that the preεent opsonin iε a complex of a proteaεe and a εubεtrate for εuch protease, certain experimentation has determined that the activity of the opsonin may be blocked by the action of protease inhibitors. More particularly, certain protease inhibitors have been examined, and εuch inhibitorε showing activity against the preεent opsonin may be selected from the group consisting of antipain, leupeptin, benzamidine, chymostatin, pepstatin A, aprotinin and mixtures of these. Accordingly, methods for blocking the action of the opsonin and any consequent diagnostic or therapeutic utilities to which such methods pertain, would comprise the administration or application, as the case may be, of the noted protease inhibitorε. The present opεonin poεεesses additional affirmative characteristics, among them that it is present in high levels in normal serum, and enhances the elaboration of TNF by monocyteε in reεponεe to lipopolysaccharide. Alεo, when the opεonin iε in a complex with lipopolysaccharide, it stimulateε polymorphonuclear cell activity, promoteε the increaεed adheεion of polymorphonuclear cells to endothelium, upregulates the expreεsion of the adhesion molecule CR3, and cauεeε the degranulation of said polymorphonuclear cells. Further properties of the preεent opsonin include itε inability to bind to the receptor CD14 when the opεonin is first bound in a complex with the biosynthetic precurεor of lipopolysaccharide known as Lipid IVa. The present invention contemplates methods of treating and/or preventing one or more of the symptoms of sepsis, particularly those associated with a transient increase in the blood level of TNF, such as fever, hypotension, neutropenia, leukopenia, thrombocytopenia, shock and multiple organ failure. Patients in need of such treatment include those at risk for or εuffering toxemia, such as endotoxemia resulting from a gram-negative bacterial infection, serpent venom poisoning, hepatic failure, and the like. In addition, some patients having a gram-positive bacterial, viral or fungal infection display the εymptomε of sepεis and may benefit from a therapeutic method of thiε invention. Patients particularly able to benefit from the preεent invention are thoεe εuffering infection by E. coli. Haemophilus influenza B, Neisεeria menin itides. staphylococci, or pneumococci. Patientε at risk for sepsis include those εuffering burns, gunεhot woundε, renal or hepatic failure due to chemical poiεoning or abuεe, and the like. Thuε, in one embodiment, the preεent invention contemplateε a method of ameliorating one or more of the εymptomε of εepsis by administering to a patient in need of such therapy a therapeutically effective amount of an anti-opsonin antibody. Preferred therapeutically 25 effective amounts for the agents used herein as active ingredients include those described hereinafter. A clinically significant increase in the plasma level of TNF iε an increaεe to at least about 25 pg/ml. Methods for determining the plasma TNF levels are well-known in the art, particularly preferred methods being those described herein. It εhould be noted that levelε of TNF in normal healthy humans or in laboratory animals are estimated to be no more than about 10 pg/ml, a value that is at the limit of detection by the most sensitive assays for TNF [Michie et al., New Enσ. J. Med. 318:1481-1486 (1988); Mathison, et. al., J. Clin. Invest. 1:1925 (1988 * ) and Waage et al., Laucet, 1:355-357 (1987)]. Following exposure to LPS, the levels of TNF have been shown to rise 10-20 fold to levels of up to 400 pg/ml (vide supra) . Recently, a good correlation haε been εhown between serum TNF levels and fatal outcome in infection with gram-negative, LPS- containing meningococcal bacteria [Waage et al., Lancet, 1:355-357 (1987)]. Further, in animal models of sepsis with subhuman primates, similar increases in TNF were noted and these changes were directly correlated with lethality [Tracey et al.. Nature. 330:662-664. (1987)]. As discuεsed earlier, the opsonin or itε binding partner(ε) or other ligands or agents exhibiting either mimicry or antagonism to the opsonin or control over its production, may be prepared in pharmaceutical compoεitions, with a suitable carrier and at a strength effective for administration by various means to a patient having a tissue * infection or other pathological derangement, for the treatment thereof. A variety of administrative techniques may be utilized, among them topical applications as in ointmentε or on surgical and other topical appliances such as, surgical sponges, bandages, gauze pads, and the like. Alεo, such compositions may be administered by parenteral techniques such as subcutaneous, intravenous and intraperitoneal injections, including delivery in an irrigation fluid used to wash body wound areas, catheterizationε and the like. Average quantitieε of the opεonin may vary and in particular should be based upon the recommendations and prescription of a qualified physician or veterinarian. Also, antibodies including both polyclonal and monoclonal antibodies, and drugs that modulate the production or activity of the opsonin may possess certain therapeutic applications and may thus be utilized for the purpose of treating the effects of post infection attributable the action of the opsonin, such as inflammation and fever. In particular, the opεonin may be used to produce both polyclonal and monoclonal antibodies to itself in a variety of cellular media, by known techniques such as the hybridoma technique utilizing, for example, fused mouεe spleen lymphocyteε and myeloma cellε. Suitable antibodies would also extend to antibodies that may be raised against a component of the protease caεcade that giveε rise to the opsonin, as well aε to the perceived component parts of the opεonin, namely the proteaεe and/or itε εubstrate. Accordingly, antibodies to any of these antigens would interrupt the synthesiε and/or activity of the opsonin and would thereby inhibit or block its action. The general methodology for making monoclonal antibodies by hybridomaε iε well known. Immortal, antibody- producing cell lineε can also be created by techniques other than fusion, such as direct tranεformation of B lymphocytes with oncogenic DNA, or transfection with Epstein-Barr virus. See, e.g., M. Schreier et al., "Hybridoma Techniques" (1980); Hammerling et al., "Monoclonal Antibodies And T-cell Hybridomas" (1981) ; Kennett et al., "Monoclonal Antibodieε" (1980); see also U.S. Patent Noε. 4,341,761; 4,399,121; 4,427,783; 27 4 , 444 , 887 ; 4 , 451 , 570 ; 4 , 466 , 917 ' ; 4 , 472 , 500 ; 4 , 491 , 632 ; 4 , 493 , 890 . Panels of monoclonal antibodies produced againεt opsonin peptides can be screened * for variouε propertieε; i.e., isotype, epitope, affinity, etc. Of particular interest are monoclonal antibodies that neutralize the activity of opsonin. Such monoclonals can be readily identified in opsonin activity asεays. High affinity antibodies are also useful in immunoaffinity purification of native or recombinant opsonin. Preferably, the anti-opsonin antibody used in a therapeutic method of this invention is an affinity purified polyclonal antibody. More preferably, the antibody iε a monoclonal antibody (mAb) . In addition, it iε preferable for the anti-CD14 antibody moleculeε uεed herein be in the form of Fab, Fab'V F(ab » ) 2 or F(V) portions of whole antibody molecules. Preferred monoclonal antibodies display an immunoreactivity for the opsonin that iε similar to that of thoεe produced by the above-deεcribed hybridomaε. As used herein, the term "immunoreactivity" in its various grammatical forms refers to the concentration of antigen required to achieve a 50% inhibition of the immunoreaction between a given amount of the antibody and a given amount of the opsonin antigen. That is, immunoreactivity is the concentration of antigen required to achieve a B/B 0 value df 0.5, where B 0 is the maximum amount of antibody bound in the absence of competing antigen and B iε the amount of antibody bound in the presence of competing antigen, and both B 0 and B have been adjusted for background. See Robard, Clin. Chem. f 20_:1255-1270 (1974). In another particular embodiment, the therapeutic method of the present invention compriseε administering a therapeutically effective amount of an anti-opεonin antibody, preferably an affinity-purified polyclonal antibody, and more preferably a mAb. In addition, it iε preferable for the anti-opsonin antibody molecules uεed herein be in the form of Fab, Fab 1 , F(ab') 2 or F (v) portionε or whole antibody moleculeε. Preferably, the amount of anti-opεonin antibody adminiεtered iε sufficient to reduce by at least about 30 percent, preferably by at least 80 percent, an opsonin-LPS complex induced clinically εignificant increase in the blood level of TNF in a patient displaying at least one of the symptoms of sepsis. As previously discuεεed, patientε capable of benefiting from thiε method include thoεe εuffering endotoxemia as a reεult of a gram-negative bacterial infection. Methods for isolating the opεonin and inducing anti-opsonin antibodies and for determining and optimizing the ability of an anti-opsonin antibody to inhibit the binding of opsonin-LPS complexes to CD14 and thereby inhibit opεonin-induced TNF εecretionε are all well-known in the art. Methods for producing polyclonal anti-polypeptide antibodies are well-known in the art. See U.S. Patent No. 4,493,795 to Nestor et al. A monoclonal antibody, typically containing Fab and/or F(ab*) 2 portions of useful antibody moleculeε, can be prepared uεing the hybridoma technology described in Antibodies - A Laboratory Manual, Harlow and Lane, eds., Cold Spring Harbor Laboratory, New York (1988) , which is incorporated herein by reference. Briefly, to form the hybridoma from which the monoclonal antibody composition is produced, a myeloma or other self-perpetuating cell line is fused with lymphocytes obtained from the spleen of a mammal hyperimmunized with CD14 or an opεonin-binding portion thereof, or opεonin or a CDl4-binding portion thereof. It iε preferred that the myeloma cell line be from the same species as the lymphocytes. Typically, a mouse of the strain 129 G1X + is the preferred mammal. Suitable mouse myelomas for use in the present invention include the hypoxanthine-aminopterin-thymidine-sensitive (HAT) cell lineε P3X63-Ag8.653, and Sp2/0-Agl4 that are available from the American Type Culture Collection, Rockville, MD, under he deεignationε CRL 1580 and CRL 1581, reεpectively. Splenocyteε are typically fused with myeloma cells using polyethylene glycol (PEG) 6000. Fused hybrids are selected by their sensitivity to HAT. Hybridomas producing a monoclonal antibody useful in practicing this invention are identified by their ability to immunoreact with CD14 or the present opsonin and their ability to inhibit LPS-induced TNF secretion. A monoclonal antibody useful in practicing the present invention can be produced by initiating a monoclonal hybridoma culture comprising a nutrient medium containing a hybridoma that secretes antibody molecules of the appropriate antigen specificity. The culture is maintained under conditions and for a time period sufficient for the hybridoma to secrete the antibody molecules into the medium. The antibody-containing medium iε then collected. The antibody moleculeε can then be further isolated by well-known techniques. Media useful for the preparation of these compositions are both well-known in the art and commercially available and include synthetic culture media, inbred mice and the like. An exemplary synthetic medium is Dulbecco's minimal essential medium (DMEM; Dulbecco et al., Virol. 8 . :396 (1959)) supplemented with 4.5 gm/1 glucose, 20 mm glutamine, and 20% fetal calf serum. An exemplary inbred mouεe strain iε the Balb/c. Methodε for producing monoclonal anti-opεonin antibodies are also well-known in the art. 'See Niman et al., Proc. Natl. Acad. Sci. USA. 80.-4949-4953 (1983). Typically, the preεent opεonin or a peptide analog is used either alone or conjugated to an immunogenic carrier, as the immunogen in the before described procedure for producing anti-CD14 monoclonal antibodies. The hybridomaε are εcreened for the ability to produce an antibody that immunoreactε with the opεonin peptide analog and the preεent opsonin. Patients at a risk for or exhibiting the symptomε of sepsis are capable of benefiting from the administration of therapeutic modalitieε known in the art to prevent or ameliorate thoεe εymptomε. Thuε, the preεent invention contemplateε adminiεtering a therapeutically effective amount of an anti-opsonin antibody, opsonin peptide analog, a subcombination or combination thereof, subεtantially simultaneouεly with therapeutic adminiεtration of a modality known to prevent or treat the εymptomε of εepsis. For instance, intervention in the role of TNF in sepεiε, either directly or indirectly, εuch aε by uεe of an anti-TNF antibody and/or a TNF antagoniεt, can prevent or ameliorate the symptoms of sepsis. Particularly preferred is the use of an anti-TNF ' antibody aε an active ingredient, such as a monoclonal antibody having an immunologic specificity for TNF correεponding to that deεcribed by [Tracey et al., Nature, 330:662-664 (1987)]. Similarly, a therapeutic method of this invention can further include substantially simultaneouε treatment with a εteroid, εuch aε cortiεol, hydrocortiεone and the like. A patient exhibiting the εymptomε of εepsiε iε usually treated with an antibiotic, typically an aminoglycoεide such as gentamicin or a beta-lactim such aε penicillin, cephaloεporin and the like. Thuε, a preferred therapeutic method includeε administering a therapeutically effective amount of an anti-opsonin 31 antibody, a peptide analog or subcombination thereof as described herein, substantially simultaneously with adminiεtering a bactericidal amount of an antibiotic. • Mr The phraεe "bactericidal, amount" iε uεed herein to mean an amount of sufficient to achieve a bapteria-killing blood concentration in the patient receiving the treatment. The bactericidal amount of antibioticε generally recognized aε εafe for administration to humans is an amount well-known in the art and varieε, aε iε alεo well-known, with the antibiotic and the type of bacterial infection being treated. In preferred embodimentε, adminiεtration of an anti- opεonin antibody, peptide analog- or combination thereof aε deεcribed herein occujrε within about 48 hourε, preferably within about 12-36 hours, more preferably within about 2-8 hours and most preferably substantially concurrently with administration of the antibiotic. Antibioticε useful in practicing the preεent invention include those antibiotic, antibacterial and antiseptic agents having formulations described in the Physicianε• Deεk Reference, Huff, B.B. ed. , Medical Economicε Company, Inc., Oradell, N.J. (1989). In another embodiment, the preεent invention contemplateε adminiεtering a therapeutically effective amount of CD14, preferably a soluble portion thereof that binds LPS- opεonin complexeε, alone or in εubσombination or combination with a therapeutically effective amount of an anti-TNF antibody, an anti-opεonin antibody, and an antibiotic. The cDNA-^cqding for CD14 and itε deduced amino acid reεidue εequence are well-known in the art. See Goyert et al, Science. 2_39 . :497-500 (1988), Ferrero et al., Nuc. Acids Res.. 16:4173 (1988), and Bazil et al., Eur. J. Immunol.. 16:1583-1589 (1986). The present invention further contemplates therapeutic compositions useful in practicing the therapeutic methodε of thiε invention. A subject therapeutic composition includes, in admixture, a pharmaceutically acceptable excipient (carrier) and one or more of an anti-opsonin antibody, or polypeptide analog thereof, aε deεcribed herein aε an active ingredient. In preferred embodimentε, the composition compriseε an antibody or antigen capable of inhibiting either the binding of LPS to the preεent opεonin, or the binding of LPS-opsonin complexes to CD14. A possible antigenic antagonist iε Lipid IVa. In another preferred embodiment, the compositions comprise an anti-opεonin antibody, preferably a mAb, that inhibitε the binding of LPS-opsonin complexes to CD14. Preferred therapeutic compositions further include an effective amount of the anti-opsonin antibody of the invention and one or more of the following active ingredientε: an antibiotic, a εteroid, and anti-TNF antibody an a TNF antagoniεt. Exemplary formulations are given below: Formulation A Ingredient Dose (mg/ml) gentamicin (εulfate) 40 anti-opεonin antibody 10 εodium biεulfite USP 3.2 diεodium EDTA USP 0.1 water for injection q.ε.a.d. 1.0 ml Formulation B Ingredient anti-TNF antibody anti-opεonin antibody εodium biεulfite USP diεodium EDTA USP water for injection q.ε.a.d. 33 In another embodiment, the preεent invention contemplateε a therapeutic compoεition uεeful in treating εepεiε comprised of CD14 or an opsonin-binding soluble portion thereof in a pharmaceutically acceptable carrier. Preferably, the compoεition further includeε a therapeutically effective concentration of one or more of an anti-TNF antibody, an anti-opsonin antibody and an antibiotic. The preparation of therapeutic compoεitionε which contain polypeptideε or antibody moleculeε aε active ingredientε iε well underεtood in the art. Typically, such compositionε are * prepared aε injectables, either as liquid solutions or suspensions, however, solid forms εuitable for εolution in, or suspenεion in, liquid prior to injection can alεo be prepared. The preparation can alεo be emulεified. The active therapeutic ingredient is often mixed with excipiέnts which are pharmaceutically acceptable and compatible with the active ingredient. Suitable excipientε are, for example, water, εaline, dextroεe, glycerol, ethanol, or the like and combinationε thereof. In addition, if desired, the composition can contain minor amounts of auxiliary εubstances εuch as wetting or emulsifying agents, pH buffering agents which enhance the effectiveness of the active ingredient. A polypeptide or antibody can be formulated into the therapeutic composition as neutralized pharmaceutically acceptable salt forms. Pharmaceutically acceptable salts include the acid addition -saltε (formed with the free amino groupε of the polypeptide or antibody molecule) and which are formed with inorganic acidε εuch aε, for example, hydrochloric or phoεphoric acidε, or εuch organic acidε aε acetic/ oxalic, " tartaric, mandelic, and the like. Saltε formed from the free carboxyl groupε can alεo be derived from inorganic* baεeε εuch aε, for example, εodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic baεeε aε iεopropylamine, trimethylamine, 2-ethylamino ethanol, histidine, procaine, and the like. The therapeutic polypeptide- or antibody-containing compoεitionε are conventionally adminiεtered intravenouεly, aε by injection of a unit doεe, for example. The term "unit dose" when used in reference to a therapeutic composition of the preεent invention refers to phyεically diεcrete units suitable as unitary dosage for humanε, each unit containing a predetermined quantity of active material calculated to produce the deεired therapeutic effect in association with the required diluent; i.e., carrier, or vehicle. The compositionε are adminiεtered in a manner compatible with the doεage formulation, and in a therapeutically effective amount. The quantity to be administered depends on the subject to be treated, capacity of the subject's immune system to utilize the active ingredient, and degree of inhibition or neutralization of CD14 or LPS-opsonin complex binding capacity desired. Precise amounts of active ingredient required to be adminiεtered depend on the judgment of the practitioner and are peculiar to each individual. However, εuitable doεage rangeε are of the order of 0.1 to 20, preferably about 0.5 to about 10, and more preferably one to εeveral, milligramε of active ingredient per kilogram bodyweight of individual per day and depend on the route of administration. Suitable regimes for initial adminiεtration and booεter εhotε are alεo variable, but are typified by an initial adminiεtration followed by repeated doεeε at one or more hour intervalε by a εubεequent injection or other adminiεtration. Alternatively, continuouε intravenous infusion εufficient to maintain concentrations of ten nano molar to ten micromolar in the blood are contemplated. As used herein, "pg" meanε picogram, "ng" means nanogram, "ug" or "μg" mean microgram, "mg" means milligram, "ul" or "μl" mean microliter, "ml" means milliliter, "1" means liter. It is further intended that opsonin analogε may be prepared from nucleotide sequences of the opsonin derived within the scope of the present invention. Analogs, such as fragments, may be produced, for example, by pepsin digestion of opεonin. Other analogs, such as muteins, can be produced by standard site-directed mutagenesis of opsonin coding sequences. Analogs exhibiting "opsonin activity" may be identified by known in vivo and/or in vitro aεεayε. Aε mentioned above, a DNA εequence encoding opεonin can be prepared εynthetically rather than cloned. The DNA sequence can be designed with the appropriate codons for the opsonin amino acid sequence. In general, one will select preferred codons for the intended host if the sequence will be used for expresεion. The complete sequence is assembled from overlapping oligonucleotides prepared by standard methods and assembled into a complete coding sequence. See, e.g., Edge Nature. 292:756 (1981); Nambair et al. Science. 223:1299 (1984); Jay et al., J. Biol. Chem. 259:6311 (1984). Synthetic DNA sequenceε allow convenient conεtruction of geneε which will expreεs opsonin analogs or "muteins". Alternatively, DNA encoding muteins can be made by site- directed mutageneεis of native opsonin geneε or cDNAs, and muteins can be made directly using conventional polypeptide synthesis. Site-directed mutageneεis is generally uεed to create analogs from a complete coding sequence. Site-directed mutagenesis iε conducted using a primer synthetic oligonucleotide complementary to a single stranded phage DNA to be mutagenized except for limited mismatching, representing the deεired mutation. Briefly, the synthetic oligonucleotide is used aε a primer to direct εyntheεiε of a εtrand complementary to the phage, and the resulting double-stranded DNA is transformed into a phage-supporting hoεt bacterium. Cultureε of the tranεformed bacteria are plated in top agar, permitting plaque formation from single cells which harbor the phage. Theoretically, 50% of the new plaqueε will contain the phage having, aε a single strand, the mutated form; 50% will have the original sequence. The resulting plaques are hybridized with kinased εynthetic primer at a temperature which permitε hybridization of an exact match, but at which the miεmatcheε with the original εtrand are εufficient to prevent hybridization. Plagueε which hybridize with the probe are then picked, cultured, and the DNA recovered. A general method for εite-εpecific incorporation of unnatural amino acidε into proteinε iε deεcribed in Chriεtopher J. Noren, Spencer J. Anthony-Cahill, Michael C. Griffith, Peter G. Schultz, Science. 244: 182-188 (April 1989) . Thiε method may be used to create analogs with unnatural amino acids. The preεent invention also relates to a variety of diagnostic applicationε, including methodε for detecting the presence of invasive stimuli by reference to their ability to elicit the activities which are affected by the preεent opsonin. Aε mentioned earlier, the opεonin can be uεed to produce antibodieε to itεelf by a variety of known techniqueε, and εuch antibodieε could then be iεolated and utilized aε in tests for the presence of the opsonin in suspect mammalian hostε. 37 Antibody(ies) to the opsonin can be produced and isolated by standard methods including the well known hybridoma techniques. For convenience-, the antibody(ies) to the opsonin will be referred to herein as Ab, and antibody(ies) raised in another species as Ab 2 . The presence of opεonin activity in mammals can be ascertained by the. usual immunolog^cal procedureε applicable to εuch determinationε. A number of uεeful procedureε are known. Three εuch procedures which are especially useful utilise either the opsonin labeled with a detectable label, " antibody Ab 1 labeled with a detectable label, or antibody Ab 2 labeled with a detectable label. The procedures may be summarized by the following equations wherein-the aεteriεk indicateε that the particle iε labeled, and "Opε" stands for the opsonin: A. Ops* + Ab 1 = OpsΛAb, B. Ops + Ab* = OpsAb.,* C. Ops + Ab, + Ab 2 * = OpεAb.,Ab 2 * The procedureε and their application are all familiar to those skilled in the art and accordingly may be utilized within the εcope of the preεent invention. The "competitive" procedure. Procedure A, iε deεcribed in U.S. Patent Nos. 3,654,090 and 3',850,752. Procedure C, the "sandwich" procedure, is described in U.S. Patent Nos. RE 31,006 and 4,016,043. Still other procedures are known such as the "double antibody", or "DASP" procedure. In each instance, the inflammatory opsonin forms complexeε with one or mote antibody(ieε) or binding partnerε and one member,,of the complex iε labeled with a detectable label. The fact that a complex haε formed and, if desired, the a o nt thereof, can be determined by known methods applicable to the detection of labelε. It will be εeen from the above * , that a characteristic property of Ab 2 iε that it will feeact with Ab,. Thiε iε because Ab, raiεed in one mammalian εpecieε haε been used in another species as an antigen to raise the antibody Ab 2 . For example, Ab 2 may be raised in goats uεing rabbit antibodieε aε antigens. Ab 2 therefore would be anti-rabbit antibody raiεed in goatε. For purpoεeε of thiε deεcription and claimε, Ab, will be referred to aε a primary or anti-opεonin antibody, and Ab 2 will be referred to aε a εecondary or anti-Ab, antibody. The labelε moεt commonly employed for theεe εtudies are radioactive elements, enzymes, chemicals which fluoresce when expoεed to ultraviolet light, and otherε. A number of fluoreεcent materialε are known and can be utilized aε labelε. Theεe include, for example, fluoreεcein, rhodamine and auramine. A particular detecting material iε anti-rabbit antibody prepared in goats and conjugated with fluorescein through an isothiocyanate. The opεonin or itε binding partner(ε) can alεo be labeled with a radioactive element or with an enzyme. The radioactive label can be detected by any of the currently available counting procedureε. The preferred isotope may be selected from 14 C, 31 I, 3 H, 125 I and 35 S. Enzyme labelε are likewiεe uεeful, and can be detected by any of the preεently utilized colorimetric, εpectrophotometric, fluoroεpectrophotometric or gaεometric techniqueε. The enzyme iε conjugated to the selected particle by reaction with bridging molecules such as carbodiimides, diisocyanates, glutaraldehyde and the like. Many enzymeε which can be uεed in theεe procedureε are known and can be utilized. The preferred are peroxidase, β-glucuronidase, β-D-glucosidase, β-D-galactosidase, ureaεe, glucoεe oxidaεe pluε peroxidaεe and alkaline phoεphataεe. U.S. Patent Noε. 3,654,090; 3,850,752; and 4,016,043 are referred to by way of example for their disclosure of alternate labeling material and methods. A particular assay system developed and utilized in accordance with the present invention, iε known as a receptor assay. In a receptor assay, the material to be asεayed is appropriately^,labeled and then certain cellular test colonieε are inoculated with a quantity of both the labeled and unlabeled material after which binding εtudieε are conducted to determine the extent to which the labeled material bindε to the cell receptors. In this way, differences in affinity between materials can be aεcertained. Accordingly, a purified quantity of the opεonin may be radiolabeled and combined, for example, with LPS, after which binding studies would be carried out using for example, recently purified neutrophils. Solutions would then be prepared that contain various quantities of labeled and unlabeled opsonin and cell sampleε would then be inoculated and thereafter incubated. The reεulting cell monolayers are then washed, solubilized and then counted in a gamma counter for a length of time sufficient to yield a standard error of <5%. These data are then subjected to Scatchard analysis after which observations and conclusions regarding material activity can be drawn. While the foregoing. is exemplary, it illustrateε the manner in which a receptor aεεay may be performed and utilized, in the instance where the cellular binding ability of the assayed material may serve aε a diεtinguiεhing characteristic. In a further embodiment of thiε invention, commercial test kits suitable for use by a medical specialiεt may be prepared to determine the preεence or absence of opsonin in a suspected mammalian host. In accordance with the testing techniques discu-εsed above, one class of εuch kits will contain at leaεt the labeled opεonin or itε binding partner, for inεtance an antibody specific thereto, and directions, of course, depending upon the method εelected, e.g., "competitive", "sandwich", "DASP" and the like. The kits may also contain peripheral reagents such as buffers, stabilizers, etc. Accordingly, a test kit may be prepared for the demonstration of the reaction of a mammalian hoεt to invasive stimuli, comprising: (a) a predetermined amount of at least one labeled immunochemically reactive component obtained by the direct or indirect attachment of the present opsonin or a specific binding partner thereto, to a detectable label; (b) other reagents; and (c) directions for use of said kit. More specifically, the diagnostic teεt kit may comprise: (a) a known amount of the opsonin aε described above (or a binding partner) generally bound to a solid phase to form an immunoεorbent, or in the alternative, bound to a εuitable tag, or plural εuch end productε, etc. (or their binding partnerε) one of each; (b) if neceεεary, other reagents; and (c) directions for use of εaid teεt kit. In a further variation, the teεt kit may be prepared and uεed for the purpoεeε εtated above, which operateε according to a predetermined protocol (e.g. "competitive", "εandwich", "double antibody", etc.), and compriεes: (a) a labeled component which has been obtained by coupling the opεonin to a detectable label; (b) one or more additional immunochemical reagents of which at leaεt one reagent iε a ligand or an immobilized ligand, which ligand iε εelected from the group consisting of: (i) a ligand capable of binding with the labeled component (a) ; (ii) a ligand capable of binding with a binding partner of the labeled component (a) ; (iii) a ligand .capable of binding with at least one of the component(ε) to be determined; and (iv) a ligand capable of binding with at least one of the binding partners of at least one of the component(ε) to be determined; and (c) directionε for the performance of a protocol for the detection and/or determination of one or more componentε of an immunochemical reaction between the opεonin and a εpecific binding partner thereto. In accordance with the above, an aεsay εyεtem for εcreening potential drugs effective to modulate the activity of the opsonin u-ay be prepared. The opεonin may be introduced into a cellular test system such as neutrophilε with 100 pg/ml LPS, and the prospective drug may also be introduced into the resulting cell culture, and the culture thereafter examined to observe any changes in the activity of the opsonin, due either to the addition of the prospective drug alone, or due to the effect of added quantities of the known opsonin. More particularly, a drug, asεay could be conducted by culturing a colony of tέ^t cells su,ch as the cell line THP1, which has a receptor for the complex of the opsonin and LPS, in a medium containing the opsonin and LPS. The drug under teεt could be added to the reεulting culture and the reactivity of the opεonin With the receptor on the teεt cellε could thereafter be meaεured to determine whether the prospective drug possesεed any activity in the inhibition of the binding of the opsonin to either LPS or to the receptor. The following examples set forth the details of the isolation and identification of the present opεonin, and obεervationε noted aε to itε activity, defining both the diεtinctionε and εimilaritieε in activity between the preεent opεonin and thoεe factorε identified earlier both by applicant and by otherε in the field. Naturally, the εpecific materials and techniques set forth hereinafter are exemplary only and may vary, εo that the following iε preεented aε illuεtrative but not reεtrictive of the preεent invention. EXAMPLE 1 Purification of Septin Previouε εtudieε by the applicant have shown that the serum protein, LBP, binds to LPS-coated erythrocyteε and mediateε their binding to CD14 on human macrophageε. To determine if additional εerum proteinε with the ability to bind LPS and CD14 exiεt, human serum was fractionated and its capacity asεayed to each fraction to mediate interaction of LPS-coated erythrocyteε with macrophageε. Human plaεma and fractionated εampleε of plaεma were diluted in PBS containing 1 mM EDTA and incubated with LPS-coated erythrocyteε (ELPS) and human macrophages as previously deεcribed for 15 minuteε at 0°C, then an additional 15 minutes at 20°C. The binding of erythrocytes to macrophageε was then scored aε attachment index, the number of erythrocyteε bound per 100 phagocyteε. Materialε and Methodε 250 ml of freεh frozen human Plaεma (Greater New York Blood Center) waε brought to 2 mM EDTA and εhaken at 4°C overnight with 15 mlε of packed, equilibrated, BioRex 70 reεin. The reεin waε waεhed twice and packed into a column. Elution waε carried out by waεhing with 100 mlε of buffer A (50 mM Phoεphate, pH 7.3, 40 mM NaCl, 2 mM EDTA) , followed by a gradient of buffer A mixed with Buffer B (Buffer A containing 1.0 M NaCl; see Figure 1). Additional studies have indicated that Heparin-Sepharose binds septin, and that septin can be eluted with εodium chloride. Heparin-εepharoεe may be εubεtituted for BioRex in thiε procedure. Fractionε active in the bioaεεay were pooled and dialyzed against 20 mM Tris pH 8.5. The pooled samples were then applied to a Mono Q column and eluted with a gradient of buffer from 0-1 M NaCl. Fractionε with activity were again pooled and analyzed by electrophoreεiε. Reεultε Dilutionε of human plasma (or serum) up to 1:200 exhibit significant activity when asεayed for the ability to mediate binding of ELPS to macrophages. Plaεma did not influence binding of E to MO unless the E were coated with LPS, and all the plasma-mediated binding- of ELPS to MO was inhibited by the anti-CD14 mAb, 3.C10. This assay thus detects molecules that bind LPS and CD1 . The capacity of plasma to mediate binding of ELPS iε completely lost after incubation of the plasma with BioRex, indicating that thiε ion exchange reεin quantitatively adεorbε the active moleculeε from plasma (data not shown) . Isolation of Septin Elution of the BioRex with a gradient of NaCl gave rise to two peaks of activity, the firεt centered at approximately 200 mM NaCl, and a εecond at >500 mM NaCl (Figure 1) . The εecond peak has the reported elution characteristicε of LBP, and further purification of thiε material on Mono Q yielded a 60 kD protein with the characteriεticε of LPB. However, LPB accounted for leεs than 4% of the activity of plaεma. The major peak, accounting for >96% of the activity of plaεma waε further purified on a Mono Q column. Elution with a gradient of NaCl gave riεe to a single peak of activity at 190 mM NaCl. Further purification on a Superose 10 εizing column reεulted in the iεolation of a εingle molecular εpecieε. We have named thiε material septin. Analysis of dilutions of septin showed that the material eluted from Mono Q contained leεε than 1% of the initial activity, indicating that εubεtantial loεε of activity occurred upon chromatography on Mono Q. Propertieε of Septin Analysis of septin by SDS-PAGE reveals a single band of 90,000 (±3,000) Daltons. Septin mediates very avid binding of ELPS to macrophages. The concentration of septin needed for maximal binding is <0.05 μg/ml. Previous studies showed that 1 μg/ml of LBP is necesεary for comparable binding [Wright et al., J. Exp. Med. ,- 110:1231-1241 (1989)]. Thus, septin is 20-fold more active than LBP in mediating the interaction * of ELPS .with macrophages. All of the septin-mediated binding of ELPS to macrophageε iε blocked by the anti-CD14 mAb, 3C10, indicating that CD14 iε the receptor reεponεible for recognizing εeptin- LPS complexeε. Pretreatment of ELPS but not macrophageε with septin resultε in adheεion, indicating that septin binds to LPS and that CD14 recognizes septin-LPS complexes, not septin alone. EXAMPLE 2 Mononuclear Cells One of the activities that the opsonin septin waε εpeculated to poεεeεε iε the ability to promote and enhance the ability of monocyteε to produce and elaborate TNF in reεponse to invasive stimuli such aε LPS challenge. Thiε hypotheεiε waε teεted by the following experiment. Accordingly, mononuclear cellε were iεolated from freεh human blood on Ficoll gradientε and εuεpended to 2 x 10 6 cellε/ml in RPMI containing 0.5 mg/ml human serum albumin, 0.5 u/ml Aprotinin, and the indicated doses of Re endotoxin. After a 16 hour incubation, TNF in the supernatant was measured-by a sandwich RIA. The resultε are εet forth in Table I, below. TABLE I Secretion of TNF by Human Mononuclear Cells TNF Production (ng/ml) From the above, it can be seen that TNF production which is known to be promoted by LPS, is substantially enhanced by the presence of both LPS and septin. While 1 μg/ml of septin alone accounted for a trebling of TNF production, the presence of the same..,amount of septin in combination with 0.01 ng/ml of LPS resulted in a more than eight-fold increaεe over the preεen e of the same amount of LPS alone. Similar enhancement was evident in the instance of 0.05 ng/ml LPS and the same concentration of εeptin, where a greater than εeven-fold increaεe waε noted. EXAMPLE 3 Stimulation of PMN Reportε in the literature regarding the activities and characteristics of polymorphonuclear cells (PMN) εuggeεt that low and variable amounts of CD14 are expressed on PMN. The expression of CD14 on PMN has been confirmed, showing that expression is upregulated two-to three-fold by degranulating stimuli such as GM-CSF, GCSP, and fNLLP. The CD14 on PMN is capable of mediating the binding of ELPS in the presence of either LBP or septin, and binding is increased 2- to 3-fold upon stimulation of the PMN with the same agoniεtε that induce expression. Complexeε of εeptin and LPS cauεe dramatic εtimulation of PMN. Expreεεion of CR3 (CDllb/CD18) , an important adheεion molecule, iε upregulated two-fold upon exposure of PMN to 1 ng/ml LPS-εeptin complexes, but neither septin (1 μg/ml) alone nor LPS at concentrations aε high as 5 ng/ml cause upregulation (Figure 2) . CR3 reεides within secretory granules of PMN, and these data thus suggeεt that interaction of septin-LPS complexes with CD14 on PMN cauεe degranulation. The degranulation cauεed by septin-LPS complexes is clearly not complete however, because parallel studies with the strong agonist, PMA, showed a five-fold increase in expression of CR3 (data not shown) . PMN were admixed with the indicated concentrations of εeptin and LPS (Re) and added to monolayers of endothelial cellε. After 15 minuteε at 37"C, the preparationε were waεhed and attachment was measured as described [Lo et al., J. Exp. Med.. 169:1779-1793 (1989)], and the results are set forth in Table II, Below. Basal adheεion values for unstimulated cells were subtracted from the data shown. TABLE II Binding of PMN to Umbilical Vein Endothelium LPS (ng/ml) -Septin +Septin (lu/ml) 0 0 115 0.05 135 339 0.20 132 ' 330 An early event in the response of animals to endotoxin iε adheεion of PMN to the endothelium. Thiε adhesive capacity iε alεo εtimulated by εeptin-LPS complexeε but not by εeptin or LPS alone (Table II) . CR3 is a dominant receptor that mediates adhesion of εtimulated PMN to unεtimulated endothelium and incubation of PMN with εeptin-LPS complexeε, but not εeptin or LPS assayed by ability of CR3 to mediate binding of C3bi-coated erythrocyteε (Figure 3) . Other stimuli of PMN such aε PMA or IL-8 cause similar increases in CR3 activity, and previous work indicates increased receptor activity is caused both by changes in the number of CR3 on the surface and by changes in the binding activity of existing CR3. Further preliminary studies indicate that concentrations of septin—TPS complexes that cause a strong adhesion reεponse do not stimulate the release of hydrogen peroxide ([J. Cell. Biol. , 109:1341 (1980)], not shown) . EXAMPLE 4 Losε of CD14 from the Surface of Stimulated Macrophageε In the courεe of εtudies on the response of macrophages to LPS, it was discovered that addition of LPS to macrophageε ill the presence of 10% human serum caused a dramatic loss of CD14 from the macrophage cell surface. Additional preliminary studies indicate that loss iε complete by 3 hourε and iε cauεed by doseε of LPS aε low aε 0.1 ng/ml. The following describes experiments that were performed and contributed to thiε finding. Accordingly, the εtimuli liεted in Table III were added to four-day cultures of human monocytes (10 6 cells/ml in RPMI 1640 containing 10% normal serum) in Teflon beakers. After an additional 18 hours' of culture, cellε were waεhed, εtained with monoclonal antibodieε and fluoreεceinated F(ab) 2 , and analyzed by FACS. The reεults are likewise preεented in the below Table, with data presented as mean fluorescent intensity (linear scale) . TABLE III Losε of CD14 from Macrophageε during Reεponεe to LPS Aε illuεtrated by the above data, theεe studies suggest that the signalling of cellular reεponses by LPS is asεociated with loεε of CD14. Losε of εurface CD14 jdoeε appear to require signalling by LPS since biologically inactive LPS analogs do not cauεe loεε. It iε unlikely that the loss is caused by an autocrine loop involving TNF since TNF caused an increase, not a decrease, in expresεion of CD14 (Table III) . The bioεynthetic precursor of LPS termed Lipid IVa binds strongly to LBP and septin (not shown) . Complexes of LBP and Lipid IVa also appear to bind normally to CD14 εince the dose of lipid IVa/erythrocyte needed for half-maximal LBP-dependent binding to MO is the same aε the doεe of Re endotoxin (not shown) . By contraεt, complexeε of Lipid IVa and the opεonin εeptin do not bind to CD14, diεtinguiεhing the present opsonin from LBP and suggeεting that Lipid IVa may function as an inhibitor of septin activity. Also, Lipid IVa does not trigger TNF synthesis, and recent studies show that addition of lipid IVa strongly antagonizeε TNF εyntheεiε in response to Re endotoxin. It was obεerved that lipid IVa doeε not cauεe loεε of surface CD14, and in some experimentε, it cauεed an increase (perhaps by antagonizing the effect of contaminating LPS) . EXAMPLE 5 Anti-septin Blockε the Ability of Plasma to Support Binding of ELPS to CD14 Purified septin was mixed with alumagel and injected (4x) into a rabbit. The IgG from preimmune and immune serum was purified and mixed with whole human plasma. While pre-immune IgG had no effect on the binding of ELPS to MO, anti-septin completely blocked binding (Table IV) . This experiment indicates that we have developed a blocking antibody and that septin is the protein in plasma with the greatest contribution to the interaction of LPS with macrophages. Table IV Anti-septin Blockε Septin Activity Antibody Attachment Index (ELPS) None 419 Preimmune (150 μg/ml) 488 Anti-εeptin (150 μg/ml) 24 Antibody waε added to plaεma and held for 60 in. on ice. Samples were then diluted 1:100 and mixed with macrophages and ELPS. Attachment of erythrocyteε to macrophageε was then measured. EXAMPLE 6 Structural Analvsiε of Septin Septin was blotted from an SDS gel onto immobilon, and a partial amino acid εequence waε obtained. This partial sequence shows no similarity to the functionality related proteins LBP, BPI or CETP, thus confirming the novel nature of septin. However, the partial sequence iε similar to a residue of human protein C inhibitor (PCI) * , a plasma protein of the serpin (serine protease inhibitor) family. This εimilarity in εequence prompted consideration of the hypothesis that septin iε identical with PCI. Purified PCI and two monoclonal anti-PCI antibodies were provided by Dr. Johan Stenflow (Sweden) . Purified PCI had none of the biological activities of septin when asεayed over a wide range of concentrationε, and monoclonal anti-PCI antibodieε failed to either neutralize εeptin or react in weεtern blots of septin. It iε thuε believed that εeptin iε εtructurally related to but distinct from PCI, and may represent a new member of the serpin family. There is precedent for members of the serpin family serving as binding proteinε. Thyroxine binding globulin and corticoεteroid binding globulin are both human plasma transport proteinε that belong to the εerpin family, and it iε thuε reaεonable to hypotheεize that a serpin could bind LPS. Similarity of septin to the serpin, PCI, also offerε an intriguing potential link to an unexplained phenomenon in εepεiε. Infuεion of Activated Protein C (APC) , an inhibitor of coagulation, preventε death from endotoxic εhock by preventing the εynthesis of TNF (F. Taylor, perεonal communication). If εeptin*ε εimilarity to PCI allowε it to εerve as an inhibitor of APC, then infusion of APC may conεume septin and prevent responses to endotoxin. The typical molecular weight of a serpin (50 kDa) iε significantly different from that of septin (90 kDa) . However, it is known that serpins form covalent complexes with their target proteaεeε, and theεe complexeε run on SDS gelε aε the εum of the molecular weightε of the εerpin and proteaεe. The acyl intermediate can be diεrupted by incubation of the εerpin-proteaεe complex with baεe. We have observed that incubation of septin with 1 M ammonium hydroxide resultε in a shift in molecular weight, giving rise to a 55 kDa and a 34 kDa species. These are most compatible with a model in which εeptin iε actually a complex between a εerpin related to PCI, and a proteaεe of 34 4 kDa. -? *** EXAMPLE 7 Protease Inhibitors Block Septin Activity in Plaεma The finding that septin is apparently compoεed of a proteaεe and subεtrate prompted ,the teεting of proteaεe inhibitorε. Addition of a mixture of proteaεe inhibitorε profoundly reduced the capacity of plasma to support interaction of ELPS with MO (Table V) . Additional studies indicate that protease inhibitors blocked interaction of septin with ELPS (Table V) , protocol II) , not binding of septin-LPS complexes to CD14. The two most effective pcptease inhibitorε found to date are aprotinin and chymoεtatin. Since chymostatin preferentially inhibits chymotryptic-like proteaseε which cleave after hydrophobic reεidues and aprotinin preferentially inhibits enzymes with trypsin-like enzymeε which cleave after baεic residues, our reεultε. suggest that inhibition of either of two proteaseε iε .sufficient to halt the production of septin. Further studies indicate that the nontoxic proteaεe inhibitor, aprotinin, alεo interruptε the εtimulation of PMN by LPS and septin (Table VI) .*- These data suggest that a proteolytic event, perhaps the interaction of a proteaεe with a serpin, is necessary to generate septin. Chymoεtatin 5 μg/ml + Pepstatin 5 μg/ml 5.6 Chymostatin 100 μg/ml 18 Aprotinin 100 μg/ml 94 PROTOCOL I 11 Antipain + Leupeptin + Benzamide 3.0 Chymoεtatin + Pepεtatin A 3.3 All together 10.3 1 In Protocol I, plaεma was diluted 100-fold with the indicated concentration of inhibitors and mixed with ELPS and macrophages. The attachment of ELPS to macrophageε waε determined after a 30 min. incubation, and the decreaεe in attachment caused by protease inhibitors waε determined. 2 In Protocol II, plaεma waε diluted 100-fold with the indicated concentration of inhibitorε and mixed with ELPS. Following a 20 min. incubation, the ELPS were waεhed and incubated with macrophageε. Attachment waε determined aε described above. 53 * TABLE VI Aprotinin Blocks the Serum-dependent Stimulation of PMN bv LPS Stimulus Aprotinin Attachment Index (EC3bi) LPS (1 ng/ml) Serum (1:100) - - - 18 + - - 47 + - 9 + + - 480 + + 50 u ' g/ml 118 PMN were incubated with the indicated dilutions of human εerum and LPS in the preεence or abεence of aprotinin for 30 inε. at 37°C. The cellε were then waεhed and activation of CR3 was assayed by measuring the binding of C3bi-coated sheep erythrocytes (EC3bi) . Further evidence that a complex between protease and inhibitor iε required to form septin derives from experimentε in which εeveral fractionε from a Mono Q column were combined. While the septin peak contains an amount of activity equal to 0.2-1% of the septin activity applied, a pool of all peaks contains 50-80% of the activity loaded. Thus, a mixture of proteins, presumably protease and substrate, must be combined to form septin. We believe that the activity present in the "septin" peak represents a small amount of pre-formed proteaεe-εerpin complex. Other proteinε in plaεma function in a protease cascade to initiate biological effects. For example, the complement caεcade iε initiated by very small amounts of immune complex, and the contact system of the clotting cascade iε initiated by anionic surfaces. Septin appears to be the product of a similar cascade. To rule out the possibility that proteins from known protease cascades participate in the "septin cascade," we meaεured the εeptin activity in plaεma depleted of particular proteinε. Serum deficient in complement protein C5, and complement proteins C2 and Factor B (heated serum) had normal septin levels. Septin levels were not affected by clotting of plasma. Further, plasma deficient in Protein C, Hageman Factor, prekallikrein, High molecular weight kininogen, or Factor IX showed normal septin levels. Thus, the enzymatic reactions described here represent a novel proteaεe caεcade and thiε caεcade iε an object of the current invention. Thiε invention may be embodied in other formε or carried out in other ways without departing from the spirit or esεential characteristics thereof. The present discloεure is therefore to be considered as in all respects illustrative and not restrictive, the scope of the invention being indicated by the appended Claims, and all changes which come within the meaning and range of equivalency are intended to be embraced therein.

Claims: 55 WHAT IS CLAIMED IS: 1. An opεonin compriεing a protein in purified form that iε capable of binding to lipopolysaccharide to form a complex that is recognized by a receptor on monocytes, macrophage cells and polymorphonuclear cells, and that possesεeε an apparent molecular weight of about 90 kD aε determined by SDS-PAGE analysis. 2. The opsonin of Claim 1 wherein said opsonin is unable to bind to the receptor CD14 when first bound in a complex with the biosynthetic precurεor of lipopolysaccharide known as Lipid IVa. 3. The opεonin of Claim 1 wherein εaid opεonin iε preεent in high levelε in normal serum, and enhances the elaboration of TNF in responεe to lipopolyεaccharide. 4. The opεonin of Claim 1 wherein* εaid opεonin iε εerum-derived. 5. The opεonin of Claims 1, 2 or 3 wherein said opsonin in εaid complex with lipopolysaccharide εtimulateε polymorphonuclear cell activity, promoteε the increaεed adheεion of said polymorphonuclear cells to endothelium, upregulates the expreεεion of the adhesion molecule CR3, and causes the degranulation of said polymorphonuclear cells. 6. The opsonin of Claim 3 wherein εaid opεonin iε preεent in normal serum in amounts ranging up to on the order of about 4 μg/ml. 7. The opεonin of Claim.,1 wherein maximal binding of lipopolysaccharide to εaid monocyteε, macrophage cellε and polymorphonuclear cells as meaεured by the binding activity of LPS-coated erythrocyteε to human macrophage cellε iε achieved by the presence and binding with said erythrocytes of a concentration of no more than about 0.05 μg/ml of εaid opεonin. 8. The opεonin of Claim 1 wherein said opεonin iε a part of a proteaεe caεcade and is capable of binding to lipopolysaccharide. 9. The opsonin of Claim 1 wherein said opsonin iε a complex of a proteaεe and a substrate for said protease. 10. The opεonin of Claim 9 wherein said substrate bears some structural similarity to human protein C inhibitor. 11. The opsonin of Claim 1 wherein the activity of said opεonin iε εubεtantially diminished by protease inhibitors. 12. The opsonin of Claim 11 wherein said protease inhibitors are εelected from the group consisting of antipain, leupeptin, benza idine, chymostatin, pepεtatin A, aprotinin and mixtures thereof. 13. A protease caεcade that giveε riεe to the opsonin of any of Claimε 8, 9, 10, 11 or 12. 14. The opsonin of Claims 1, 2 or 3 labeled with a detectable label. 15. The opsonin of Claim 14 wherein the label is selected from enzymes, chemicals which fluoresce and radioactive elements. 16. A method for preparing an opsonin capable of binding to lipopolysaccharide to form a complex that is recognized by a receptor on monocytes, macrophage cellε and polymorphonuclear cellε, and that poεεeεses an apparent molecular weight of about 90 kD as determined by SDS-PAGE analysiε compriεing: A. gathering a sample of serum from a mammal; and • ' • ' - B. isolating said opsonin from said εerum. 17. An antibody to an opsonin, the opεonin to which εaid antibody is raised comprising a protein in purified form capable of binding to lipopolysaccharide to' form a complex that is recognized by a receptor on monocytes, macrophage cells and polymorphonuclear cells, and that posεesses an apparent molecular weight of about 90 kD aε determined by SDS-PAGE analysis. 18. The antibody of Claim 17 as raised in rabbits and developed to an immunoglobulin (IgG) from immune serum. 19. The antibody of Claim 17 comprising a polyclonal antibody. 20. The antibody of Claim 17 comprising a monoclonal antibody. 21. An immortal cell line that produces a monoclonal antibody according to Claim 20. 22. The antibody of Claim 17 labeled with a detectable label. 23. The antibody of Claim 22 wherein the label is selected from enzymes, chemicalε which fluoreεce and radioactive elementε. 24. A method for measuring the presence of an opsonin capable of binding to lipopolysaccharide to form a complex that is recognized by a receptor on monocytes, macrophage cells and poly _*•morphonuclear cellε, and that possesseε an apparent molecular weight of about 90 kD aε determined by SDS-ΪΑGE analyεis, wherein said opεonin iε meaεured by: A. preparing at least one sample of said opsonin from serum or plasma; B. preparing at least one corresponding antibody or binding partner directed to said opsonin sampleε; C. placing a detectible label on a material εelected from the group conεiεting of εaid opεonin εampleε and said antibody or binding partners thereto; D. immobilizing a material selected from the group consiεting of the material from Step C that is not labeled, and a biological sample from a mammal in which said opsonin is suspected, on a suitable subεtrate; E. placing the labeled material from Step C in contact with εaid biological sample, and in contact with the immobilized material; F. separating the material from Step C that is bound to said immobilized material from material from Step C not bound to said immobilized material; and G ' examining said bound material for the presence of εaid labeled material. 25. A method for measuring the binding sites for an opεonin capable of binding to lipopolysaccharide to form a complex that is recognized by a receptor on monocytes, macrophage cellε and polymorphonuclear cellε, and that posseεεeε an apparent molecular weight of about 90 kD aε determined by SDS-PAGE analysis, wherein the binding siteε for εaid opεonin are measured by: A. providing at least one sample of said opsonin; B. placing a detectible label on said opsonin sample; C. placing the labeled opsonin εample in contact with a biological εample from a mammal in which binding εiteε for εaid opεonin are εuspected in the presence and abεence of lipopolyεaccharide; and D. examining εaid biological εample in binding studies for the presence of εaid labeled opεonin sample. 26. The method of Claim 24 comprising a method for meaεuring the presence of an opsonin associated with a given invasive εtimuluε .in mammals. 27. The method of Claim 26 wherein said invasive stimuluε iε an infection. 28. The method of Claim 26 wherein εaid invasive stimulus is selected from the group consisting of bacterial infection, viral infection, protozoan infection, tumorous mammalian cells, and toxins. 29. The method of Claim 24 comprising a method for determining the preεence of invaεive or idiopathic stimuli in mammals. 30. A method of testing the ability of a drug to modulate the activity of an opsonin which compriseε culturing a colony of teεt cellε which haε a receptor for a complex of the opεonin and lipopolysaccharide, in a growth medium containing the opsonin and lipopolysaccharide, adding the drug under teεt and thereafter measuring the reactivity of said opsonin with the receptor on said colony of*test cells, εaid opsonin comprising a protein material capable of binding to lipopolysaccharide to form a complex that is recognized by a receptor on monocytes, macrophage cellε and polymorphonuclear cellε, and that posseεεeε an apparent molecular weight of about 90 kD aε determined by SDS-PAGE analyεiε. 31. An aεεay εyεtem for εcreening drugε and other agentε for ability to modulate the production of an opsonin, comprising an observable cellular test colony inoculated with a drug or agent, and yielding a resulting supernatant, said supernatant then to be examined for the presence of said opsonin, -said opsonin comprising a protein capable of binding to lipopolyεaccharide to form a complex that iε recognized by a receptor on monocyteε, macrophage cellε and polymorphonuclear cellε, and that poεεeεses an apparent molecular weight of about 90 kD aε determined by SDS-PAGE analyεiε. 32. A teεt kit for the demonεtration of an opεonin in serum or an aqueous medium, compriεing: A. a predetermined amount of at leaεt one labeled immunochemically reactive component obtained by the direct or indirect attachment of εaid opsonin or a specific binding partner thereto, to a detectable label, said opsonin .comprising a protein capable of binding to lipopolysaccharide to form a complex that is recognized by a receptor on monocytes, macrophage cellε and polymorphonuclear cellε, and that poεεeεεeε an apparent molecular weight of about 90 kD aε determined by SDS-PAGE analysis; B. other reagents; and C. directions for uεe of εaid kit. 33. A method of treating inflammation in mammalε, compriεing adminiεtering to a mammal an inflammation- reducing amount of a material εelected from the group consisting of an antibody specific to an opsonin that iε capable of blocking the binding of εaid opεonin to lipopolyεaccharide or to cellular receptorε for εaid opεonin, an agent capable of inhibiting the production of said opsonin, an agent not an antibody to said opsonin capable of acting aε an antagonist to said opsonin, and mixtures thereof, said opεonin compriεing a protein that is capable of binding to lipopolysaccharide to form a complex that iε recognized by a receptor on monocytes, macrophage cellε and polymorphonuclear cellε, and that poεεeεses an apparent molecular weight of about 90 kD as determined by SDS-PAGE analyεiε. 34. The method of Claim 33 wherein εaid antibody to said opεonin iε a polyclonal antibody. 35. The method of Claim 33 wherein εaid antibody iε raised in rabbits and derived from the IgG of immune serum. 36. The method of Claim 33 wherein the said agent not an antibody to said opsonin comprises at least one protease inhibitor. 37. The method of Claim 36 wherein said protease inhibitors are selected, from the group consisting of antipain, leupeptin, benzamidine, chymostatin, pepεtatin A, aprotinin and mixtureε thereof. 38. The method of Cla m,--33 wherein said antibody is raised against a component of the protease cascade that gives rise to the opsonin. 39. A method for preventing the occurrence of inflammation and/or fever in a mammal comprising, adminiεtering to said mammal an amount of a material selected from the group consisting of an antibody specific to an opεonin that blockε itε binding to lipopolyεaccharide or to cellular receptors for the opεonin, an agent capable of inhibiting the production of εaid opεonin, an agent not an antibody to said opsonin capable of acting aε an ^ antagonist to said opsonin, and mixtures thereof, effective to avert the onset of said inflammation and/or said fever, εaid opsonin comprising a protein that is capable jpf binding to lipopolysaccharide to form a complex that is recognized by a receptor on monocytes, macrophage cells and polymorphonuclear cells, and that posseεεeε an apparent molecular weight of about 90 kD as determined by SDS-PAGE analysiε. 40. The method of Claim 39 wherein said antibody to said opsonin is a polyclonal antibody. 41. The method of Claim 39 wherein εaid antibody iε raiεed in rabbitε and derived from the IgG of immune εerum. 42. The method of Claim 39 wherein the said agent not an antibody to said opsonin compriεeε at leaεt one proteaεe inhibitor. 43. The method of Claim 42 wherein εaid proteaεe inhibitorε are εelected from the group conεiεting of antipain, leupeptin, benzamidine, chymostatin, pepstatin A, aprotinin and mixtureε thereof. 44. The method of Claim 39 wherein εaid antibody wherein said antibody iε raiεed againεt a component of the protease cascade that gives rise to the opsonin. 45. A method of treating infectious and noninfectiouε diseases in a mammal, comprising adminiεtering to εaid mammal an disease-reducing amount of a material selected from the group consisting of an opsonin, an agent capable of promoting the production and/or activity of εaid opεonin, an agent capable of mimicking the activity of εaid opεonin, and mixture thereof, εaid opεonin compriεing a protein that iε capable of binding to lipopolyεaccharide to form a complex that iε recognized by a receptor on monocyteε, macrophage cellε and polymorphonuclear cellε, and that poεεeεεeε an apparent molecular weight of about 90 kD aε determined by SDS-PAGE analyεiε. 46. A method of ameliorating sepεiε in a patient, which method compriεes administering to said patient a therapeutically effective amount of an anti-opsonin antibody, said opsonin comprising a protein in purified form that is capable of binding to lipopolysaccharide to form a complex that is recognized by a receptor on monocytes, macrophage cellε and polymorphonuclear cellε, and that possesses an apparent molecular weight of about 90 kD as determined by SDS-PAGE analysiε. 47. The method of Claim 46 wherein εaid antibody to εaid opεonin iε a polyclonal antibody. 48. The method of Claim 46 wherein said antibody is raised in rabbits and derived from the IgG of immune serum. v 49. The method of Claim 46 wherein said antibody is raised against a component of the protease cascade that gives rise to the opsonin. 50. The method of Claim 46 wherein εaid anti-opεonin antibody is a monoclonal antibody that inhibits the binding of said opsonin to lipopolysaccharide. 51. The method of Claim 46 wherein said anti-opsonin antibody iε a monoclonal antibody that inhibitε the binding of complexeε of lipopolyεaccharide and εaid opsonin to CD14. 52. The method of Claims 50 or 51 wherein εaid therapeutically effective amount iε 0.1 to 20 milligrams per kilogram body weight per day. 53. The method of Claim 46 wherein εaid method further comprises substantially simultaneously administering to εaid patient a bactericidal amount of an antibiotic. 54. The method of Claim 53 wherein εaid antibiotic iε an anti-bacterial agent effective againεt gram-negative bacteria. 55. The method of Claim 46 wherein said sepsis is caused by a gram-negative bacterial infection. 56. The method of Claim 46 wherein said sepsis is cauεed by infection with a viruε, gram-poεitive bacteria or fungu . 57. The method of Claim 46 wherein said method further compriεes subεtantially simultaneously administering to said patient a TNF blood concentration-reducing amount of an anti-TNF antibody. 58. The method of Claim 57 wherein said method further co priseε adminiεtering, εubεtantially simultaneously with said anti-opεonin antibody, a ' bactericidal amount of an antibiotic to εaid patient. 59. The method of Claim 46 wherein said patient displays the symptomε of one or more of the following: adult reεpiratory distresε syndrome, diεεeminated intravaεcular coagulation, renal failure and hepatic failure. 60. The method of Claim 46 wherein εaid sepsiε is the reεult of chemical or physical trauma. 61. A method of ameliorating the symptoms of endotoxe ia in a patient, which method compriseε adminiεtering to εaid patient an amount of an anti-opεonin antibody εufficient to inhibit in εaid patient lipopolysaccharide- induced tumor necrosis factor secretion by cells of the monocyte macrophage lineage, wherein said opsonin compriεeε a protein in purified form that iε capable of binding to lipopolyεaccharide to form a complex that is recognized by a receptor on monocytes, macrophage cells and polymorphonuclear cellε, and that posseεεes an apparent molecular weight of about 90 kD as determined by SDS-PAGE analyεiε. 62. The method of Claim 61 wherein said antibody to said opsonin iε a polyclonal antibody. 63. The method of Claim 61 wherein said antibody is raised in rabbits and derived from the IgG of immune serum. 64. The method of Claim 61 wherein the said agent not an antibody to said opsonin comprises at least one protease inhibitor. 65. The method of Claim 64 wherein said protease inhibitors are selected from the group consiεting of antipain, leupeptin, benzamidine, chymoεtatin, pepεtatin A, aprotinin and mixtureε thereof. 66. The method of Claim 61 wherein said antibody iε raised againεt a component of the proteaεe caεcade that giveε rise to the opsonin. 67. The method of Claim 61 wherein εaid anti-opεonin antibody iε a monoclonal antibody that inhibits the binding of said opsonin to lipopolyεaccharide. 68. The method of Claim 61 wherein said anti-opεonin antibody iε a monoclonal antibody that inhibits the binding of complexes of lipopolysaccharide and said opsonin to CD14. 69. A pharmaceutical composition for the treatment of inflammation and/or fever in mammals, comprising: A. a therapeutically effective amount of a material εelected from the group consisting of an antibody to an opsonin, an agent capable of inhibiting the production of said opsonin, an agent not an antibody to εaid opεonin capable of antagonizing the activity of εaid opεonin, and mixtureε thereof, or a εpecific binding partner thereto, εaid opεonin comprising a protein that is capable of binding to lipopolysaccharide to form a complex that is recognized by a receptor on monocytes, macrophage cellε and polymorphonuclear cellε, and that poεεesseε an apparent molecular weight of about 90 kD as determined by SDS-PAGE analysis; and B. a pharmaceutically acceptable carrier. 70. The pharmaceutical composition of Claim 69 wherein said antibody to said opsonin is a polyclonal antibody. 71. The pharmaceutical composition of Claim 69 wherein said antibody is raised in rabbits and derived from the IgG of immune serum. 72. The pharmaceutical composition of Claim 69 wherein the said agent not an antibody to said opεonin compriεeε at leaεt one protease inhibitor. 73. The pharmaceutical composition of Claim 69 wherein said protease inhibitors are selected from the group consiεting of antipain, leupeptin, benzamidine, chymoεtatin, pepstatin A, aprotinin and mixtures thereof. 74. The pharmaceutical compoεition of Claim 69 wherein εaid antibody iε raised againεt a component of the proteεe caεcade that gives rise to the opsonin. 75. A therapeutic composition comprising, in unit dose form, anti-opsonin antibody molecules in a pharmaceutically acceptable excipient, said antibody moleculeε being capable of inhibiting the binding of said opsonin to lipopolysaccharide. 76. The therapeutic composition of Claim 75 wherein said antibody to said opsonin is a polyclonal antibody. 67 77. The therapeutic compoεition of Claim 75 wherein εaid antibody iε raiεed in rabbitε and derived from the IgG of immune serum. 78. The therapeutic composition of Claim 75 wherein the said agent not an antibody to said opsonin comprises at least one protease inhibitor. 79. The therapeutic composition of Claim 78 wherein εaid proteaεe inhibitorε are selected from the group consiεting of antipain, leupeptin, benzamidine, chymostatin, pepstatin A, aprotinin and mixtures thereof. 80. The therapeutic composition of Claim 75 wherein εaid antibody is raised against a component of the protease caεcade that giveε riεe to the opεonin. 81. The therapeutic compoεition of Claim 75 further including a unit doεe of anti-TNF antibody moleculeε. 82. The therapeutic compoεition of Claim 75 further including a bactericidal amount of an antibiotic. 83. The therapeutic compoεition of Claim 75 further including a bactericidal amount of an antibiotic. 84. A compoεition comprising, as active ingredients in concentrationε suitable for administration to humans for the treatment of sepεiε, anti-opεonin antibody moleculeε capable of inhibiting the binding of said opsonin to lipopolysaccharide, and one or both of an antibiotic and anti-TNF antibody molecules. 85. The composition of Claim 84 wherein said antibody to said opsonin is a polyclonal antibody. 86. The compoεition of Claim 84 wherein εaid antibody iε raised in rabbits and derived from the IgG of immune serum. 87. The composition of Claim 84 wherein the said agent not an antibody to said opsonin compriseε at leaεt one proteaεe inhibitor. 88. The compoεition of Claim 87 wherein εaid proteaεe inhibitorε are selected from the group consisting of antipain, leupeptin, benzamidine, chymostatin, pepεtatin A, aprotinin and mixtureε thereof. 89. The compoεition of Claim 84 wherein εaid antibody iε raiεed againεt a component of the proteaεe caεcade that giveε riεe to the opεonin. 90. A pharmaceutical compoεition for the treatment of infectious and non-infectious diseaseε in mammalε, comprising: A. a therapeutically effective amount of a material selected from the group consiεting of an * opεonin, an agent capable of promoting the production and/or activity of εaid opεonin, an agent capable of mimicking the activity of εaid opεonin, and mixtureε thereof, εaid opεonin compriεing a protein in purified form that iε capable of binding to lipopolyεaccharide to form a complex that iε recognized by a receptor on monocyteε, macrophage cellε and polymorphonuclear cellε, and that posseεεeε an apparent molecular weight of about 90 kD aε determined by SDS-PAGE analyεiε, or a εpecific binding partner thereto; and B. a pharmaceutically acceptable carrier. 91. An opεonin compriεing a protein in purified form that is capable of binding to lipopolyεaccharide to form a complex that iε recognized by a receptor on monocytes, macrophage cellε and polymorphonuclear cells, and that posseεses an elution profile based on elution with a gradient of NaCl that appears as a peak at approximately 200 mM NaCl, as shown in FIGURE 1.

Inventors: WRIGHT SAMUEL D, WRIGHT, SAMUEL, D.
Applicants: UNIV ROCKEFELLER, THE ROCKEFELLER UNIVERSITY
Application year: 1991
Main classification: C07K15
IPC codes: A61K38, A61K39, A61P29, A61P31, C07K14, C07K16, C07K19, C12N9, C12P21, G01N33