Abstract: The invention described herein relates to compositions and methods for stimulating immune responses in vivo against a tolerogen. Novel biotechnological tools, pharmaceuticals, therapeutics and prophylactics, which concern chimeric or conjugated virus-like particles, and methods of use of the foregoing are provided for the study of B cell tolerance and the treatment or prevention of human diseases, which involve the onset of B cell tolerance, such as chronic viral infection, chronic inflammatory disease, and neoplasia.

Abstract: The present invention provides a monomolecular multi-epitope peptide prepared by binding T cell epitope regions derived from different allergen molecules with each other. A peptide-based immunotherapeutic agent containing an effective amount of the multi-epitope peptide can treat a wide range of allergic diseases.

Abstract: A carbohydrate peptide conjugate containing: (i) a carrier containing a dendrimeric poly-lysine enabling multiple epitopes to be covalently attached thereto, (ii) at least one peptide containing one T epitope or several identical or different T-epitopes, (iii) at least one carbohydrate moiety which is tumor antigen, or a derivative thereof, containing a B epitope, provided it is not a sialoside, or several identical or different epitopes, wherein said conjugate containing at least 3-lysines and up to 15 lysine covalently linked to one another, and wherein: (a) to the NH2 and of at least two lysine residues is bound at least one carbohydrate residue being not a sialoside, optionally substituted and containing an epitope and wherein the peptide containing one T epitope is covalently bound to the end of said carbohydrate which induces immune responses.

Abstract: A method is provided for covalently linking carbohydrates, proteins, nucleic acids, and other biomolecules under neutral conditions, using a Diels-Alder cycloaddition reaction. In an example, activated carbon-carbon double bonds were attached to free amino sites of a carrier protein, and a conjugated diene was attached to a carbohydrate hapten. Spontaneous coupling of the carbohydrate and the protein components under very mild conditions provided glycoconjugates containing up to 37 carbohydrate hapten units per carrier protein molecule. The method is also applicable to the immobilization of biomolecules on gel or solid supports. The conjugated products are useful as immunogens and as analytical and diagnostic reagents.

Abstract: A homogeneous polyoxime composition is provided, in which the polyoxime molecules present comprise a first organic baseplate molecule, which is a polypeptide, wherein the baseplate molecule is linked to at least two second organic molecules, which may be the same or different from one another. In the compositions, the linkages between the baseplate and said organic molecules are oxime linkages formed by reaction of an orthogonal reactive group on each the organic molecules with a complementary orthogonal reactive group on the baseplate.

Abstract: A method for raising antibodies against molecules, particularly molecules with low immunogenicity, by coupling the molecule to a carrier containing a balanced charge mixture of proteins is provided. Also provided are antibodies and immunoassays containing antibodies raised in accordance with these methods. Pharmaceutical compositions containing these antibodies or a part thereof and methods of using these compositions to treat various diseases and infections are also provided. In addition, vaccines containing an antibody or an immunogenically stimulatory amount of a molecule coupled to the carrier of a balanced charge mixture of proteins and methods of inducing an immune response in an animal against the molecule by administration of these vaccines are provided.

Abstract: A compound for delivering a non-cytotoxic therapeutic moiety into nerve cells, the compound having the general formula: B—L—TM where: B is a binding agent capable of selectively binding to a nerve cell surface receptor and mediating absorption of the compound by the nerve cell; TM is a therapeutic moiety which has a non-cytotoxic therapeutic effect when absorbed by a nerve cell; and L is a linker coupling B to TM.

Abstract: Antigenic conjugates are provided which comprise a carrier protein covalently bonded to the conserved portion of a lipopolysaccharide of a gram negative bacteria, wherein the conserved portion of the lipopolysaccharide comprises the inner core and lipid A portions of the lipopolysaccharide, the conjugate eliciting a cross reactive immune response against heterologous strains of the gram negative bacteria.

Abstract: The present invention relates to a polysaccharide-protein conjugate. The invention also relates to a method of using the conjugate to prevent systemic infections. The invention further relates to a pharmaceutical composition. The invention also relates to a method of producing a polysaccharide-protein conjugate.

Abstract: This invention relates to hepatitis B virus (“HBV”) core antigen particles that are characterized by multiple immunogen specificities. More particularly, the invention relates to HBV cote antigen particles comprising immunogens, epitopes, or other related structures, crosslinked thereto by ligands which are HBV capsid-binding peptides that selectively bind to HBV core protein. Such particles may be used as delivery systems for a diverse range of immunogenic epitopes, including the HBV capsid-binding peptides, which advantageously also inhibit and interfere with HBV viral assembly by blocking the interaction between HBV core protein and HBV surface proteins. Mixtures of different immunogens and/or capsid-binding peptide ligands may be crosslinked to the same HBV core particle. Such resulting multicomponent or multivalent HBV core particles may be advantageously used in therapeutic and prophylactic vaccines and compositions, as well as in diagnostic compositions and methods using them.

Abstract: The process for depolymerizing Group B Types II and III streptococcal polysaccharide is disclosed which results in polysaccharide fragments having a reducing end suitable for conjugating to protein. Conjugate molecules, vaccines and their use to immunize mammals including humans are also disclosed.

Abstract: Synthetic polypeptides from the conserved exposed region of streptococcal M protein are useful to prepare vaccines for oral or intranasal administration which will protect against streptococcal infection.

Abstract: Compounds and methods for inducing protective immunity against tuberculosis are disclosed. The compounds provided include polypeptides that contain at least one immunogenic portion of one or more M. tuberculosis proteins and DNA molecules encoding such polypeptides. Such compounds may be formulated into vaccines and/or pharmaceutical compositions for immunization against M. tuberculosis infection, or may be used for the diagnosis of tuberculosis.

Abstract: The present invention provides antiviral proteins, peptides and conjugates, as well as methods of obtaining these agents. The antiviral proteins, peptides and conjugates of the present invention can be used alone or in combination with other antiviral agents in compositions, such as pharmaceutical compositions, to inhibit the infectivity, replication and cytopathic effects of a virus, such as a retrovirus, in particular a human immunodeficiency virus, specifically HIV-1 or HIV-2, in the treatment or prevention of viral infection.

Abstract: A method of preparing conjugate vaccines by adsorbing a protein to a solid phase adjuvant, and covalently linking a carbohydrate to the adsorbed protein. Alternatively, the carbohydrate is first adsorbed to the solid phase adjuvant, then the protein is covalently linked to the carbohydrate. The carbohydrate may be chemically activated. Unconjugated protein may be present.

Abstract: Conjugates of erythropoietin with poly(ethylene glycol) comprise an erythropoietin glycoprotein having at least one free amino group and having the in vivo biological activity of causing bone marrow cells to increase production of reticulocytes and red blood cells and selected from the group consisting of human erythropoietin and analogs thereof which have sequence of human erythropoietin modified by the addition of from 1 to 6 glycosylation sites or a rearrangement of at least one glycosylation site; the glycoprotein being covalently linked to “n” poly(ethylene glycol) groups of the formula —CO—(CH2)x(OCH2CH2)m—OR with the carbonyl of each poly(ethylene glycol) group forming an amide bond with one of said amino groups; wherein R is lower alkyl; x is 2 or 3; m is about 450 to about 900; n is from 1 to 3; and n and m are chosen so that the molecular weight of the conjugate minus the erythropoietin glycoprotein is from 20 kilodaltons to 100 kilodaltons.

Abstract: The present invention concerns a synthetic construct comprising a linear core chain having two or more side chains pending directly from different points on the linear core chain. Each of the side chains comprises an epitopic site of an antigen or a peptide. The synthetic constructs are monomeric units that can be linked together or polymerized to form a polymer. In this embodiment the epitopic sites of the side chains may be the same or different. The linear core chain may be a linear sequence of amino acids having two or more of the same peptide pending directly from different points on the linear sequence. Another aspect of the present invention concerns a support having one or more of the above synthetic constructs or polymers coupled thereto. Another embodiment of the present invention is directed to antibodies raised against the above synthetic constructs or polymers. The antibodies can be purified using the above mentioned supports.

Abstract: The present invention provides synthetic chimeric fimbrin peptides which induce an immunogenic response in animals to non-typable Haemophilus influenzae and that do not require tedious purification techniques. The synthetic chimeric fimbrin peptides reduce the severity of otitis media caused by Haemophilus influenzae. The synthetic chimeric fimbrin peptides are synthesized using commercially available peptide synthesizers. The synthetic chimeric fimbrin peptides comprises three peptide units. The first peptide unit is a subunit of the fimbrin protein. Preferably, the fimbrin subunit is comprised of the amino acids of Sequence ID No. 1 or Sequence ID No. 2. The second peptide unit is a t cell epitope, and preferably has the amino acid sequence of SEQ ID NO. 3. The third peptide unit is a linker peptide unit which joins the first and second peptide unit.

Abstract: A method of producing a diagnostic or therapeutic conjugate of a protein, polypeptide or peptide containing at least one disulfide bond which is necessary to maintain its biological activity, and bearing at least one thiol-containing moiety linked thereto through a hydrazone or hydrazine linkage, is effected by contacting said protein, polypeptide or peptide with a thiol-reactive diagnostic or therapeutic agent, either preformed or generated in situ, to form a stable diagnostic or therapeutic conjugate of the protein, polypeptide or peptide without substantial cleavage of the disulfide bond. Diagnostic and therapeutic conjugates produced using the foregoing method, as well as kits for carrying out the method are provided.

Abstract: Peptide constructs chemically synthesized to contain a Herpes Simplex Virus specific antigenic peptide, such as, the 322-332 peptide (H1) from the ICP27 protein of Herpes Simplex Virus (HSV-1) and a peptide from a T cell binding ligand (TCBL), such as &bgr;-2M (aa 35-50), which elicits a TH1-like response in vitro tests in mice, were protective against challenge with HSV.

Abstract: The present invention is directed to chemical conjugates (herein referred to as polysaccharide adjuvant-antigen conjugates) that have a polysaccharide backbone capable of binding to the cell surface of Antigen Presenting Cells (APCs), to which is covalently attached (a) one or more molecules having a stable carbonyl group (i.e. an aldehyde and ketone group that is capable of reacting with amino groups to form an imine or Schiff base), and (b) one or more polypeptides or peptides that are capable of eliciting an immunogenic response when covalently attached to polysaccharide backbone. Also disclosed are methods for making the conjugates and methods of using the conjugates to enhance the potentiation of an immune response in a mammal. Also disclosed is a method of vaccination, and pharmaceutical and veterinary compositions comprising one or more of the polysaccharide adjuvant-antigen conjugates of the present invention.

Abstract: One aspect of the present invention relates to methods and compositions for attenuating xenograft rejection by administering, to an animal receiving the xenograft, an amount of a polymer-derivatized xenoantigen (hereinafter “xenopolymer”) effective for inhibiting or lessening the severity of hyperacute rejection response (HAR), or other immunological response to the graft, that is dependent on the presence of the xenoantigen on the grafted tissues or cells. In certain embodiments, the xenopolymer is administered in an amount sufficient to neutralize host antibodies (“xenoreactive antibodies” or “XNA”) immunoreactive with the xenoantigen. The xenopolymer may additionally, or alternatively, be used as a tolerogen (or anergen) for the xenoantigen, e.g., able to suppress, to some degree, the production/secretion of XNAs by the immune system of the host.

Abstract: The invention provides a method of activating hepatitis C virus (HCV)-specific T cells, including CD4+ and CD8+ T cells. HCV-specific T cells are activated using fusion proteins comprising HCV NS3, NS4, NS5a, and NS5b polypeptides, polynucleotides encoding such fusion proteins, or polypeptide or polynucleotide compositions containing the individual components of these fusions. The method can be used in model systems to develop HCV-specific immunogenic compositions, as well as to immunize a mammal against HCV.

Abstract: The ethyl ester of derivatives of benzoyl ecgonine are provided having a linking group at the para position of the benzoyl group. The derivatives are used to bond to immunogenic polypeptides for production of antisera and monoclonal antibodies. The antisera and antibodies find use in assays, for treatment of cocaine overdose and detoxification.

Abstract: The present invention relates to a method for the preparation of a conjugate comprising a first and a second polypeptide, said method comprising the steps of (a) incubating said first polypeptide in the presence of a heterobifunctional crosslinker comprising an N-hydroxylsuccinimide ester group and a maleimide group linked via a polyethylene oxide spacer; (b) removing excess heterobifunctional crosslinker; and (c) incubating the reaction product of step (b) with said second polypeptide, wherein said second polypeptide comprises at least one sulfhydryl group. Furthermore, the present invention relates to a conjugate obtainable by the method of the present invention. Also described is a pharmaceutical composition comprising the conjugate of the present invention and, optionally, a pharmaceutically acceptable carrier and/or diluent, and the use of the conjugate for the preparation of a pharmaceutical composition for preventing and/or treating an allergic disease or an autoimmune disease.

Abstract: The present invention provides methods for preparing, and compositions comprising, stabilized protein-polymer conjugates. More particularly, the present invention relates to the stabilization of individual and complexed subunits of multisubunit protein complexes by conjugation to polymers. Such conjugation acts to stabilize the specific subunit complexes in their native conformation in liquid medium.

Abstract: A conjugate vaccine for Neisseria meningitidis comprising lipooligosaccharide which does not contain a lacto-N-tetraose antigen from which at least one primary O-linked fatty acid has been removed conjugated to an immunogenic carrier. The vaccine is useful for prevention of meningitis and septic shock in mammals.

Abstract: A chimeric protein comprising a Pseudomonas aeruginosa exotoxin (PE) moiety linked to a myelin basic protein (MBP) moiety is disclosed. The MBP moiety is selected from the group comprising: (a) MBP; (b) amino acids 69-88 of guinea-pig myelin basic protein or an antigenic portion thereof; (c) amino acids 84-102 of human myelin basic protein or an antigenic portion thereof; (d) amino acids 143-168 of human myelin basic protein or an antigenic portion thereof; and (e) an amino acid sequence in which one or more amino acids have been deleted, added, substituted or mutated in the amino acid sequences of (a), (b), (c) or (d), the modified sequence of (e) retaining at least 75% homology with the amino acid sequences of (a), (b), (c) or (d), respectively. Each of the MBP moieties of (b), (c) and (d) are linked to the PE moiety by a pentapeptide linker repeated 1-3 times. The chimeric protein is useful in treating autoimmune diseases, and especially multiple sclerosis.

Abstract: Methods for inducing interleukin-12 production and inducing a type 1/Th1 T cell response in a subject, thereby stimulating cell-mediated immunity for prevention or treatment of pathogen infections or treatment of a interferon (-sensitive tumor, are provided. Compounds effective in the above-described methods include a lipopeptide having an N-terminal ester- or amide-linked fatty acyl group and are administered in an amount effective to induce interleukin-12 and to induce the type 1/Th1 T-cell response. Preferably, the subject is a human patient, and the lipopeptide is an N-terminal moiety of a 19 kDa or a 38 kDa lipoprotein of Mycobacterium tuberculosis.

Abstract: A conjugate between a target-seeking moiety and a modified superantigen, characterized in that the superantigen is a wild-type superantigen (SA I) in which an amino acid residue in a superantigen region (region I) determining binding to TCR, referably TCRV&bgr;, and T cell activation has been replaced by another amino acid residue while retaining the ability to activate a subset of T cells. In a preferred embodiment the modified superantigen is a chimer between at least two wild-type superantigens (SA I, SA II etc) characterized in that one or more amino acid residues in a region determining binding to TCR and T cell activation have been interchanged between various wild-type superantigens. A therapeutic method making use of modified/chimeric superantigens as defined in the preceding paragraphs.

Abstract: Described are peptides and peptide mimetics that bind to and activate the thrombopoietin receptor. Such peptides and peptide mimetics are useful in methods for treating hematological disorders and particularly, thrombocytopenia resulting from chemotherapy, radiation therapy, or bone marrow transfusions as well as in diagnostic methods employing labeled peptides and peptide mimetics.

Abstract: The present invention relates to the field of carbohydrate crosslinked glycoprotein crystals. Advantageously, such crosslinked glycoprotein crystals display stability to harsh environmental conditions, while maintaining the structural and functional integrity of the glycoprotein backbone. According to one embodiment, this invention relates to methods for concentrating proteins that have been modified by carbohydrates and for releasing their activity at controlled rates. This invention also provides methods for producing carbohydrate crosslinked glycoprotein crystals and methods for using them in pharmaceutical formulations, vaccines, immunotherapeutics, personal care compositions, including cosmetics, veterinary pharmaceutical compositions and vaccines, foods, feeds, diagnostics, cleaning agents, including detergents and decontamination formulations.

Abstract: The present invention relates to methods and compositions that can be employed to introduce toxins and nucleic acids into the cytoplasm or nucleus of a eukaryotic cell, particularly a cell of a higher vertebate. The invention particularly concerns the use of a fusion protein of streptavidin and protein A sequences to form a non-covalent complex of a toxin or nucleic acid and an antibody.

Abstract: The invention provides a sterically hindered polymer that comprises a water-soluble and non-peptidic polymer backbone having at least one terminus covalently bonded to an alkanoic acid or alkanoic acid derivative, wherein the carbon adjacent to the carbonyl group of the acid or acid derivative group has an alkyl or aryl group pendent thereto. The steric effects of the alkyl or aryl group allow greater control of the hydrolytic stability of polymer derivatives. The polymer backbone may be poly(ethylene glycol).

Abstract: A polypeptide is provided that has a secondary structure characterized by at least three beta-sheet/beta-turn structures, and that is not a naturally occurring fibrous protein. Such polypeptides, illustrated by one modeled on elastin, are useful in prosthesis.

Abstract: The invention relates to a novel complex for oral delivery of drugs, therapeutic protein/peptides and vaccines which are loaded in a Vitamin B12 (VB12) coupled particulate carrier system with spacers in between, the carrier system with spacers having a formula VB12—R′/R″—N wherein, R′ or R″ is spacer and/or agents for derivatization of VB12 to provide either NH2 or COOH or SH groups, and N is the micro or nano particle carriers for the delivery of injectable drugs, therapeutic protein/peptides and vaccines.

Abstract: Construct-complexes of a hemoglobin, a hepatocyte modifying substance bound to the hemoglobin, and a haptoglobin bound to the hemoglobin, are provided, for administration to mammalian patients. The construct-complex may be formed ex vivo, or a hemoglobin-hepatocyte modifying substance combination may be administered to the patient so that haptoglobin in the mammalian body bonds thereto to form the construct-complex in vivo. Disorders of the liver may be diagnosed and treated using construct-complexes described herein.

Abstract: The invention relates to methods and compositions for the promotion of tissue repair. Specifically, compositions comprising heat shock proteins, including gp96, hsp90, and hsp70, uncomplexed or complexed noncovalently with antigenic molecules, are disclosed. Therapeutic methods for administering the hsp-containing compositions are disclosed. The disclosed methods are useful for promoting repair of tissues that were disrupted by a variety of causes including trauma (e.g., surgery, injury or burns) or disease or disorder (e.g., atherosclerosis and multiple sclerosis).

Abstract: This invention relates to prevention and/or treatment of antibiotic associated diarrhea, including Clostridium difficile associated diarrhea (CDAD), pseudomembranous colitis (PMC) and other conditions associated with C. difficile infection, using oligosaccharide compositions which bind C. difficile toxin B. More specifically, the invention concerns neutralization of C. difficile toxin B associated with such conditions.

Abstract: The present invention relates to immunogenic complexes of heat shock proteins (hsp) noncovalently bound to exogenous antigenic molecules which when administered to an individual elicit specific immunological responses in the host. Methods of prevention and treatment of cancer and infectious disease are provided.

Abstract: The invention relates to a diagnostic test for the detection and identification of Mycobacterium species in biological specimens of human and animal origin. The test is based on the immunological detection of one or more antigens originating from Mycobacterium. To enable the detection of an antibody-antigen reaction, the antibodies specific for these antigens can be labelled with an enzyme or fluorescent dye or attached to latex particles or any other suitable label. The diagnostic test may be in a form of ELISA and may or may not require concentration of the Mycobacterium antigens prior to the actual test.

Abstract: This invention is directed to a soluble recombinant fused protein which is stable in the mammalian circulatory system comprising a polypeptide which contains a recognition site for a target molecule, such as a complement receptor site, and is joined to the N-terminal end of an immunoglobulin chain. The invention is also directed to a construct comprising a plurality of peptides containing short consensus repeats having a complement binding site attached to a soluble, physiologically compatible, macromolecular carrier. The invention is particularly useful for inhibiting complement activation or complement-dependent cellular activation in mammals.

Abstract: A method of improving specific immune responses to small immunogens, haptens, has been developed by changing the linkage between the hapten and carrier being used for immunization. High affinity antibodies to the hapten cotinine have been produced using this method. Antibodies to a glycated protein have also been developed, utilizing an immunogen which is composed of a glycated peptide mimic of the glycated peptide sequence which is the target epitope, wherein the peptide mimic is constructed to conformationally mimic the conformation of the peptide in the native protein, the peptide mimic contains no charged groups or other immunodominant group, and the peptide mimic is connected to a spacer sequence equivalent to a peptide spacer of between one and thirty amino acids in length, which serves to position the peptide epitope in a conformation that approximates its conformation in the native protein. In a further embodiment the peptide mimic and spacer are linked to a carrier molecule.

Abstract: The present invention relates to novel human secreted proteins and isolated nucleic acids containing the coding regions of the genes encoding such proteins. Also provided are vectors, host cells, antibodies, and recombinant methods for producing human secreted proteins. The invention further relates to diagnostic and therapeutic methods useful for diagnosing and treating disorders related to these novel human secreted proteins.

Abstract: The present invention provides for peptide conjugate compositions, methods of using the peptide conjugate compositions, and pharmaceutical compositions comprising the peptide conjugate compositions. The peptide conjugate compositions comprise peptides with amino acid sequences similar to the gp120 principal neutralizing domain (PND) of HIV, gp41, and Nef (p27) of HIV and carriers which enhance immunogenicity. The peptide conjugate compositions of the present invention may comprise a multivalent cocktail of several different peptide conjugates. Also provided by present invention is a method for reducing the level of HIV titers in a mammal by administering to the mammal a peptide composition of the present invention in an amount effective to reduce the level of HIV titers. The peptide conjugate compositions of the present invention induce prolonged antibody response in serum, a high level of antibody in the mucosa, and the production of cytotoxic lymphocytes.

Abstract: The present invention relates to immunogenic complexes of heat shock proteins (hsp) noncovalently bound to exogenous antigenic molecules which when administered to an individual elicit specific immunological responses in the host. Methods of prevention and treatment of cancer and infectious disease are provided.

Abstract: A hybrid botulinal neurotoxin is disclosed. In one embodiment, the neurotoxin comprises a combination of a botulinal neurotoxin heavy chain and light chain, wherein the light chain and heavy chain are not of the same serotype and wherein the heavy and light chains are linked by a homobifunctional sulfydryl linker. A method for creating hybrid neurotoxins comprised of different functional domains is also disclosed.

Abstract: The present invention provides synthetic chimeric fimbrin peptides which induce an immunogenic response in animals to non-typable Haemophilus influenzae and that do not require tedious purification techniques. The synthetic chimeric fimbrin peptides reduce the severity of otitis media caused by Haemophilus influenzae. The synthetic chimeric fimbrin peptides are synthesized using commercially available peptide synthesizers. The first peptide subunit is comprised of the amino acids of Sequence ID No. 1 or Sequence ID No. 2. The second peptide unit is a t cell epitope, and preferably has the amino acid sequence of SEQ ID NO. 3. The third peptide unit is a linker peptide unit which joins the first and second peptide unit. The linking sequence preferably has from about 2 to about 15 amino acids, more preferably from about 2 to about 10 amino acids, most preferably from about 5 to about 6 amino acids.

Abstract: A method is provided for preparing a biologically active molecule having an increased serum half-life. The method involves conjugating a polymer such as polyethylene glycol to the biologically active molecule. Also provided are polypeptide drugs having an increased serum half-life, e.g., human urokinase plasminogen activator (human “uPA” or “hUPA”) or a fragment or derivative thereof. Pharmaceutical compositions containing such molecules and methods of using them to treat uPA-mediated and uPA receptor-mediated disorders are also provided.

Abstract: This invention is related to an adhesive composition which may be used to bond or seal tissue in vivo. The adhesive composition is readily formed from a two component mixture which includes a first part of a protein, preferably a serum albumin protein, in an aqueous buffer having a pH in the range of about 8.0-11.0 and a second part of a water-compatible or water-soluble bifunctional crosslinking agent. When the two parts of the mixture are combined, the mixture is initially a liquid which cures in vivo on the surface of tissue in less than about one minute to give a strong, flexible, pliant substantive composition which bonds to the tissue and is absorbed in about four to sixty days. The adhesive composition may be used either to bond tissue, to seal tissue or to prevent tissue adhesions caused by surgery.