METHODS AND COMPOSITIONS FOR AMELIORATING THE SYMPTOMS OF SEPSIS

Abstract: The present invention concerns a method of treating sepsis comprising administering a therapeutically effective amount of anti-CD14 antibody molecules. A therapeutic composition comprising anti-CD14 antibody molcules in a pharmaceutically acceptable excipient is also contemplated.

Description: Methods And Compositions For Ameliorating The Symptoms Of Sepsis Description Technical Field The present invention relates to methods and compositions for preventing or treating sepsis. More particularly, the present invention relates to molecules that bind the CD14 monocyte differentiation antigen or LPS-LBP complexes, thereby inhibiting the binding of LPS-LBP complexes by CD14-expresεing cells. Background Sepsis is a morbid condition induced by a toxin, the introduction or accumulation of which iε 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 coagulation, adult respiratory distress syndrome and multiple organ 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 chemical structure of most of the LPS molecule is complex and diverse, a common feature iε the lipid A region of LPS [Rietschel, 1 E. Th. 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 organismε, common pathophysiologic changes characterize gram-negative 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/ acrophage 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 and endothelial cells; each of these cell types are also capable of responding to LPS with the elaboration of potent inflammatory εubstanceε. LPS iε believed to be a primary cause of death in huroanε 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. Enrf. J. Med.. 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). Mathison et al., J. Clin. Invest. 81: 1925 (1988) . Evidence that TNF iε a critical mediator of εeptic shock comes primarily from experimentε in which pretreatment of animals with anti-TNF antibodies reduces lethality. Beutler et al., Science. 229:869, (1985). Mathison et al., J. Clin. Invest. 81: 1925 (1988). These reportε εuggeεt that interruption of the εecretion of TNF caused by LPS or other factors would ameliorate the often lethal symptoms of sepsis. Upon introduction of LPS into the blood, it may bind to a protein termed lipopolysaccharide binding protein (LBP) . LBP iε 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 iε synthesized by hepatocytes, and reacheε concentrationε of 30-50 ug/ l in εeru . LBP can be purified from acute phaεe human and rabbit εerum. Tobiaε, et al., J. EXP. Med.. 164:777-793 (1986). LBP recognizeε the lipid A region of LPS and formε high affinity, 1:1 εtoichiometric complexeε with both rough and εmooth form LPS. Tobias, et al., J. Biol. Chem.. 264:10867-10871 (1989). LBP bears N-terminal sequence homology with the LPS-binding protein known aε 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. r 132:3109-3115, (1984). In contrast to BPI, LBP iε not directly cytotoxic for gram-negative bacteria [Tobias, et al., J. Biol. Chem.. 263:13479-13481, (1988)] and its precise biological function has been obεcure. By way of further background, the cellε of the monocyte/macrophage lineage perform diverse immune function including the phagocytoεis of icroorganiεmε, 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 componentε and cytokineε. Surface membrane antigenε play a critical role in regulating these activities. Several monocyte/macrophage εurface antigenε have been identified and their molecular weight haε been determined. One εuch antigen, CD14, iε a 55-kD glycoprotein expreεsed 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 unction haε yet been ascribed to CD14, itε reεtricted expresεion on mature cellε εuggeεtε an important effector function. The nucleotide εequence of the gene encoding the monocyte cell εurface differentiation antigen CD14 haε been determined and the amino acid residue εequence of CD14 haε been deduced therefrom. (Ferrero et al.. Nucleic Acids Research Vol. 16:4173 (1988) Brief Summary of the Invention The preεent invention waε born out of the discovery that a primary regulator of cytokine production and release is the CD14 receptor, particularly in cells of the monocyte/macrophage lineage. Inasmuch as cytokineε secretion plays an important role in producing the symptoms of sepsis, the present invention contemplates methods and agents for inhibiting the secretion of cytokines, particularly TNF. Therefore, in one embodiment, the present invention contemplates administering, preferably intravenously, to a pateint at risk for or suffering the symptoms of εepis a therapeutically effective amount of an anti-CD14 antibody, an anti- LBP antibody, an LBP peptide analog or a εubcombination or combination thereof. The method can be practiced alone or in combination with the subεtantially simultaneouε adminiεtration of other therapeutic modalities known to prevent or ameliorate the symptomε of εepεiε, including treatment with one or more of an antiboiotic, εteroidε, anti-TNF antibody, TNF antagonist and the like. Further contemplated by the preεent invention are therapeutic compositions, typically in unit dose form, useful for preventing or ameliorating the symptomε of εepsis. The compositionε comprise a pharmaceutically acceptible carrier containing one or more of an anti-CD14 antibody, an anti-LBP antibody, and LBP peptide analog that acts as an LBP antagonist, aε an active ingredient. In preferred embodiments, a therapeutic compoεition of this invention further containε, aε active ingredientε an agent known to prevent or ameliorate the εymptomε of εepεiε, such aε an antibiotic, steroid, anti-TNF antibody, a TNF antagoniεt, soluble CD14 and the like, either alone, in sub-combination or combination. -6- Brief Description of the Drawingε In the Figureε forming a portion of the diεcloεure of £hiε invention: Figure 1 illuεtrateε that LBP enhanceε the interaction of ELPS with MO. Monolayerε of MO were incubated with E or ELPS 10 in the preεence of varying doεeε of LBP, and attachment index was scored. A control acute phaεe protein, annose binding protein (MBP) (5 ug/ml) cauεed no enhancement of binding of ELPS 10 (attachment index 4.9). Reεultε are repreεentative of 4 separate experiments. Figure 2 illustrates LBP-dependent binding of ELPS to MO depends on the density of LPS in the E membrane. ELPS were prepared with varying doseε of LPS then incubated with monolayerε of MO in the presence or absence of 5 ug/ml LBP. Results are representative of 4 separate experiments. Figure 3 illustrates that MO do not recognize LBP in the absence of LPS. E coated with biotin and streptavidin alone (EBAV) were incubated with Biotinylated LBP to yield ELBP. Both ELBP and EBAV were incubated with graded doses of LPS for 20 min at 37 C, washed, and binding to monolayers of MO was measured. Figure 4 illustrateε that LBP enhances Fc-mediated phagocytosiε. Monolayerε of MO (day 5 culture) were incubated for 45 min with E, ELBP, or EC3bi in the preεence of varying dilutions of anti- E-IgG. Phagocytosis of the E was determined as described in Materials and Methodε. ELBP were obtained by adding 1 ug/ml LBP to ELPS 10 (0.3 ug LPS/3 x 10 7 E) during incubation with MO. Attachment of these E in the absence of anti-E IgG was as followε: E, Attachment index (AI)-O; EC3bi, AI- 417; ELBP, AI-404. Reεults are representative of six εeparate experimentε. Figure 5 illuεtrateε that secretion of hydrogen peroxide during spreading of MO on ligand- coated εurfaceε. 3 x 10* MO (day 3 of culture) were added to coated microtitre wellε and the evolution of hydrogen peroxide was measured at intervals. Briεk production of peroxide occurred during εpreading on immune complexes (HSA-anti-HSA, closed circles) or in response to the soluble agonist, PMA (closed diamonds) . Low but reproducible peroxide releaεe waε obεerved during interaction with LPS- coated εurfaceε (open triangles) . However, εpreading on LBP-coated εurfaceε (open εquare) cauεed no releaεe, and coating of LPS-coated surfaces with LBP (open diamond) prevented the LPS- induced generation of peroxide. LBP did not impair the production or measurement of peroxide since MO in LBP-coated wells exhibited normal peroxide evolution in reεponεe to PMA. Figure 6 illustrates the inhibition of LPS-LBP complex binding by monoclonal anti-CD14 antibodies. Monolayerε of human MO were incubated for 15 min at 0 C with the indicated concentrations of monoclonal antibodies. Erythroctyeε coated sequentially with LPS and LBP were added and attachment waε meaεured. Results are representative of three separate dose response experiments and of ten experiments performed at a fixed concentration of antibody. High concentrations of a large panel of mAbs directed against other determinants on acrophages had no effect on the binding ELBP. Figure 7 illustrates that surface-bound anti-CD-14 mabs down-modulate binding of LBP-LPS complexes. Monolayers of human macrophageε were eεtablished on substrates coated with 25 ug/ml of the indicated monoclonal antibodies. The cells were washed, ELPS le> were added, and attachment waε measured. Figure 8 illustrateε that native LBP iε required for LPS to induce TNF production. Rabbit peritoneal exudate macrophageε (PEM) were challenged with LPS in the preεence of the indicated ' concentrations of native LBP (LBP) , heated (dentured) LBP, bovine εerum albumin (BSA) or fetal calf serum (FCS) . The amount of TNF produced by the challenged PEM was then determined. Figure 9 illuεtrates the susceptibility of LBP to tryptic digestion in the preεence or absence of a ligand to which it binds, i.e., Re595 LPS. Molecular weight markers (Pharmacia, Piscataway, N.J. ; catalog No. 17-0446-01; phoεphorylaεe B at 94 kilodaltonε (kD) , bovine serum albumin at 67 kD, ovalbu in at 43 kDa, carbonic anhdrase at 30 kD, soybean trypεin inhibitor at 20.1 kD and alpha lactalbumin at 14.4 kD.) appear in lanes adjacent to thoεe containing LBP. The reεultε εuggest that LBP binding to LPS results in a conformational change in LBP that may account for its ability to bind CD14 only when present as part of an LPS-LBP complex. Detailed Description of the Invention A. Definitions Amino Acid Reεidue: The amino acid reεidueε deεcribed herein are preferred to be in the "L" iso eric form. However, residues in the "D" iεo eric form can be εubεtituted for any L- a ino acid reεidue, aε long aε the deεired functional property of immunoglobulin-binding is retained by the polypeptide. NH2 refers to the free amino group preεent at the amino terminus of a polypeptide. C00H referε to the free carboxy group preεent at the carboxy terminus of a polypeptide. In keeping with standard polypeptide nomenclature, J. Biol. Chem.. 243:3552-59 (1969), abbreviations for amino acid residues are shown in the following Table of Correspondence: TABLE OF CORRESPONDENCE SYMBOL AMINO ACID w R D N C It εhould be noted that all amino acid reεidue εequenceε are repreεented herein by formulae whose left and right orientation is in the conventional direction of amino-terminuε to carboxy-terminuε. Furthermore, it εhould be noted that a daεh at the beginning or end of an amino acid reεidue εequence indicateε a peptide bond to a further εequence of one or more amino acid reεidueε. The term "antibody" in itε variouε grammatical ϊormε referε to a compoεition containing immunoglobulm oleculeε and/or immunologically active portionε of immunoglobulm moleculeε, i.e., moleculeε that contain an antibody combining εite or paratope. In preferred embodiment, the antibodieε uεed herein have been affinity purified. An "antibody combining εite" iε that εtructural portion of an antibody molecule co priεed of heavy and light chain variable and hypervariable regionε that εpecifically bindε antigen. The phaεe "antibody molecule" in itε variouε grammatical formε aε uεed herein contemplates both an intact immunoglobulm molecule and an immunologically active portion of an immunoglobulm molecule. Exemplary antibody moleculeε are intact immunoglobulm moleculeε, εubstantially intact immunoglobulm moleculeε and thoεe portionε of an immunoglobulm molecule that containε the paratope, including those portionε known in the art aε Fab, Fab 1 , F(ab') 2 and F(v), which portions are preferred for uεe in the thereapeutic ethodε deεcribed herein. Fab and F(ab') 2 portionε of antibody moleculeε are prepared by the proteolytic reaction • of papin and pepεin, reεpectively, on εubεtantially intact antibody molecules by methods that are well known. See for example, U.S. Patent No. 4,342,566 to Theofilopolouε et al. (The diεcloεureε of the art cited herein are hereby incorporated by reference.). Fab 1 antibody molecule portions are also well known and are produced from F(ab') i2 portions followed by reduction of the disulfide bohdε linking the two heavy chain portionε aε with mercaptoethanol, and followed by alkylation of the resulting protein ercaptan with a reagent such aε iodoaceta ide. An antibody containing intact antibody molecules iε preferred, and iε utilized aε illustrative herein. The phraεe "monoclonal antibody" in itε variouε grammatical formε referε to an antibody containing having only one εpecieε of antibody combining site capable of immunoreact ng with a particular antigen. A monoclonal antibody thuε typically displays a εingle binding affinity for any antigen with which it i munoreacts. A monoclonal antibody may therefore contain an antibody molecule having a plurality of antibody combining siteε, each i munospecific for a different antigen, e.g., a biεpecific (chimeric) monoclonal antibody. The phraεe "subεtantially simultaneously" is used herein to mean within a time period sufficient to produce concurrent resultε, e.g., bacterial lyεiε aε a reεult of antibiotic adminiεtration and amelioration or prevention of εymptomε of εepεiε that may occur aε a reεult of that lyεiε by adminiεtration of an anti-CD14 antibody, anti-LBP antibody, LBP peptide analog, or a εubco bination or combination thereof, aε deεcribed herein. The phraεe "pharmaceutically acceptable" referε to molecular entitieε and compositions that are phyεiologically tolerable and do not typically produce an allergic or εimilar untoward reaction, εuch aε gaεtric upεet, dizzineεs and the like, when administered to a human. B. Therapeutic Methods The preεent invention contemplates methods of treating and/or preventing one or more of the symptoms of εepεiε, particularly thoεe aεεociated with a tranεient increaεe in the blood level of TNF, έuch aε fever, hypotenεion, neutropenia, leukopenia, thrombocytopenia, shock and multiple organ failure. Patients in need of such treatment include those at risk for or suffering toxemia, εuch aε endotoxemia reεulting from a gram-negative bacterial infection, εerpent venom poisoning, hepatic failure, and the like. In addition, some patientε having a gram-positive bacterial, viral or fungal infection diεplay the symptomε of εepεiε 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, Hae ophiluε influenza B, Neiεεeria meninσitideε. εtaphylococci, or pneumococci. Patientε at risk for εepεis include thoεe εuffering burnε, gunshot wounds, renal or hepatic failure due to chemical poisoning or abuse, and the like. Thuε, in one embodiment, the preεent invention contemplateε a method of ameliorating one or more of the εymptomε of εepεis by adminiεtering to a patient in need of εuch therapy a therapeutically effective amount of an anti-CD14 antibody. The phraεe "therapeutically effective amount" iε used herein to mean an amount sufficient to prevent, and preferably reduce by at least about 30 percent, more preferably by at least 50 percent, moεt preferably by ' at leaεt 90 percent, a clinically εignificant increaεe in the plaε a level of TNF. Preferred therapeutically effective amountε for the agentε uεed herein aε active ingredientε include thoεe deεcribed in Section C. A clinically εignificant increaεe in the plaεma level of TNF iε an increaεe to at least about 25 pg/ l. Methods for determining the plaεma TNF levelε are well known in the art, particularly preferred methodε being thoεe described herein. It εhould be noted that levels of TNF in normal healthy humans or in laboratory animals are estimated to be no more than about 10 pg/ml, a value that iε at the limit of detection by the moεt εenεitive aεayε for TNF. Michie et al., New Enσ. J. Med. 318:1481-1486 (1988); Mathiεon et al., J. Clin. Inveεt. 81:1925 (1988) and Waage et al.. Laucet, 1:355-357 (1987). Following expoεure to LPS, the levels of TNF have been εhown to riεe 10- 20 fold to levalε of up to 400 pg/ml (vide εupra) . Recently a good correlation haε been εhown between εerum 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 εepsiε with εubhuman primates εimilar increases in TNF were noted and these changeε were directly correlated with lethality. Tracey et-al., Nature. 330:662-664, (1987) . In another embodiment, the method co priεeε adminiεtering to a patient in need of treatment or at riεk for Sepεiε a therapeutically effective amount of an anti-CD14 antibody, preferably an amount εufficient to inhibit LPS- induced TNF εecretion in vivo by cellε, εuch aε cellε of the monocyte/macrophage lineage, preferably monocyte derived macrophageε. Preferably, the anti-CD14 antibody uεed in a therapeutic method of thiε invention iε an affinity purified polyclonal antibody. More preferably, the antibody iε a monoclonal antibody ( Ab) . In addition, ' it iε preferable for the anti- CD14 antibody moleculeε uεed herin be in the form of Fab, Fab', F(ab*) 2 or F(v) portionε of whole antibody moleculeε. Preferred monoclonal antibodieε uεeful in practicing the preεent invention are thoεe capable of being produced by a hybridoma εuch aε 60b deεcribecf in Ashman, et al., Blood. 69:886-892, 1987, arid moεt preferably by 3C10 (depoεit number TIB22B at American Type Culture Collection, Rockville, MD) , described in Van Voorhiε, et al., J. Exp. Med.. 158:126-145, 1983, and the like. While Abs 60b and 3C10 can be produced by hybrido a culture, the invention is not so limited. Alεo contemplated iε the uεe of mAbε produced by an anti-CD14 immunoglobulm expreεεing nucleic acid cloned from a hybridoma εuch aε 60b and/or T ΓCIO. That iε, the nucleic acid expressing the anti-CD14 antibody molecules secreted by hybridoma 3C10 or the like can be transferred into another cell line to produce a tranεfor ant. The tranεformant iε genotypically diεtinct from the original hybridoma but iε also capable of producing anti-CD14 antibody moleculeε, including immunologically active fragmentε of whole antibody moleculeε, correεponding to thoεe εecreted by the hybridoma. See, for example, United States Patent No. 4,642,334 to Reading; PCT Publication No. WO 890099 to Robinεon et al. ; European Patent Publicationε No. 0239400 to Winter et al. and No. 0125023 to Cabilly et al. Preferred monoclonal antibodieε diεplay an immunoreactivity for CD14 that iε εi ilar to that of those produced by the above-deεcribed hybrido aε. Aε uεed herein, the term "immunoreactivity" in its variouε grammatical formε referε 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 CD14 antigen. That iε, immunoreactivity iε the concentration of antigen required to achieve a B/B 0 value of 0.5, where B 0 iε the maximum amount of antibody bound in the abεence 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.. 20:1255-1270 (1974). In another embodiment, a therapeutic method of the present invention compriseε adminiεtering a therapeutically effective amount of an anti-LBP antibody preferably an affinity- purified polyclonal antibody and more preferably a mAb. In addition, it iε preferable for the anti- LBP antibody irφleculeε uεed herein be in the form of Fab, Fab 1 , " F(ab') 2 or F (v) portions of whole antibody moleculeε. Preferably, the amount of anti-LBP antibody adminiεtered iε εufficient to reduce by at leaεt about 30 percent, preferably by at leaεt 80 percent, an LBP-LPS complex induced clinically εignificant increaεe in the blood level of TNF in a patient displaying at leaεt one of the εymptomε of εepεiε. Aε previouεly diεcuεεed, patientε capable of benefiting from thiε method include thoεe εuffering endotoxemia aε a reεult of a gram-negative bacterial infection. Methodε for iεolating LBP and inducing anti-LBP antibodieε are well known in -the art. See, for example Tobiaε et al., J. EX . -Med.. 164: 777-793 (1986). Methodε for determining and optimizing the ability of an anti-LBP antibody to inhibit the binding of LBP-LPS complexeε to CD14 and thereby inhibit LBP-induced TNF εecretion, are well known in the art. For inεtance, an anti-LBP antibody can be εubεtituted for the anti-CD14 antibody in the aεεay deεcribed in Example 16. Preferred anti-LBP antibodieε uεeful in practicing the preεent invention immunologically croεε-react with a peptide analog of LBP. A "LBP peptide analog" iε a polypeptide capable of competitively inhibiting the binding of LPS-LBP complexes to CD14 expressed on the εurface of onocyte derived macrophages. Preferred LBP peptide analogε are thoεe εhown in Table 1. Table 1 Deεiqnation Amino Acid Residue Sequence C16Y CNRLNRAPQPDELY Y16C YTTPEPSELDDEDFRC K16C KRVDADADPRQYADTC Methodε for producing polyclonal anti- polypeptide antibodieε are well known in the art. See U.S. Patent No. 4,493,795 to Neεtor, et al. A monoclonal antibody, typically containing Fab and/or F(ab') 2 portions of uεeful antibody moleculeε, can be prepared using the hybridoma technology deεcribed in Antibodieε A Laboratory Manual. Harlow and Lane, eds.. Cold Spring Harbor Laboratory, New York (19S8) , which is incorporated herein by reference. Briefly, to form the hybridoma from which the monoclonal antibody compoεition iε produced, a myeloma or other self- perpetuating cell line iε fuεed with ly phocyteε obtained from the εpleen of a mammal hyperimmunized with CD14 or an LBP-binding portion thereof, or LBP or a CD14-binding portion thereof. It iε preferred that the myeloma cell line be from the εame εpecieε aε the lymphocytes. Typically, a mouse of the strain 129 G1X * iε the preferred mammal. Suitable ouεe myelomaε for uεe in the preεent invention include the hypoxanthine- aminopterin-thymidine-εenεitive (HAT) cell lineε P3X63-Ag8.653, and Sp2/0-Agl4 that are available from the American Type Culture Collection, Rockville, MD, under the deεignationε CRL 1580 and CRL 1581, reεpectively. Splenocyteε are typically fuεed with myeloma cellε uεing polyethylene glycol (PEG) 6000. Fuεed hybridε are εelected by their εenεitivity to HAT. Hybrido as producing a monoclonal antibody useful in practicing this invention are identified by their ability to im unoreact with CD14 or LBP and their ability to inhibit LPS-induced TNF εecretion uεing the method deεcribed in Example 16. A monoclonal antibody uεeful in practicing the preεent invention can be produced by initiating a monoclonal hybridoma culture compriεing a nutrient medium containing a hybridoma that εecreteε antibody moleculeε of the appropriate antigen εpecificity. The culture iε maintained under conditionε and for a time period εufficient for the hybridoma to εecrete the antibody moleculeε into the medium. The antibody-containing medium iε then collected. The antibody molecules can then be further isolated by well known techniques. Media uεeful for the preparation of theεe compoεitionε are both well known in the art and commercially available and include εynthetic culture media, inbred mice and the like. An exemplary εynthetic medium iε Dulbecco's minimal esεential medium (DMEM; Dulbecco et al., Virol. 8:396 (1959)) supplemented with 4.5 gm/1 glucoεe, 20 mm glutamine, and 20% fetal calf εerum. An exemplary inbred ouεe εtrain iε the Balb/c. Methods for producing monoclonal anti- polypeptide antibodieε are alεo well known in the art. See Niman, et al., Proc. Natl. Acad. Sci. USA, 80:4949-4953 (1983). Typically, one or more of LBP peptide analog iε uεed either alone or conjugated to an im unogenic carrier, aε the immunogen in the before deεcribed procedure for producing anti-CD14 monoclonal antibodieε. The hybridomaε are εcreened for the ability to produce an antibody that immunoreactε with the LBP peptide analog and LBP. The ability to inhibit LPS-LBP complex binding to CD14 by mAbε de onεtrating the appropriate immunologic croεε-reacting iε confirmed uεing the aεεay of Example 16. In another embodiment, a therapeutic method of the preεent invention involveε adminiεtering a therapeutically effective amount of a LBP peptide analog, preferably an analog having a εequence aε εhown in Table 1. Patientε at riεk for or exhibiting the εy ptomε of εepεiε are capable of benefiting from the adminiεtration of therapeutic odalitieε known * in the art to prevent or ameliorate thoεe εymptomε. Thuε, the preεent invention contemplateε adminiεtering a therapeutically effective amount of an anti-CD14 antibody, anti-LBP antibody, LBP peptide analog, a εubcombination or combination thereof, εubεtnatially εimultaneously with therapeutic adminiεtration of a modality known to prevent or treat the εymptomε of εepεiε. For inεtance, intervention in the role of TNF in εepεiε, 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 εepεiε. Particularly preferred iε the uεe of an- anti-TNF antibody aε an active ingredient, such aε a monoclonal antibody having an immunologic specificity or TNF corresponding to that described by [Tracey et al.. Natur . 330:662-664 (1987)]. Similarly, a therapeutic method of this invention can further include εubεtantially εimultaneous treatment with a εteroid, εuch aε cortiεol, hydrocortiεone and the like. A patient exhibiting the εymptomε of εepεiε iε usually treated with an antibiotic, typically an a inoglycoεide εuch aε gentamycin or a beta-lactam εuch as penicillin, cephaloεporin and the like. Thuε, a preferred therapeutic method includeε adminiεtering a therapeutically effective amount of an anti-CD14 antibody, anti-LBP antibody, L3P peptide analog subcombination or combination thereof aε deεcribed herein, εubstantially εi ultaneouεly with adminiεtering a bactericidal a ounfe of an antibiotic. The phraεe "bactericidal amount" iε uεed herein to mean an amount εufficient to achieve a bacteria-killing blood concentration in the patient receiving the treatment. The bactericidal amount of antibiotics generally recognized aε εafe for adminiεtration to humanε iε 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-CD14 antibody, anti-LBP antibody, LBP peptide analog or combination thereof aε described herein gccurs within about 48 hours, 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 formulationε deεcribed in the Phyεicianε' 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-LBP complexes, alone or in εubcombmation or combination with a therapeutically effective amount of an anti-TNF antibody, an anti-LBP antibody, and an antibiotic. The cDNA coding for CD14 and itε deduced amino acid reεidue εequence are well known in the art. See Goyert et al, Science. 239:497-500 (1988), Ferrero et al., Nuc. Acids Res. , 16:4173 (1988), and Bazil et al., Eur. J. Immunol.. 16:1583-1589 (1936). C. Therapeutic Co m positions The present invention further contemplates therapeutic compositions useful in practicing the therapeutic methods of this invention. A subject therapeutic composition includes, in admixture, a pharmaceutically acceptable excipient (carrier) and one or more of an anti-CD14 antibody, anti-LBP antibody, and LBP polypeptide analog as described herein as an active ingredient. In preferred embodiments, the composition compriseε an anti-CD14 mAb capable of inhibiting the binding of LPS-LBP complexeε to CD14. A preferred mAb iε 60b, and more preferably iε 3C10. In another preferred embodiment, the • compositionε compriεe an anti-LBP antibody, preferably a mAb, that inhibitε the binding of LPS- LBP complexeε to CD14. Particularly preferred are compositionε wherein the anti-LBP antibody i uoreactε with a LBP peptide analog having a εequence εhown in Table 1. A preferred compoεition compriεeε a LBP peptide analog that actε aε an antagoniεt to LPS- LBP complexeε in binding to CD14. Preferred LBP peptide analogε for uεe in compoεitionε of thiε invention are thoεe having a εequence εhown in Table 1. Preferred therapeutic compoεitionε further include an effective amount of one or more of the following active ingredientε: an antibiotic, a εteroid, and anti-TNF antibody and a TNF antagoniεt. Exemplary for ulationε are given below: Formulation A Ingredient ' Dose fπσ/ml gentamicin (εulfate) 40 Anti-CD14 (mAb 3C10) 10 εodium biεulfite USP 3.2 diεodiu EDTA USP 0.1 water for injection q.ε.a.d. 1.0 ml Formulation B Ingredient anti-TNF antibody anti-CD14 (mAb 3C10) εodium biεulfite USP diεodum EDTA USP water for injection q.s.a.d. Formulation C Ingredient gemtamicin (εulfate) anti-TNF antibody anti-CD14 (mAb 3C10) εodium biεulfite USP diεodium EDTA USP water for injection q.ε.a.d. In another embodiment, the present invertium contemplates a therapeutic composition useful in treating sepεiε compriεed of CD14 or a LBP-binding εoluble portion thereof in a pharmaceutically acceptable carrier. Preferably, the composition further includes a therapeutically effective concentration of one or more of an anti-TNF antibody, an anti-LBP antibody and an antibiotic. The preparation of therapeutic compositionε which contain polypeptideε or antibody moleculeε aε active ingredientε iε well underεtood in the art. Typically, εuch compoεitionε are prepared aε injectables, either as liquid εolutions or εuεpenεionε, however, εolid formε εuitable for εolution in, or εuεpenεion in, liquid prior to injection can alεo be prepared. The preparation can alεo be emulsified. The active therapeutic ingredient is often mixed with excipientε which are pharmaceutically acceptable and compatible with the active ingredient. Suitable excipients are, for example, water, εaline, dextroεe, glycerol, ethanol, or the like and combinationε thereof. In addition, if deεired,the compoεition can contain minor amountε of auxiliary εubεtanceε εuch as ' wetting or emulsifying agents, pH buffering agentε which enhance the effectiveneεε of the active ingredient. A polypeptide or antibody can be formulated into the therapeutic compoεition aε neutralized pharmaceutically acceptable εalt formε. Pharmaceutically acceptable εaltε include the acid addition salts (formed with the free amino groups of the polypeptide or antibody molecule) and which are formed with inorganic acids such as, for example, hydrochloric or phoεphoric acidε,or εuch organic aci ε aε acetic, oxalic, tartaric, mandelic, and the like. Saltε formed from the free carboxyl groupε can alεo be derived from inorganic baεeε such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and εuch organic baεeε aε iεopropylamine, trimethylamine, 2- ethyla ino ethanol, hiεtidine, procaine, and the like. The therapeutic polypeptide- or antibody- containing co poεitions are conventionally administered intravenously, aε by injection of a unit doεe, for example. The term "unit doεe" when used in reference to a therapeutic compoεition of the preεent invention referε to phyεically diεcrete units εuitable aε unitary doεage for humanε, each unit containing a predetermined quantity of active material calculated to produce the deεired therapeutic effect in aεsociation 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 adminiεtered dependε on the εubject to be treated, capacity of the εubject'ε immune εystem to utilize the active ingredient, and degree of inhibition or neutralization of -CD14 or LPS-LBP complex binding capacity deεired. Preciεe amountε of active ingredient required to be adminiεtered depend on the judgment of the practitioner and are peculiar to each individual. However, suitable dosage ranges are of the order of 0.1 to 20, preferably about 0.5 to about 10, and more preferably one to several, milligrams of active ingredient per kilogram bodyweight of individual per day and depend on the route of administration. Suitable regimes for initial administration and booεter εhotε are alεo variable, but are typified by an initial adminiεtration followed by repeated doses at one or more hour intervalε by a εubεequent injection or other administration. Alternatively, continuouε intravenouε infuεion sufficient to maintain concentrationε of ten nano molar to ten micromolar in the blood are contemplated. Aε used herin, "pg" means picogram, "ng" meanε nanogram, "ug" means microgram, "mg" meanε milligram, "ul" meanε microliter, "ml" meanε milliliter, "1" meanε liter. Examples The following examples are intended to illustrate, but not limit, the preεent invention. Exampleε 1-11 illustrate studieε eεtabliεhing that human cellε of the monocyte/macrophage lineage bind LPS-LBP complexeε via a cell surface receptor that iε mobile in the plane of the membrane. Example 12 illustrates that anti-CD14 antibodieε can specifically inhibit the binding of LPS-LBP complexeε to CD14. Exampleε 13-15 demonεtrate that CD14 specifically bindε LPS-LBP complexeε and that that binding induceε TNF εecretion from MO. Example 16 demonεtrates that anti-CD14 mAbε inhibit LPS-LBP complex induced TNF εecretion in human blood. Example 17 provideε a εummary and diεcuεεion of the reεultε of Examples 1-16. 1. Reagents ISP was purified from acute phase rabbit serum (Tobias, et al., J. Exp. Med.. 164:777-793 (1986)), and appeared homogeneouε on εilver εtained gelε. Anti-rabbit LBP waε raiεed in goatε. MBP waε obtained from Dr. R.A.B. Ezekowitz (Boston, MA) . Bactericidal/permeability-increasing factor (BPI) was obtained from Dr. J. Gabay (New York, NY) . LPS from Salmonella innesota (Re595 or wild type) -was obtained from List Biological (Campbell, CA) . Monoclonal antibodieε (mAbε) IB4 againεt CD18 and 3G8 againεt FcyRIII (CD16) were deεcribed in Wright, et al., Proc. Natl. Acad. Sci. USA. 80:5699-5703, (1983). mAb 543 againεt CR1 waε obtained from Dr. R. Schreiber (St. Louiε, MO) , and mAbε 22 and IV.3, againεt FcyRI and FcyRII, were obtained from Dr. M. Fanger (Hanover, NH) . Pyrogen-free human εerum albumin (HSA) waε from Armour Pharmaceuticalε, and pyrogen-free PBS and DGVB++ were from Whitaker MA Bioproductε. NHS- biotin, Sulfo-NHS-biotin, and εtreptavidin were from Pierce Chemical. 2. Surfaceε Tiεsue culture plastic surfaceε were coated by incubation with 25 ug/ml protein (antibody, LBP, or HSA) or 1 (ug/ml) per microgram/milliliter LPS for 1 hour(hr) at 20 degreeε C. To form immune complexeε, HSA-coated εurfaceε were incubated with anti-HSA antiεerum (1:50) for an additional 30 minuteε (min). In εome caεeε, LPS-coated εurfaceε were εubεequently treated with 10 ug/ml LBP for 30 min at 20 C. For aεεayε of hydrogen peroxide production, all coated εurfaceε were expoεed to 1 milligram per milliliter (mg/ml) HSA for 1 hr prior to the addition of phagocyteε. Coated εurfaceε were carefully waεhed with pyrόgen free PBS before the aεεayε. 3. Cellε Monocyte-derived macrophageε (MO) were obtained by culturing purified human monocyteε in Teflon beakerε for 3-10 dayε as described by Wright, et al., J. EXP. Me .. 156:1149-1164, (1982) . Monolayerε of fresh monocyteε were obtained by allowing peripheral blood mononuclear cellε to adhere to protein-coated plaεtic for 45 min at 37 C. PMN were purified from freεh blood by the method of Engliεh, et al., J. Immunol. Methodε. 5:249, (1974). T cellε, purified by roεetting with erythrocyteε, were obtained from J. Ming (Rockefeller U.). Human umbilical vein endothelial cell onolayers (Lo, et al., J. EXP. Med. , 169:1779-1793, (1989)) were obtained from Dr. S.K. Lo (Rockefeller U.) . Sheep erythrocyteε (E) were coated with IgG (ElgG) or IgM (ElgM) aε deεcribed by Wright, et al., J. EXP. Med.. 156:1149-1164, (1982). C3bi waε depoεited on ElgM by incubating 2-10 x 10 8 ElgM in 1 ml of 10% C5-deficient human εerum (Sigma) for 30 min at 37 C. The erythrocyteε were then waεhed and incubated for 10 min at 0 C in a buffer containing 2.5 mM ethylenediametetracetate (EDTA) . The reεulting EC3bi bore no C3b aε aεεayed by EDTA-reεiεtant roεetting with MO. E were coated with LPS aε deεcribed by Wright, et al. , J. EXP. Med.. 164:1876-1888, (1986) . The amount of LPS uεed in the preparation waε varied to yield ELPS hi (1-10 ug/4 x 10 7 E) or ELPS lo (0.2-l Λig/4 x 10 7 E) . ELPS 10 were coated with LBP by incubating equal volumes of ELPS 10 (10 8 /ml) and LBP (UL.ug/ml) for 20 min at 37 C. The resulting LBP-coated ELPS (ligand-coated E) were washed and used immediately. For some studieε E were alεo coated with LBP by an alternative method. E were firεt biotinylated by incubating 5 x 10 8 E with 250 ug Sulfo-NHS-biotin for 20 min at 5 C in 0.1 M εodium carbonate pH 9,2, and LBP was biotinylated by incubating 50 ug LBP with 5 ug Sulfo-NHS-Biotin and dialyzing against PBS. The biotinylated protein waε then linked to the biotinylated E through a εtreptavidin bridge. 10 8 waεhed, biotinylated E (EB) were incubated with 10 ug Streptavidin for 30 min at 20 C to yield avidin coated erythrocytes (EBAV)i. Preliminary experiments using fluoresceinated streptavidin εhowed that the EBAV were uniformly and intenεely fluoreεcent, and no agglutination could be seen. 2.5 x 10 7 washed EBAV were incubated with 2.5 ug of biotinylated LBP for 30 min at 20 C to yield EBAV-LBP. Salmonella typhimurium LT2 Gal E was grown in the presence or absence of galactose to yield cellε with a complete or truncated LPS, reεpectively. Wright, et al., J. EXP. Med.. 164:1876-1888, (1986). Exponentially growing cultures were waεhed, labelled with fluoreεcein, and adjuεted to 2 x 10 8 /microliter(ul) in PBS aε previously described. Wright, et al., J. Exp. Med.. 164:1876-1888, (1986). 4. Assays Agglutination of LPS-coated erythrocytes (Example 3) waε meaεured by εhaking 10 6 ELPS in 10 ul of diluted LBP for 30 min at 21 C in a round bottom microteεt plate. Agglutination was read from the settling pattern. Binding of ligand-coated E (Example 3) to MO waε meaεured aε deεcribed by Wright, et al., J. EXP. Med.. 156:1149-1164, (1982). Briefly, Teraεaki tiεεue culture plates were coated with HSA or other proteins (Example 2) , and monolayers of MO were establiεhed by incubating 5 ul of cellε (0.5 x 10 6 /ml in PBS containing 3 mM glucoεe, 0.5 mg/ml HSA, and 0.3 u/ml aprotinin (Sigma), for 45 min at 37 C. Ligand coated E and the indicated proteinε were added to the monolayerε. E were allowed to εettle for 10 min at 0 C, then the plate waε warmed to 37 C for 15 min. Unattached E were removed by waεhing and attachment was εcored by phaεe contraεt microεcopy. Binding of fluoreεceinated Salmonella waε aεεeεsed by a εimilar method employing a 15 min incubation at 37 C aε described by Wright, et al., J. EXP. Med.. 164:1876-1888, (1986). Reεultε are reported aε attachment index, the number of E or bacteria per 100 MO. Phagocytoεiε of ligand-coated E waε measured by εimilar methodε (Wright, et al., J. EXP. Med.. 156:1149-1164, (1982)), with the exception that incubation of MO with the E waε for 45 min at 37 C, and uningeεted E were lyεed by ' brief expoεure to hypotonic medium before scoring the wellε . 5. LBP Bindε To LPS Inεerted Into Ervthrocvte Membraneε Addition of aε little aε 0.5 ug/ml of LBP to ELPS hl cauεed agglutination. Since LPS partitionε into the membrane of E by hydrophobic interactionε with phoεpholipidε, thiε obεervation εuggeεtε that LBP recognizeε the expoεed hydrophilic portion of lipid A, and that LBP haε the potential to form multimerε. The ELPS were not εtrongly agglutinated and could be diεrupted by gentle pipetting. 6. LBP Enhances Binding Of ELPS And Salmonella to Macrophaσes Gram-negative bacteria and LPS- coated erythrocytes bind to MO through an interaction of LPS with memberε of the CD18 complex of receptorε on leukocyteε. Wright, et al., J. EXP. Med.. 164:1876-1888, (1986). The ability of LBP to perturb that interaction waε therefore examined. Initial εtudieε employed E prepared with high levelε of LPS. Theεe ELPS hl bound avidly to MO, and the addition of LBP εlightly enhanced binding. To examine the nature of thiε enhancement,. E were prepared with low levelε of LPS. Monolayerε of MO were incubated with ELPS 10 in the preεence or absence of 5 micorgrmε (ug) per millileter (ml) LBP. ELPS 10 were poorly bound by MO, but the addition of LBP cauεed a dramatic enhancement of binding (Figure 1) . Enhanced binding waε doεe dependent with a maximal effect at 1 ug/ml LBP. The εpecificity of thiε effect iε indicated by the obεervation that another acute phaεe reactant, mannoεe binding protein, did not affect binding of ELPS 10 to MO (Figure 1) at concentrationε aε high aε 100 ug/ml; another LPS- binding protein, BPI, did not affect binding at concentrationε aε high aε 10 ug/ml; and polyclonal anti-LBP antiεerum (1:200) cauεed a 20-fold reduction in the roεetting of ELPS 10 cauεe by LBP. The capacity of LBP to enhance interaction of ELPS with MO waε alεo dependent on the amount of LPS in the erythrocyte membrane (Figure 2). LBP could effectively mediate binding of E prepared with amountε of LPS 20-100 fold leεε than the amount needed to εuεtain a direct interaction between ELPS and MO. Strainε of gram-negative bacteria that expreεε a truncated LPS (rough εtrains) are avidly bound by MO, but εmooth εtrainε, with a complete LPS, are bound poorly. Wright, et al., J. EXP. Med.. 164:1876-1888, (1986). Becauεe LBP bindε equally well to both smooth and rough LPS, [Tobias, et al., J. Biol. Chem.. 264:10867-10871, (1989)], the ability of LBP to opεonize εmooth Salmonella waε examined. Aε illuεtrated by the data εhown in Table II, the addition of LBP cauεed a dramatic enhancement in the binding of εmooth Salmonella to MO. Table II LBP Enhanceε Binding Of Salmonella To MO Attachment Index εmooth S. typhimuriu rough S.typhimuriu -LBP 273 1,096 +LBP 1,661 2,109 1 Smooth and rough form preparations of S. tvphimurium LT2 were obtained by growing GalE mutantε of thiε strain in the preεence or abεence of galactoεe aε deεcribed by Wright, et al., i t . EXP. Med.. 164:1876-1888, (1986). The binding of bacteria to monolayerε of macrophageε waε then meaεured in the preεence of absence of 2.5 ug/ml LBP. Addition of LBP cauεed a 5.9 ± 1.9 (n-4) fold enhancement in the binding of εmooth bacteria to MO. Table II illuεtrateε that the addition of LBP alεo enhanced the binding of rough Salmonella, but the effect appeared leεε dramatic than that εeen with smooth S. typhimuriu due to the avid binding of unopsonized bacteria. Thuε, LBP can enhance the interaction of live, intact bacterium with MO. 7. MO Recognize Conplexeε Of LBP With LPS In Example 6, LBP was added together with the MO and the ELPS. To determine if LBP binds to MO or ELPS, the cells were separately incubated (treated) with LBP, washed, and then combined. The results of this study are εhown in Table III. Table III Pretreatment Of ELPS But Not MO With LBP Enhanceε Their Interaction 1 * Attachment Index coincubate LPB, 629 520 796 ELPS 10 and MO 1 Binding of ELPS 10 (0.2 ug/4 x 10 8 E) to monolayers of MO waε meaεured as described in Example 4. ELPS 10 or MO pretreated at 37 C with 5 ug/ml for 20 min and washed before the asεay. Alternatively, 5 ug/ml LBP waε added during the assay of attachment. Pre-treatment of ELPS 10 with LBP εtrongly enhanced binding to MO (Table III) with a doεe reεponεe curve identical to that obεerved in the coincubation experiments (data not εhown) . Thiε result εuggeεtε that LBP asεociateε εtably with ELPS and that the εurface-bound LBP iε recognized by MO. Pre-treatment of MO, on the other hand, did not affect the subεeguent binding of ELPS (Table III) . LBP on the εurface of ELPS iε complexed with LPS. To determine if MO bind to LBP in the absence of LPS, LBP was biotinylated and attached to streptavidin-coated erythrocytes. The reεulting EBAV-LBP were not bound by MO (Figure 3), but addition of LPS cauεed εtrong attachment of ELBP to MO. The LPS appeared to enhance adherence of EBAV- LBP by binding to LBP εince the amount of LPS needed to cauεe attachment of ELBP waε -50-fold leεε than needed to cause attachment of E lacking LBP (Figure 3). Further, the LPS-treated ELBP bound avidly to CD18-deficient MO, which do not bind ELPS. Thus, LP must be complexed with LPS in order to be recognized by MO. 8. LBP Iε Recognized By A Mobile Receptor Reεtricted To Mononuclear Phagocvteε LBP-treated ELPS bound to virtually 100% of monocyteε and MO, εuggeεting that binding activity is present on all members of theεe populationε. To determine whether LBP interacts with other cell typeε, monolayerε of PMN, T-cellε, and umbilical vein endothelial cellε were incubated with LBP-treated ELPS 10 . No binding was obεerved. Similarly, lymphocyteε that occasionally contaminate MO preparations were never obεerved to bind LBP-coated E. Thuε, the capacity to bind LBP- coated particleε appearε to be a property restricted to mononuclear phagocytes. The existence of a specific receptor for LBP was demonstrated by allowing MO to εpread on εurfaceε coated with complexes of LPS and LBP. Table IV illuεtrateε that εurface-bound LBP εtrongly down-modulated binding of LBP-treated ELPS but had no effect on the binding ElgG or EC3bi. Table IV Receptorε For LBP Are Mobile In The Plane Of The Membrane 1 1 Plaεtic εurfaceε were coated with HSA (500 ug/ml) , mAb IB4 (25 ug/ml) or LPS (1 ug/ml) for 2 hr at 21 C and waεhed thoroughly. Where indicated, anti-HSA (1:40 dilution of rabbit anti-HSA antiεerum) or LBP (5 ug/ml) waε added and incubated for 30 min at 20 C. MO were allowed to εpread on the washed, coated εurfaceε for 45 min at 37 C, and after an additional waεh, the ligand-coated erythrocyteε were added. ELPS hl were prepared with 3 ug LPS/4 x 10 7 E. ELPS 10 were prepared with 0.3 ug LPS/4 x 10 7 E then treated with 5 ug/ml LBP as deεcribed in Example 3. Data εhown are repreεentative of four εeparate experimentε. The above results indicate that LBP is recognized by a molecule that is mobile in the plane of the membrane, and suggest that thiε receptor iε different from CR3 and FcR. 9. LBP Does Not Interact With CR3 Or FcR Becauεe LPS iε known to be recognized by CR3 and other memberε of the CD18 complex (LFA-1 and pl50,95) (Wright, et al., J. EXP. Med.. 164:1876-1888, (19S6) ) , it appeared poεεible that LBP enhanced binding of ELPS by facilitating the interaction of a low amount of LPS with theεe receptorε. Several observationε, however, rule out thiε poεεibility. The reεultε illustrated in Table V indicate that LEP cauεed strong binding of ELPS to monocyteε iεolated from two patientε with a congenital deficiency of CD18. The CD18-deficient cellε exhibited negligible binding of ELPS h ' or EC3bi in parallel aεεayε. Table V LBP Mediateε Binding Of ELPS 10 To Monocytes From CD18 Deficient Patientε 1 t c m ndex 1 Monolayerε of monocyteε from two CD1S deficient patientε (CD18 deficient leukocytes respond to LPS in vitro) and two normal adult controls were iinnccuubbaatteedd wwiitthh EECC33bbii,, EELLPPSS ((33 uugg//44 xx 1100 δδ EE)) ,, ELPS 10 (1 ug/4 x 10 3 88 EI) , and attachment index was measured. WWhheerrte indicated, 2.5 ug/ml LBP was added with the Further evidence against the participation of CD18 molecules in recognition of LBP-treated ELPS 10 comes from experiments in which CD18 molecules were depleted from the apical εurface of MO by allowing them to εpread on εurfaceε coated with an i-CD18 mAbε. Ma IB4 down- modulated CD18 moleculeε aε εhown by the decreaεed binding of EC3bi and ELPS hi , but LBP-treated ELPS 10 bound normally to these cellε (Table IV) . Finally, depletion of Ca++ and Mg++ completely blockε binding of both C3bi and LPS to the CD18 complex [Wright et al., . EXP. Med.. 156:1149-1164 (1982) and Wright et al., J. EXP. Med.. 164:1876-1888 (1986)] but binding of LBP-treated ELPS 10 waε equivalent in EDTA-containing bufferε. The participation of Fc receptors in the recognition LBP was also ruled out. Spreading of cellε on an immune-complex coated εurface εtrongly down-modulated Fc receptorε as aεεayed by the binding of ElgG. However, the binding of LBP- coated ELPS 10 waε unaffected (Table IV) . Similar εtudieε εhowed that εurface-bound mannoεe binding protein and surface-bound Abs against FcRI, FcRII, FcRIII, and CRl had no effect on the binding of LBP to MO. Theεe data εuggeεt that LBP iε not recognized by CRl, CR3, FcR or mannoεe binding protein receptorε. 10. Receptors For LBP Enhance Fc- Mediated Phagocytosis Addition of anti-E IgG caused LBP-coated ELPS 10 to be avidly phagocytosed by MO (Figure 4) . The dose of anti-E IgG needed for half-maximal phagocytoεiε waε 5-fold leεε than that needed to induce phagocytoεiε of uncoated E (Figure 4) . LBP thus appearε to act synergistically with IgG to induce a phagocytic reεponse. In keeping with previous reports [Ehlenberger, et al., J. EXP. Me . , 145:357-371, (1977)], deposition of C3bi on E also enhanced phagocytoεiε mediated by IgG, and the extent of thiε enhancement waε εimilar to that cauεed by LBP (Figure 4) . Phagocytoεiε mediated by LBP alone waε alεo examined. Though LEP-coated ELPS formed florid roεetteε with MO, none of the bound E were phagocytoεed by either reεting (Figure 4), fibronectin-, or PMA-εtimulated MO. Parallel εtudieε εhowed εtrong fibronectin- and PMA- εtimulated phagocytoεiε of EC3bi. A poεεible explanation for the abεence of LBP-mediated phagocytoεiε iε the high lateral mobility of LPS on the εurface of an erythrocyte. The LPS could "cap" on the pole of the E attached to the MO, leaving inεufficient ligand on the circumference of the E to guide an advancing pεeudopod. To prevent such capping, biotinylated LBP waε linked to biotinylated E proteinε as deεcribed in Figure 4 above. Again, none of the E bound in thiε way were phagocytoεed by either E coated reεting or PMA- biεtimulate MO (Phagocytic index = 0) . Parallel εtudieε εhowed that with biotinylated F(ab) 2 of an anti-CD18 mAb (IB4) were readily phagocytosed (phagocytic index-482) . Thuε, receptors for LBP cannot by the εelves initiate phagocytoεiε of a coated erythrocyte. 11. Receptors For LB? Do Not Initiate An Oxidative Burst To determine whether interaction of LBP with its receptor initiates a cytotoxic responεe from MO, the production of hydrogen peroxide during the interaction of MO with coated surfaceε waε measured. Releaεe of hydrogen peroxide during εpreading of MO on coated surfaces waε meaεured aε deεcribed by delaHarpe, et al., J. Immunol. Methodε. 78:323-336, (1985). Briefly, 3-4 x 10* MO (day 3 or 4) were added to protein-coated tiεεue culture wellε containing horεeradish peroxidaεe and 2.4 n oleε of εcopoletin. The plate waε incubated at 37 C, and at intervalε the conεumption of εcopoletin was measured using an automated fluorescence plate reader. Reεultε are averaged from triplicate wellε and are presented as nmoles peroxide produced per well. Addition of the control εtimulant, PMA (100 ng/ml) , reεulted in rapid evolution of peroxide that waε identical in rate and extent for all coated εurfaces tested. Figure 5 illuεtrateε that MO binding to LPS-coated εurfaceε cauεed a εmall releaεe of peroxide (12% of that εti ulated by immune complexeε or PMA) . Surfaceε coated with LBP, however, cauεed no release of peroxide above baεeline. Further, addition of LBP to LPS-coated εurfaceε blocked the release cauεed by LPS, thus confirming that LBP effectively interacted with LPS in thiε experiment. Parallel experiments shoved that εpreading of MO on LBP or LPS+LBP-coated εurfaceε cauεed down-modulation of the binding of LBP-treated ELPS 10 , thuε confirming that ligaticn of LBP receptorε had occurred. Thuε LBP receptorε appear incapable of triggering an oxidative burεt. 12. Inhibition Of LPS-LBP Complex Binding To KO Bv Anti-CD14 Antibodies The ability of three anti-CD14 mAbε to inhibit the binding of LPS-LBP complexes to MO was examined. Monolayerε of human MO were incubated for 15 minutes at O C with mAb 3CIO, 60b or 26ic at concentrations of 0 ug/ml, 0.15 ug/ml, 0.5 ug/ml, 1.5 ug/ml, 5 ug/ml, and 15 ug/ml. The ability of the onolayers to bind LEP-treated ELPS 10 (Example 3) was aεεayed aε deεcribed in Example 4. The reεultε of thiε εtudy, illuεtrated in Figure 6, indicate that mAbε 3C10 and 60b produced an attachment index that diminiεhed with increaεing concentration of mAb uεed, whereaε mAb 26ic, which recognizeε an epitope different from that recognized by mAbε 3C10 and 60b, failed to reduce the index below levelε attained at the control mAb concentration (-0 ug/ml), i.e., did not inhibit binding. Thuε, mAbε 3C10 and 60b have the ability to inhibit €he binding of LPS-LBP complexeε to MO. The εpecificity of the inhibition is indicated by the obεervation that mAbε againεt CDllb, CD18, CD16 and HLA did not inhibit binding (data not εhown) . In contraεt, Figure 7 illuεtrateε that mAbε 26ic, 3C10 and 60b were all able to down- modulate binding of LPS-LBP complexeε to MO. Monoclonal antibodies were affixed to the tissue culture plates prior to establiεhing the MO monolayer. Thiε waε accompliεhed by admixing mAb into a plate at a concentration of 25 ug protein/ml, maintaining the mAb in the plateε for 60 inuteε at 20 C and then rinsing non-bound mAb from the plate prior to εeeding with MO. MO attached to surfaced coated with anti-CD14 mAbε, but not other mAbε, εhowed decreaεed binding of erythrocyteε coated with LPS-LBP complexeε. Thuε, CD14 which iε rediεtributed to the baεal εurface of attached macrophageε, iε neceεsary for binding of LPS-LBP complexeε. Thiε reεult confirms the concluεion of Figure 6 that CD14 serves as a receptor for LPS-LBP complexeε. 13. CD14 Specifically Binds LPS-LBP LPS- LBP Complexes The ability of purified CD14 to εpecifically bind LPS-LBP complexeε waε examined. CD14 waε immobilized on εurfaceε by coating them first with anti-CD14 mAbε then with a Triton X-100 extract of monocyteε. 10 8 raonocyteε were suspended in 1% Triton in PBS, incubated for 15 min at 0 C, then insoluble material was removed by centrifugation. The extract, which containε CD14, waε applied to the antibody-coated εurfaceε. Thiε procedure reεultε in surfaces coated with CD14. In control wellε bearing antibodieε againεt antigenε other than CD14 , thiε procedure reεultε in εurfaceε coated with proteinε other than CD14. After thorough waεhing, erythrocyteε coated with LPS-LBP complexeε were added to the coated wellε, and attachment of the erythrocyteε (ELPS 10 ) waε documented by photography. CD14 adεorbed to the εurface via mAb 26ic, an antibody to CD14 which does not block the binding εite for LPS-LBP binding εiteε, εtrongly bound the coated erythrocyteε. Surfaceε coated with other antigenε did not have this activity. Thus, the purified CD14 molecule has the ability to bind LPS-LBP complexeε. Thiε observation proves that CD14 εerveε aε a receptor for LPS-LBP complexes. 1 . LPS-LBP Complexes Induce TNF Secretion In MO The ability of LPS in the presence of LBP, heat treated LBP, bovine εerum albumin (BSA) or fetal calf εerum (FCS) to induce TNF εecretion in peritoneal exudate acrcphages (PEM) was examined. To produce rabbit PEM, NZW rabbits (2-2.5 kg) were given an intraperitoneal injection of 35 mineral oil (Drakeol 6VR, Pennreco, Butler, PA) containing 10 ug cell wall preparation from BCG (BCG Cell Walls, R-200, Ribi Immunochem Research, Inc. Hamilton, MT) . Three days later, a bolus i.v. injection of 120 mg sodium pentobarbital (Western Medical Supply Inc., Arcadia, CA) was made, followed by aεeptic lavage of the peritoneum with 500 ml ice cold RPMI-1640 εupplemented with 2 M L- glutamine, 1 mM Na pyruvate, 50 U/ 50 ug penicillin/εtrepto ycin per ml, 10 mM Hepes, 2% fetal bovine εerum and 5 U/ml heparin. The harveεted cellε were centrifuged (1000 x G, 10 minuteε, 4 C) and reεuεpended in the above medium without FBS iεerum-free medium) . Following an additional spin and reεuεpension in εerum-free medium, the cellε were counted uεing a he ocytometer and plated in 150 cm 2 flaskε at a denεity of 8-10 x 10 7 macrophageε/flaεk. After 2 h at 37 C, 5% C0 2/ non-adherent cellε were removed from the flaεkε by vigorouε waεhing and repleniεh ent with 20 ml εerum-free medium. The mineral oil induced peritoneal exudate cellε, when examined uεing Wright'ε εtained cytocentrifuge preparationε, contained approximately 60% macrophageε, 35% neutrophilε and 5% lymphocytes. After plating and washing, the adherent cellε were > 90% macrophageε. The rabbit PEM thuε produced were treated with LPS iεolated from Salmonella ineεota Re595 (100 pg/ml) in the preεence and absence of the proteinε noted above for 12 hours and the cell-free εupernatant aεεayed for TNF as eεcribed above uεing a modification of the L929 asεay of Ruff et al., Lyr.oho ineε, 2: 235-242, (1981) aε deεcribed in Mathison et al., J. Clin. Invest.. 81: 1925(1988). Briefly, L929 cellε (CCL 1, American Type Culture Collection, Rockville, MD) were maintained in RPMI 1640 εupplemented with 10 mM Hepeε and 10% fetal bovine εerum (Hyclone, Rehatuin F.S., Reheiε Chemical Co., Phoenix, AZ) . Confluent cultureε (3- 4 x 10 7 cellε/75 cm flaεk) were rinεed briefly with 0.5% trypεin (TRL3, Worthington Biochemical Corporation, Freehold, NJ) in phyεiologic εalt εolution containing 5 mM EDTA and 10 mM Hepeε, pH 7. , ' resuεpended in freεh medium containing actinomycin D (1 ug/ml) and added to 96-well plateε (5-7 x 10* cellε/well) . After 2 hours in culture, εerially diluted sampleε were added to the wellε and the plateε were incubated overnight (5% C0 2 , 37°C) . Following microscopic evaluation, the medium waε decanted, and the wellε were filled with a εolution of 0.2% cryεtal violet, 10% formalin and 0.01 M phoεphate, pH 7-7.5 for 5 , waεhed thoroughly with water and dried. The degree of lyεiε waε quantitated εpectrophotometrically (550 n ) uεing a Bio-Tek Model EL310 plate reader (Bio- Tek Inεtru entε, Inc., Burlington, VT) interfaced with an IEM-PC computer. Assay reεults were expresεed aε U/ml, with one unit (U) defined aε the amount of TNF reεulting in lyεiε of 50% of the cellε. Routinely, 8-12 plates were εet up per aεεay. Each plate included two laboratory standards, conditioned medium from Re595 LPS- treated RAW 264.7 cellε (6 x 10 3 U/ml) and conditioned medium from Re595 LPS-treated rabbit FΞN (1.3 x 10 3 U/ml). These εtandardε, in turn, were calibrated againεt human recombinant TNF (Cetuε Corporation, Emeryville, CA, 2 x 10 7 U/mg) and aεεay reεults were normalized accordingly. Sampleε were aεsayed in quadruplicate, and a coefficient of variation (SD/ ean) of 0.12 + 0.08 (SD) waε obεerved. Using this asεay, as little as 10 pg/ml of rabbit macrophage-derived TNF (specific activity 1 x 10 8 U/mg) could be detected. However becauεe εerum concentrationε greater than 10% caused nonεpecific rounding and loεε of adherence of the L929 Cells, the lower limit of detection of rabbit TNF in εerum waε 20 U/ml (correεponding to 0.2 ng TNF/ l) . The resultε of thiε εtudy, εhown in Figure 8, demonstrate that TNF iε only produced if both LPS and active LBP are present. Re595 LPS is from a rough strain of Salmonella; identical resultε are, obtained if LPS iεolated from εmooth εtrain organiεms is used such as LPS from E. coli 0111:B4 indicating the generality of the effectε cbεerved here. 15. The Binding Of LPS TO LBP Protects LBP from Trvosin Cleavage Samples containing LBP at a final concentration .of 0.3 mg/ml in a buffer containing 50 M KEPES, 10 mM ' EDTA pK 7.4 were prepared. To one εample waε admixed LPS to a final concentration of 0.125 mg/ml. To the εecond sample waε admixed dextran εulfate to a final concentration of 0.125 mg/ml. Subεequently, trypin was admixed to all three εa pleε to a final concentration of 2 ug/ml. Aliquotε were removed from the trypεin-treated εampleε at time intervalε of 5, 25, 60 and 120 minuteε while being maintained at 37 C. The aliquotε were then analyzed by εodium dodecyl εulfate polyacrylamide gel electrophoreεiε (SDS- FAGE) uεing 12% gelε. The reεultε of thiε εtudy, εhcvn in Figure 9, indicate that the binding of LPS by LBP protectε LBP from enzymatic degradation. LPS may protect LBP by either inducing a conformational change in LBP that preventε cleavage or εterically hindering acceεε to the cleavage εite . 16. Anti-CD14 Monoclonal Antibodieε Inhibit LPS-LBP Complex Induced TNF Production In Whole Human Blood The ability of anti-CD14 mAbε to inhibit TNF secretion by MO in human blood was examined using the TNF-induced cytotoxic activity aεεay described by Eεpevik et al., J. Immunol. Meth. , 95: 99-105, (1986) . Briefly, whole human blood anticoagulated with heparin was prepared and incubated with mAb 3C10, 60b or IB4 at a final concentration of 1 ug/ml at 37 C for 30 inuteε. Subsequently, the cellε were incubated with Re595 LPS at a final concetration of 0, 0.01, 0.1, or 1.0 ng/ml at 37 C for 12 hours in a humidified, 10% C0 2 incubator. Plaεma waε then collected from each εample and examined for the presence of TNF. For theεe εtudies it was not neceεεary to add additional LBP εince ccnεtitutive levelε of LE? in blood of healthy subjectε iε estimated to be 100-250 ng/ml. Tobiaε et al., J. EXP. Me . 164:777 (1986) and Tobiaε et al., Infect. Ir.mun. 50:73-76 (1985) . Baεed on eεti ates of the affinity of LPS for LBP Tobiaε et al., J. Eiol. Chem. 264:10867- 10S71 (1989) the conεtitutive levelε of LBP are more than εufficient to bind all of the added LPS. WEHI clone 13 cellε were obtained from T. Ezpevik at Univerεity of Trondheim, Norway and cultured in RPMI 1640 culture media (Gibco) containing 10% FCS, 0.1 M glutamine and 30 ug/ml gentamicin. The cellε were εeeded in microtiter plateε at a concentration of 2 x 10* cells per well in 100 microliterε (ul) of RPMI 1640 culture medium. Sampleε of 5 to 50 microliterε (ul) of MO culture supernatant was then admixed to the WEHI clone 13 cell growth media and incubated for 20 hr at 37 C. Subsequently, 10 icroliters of MTT tetrazolium (M-2128 Sigma Chemical Company, St. Louis, MO) at a concentration of 5 mg/ml in PBS was added to each microtiter plate well and the wells were further incubated for 4 hr at 37 C. After aspirating 100 microliters of the supernatant from the wellε, 100 microliterε iεopropanol with 0.04 N HCL waε added to each well. After dissolving the dark blue formazan crystalε, the plateε were read on a microtiter plate reader, using a teεt wavelength of 570 n and a reference wavelength of 630 nm. Percentage of dead target cellε waε determined aε followε: ■ *= loo - —op • *tical density in wells with CF/TN o-pti:—cal:—d:ensi.ty i:n cont r—rol wel flz F s x 1,00 The percentage of dead cellε obtained in the experimental cultureε was then compared to the percentage obtained from various known dilutionε of TNF to determine the correεponding TNF concentration of each experimental culture. The reεultε of thiε εtudy are εhown in Table VI. Table VI Effect of Monoclonal Antibodieε on LPS-Induced TNF Production in Whole Human Blood TRe595 LPS1.no/ml Antibody 1 TTNF1.U/ml 2 <0.5 0.01 <0.5 0.1 4.8 1.0 39 3C10 <0.5 0.01 3C10 <0.5 0.1 3C10 <0.5 1.0 3C10 3 60b <0.5 0.01 60b <0.5 0.1 60b 2 1.0 60b 12 IB4 3 <0.5 0.01 IB4 2 0.1 IB4 13 1.0 IB4 40 1 A11 monoclonal antibodies added at a final concentration of 1 ug/ml. 2 TKF aεεayε performed with the WEHI clone 13 aεεay uεing recombinant TNF having a εpecific activity of 2x10 unitε (u) per mg aε a εtandard. 3 An Anti-CD18 mAB. From Table VI it can be εeen that LPS induced TNF production in whole human blood •increaseε with increaεing concentration of LPS. In addition, it can be εeen that LPS-LBP complex induced TNF production was significantly inhibited by anti-CD14 monoclonal antibodieε 3C10 and 60b, while the anti-CD18 IB4 monoclonal antibody produced no εignificant inhibition of TNF production. Similar experimentε were performed with LPS iεolated from the εmooth form bacteria E. coli 0111:B4 indicating the generality of the effect on LPS preparationε with varying carbohydrates content but containing conεerved lipid A εtructureε. The TNF εpecificity of the cytotoxic activity found in the whole blood waε establiεhed uεing a polyclonal goat anti-human TNF IgG antibody aε described by Mathiεon et al., J. Clin. Inveεt.. 81: 1925(1988) . Thiε antibody completely neutralized all of the cytotoxic activity found in * the εampleε of LPS-treated whole blood. 17. Diεcuεsicn of the Reεultε of Examples 1-16 The foregoing demonstrates that LBP functions aε an opεqnin becauεe it bindε bacteria and facilitates their binding and phagocytosiε by macrophageε. It iε believed that while LBP bindε LPS through a domain which iε homologous with the LPS-binding. domain of BPI, the attachment of LBP to cellε is mediated by a domain unique to LBP. LBP on the surface of LPS-coated particles is recognized by a εpecific receptor, CD14, whcih on MO iε mobile in the plane of the membrane. LBP-coated particles bind to CD14- expreεεing cellε, εuch aε MO, but not other blood cellε. The binding activity on the apical surface of MO iε depleted by εpreading of cellε on εubεtrateε coated with LBP-LPS complexeε. The receptor for LBP, CD14, iε diεtinct from other opεonic receptors εince surface-bound antibodieε to CR1, CR3, and FcR did not reduce the binding of LBP-coated particleε. Aε an opεonin LBP promotes clearance of εepsis-inducing infectiouε agentε, εuch aε gram- negative bacteria. However, during εepεiε bacteriolyεiε may occur, either through the action of endogenouε lytic mechaniεmε including complement and degradative enzymeε or following antibiotic treatmentε. Lyεiε leadε to the εyεtemic releaεe of LPS cauεing increaεeε in blood levelε of LPS. Since theεe levelε are eεtimated to be between 1- 1000 pg LPS/ml there iε εufficient LBP preεent to form high-affinity LPS-LBP complexeε. [Sturk et al., in Detection of Bacterial Endotoxins with the Lir.ulus Amebocyte Lyεtate Test, edε. Watεon, S. W. Allan R. Liεε, NY 1987:371-385.] van Deventer, S.J.H. Lancet 1:605-608 (1988), et al. LPS-LBP complexeε bind to CD14 on cellε of the macrophage/monocyte lineage and initiate rapid εyntheεiε and releaεe of the monokine, TNF and thereby contribute εignificantly to the development of the full-blown εepεiε εyndrome. The claεεical opεonin, IgG, facilitateε the binding of IgG-coated particles, their phagocytic engulfment, and the releaεe of toxic compoundε εuch aε hydrogen peroxide. The other claεεical opεonin, C3, facilitateε principally the binding of C3-coated particleε. Phagocytosis by unεtimulated MO iε obεerved only if the C3-coated particleε alεo bear IgG (Ehlenberger, et al., j. EXP. Med.. 145:357-371, (1977)), and the evolution of hydrogen peroxide iε not initiated. Wright, et al., J. EXP. Med.. 158:2016-2023, (1983). The opεonic activity LBP moεt cloεely reεembleε that of C3. LBP-coated particleε are avidly bound by MO, but binding doeε not initiate phagocytoεiε or releaεe of hydrogen ' peroxide (Figure 5) . LBP also acts like C3 in that it enhances phagocytoεiε of particleε coated with low amountε of IgG (Figure 4) . The opεonic effect of LBP differε from that of C3 in only one reεpect. While complement proteinε may initiate phagocytoεiε if MO are treated with an ancillary εtimuluε εuch aε PMA (Wright, et al., J. Exo. Med.. 156:1149- 1164, (1982)) or fibronectin (Wright, et al., J^. EXP. Med.. 158:1338-1343, (1983), LBP doeε not mediate phagocytoεiε even in εuch optimally εti ulated cellε. By acting aε an cpεonin, LBP limitε the εpread of gram negative bacteria in an animal. The appearance of LBP during the acute phaεe makeε it well εuited to combating infection, and it iε therefore believed that LBP repreεentε a defenεe mechanism againεt infectiouε agents εuch aε gram negative bacteria. The foregoing εpecification, including the εpecific embodiments and exa pleε, iε intended to be illuεtrative of the preεent invention and iε not to be taken aε limiting. Numerous other variations and modifications can be effected without departing from the true εpirit and scope of the invention.

Claims: What iε claimed iε: 1. A method of ameliorating εepεiε in a patient, which method compriεes adminiεtering a therapeutically effective amount of an anti-CD14 antibody to εaid patient. 2. The method of claim 1 wherein said anti-CD14 antibody iε a monoclonal antibody that inhibitε the binding of lipopolyεaccharide- lipopolyεaccharide binding protein complexeε to CD14. 3. The method of claim 2 wherein εaid monoclonal antibody iε produced by hybridoma ATCC TIB22B or an anti-CD14 antibody molecule-expreεεing nucleic acid thereof. 4. The method of claim 2 wherein εaid monoclonal antibody iε comprised of F(ab) 2 portions of anti-CD14 antibody moleculeε. 5. The method of claim 2 wherein εaid therapeutically effective amount iε 0.1 to 20 milligrams per kilogram body weight per day. 6. The method of claim 1 wherein said method further comprises subεtantially simultaneously administering to said patient a bactericidal amount of an antibiotic. 7. The method of claim 6 wherein εaid antibiotic is an anti-bacterial agent effective againεt gram-negative bacteria. 8. The method of claim 1 wherein εaid εepεiε is cauεed by a gram-negative bacterial infection. 9. The method of claim 1 wherein εaid εepεiε is cauεed by infection with a viruε, gram- poεitive bacteria or funguε. 10. The method of claim 1 wherein said method further compriεeε εubεtantially εimultaneouεly adminiεtering to said patient a TNF blood concentration-reducing amount of an anti-TNF antibody. 11. The method of claim 10 wherein εaid method further compriεeε adminiεtering, εubεtantially εimultaneouεly with εaid anti-CD14 antibody, a bactericidal amount of an antibiotic to εaid patient. 12. The method of claim 1 wherein εaid patient diεplayε the εymptoms of one or more of the following: adult reεpiratory diεtreεε εyndrome, diεεe inated intravaεcular coagulation, renal failure and hepatic failure. 13. The method of claim 1 wherein εaid εepεiε iε the reεult of chemical or physical traum . 14. A method of ameliorating the εymptomε of endotoxemia in a patient, which method comprises adminiεtering to εaid patient an amount of an anti-CD14 antibody εufficient to inhibit in said patient lipopolyεaccharide-induced tumor necroεiε factor εecretion by cellε of the monocyte acrophage lineage. 15. The method of claim 14 wherein εaid anti-CD14 antibody iε a monoclonal antibody that competitively inhibitε the binding of lipopolyεaccharide-lipopolyεaccharide binding protein complexeε to CD14. 16. The method of claim 15 wherein εaid monoclonal antibody is produced by hybridoma ATCC TIB22B or anti-CD14 antibody molecule nucleic acid thereof. 17. A method of ameliorating εepεiε in a patient, which method compriεes adminiεtering to εaid patient a therapeutically effective amount of an anti-lipopolysaccharide binding protein antibody. 18. A method of ameliorating sepsis in a patient, which method compriεes administering to εaid patient a therapeutically effective amount of a peptide analog of lipopolyεaccharide binding protein. 19. The method of Claim 18 wherein εaid peptide analog haε an amino acid residue sequence repreεented by the formula: CNRCNRAPQPDELY, YTTPEPSELDDEDFRC, or KRVDADADPRQYADTC. 20-. A therapeutic compoεition compriεing, in unit doεe form, anti-CD14 antibody moleculeε in a pharmaceutically acceptable excipient, εaid antibody moleculeε being capable of inhibiting the binding of LPS-LBP complexes to CD14. 21. The composition of claim 20 further including a unit doεe of anti-TNF antibody molecules. 22. The compoεition of claim 20 further including a bactericidal amount of an antibiotic. 23. The composition of claim 21 further including a bactericidal amount of an antibiotic. 24. A compoεition compriεing, aε active ingredie tε in concentrations suitable for adminiεtration to hu anε for the treatment of εepεis, anti-CD14 antibody moleculeε capable of inhibiting the binding of LPS-LBP complexes to CD14 and one or both of an antibiotic and anti-TNF antibody molecules ,

Inventors: MATHISON JOHN C, TOBIAS PETER, ULEVITCH RICHARD, WRIGHT SAMUEL D, MATHISON, JOHN, D., TOBIAS, PETER, ULEVITCH, RICHARD, WRIGHT, SAMUEL, D.
Applicants: SCRIPPS CLINIC RES, UNIV ROCKEFELLER, ROCKEFELLER UNIVERSITY, SCRIPPS CLINIC AND RESEARCH FOUNDATION
Application year: 1990
Main classification: A61K39
IPC codes: A61K38, A61K39, A61P31, A61P43, C07K16, C12P21, C12R1