WO1993025234A1 - Methods and compositions for targeting specific tissue - Google Patents

Methods and compositions for targeting specific tissue Download PDF

Info

Publication number
WO1993025234A1
WO1993025234A1 PCT/US1993/005260 US9305260W WO9325234A1 WO 1993025234 A1 WO1993025234 A1 WO 1993025234A1 US 9305260 W US9305260 W US 9305260W WO 9325234 A1 WO9325234 A1 WO 9325234A1
Authority
WO
WIPO (PCT)
Prior art keywords
vehicle
population
cells
sub
viral
Prior art date
Application number
PCT/US1993/005260
Other languages
French (fr)
Inventor
Yuet Wai Kan
Noriyuki Kasahara
Original Assignee
The Regents Of The University Of California
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to US90609292A priority Critical
Priority to US07/906,092 priority
Application filed by The Regents Of The University Of California filed Critical The Regents Of The University Of California
Publication of WO1993025234A1 publication Critical patent/WO1993025234A1/en

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6901Conjugates being cells, cell fragments, viruses, ghosts, red blood cells or viral vectors

Abstract

Methods and compositions for preferentially targeting the delivery of a substance to a sub-population of mammalian cells. The vehicle of the invention includes a targeting moiety capable of associating with or forming an envelope defining a compartment that contains the substance to be delivered to the sub-population of cells. The targeting moiety also contains a domain capable of interacting with a member of a binding pair located on the surface of the sub-population of cells.

Description

METHODS AND COMPOSITIONS FOR TARGETING SPECIFIC TISSUE

This invention was made with Government support under Grant No. AM-16666, awarded by the National Institute of Health. The Government has certain rights in this invention.

FIELD OF THE INVENTION

The invention is directed to methods and compositions for preferentially targeting the delivery of a substance, such as a nucleic acid, to specific tissue.

BACKGROUND OF THE INVENTION

In the field of gene therapy, viral vectors and liposomes have been proposed to introduce genes into cells (Williams, D.A. (1988) Hematoloαv/Oncolo v Clinics of North America 2 : 211-281; and Mannino, R.J. et al . (1988) BioTechniques 6_:682-690) . Although such approaches may in some instances result in a localized administration of the vector or liposome, e.g., a viral vector administered via inhalation for localized delivery to lung tissue, a major drawback to such approaches is that there is no tissue- specific tropism. Thus, the DNA contained in the viral vector or liposome can be delivered non-specifically into many different types of cells.

Many genetic diseases are manifested in one tissue type and inserting genes non-specifically into many different cell types is not only unnecessary, but may be harmful under certain circumstances (Selden, R.F. et al . (1987) New Enσl. J. Med. 317:1067-1076) .

In addition, it is believed that most cancers originate from one cell type. At present, chemotherapy is the most widely-used approach to control cancer. Such chemotherapy, however, is not tissue specific in terms of delivery of the chemotherapeutic agent. Rather, the adverse effects imparted upon the rapidly dividing cancer cells are also imposed upon normal cells.

Although one recent publication reported the use of a protein covalently coupled to DNA to target liver cells, this approach resulted in low efficiency in DNA uptake compared to the higher efficiency attainable with viral vectors (Wu, G.Y. et al . (1988) J. Biol . Chem 263:14621-

14624) .

Given the state of the art, it is apparent that a need exists for methods and compositions for targeting the delivery of various substances to specific cell types.

Accordingly, it is an object of the invention herein to provide vehicles for targeting the delivery of a substance to specific cell types. More particularly, it is an object of the invention to provide methods and compositions for targeting the delivery of a substance such as a nucleic acid or a therapeutic agent to a sub-population of mammalian cells contained within a living organism.

SUMMARY OF THE INVENTION

In accordance with the foregoing objects, the invention includes a vehicle for preferentially targeting the delivery of a substance to a sub-population of mammalian cells. The cell sub-population is characterized by the presence of a sub-population-specific first member of a binding pair on the surface of the cells. The vehicle comprises an envelope comprising a recombinant targeting moiety defining a compartment and a substance contained in the compartment. The recombinant targeting moiety comprises first and second domains. The first domain is capable of forming or associating with the envelope of the vehicle whereas the second domain is capable interacting with the first binding member on the surface of the sub- population of cells. The invention also includes methods for preferentially targeting the delivery of a substance to the above sub- population of mammalian cells comprising contacting a population of mammalian cells containing the sub-population with the above vehicle.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts the construction of a hybrid erythropoietin-viral envelope gene.

FIG. 2 depicts the Western blot analysis of packaging cell sub-clones including the detection of the erythropoietin sequence.

FIG. 3 depicts the flow cytometric analysis of packaging cell lines based upon a detection of cell surface EPO epitopes by polyclonal anti-EPO antibodies.

FIG. 4 depicts the survivability of HeLa cells (wild- type or expressing the erythropoietin receptor) which have been exposed to neomycin or the retroviral vector encoding a neomycin resistant gene containing the EPO-env protein followed by a treatment with neomycin.

FIG. 5 depicts a similar experiment with NIH3T3 cells.

DETAILED DESCRIPTION OF THE INVENTION

The invention is based upon a discovery that a virus containing a hybrid viral envelope protein containing an amino acid sequence corresponding to a portion of the sequence of erythropoietin is capable of preferentially infecting cells displaying the erythropoietin receptor on their surface. As used herein, a "vehicle" of the invention is defined as any composition comprising an envelope defining a compartment and a substance contained therein that is capable of preferentially targeting the delivery of the substance to a specific sub-population of mammalian cells. The sub-population of mammalian cells is characterized by the presence of a first member of a binding pair on the surface of the sub-population. The vehicle is further defined by the envelope which comprises a "recombinant targeting moiety" capable of forming or associating with the envelope and which imparts cell specificity to the vehicle. In this regard, the targeting moiety contains at least two domains . The first domain is capable of forming or associating with the envelope of the vehicle whereas the second domain is capable of interacting with the first member of the binding pair on the surface of the sub- population of mammalian cells.

In one embodiment of the invention the vehicle comprises a "viral vehicle". In an alternate embodiment the vehicle comprises a "liposome vehicle". The viral vehicles of the invention are generally formed from naturally occurring viruses and in particular those viruses capable of infecting eukaryotic cells, such as mammalian cells. As is well known, viruses contain a genome comprising either RNA or DNA which encode a variety of genes necessary for viral transfection and reproduction. Included within the viral genome are nucleic acid sequences encoding various enzymes, e.g., DNA or RNA polymerases and the like and structural proteins which surround the viral genome referred to as "viral coat proteins".

Some viral coat proteins make up that part of the virus particle known as the capsid. In addition, some viruses further contain a lipid bilayer surrounding the capsid which often contains viral envelope proteins. Depending upon the virus used and its envelope structure, i.e., capsid proteins only or capsid proteins in combination with membrane and envelope protein, the capsid protein or envelope protein is used to form the targeting moiety for the viral vehicle of the invention.

Since the targeting moiety contains a domain which is capable of forming or associating with the envelope of the virus vehicle, all or part of the viral coat protein is used to construct the recombinant target moiety. When only a portion of the coat protein is used, that portion of the coat protein which is necessary and sufficient for envelope formation is used. For viral envelope proteins, such necessary and essential features include the anchoring region and transmembrane region utilized by the envelope protein to display the envelope protein on an infected cell. When a virus containing an envelope protein is used, it is preferred that the targeting moiety contain such anchor and transmembrane regions .

The second domain of the target moiety is capable of interacting with the first member of a binding pair which is on the surface of a sub-population of mammalian cells. As used herein, a "binding pair" includes receptor-ligand complexes, antigen-antibody complexes, enzyme-substrate complexes and the like. Thus, a sub-population of cells can be defined by the presence of one of the binding pairs on the surface of the cells of the population. For example, those cells containing an erythropoietin receptor define a cellular sub-population that can be targeted by utilizing erythropoietin (ligand) in the targeting moiety of the invention as the second domain capable of interacting with the erythropoietin receptor. Alternatively, the receptor can be used in the targeting moiety and the ligand displayed on the surface of the cells of the sub-population.

Similarly, a sub-population of cells can be defined by the presence of an antigen or antibody on the surface of the cells contained within that population. For example, a surface marker contained on the surface of a sub- population of cells can be used to generate monoclonal antibodies by methods well known to those' skilled in the art. Monoclonal antibodies (especially those containing anchor and transmembrane regions or engineered through cloning and modification of cDNA to contain such sequences) can be used either as the targeting moiety alone (e.g., in a liposome vehicle) or in combination with a protein capable of associating with a viral surface. In an example of the latter case, the targeting moiety essentially comprises a chimeric antibody containing an anchoring and transmembrane region from a viral envelope protein coupled to at least the variable region of a heavy chain Ig molecule which is also associated with the light chain from the antibody. Alternatively, the vehicle of the invention can target a sub-population of lymphoid cells displaying a membrane bound form of an immunoglobulin. In such cases, the antigen to the membrane bound antibody is used to form the second domain of the targeting moiety.

In general, the recombinant targeting moiety used to form the vehicle of the invention contains all or part of the second member of the binding pair. In some instances, the interaction between binding pairs is based upon an interaction involving a continuous epitope. In such cases, the minimal component of the second member of the binding pair that can be used in forming a targeting moiety consists of that epitope. In many instances, however, the interaction involves a discontinuous epitope. For example, in the case of proteins, two or more regions within the primary amino acid sequence of the protein are brought into close physical proximity in the tertiary structure of the protein to form the binding epitope. When only a portion of such a protein is used to form the targeting moiety, that portion of the primary amino acid sequence which encompasses such binding regions are preferably included in the targeting moiety so as to provide the strongest possible interaction with the other member of the binding pair located on the sub-population of mammalian cells.

The vehicle of the invention preferentially targets the delivery of substance to a sub-population of mammalian cells. Such preferential targeting is defined by comparing delivery of the substance to the sub-population of mammalian cells containing the first member of a binding pair as compared to a different population of a mammalian cell of the same species which does not display the first member of the binding pair. The increase in delivery as measured by binding of the vehicle to the sub-population or transferral of the substance of the vehicle into the sub- population cells, is generally greater than two-fold. However, as indicated in the examples, an increase in efficiency in infection by the viral vehicle disclosed therein ranged from 10-fold to about 30- to 40-fold as compared to wild-type cells not containing the receptor used in that experiment . In an example herein, the recombinant targeting moiety comprises a carboxy terminal portion of the envelope protein of Moloney murine leukemia virus (MoMLV) . The second domain comprises an amino terminal portion of erythropoietin. When the plasmid encoding this construct is expressed in a packaging cell line also capable of expressing the full length MoMLV envelope protein under conditions which provide for the formation of virus particles, a viral vehicle of the invention is formed. In this particular case, the recombinant targeting moiety is associated with the envelope (corresponding to the membrane and MoMLV envelope protein) defining a compartment that contains the remainder of the virus particle. As thus formed, the substance contained within the viral compartment can comprise protein surrounding the viral genome or the genome itself. In the former case, preformed proteins capable of being packaged with viral capsid proteins can comprise the substance contained in the compartment. In most embodiments, however, the substance of interest contained within such a viral vehicle is a recombinant DNA sequence introduced into the genome of the virus. Viral vehicles are preferred when the substance to be delivered to a sub-population of cells is a nucleic acid. Thus, when used to treat a genetic disease, the skilled artisan identifies the defective gene and the cell type that expresses the normal wild type gene. Then, a surface marker is identified on the cell type normally expressing the wild type gene. The viral vehicle of the invention is then designed to contain a recombinant targeting moiety capable of forming or associating with the envelope of a selected virus such that the thus modified virus is capable of recognizing and binding the selected surface marker. In conjunction with the selection of the virus to be used in practicing the invention, the size of the recombinant nucleic acid to be incorporated into the viral genome is determined to facilitate the choice of virus to be used. The genome of the virus must be such that it can either accommodate the selected recombinant nucleic acid or be modified to delete nonessential sequences such that the recombinant nucleic acid can be incorporated into the viral genome and still be packaged to form an intact viral particle containing the recombinant targeting moiety. In this regard, it is preferred that the genome of the wild type virus be modified not only to accommodate the recombinant nucleic acid to be incorporated but further to attenuate the virulence of the modified virus. Such modifications include but are not limited to the deletion of the viral genes encoding one or more DNA or RNA polymerases . Examples of viruses which can be used in practicing the invention include retroviruses, adenoviruses and adeno-associated viruses (Berkner, K.L. (1988) BioTechni ues 6.:616-629) .

The Examples describe viral vehicles that demonstrate preferential targeting to cultured mammalian cells expressing the erythropoietin receptor. Thus, when used in vivo, the viral vehicle targets those cells within the organism expressing the erythropoietin receptor. A specific utility for such a vehicle is the treatment of hemoglobinopathies such as sickle cell anemia and β- thalassemia. These diseases involve a genetic defect wherein either an abnormal globin chain is made or little if any /3-globin chain is produced. If a genomic clone encoding the /3-globin gene is inserted into the genome of the virus vehicle in the Examples, the resulting virus vehicle is capable of preferentially recognizing not only red blood cells but also those precursors of red blood cells derived from hematopoietic stem cells that have committed to erythroid differentiation as evidenced by the display of the erythropoietin receptor. When the virus transfects such erythroid progenitor cells, the /3-globin gene is integrated into the genome of the progenitor cells. As a consequence, a normal /3-globin gene becomes integrated into the genome and is capable of modulating the disease by producing either normal amounts of /3-globin or the wild type /3-globin protein. The viral vehicles of the invention can also be used to target the delivery of therapeutic agents to diseased cells such as cancer cells. For example, to the extent a surface marker is preferentially expressed on a cancer cell (i.e., solely on the surface of the cancer cell or at a level higher than that found on non-cancerous cell-types) , an appropriate targeting moiety can be used to target a viral vehicle to bind to such preferentially expressed markers. The genome of the viral vehicle is recombined with a nucleic acid expression unit capable of expressing for example toxic polypeptides such as ricin, diphtheria toxin and the like. Upon recognition, binding and transfection into the cancer cell, the expression unit produces the toxic polypeptide to preferentially kill the cancer cell. In this regard, the expression unit comprises nucleic acid encoding the toxic polypeptide and one or more expression regulation sequences that are operably linked to the nucleic acid such that the nucleic acid is expressed in the transfected cancer cell so as to produce the toxic polypeptide. Such expression regulation sequences are preferably those which demonstrate tissue specific specificity to the cell type from which the cancer cell differentiated, more preferably an expression regulation sequence expressed exclusively by the cancer cell and most preferably the expression regulation sequence controlling the expression of the preferentially expressed surface marker.

In such embodiments, the preferred virus of choice is selected from the retrovirus family. Retroviruses are preferred because they require an actively dividing cell to efficiently integrate into the genome of its host. If non- cancerous cells also express the surface marker preferentially displayed on a cancer cell, the viral vehicle of the invention is also capable of recognizing, binding and transfecting such cells. This background level depends upon the amount of the surface marker found on such normal cells and the environment within which the marker is displayed. Further, to the extent that the viral vehicle contains a normal viral coat protein, e.g., envelope protein, present in combination with the recombinant targeting moiety, the viral vehicle may also have the ability to non-specifically transfect cells independent of the presence of the surface marker utilized for recognition by the targeting moiety. When a retrovirus is used to practice the invention to treat cancer cells, however, such background infections in non-cancer cells are less likely to cause damage to normal cells that are not rapidly dividing since viral integration and expression of the toxic gene is less likely to occur.

The overexpression of oncogenes is often associated with the onset and development of cancer. In many instances, the oncogenes expressed encode receptors which are located on the surface of the cancer cell . For example, it has been recently disclosed that the proto- oncogene HER2 encodes a transmembrane tyrosine kinase whose overexpression has been correlated with several human malignancies, including breast, ovarian, gastric and endometrial cancers as well as non-small cell lung adeno carcinoma. See Holmes, et al. (1992) Science 256. As further disclosed, the protein heregulin-o; has a single affinity binding site for tumor cell lines expressing the HER2 oncogene. The heregulin-α. protein is therefore a candidate for use in treating the above identified cancers according to the teachings disclosed herein.

In addition to cancer cells, the invention can be used for treating autoimmune disease. For example, T-cell mediated autoimmune disease is characterized by a sub- population of T-cells containing a T-cell antigen receptor

(TCAR) which is capable of recognizing and interacting with a self-antigen to elicit the autoimmune response. Experimental autoimmune encephalomyelitis (EAE) is a myelin basic protein induced demyelinating disease in mice. Recently, it has been shown that this disease is based, in part, upon the presence of a sub-population of T-cells containing well-defined variable regions containing specific segment subsets from the T-cell antigen receptor repertoire. It has also been recently reported that mice treated with monoclonal antibodies specific to epitopes contained within the /3-chain of the TCAR of the sub- population of T-cells responsible for the autoimmune disease is capable of preventing onset of the disease when the animal is challenged with myelin basic protein.

Since other T-cell-mediated autoimmune diseases are believed to form the basis of various autoimmune diseases, especially in humans, the vehicle of the invention can be used as an alternate approach to treating or preventing such autoimmune diseases. In such cases, a monoclonal antibody specific for the TCAR responsible for the autoimmune disease is used to form the vehicle of the invention. When a viral vehicle is used, the substance contained within the virus is preferably a toxic gene capable of being expressed when transfected into those T- cells containing the autoimmune inducing TCAR. Alternatively, when a liposome is used, the substance contained therein can be a nucleic acid containing an expressible gene encoding a toxic polypeptide or a therapeutic agent such as a chemotherapeutic agent capable of killing the cell, e.g., the ricin or diphtheria toxin proteins.

In addition to viral vehicles, liposome vehicles can be used to practice the invention. Liposomes are well known to those skilled in the art and generally comprise membranous vesicles containing lipid bilayers which are capable of encapsulating various drugs or other chemicals. See, e.g., U.S. Pat. Nos. 4,053,585; 4,397,846; 4,411,894; 4,427,649, and Papahadjopolous, et al . (1967) Biochem. Biophvs. Acta. 135 :639; Bangham, J. et al . (1965) J. Mol. Biol. 12:238, 252; Bapzri and Korn (1973) Biochem. Biophys . Acta. 298 :1015; and Miyamato, et al . (1971) "Preparation and Characteristics of Lipid Vesicles", J. Membrane Biol. 4:252-269.

When a drug or other chemical is incorporated into a liposome, that substance is generally included in the reaction mixture used to synthesize the liposome. Accordingly, in practicing the invention to form liposome vehicles, the substance to be contained in the compartment of the liposome vehicle, e.g., nucleic acid, drug or therapeutic agent, is included during liposome synthesis. Further, the targeting moiety of the invention is also included during the formation of the liposome.

When using a liposome, the targeting moiety preferably contains a anchoring region and a transmembrane region, e.g., from immunoglobulin or other membrane bound protein, so as to associate with the lipid bilayer of the liposome. It, of course, also contains the domain capable of interacting with the first member of the binding pair contained on the sub-population of mammalian cells. A preferred targeting moiety comprises a monoclonal antibody (preferably IgM) specific for a cell surface antigen or an antibody that has been engineered through cloning and modification to contain an anchoring and transmembrane region.

Since the targeting moiety is not produced within the liposome but rather is incorporated into the liposome membrane during liposome formation, the thus formed liposome contains targeting moiety wherein the domain capable of interacting with the first binding member is displayed on the inner and outer surface of the liposome membrane.

The following is presented by way of examples and is not to be construed as limitation of the scope of the claims appended hereto.

Example 1 Construction of hybrid EPO-env genes

This example describes the construction of hybrid erythropoietin + viral envelope (EPO-env) genes in eukaryotic expression vectors.

The entire wild type moloney murine leukemia virus (MoMLV) envelope gene { env gene; from position 5760 to position 7820 of the retroviral genome; Shinnick, T.M. et al. (1981) Nature 293 :543-548) was cloned into a pBR322- based plasmid vector. Transcription of the env gene is driven by the 5' -MoMLV-long terminal repeat sequence (LTR) . The psi (packaging signal) sequence was deleted, but the vector retained the 5' and 3' splicing signals for the env mRNA. The intervening gag and pol structural genes, which are normally spliced out of the env message (Weiss, R., N. Teich, H. Varmus, J. Coffin, eds. (1984) "RNA Tumor Viruses: Molecular Biology of Tumor Viruses", 2d edition, Cold Springs Harbor Laboratory, Cold Springs Harbor, NY) , were deleted, thus leaving only a small sequence in between the splicing signals remaining to be spliced.

Portions of the envelope were then selected for removal and replaced with the EPO coding sequence. In the center of the outer protein subunit (gp70) of the envelope lies a proline-rich region which is a likely candidate domain for cell receptor recognition (Koch, W. et al . (1983) J. Virol. 4.5:1-9) . Other sites include two regions which flank a region of homology in the amino-terminal portion of the molecule (Mark, G.E. et al . (1984) J. Virol. 49:530-539) , and sites at which point mutations give rise to a paralytogenic mutant of MoMLV (Szurek, P.F. et al . (1988) J. Virol. 6_2.:357-360) . These regions are target sites for replacement with EPO. At the same time, portions of the gp70 sequence which encode the env signal peptide at the amino terminus, as well as the cysteine residues in the carboxyl-terminal region which participate in sulfhydryl bonding with the inner envelope subunit (pl5) , were left intact (Shinnick, T.M. et al . (1981) Nature 293:543-548) . Unique restriction sites exist at position 5923 (BstEII) and position 6537 (BamHI) . Deletion of the envelope sequence between these two sites preserves the env signal sequence and allows the EPO sequence (approximately 500 base pairs in length) to be inserted at the amino-terminal end of gp70. A second EPO-env hybrid was also constructed to insert the EPO sequence in a more central location, directly overlapping the proline-rich region. Since no convenient restriction sites exist in this region, unique sites were created at positions 6250 and 6750 by means of PCR-mediated mutagenesis. These new restriction sites were used to delete the intervening env sequence and insert the EPO sequence. The EPO cDNA sequence coding for the mature 166-amino acid peptide hormone without the 27 amino acid signal peptide (Jacobs, K. et al. (1985) Nature 313:806-810; and Lin, F.K. et al. (1985) Proc. Natl . Acad. Sci. USA 82:7580- 7584) , was used to replace the MoMLV env sequences (Shinnick, T.M. et al. (1981) Nature 293:543-548) which had been deleted in the amino-terminal end and the central region of the envelope protein. PCR-mediated mutagenesis (Innis, M.A., Gelfand, D.H., Sninsky, J.J., White, T.J., eds. (1990) "PCR Protocols: A Guide to Methods and Applications", Academic Press, San Diego, CA) was used to create compatible ends on the EPO sequence, so that it could be inserted via the appropriate restriction sites while maintaining the proper reading frame (Figure 1) .

Example 2 Construction of packaging cell lines containing the EPO-env genes

The EPO-env constructs were transfected into the cell line PA317 (Mann, R. et al . (1983) Cell 3_3:153-159; and

Cone, R.D. et al. (1984) Proc. Natl. Acad. Sci. USA .81:6349-6353) . The PA317 cell line is a derivative of NIH3T3 cells into which MoMLV genes have been stably integrated; the PA317 cells possess the gag and pol genes as well as the amphotropic env gene, but the psi packaging signal sequence is deleted. Thus, these cells produce viral proteins without assembling them into wild type

(endogenous) virus, and can be used to package exogenous viral vectors which do contain the psi sequence into virions with an amphotropic (i.e., capable of infecting both murine and non-murine cells) . The EPO-env plasmids were co-transfected into the PA317 cell line, along with a methotrexate-resistant dihydrofolate reductase (DHFR) gene as a selectable marker (Simonsen, C.S. et al . (1988) Nucleic Acids Res. 16:2235- 2246) , using the calcium phosphate precipitation method (Wigler, M. et al. (1979) Cell 16:77) . After transfection, the cells were selected for stable integration of the env sequences in medium containing methotrexate. Cells which had stably integrated the sequence into their genomes were methotrexate-resistant and therefore survived in this medium, growing as isolated colonies when the plating density was low enough. Stable clones were picked in this manner and grown in separate wells.

After stably transfected sub-clones were isolated, Western blot and flow cytometric analyses were performed to confirm that the recombinant envelope proteins were being expressed and that they were reaching the surface of the packaging cell. Monoclonal anti-EPO antibodies and biotinylated secondary antibodies were used to detect expression in Western blots using a chemiluminescence-based technique (Linscott, W.D. (1990) Linscott's Directory of Immunological and Biological Reagents, 6th ed. , Mill Valley, CA) , and the EPO-env hybrid protein was detected as an intact 70 kiloDalton band in some sub-clones, but seemed to have been deleted or rearranged in others (Figure 2) . Using the parental cell line PA317 as a negative control, polyclonal anti-EPO-antiserum and fluorescein-labeled secondary antibodies were used to detect EPO expression on the cell surface of hybrid EPO-env-containing cell lines by flow cytometry (Figure 3) .

Example 3 Packaging of retroviral vectors This Example discloses the use of the cell lines of Example 2 to package replication-defective retroviral vectors containing the neomycin-resistance (neoR) gene and the /3-galactosidase (/3-gal) gene.

Stable transfectants producing high levels of recombinant envelope proteins were transfected, by means of the calcium phosphate precipitation method, with replication-defective retroviral vectors which contain the psi-packaging signal, but whose gag, pol , and env genes have been deleted and replaced with genes encoding neomycin resistance (neoR) and /3-galactosidase (/3-gal) . These vectors were also transfected into the parental wild type amphotropic packaging cell line PA317 as a control. The cell culture supernatant containing these transiently expressed viruses was harvested, filtered to remove cellular debris, and used to infect target cells with or without the EPO receptor.

Example 4

Tissue specificity and infection efficiency of the packaged virus

The target cells consisted of four types: (1) wild type HeLa cells, which are non-murine and do not express the EPO receptor (D'Andrea, A. et al. (1989) Cell 57:277- 285) , (2) HeLa cells which have been stably transfected with the EPO receptor, (3) wild type NIH3T3 cells, which are murine fibroblasts and do not express the EPO receptor, and (4) NIH3T3 cells which have been stably transfected with the EPO receptor.

HeLa and NIH3T3 cells were co-transfected with the EPO receptor cDNA cloned into an appropriate eukaryotic expression vector containing a methotrexate-resistant DHFR gene (Simonsen, C.S. et al . (1988) Nucleic Acids Res. 16.:2235-2246) . After selection with methotrexate, the surviving colonies were isolated and expression of the EPO receptor was determined by a radioligand (125I-EPO) binding assay (D'Andrea, A. et al . (1989) Cell 57:277-285) . The sub-clone showing the highest levels of EPO receptor expression was selected and further grown in medium containing increasing concentrations of methotrexate, in order to further amplify the expression of EPO receptor. Receptor levels in these cells was calculated to be on the order of about 1000 receptors per cell. As an additional positive control prior to the infection experiments, the NeoR//3-gal vector alone, (unpackaged) was transfected into both cell types by calcium phosphate precipitation, to confirm that the neomycin-resistance gene, whose expression is directed by the MoMLV LTR, is expressed efficiently in these cells.

All cells exposed to virus were subjected to selection with neomycin, and the surviving colonies were examined and counted after Giemsa staining. There proved to be an increased efficiency of infection when viruses expressing the recombinant EPO-env protein were contacted with cells bearing the EPO receptor, as compared to cells without the receptor. This increased efficiency was about 10-fold in the case of HeLa cells with EPO receptor (Figure 4) , and 30- to 40-fold in the case of NIH3T3 cells with EPO receptor (Figure 5) , compared to their respective wild type cells without the receptor. Having described the preferred embodiments, it will be apparent to those skilled in the art that various modifications can be made to the embodiments disclosed herein and that such modifications are intended to be within the scope of the invention.

Claims

WHAT IS CLAIMED IS:
1. A vehicle for preferentially targeting the delivery of a substance to a sub-population of mammalian cells characterized by the presence of a first member of a binding pair on the surface of said sub-population, said vehicle comprising an envelope comprising a recombinant targeting moiety defining a compartment and a substance contained in said compartment, wherein said targeting moiety comprises first and second domains not naturally associated with each other and wherein said first domain forms or associates with the envelope defining said compartment and said second domain comprises a second member of said binding pair or portion thereof which targets said vehicle to said sub-population of mammalian cells.
2. The vehicle of Claim 1 wherein said vehicle is capable of transferring said substance into said cell.
3. The vehicle of Claim 1 wherein said substance is a therapeutic agent.
4. the vehicle of Claim 3 wherein said therapeutic agent is a nucleic acid.
5. The vehicle of Claim 2 wherein said substance comprises a recombinant viral genome.
6. The vehicle of Claim 1 wherein said envelope comprises a membrane.
7. The vehicle of Claim 1 wherein said envelope comprises a viral coat protein.
8. The vehicle of Claim 7 wherein said viral coat protein comprises a viral envelope protein.
9. The vehicle of Claim 7 wherein said first domain of said targeting moiety comprises a portion of a viral coat protein.
10. The vehicle of Claim 9 wherein said viral coat protein comprises a viral envelope protein.
11. A method for preferentially targeting the delivery of a substance to a sub-population of mammalian cells characterized by the presence of a specific surface receptor for a ligand, said method comprising contacting a population of mammalian cells containing said sub- population with any one of the vehicles of Claims 1 through 10 and 12 wherein said receptor and said ligand comprise said first and said second members of said binding pair.
12. The vehicle of Claim 1 wherein said binding pair comprises erythropoietin and erythropoietin receptor.
PCT/US1993/005260 1992-06-08 1993-06-03 Methods and compositions for targeting specific tissue WO1993025234A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US90609292A true 1992-06-08 1992-06-08
US07/906,092 1992-06-08

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP93914334A EP0650370A4 (en) 1992-06-08 1993-06-03 Methods and compositions for targeting specific tissue.
JP6501565A JPH07507689A (en) 1992-06-08 1993-06-03

Publications (1)

Publication Number Publication Date
WO1993025234A1 true WO1993025234A1 (en) 1993-12-23

Family

ID=25421920

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1993/005260 WO1993025234A1 (en) 1992-06-08 1993-06-03 Methods and compositions for targeting specific tissue

Country Status (3)

Country Link
EP (1) EP0650370A4 (en)
JP (1) JPH07507689A (en)
WO (1) WO1993025234A1 (en)

Cited By (198)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996000294A1 (en) * 1994-06-27 1996-01-04 Medical Research Council Improvements in or relating to delivery of nucleic acids
WO1997005266A1 (en) * 1995-07-25 1997-02-13 Introgene B.V. Methods and means for targeted gene delivery
WO1997012049A1 (en) * 1995-09-28 1997-04-03 Medical Research Council Materials and methods relating to the transfer of nucleic acid into quiescent cells
WO1997024453A1 (en) * 1995-12-28 1997-07-10 Chiron Corporation Receptor specific chimeric viral surface polypeptides for viral and particle incorporation and internalization in target cells
DE19605279A1 (en) * 1996-02-13 1997-08-14 Hoechst Ag Target cell-specific vectors for the introduction of genes into cells, to medicaments containing such vectors and the use thereof
US5942434A (en) * 1994-02-15 1999-08-24 Oxford Biomedica (Uk) Limited Nucleic acid constructs comprising hypoxia response elements
US5985655A (en) * 1992-11-09 1999-11-16 The United States Of America As Represented By The Department Of Health And Human Sevices Targetable vector particles
EP0959136A1 (en) * 1998-05-20 1999-11-24 Introgene B.V. Targeted delivery through a cationic amino acid transporter
EP0959135A1 (en) * 1998-05-20 1999-11-24 Introgene B.V. Display of viral proteins and targeted delivery to cellular receptor
EP0960942A2 (en) * 1998-05-20 1999-12-01 Introgene B.V. Targeted delivery through a cationic amino acid transporter
US6004798A (en) * 1997-05-14 1999-12-21 University Of Southern California Retroviral envelopes having modified hypervariable polyproline regions
EP0972841A1 (en) * 1998-05-20 2000-01-19 Introgene B.V. Display of viral proteins as ligands for cell-surface receptor
US6057155A (en) * 1995-11-28 2000-05-02 Genvec, Inc. Targeting adenovirus with use of constrained peptide motifs
WO2000032773A1 (en) 1998-11-27 2000-06-08 Darwin Discovery Ltd. Compositions and methods for increasing bone mineralization
US6153435A (en) * 1995-02-21 2000-11-28 Cornell Research Foundation, Inc. Nucleic acid that encodes a chimeric adenoviral coat protein
US6162641A (en) * 1997-06-06 2000-12-19 The Regents Of The University Of Michigan Neuregulin response element and uses therefor
US6465253B1 (en) 1994-09-08 2002-10-15 Genvec, Inc. Vectors and methods for gene transfer to cells
US6576456B2 (en) 1995-02-21 2003-06-10 Cornell Research Foundation, Inc. Chimeric adenovirus fiber protein
WO2005017148A1 (en) 2003-07-26 2005-02-24 Trubion Pharmaceuticals, Inc. Binding constructs and methods for use thereof
US6864082B2 (en) 1997-04-10 2005-03-08 University Of Southern California Modified viral surface proteins for binding to extracellular matrix components
US6864235B1 (en) 1999-04-01 2005-03-08 Eva A. Turley Compositions and methods for treating cellular response to injury and other proliferating cell disorders regulated by hyaladherin and hyaluronans
US6867189B2 (en) 2001-07-26 2005-03-15 Genset S.A. Use of adipsin/complement factor D in the treatment of metabolic related disorders
EP1514931A1 (en) 1994-05-27 2005-03-16 Ariad Gene Therapeutics, Inc. Immunosuppressant target proteins
US6875588B2 (en) 2001-11-30 2005-04-05 Avigenics, Inc. Ovomucoid promoter and methods of use
US6911429B2 (en) 1999-04-01 2005-06-28 Transition Therapeutics Inc. Compositions and methods for treating cellular response to injury and other proliferating cell disorders regulated by hyaladherin and hyaluronans
US6916918B2 (en) 1997-08-04 2005-07-12 Cell Genesys, Inc. Human glandular kallikrein enhancer, vectors comprising the enhancer and methods of use thereof
US6951839B1 (en) 1999-11-30 2005-10-04 Curis, Inc. Methods and compositions for regulating lymphocyte activity
WO2005093064A1 (en) 2004-03-29 2005-10-06 Galpharma Co., Ltd. Novel galectin 9 modification protein and use thereof
US7063850B1 (en) 1998-12-22 2006-06-20 University Of Tennessee Research Foundation Protective antigen of group A Streptococci
US7078483B2 (en) 1998-04-29 2006-07-18 University Of Southern California Retroviral vectors including modified envelope escort proteins
WO2006085979A2 (en) 2004-07-09 2006-08-17 The Henry M. Jackson Foundation For The Advancement Of Military Medicine, Inc. Soluble forms of hendra and nipah virus g glycoprotein
US7135562B2 (en) 2002-03-14 2006-11-14 University Of Cincinnati Avian iFABP gene expression controlling region
US7176300B2 (en) 2001-03-30 2007-02-13 Avigenics, Inc. Avian lysozyme promoter
US7199279B2 (en) 2001-03-30 2007-04-03 Avigenics, Inc. Recombinant promoters in avian cells
US7244565B2 (en) 2002-04-10 2007-07-17 Georgetown University Gene shinc-3 and diagnostic and therapeutic uses thereof
US7253272B2 (en) 2001-04-06 2007-08-07 Georgetown University Gene BRCC-2 and diagnostic and therapeutic uses thereof
US7270827B2 (en) 2001-10-26 2007-09-18 University Of Tennessee Research Foundation Multivalent streptococcal vaccine compositions and methods for use
US7294507B2 (en) 2001-11-30 2007-11-13 Avigenics, Inc. Ovomucoid promoters and methods of use
EP1854476A2 (en) 2000-02-09 2007-11-14 Bas Medical, Inc. Use of relaxin to treat diseases related to vasoconstriction
WO2008020335A2 (en) 2006-06-09 2008-02-21 Novartis Ag Immunogenic compositions for streptococcus agalactiae
US7335761B2 (en) 2001-11-30 2008-02-26 Avigenics, Inc. Avian gene expression controlling regions
US7351811B2 (en) 2001-04-06 2008-04-01 Georgetown University Gene SCC-112 and diagnostic and therapeutic uses thereof
EP1935979A2 (en) 1999-07-14 2008-06-25 Novartis Vaccines and Diagnostics S.r.l. Antigenic meningococcal peptides
US7396905B1 (en) 1999-05-21 2008-07-08 Mckeon Frank Calcipressins: endogenous inhibitors of calcineurin, uses and reagents related thereto
EP1950297A2 (en) 2000-05-31 2008-07-30 Novartis Vaccines and Diagnostics, Inc. Compositions and methods for treating neoplastic disease using chemotherapy and radiation sensitizers
EP1953243A2 (en) 2000-06-15 2008-08-06 Novartis Vaccines and Diagnostics, Inc. Polynucleotides related to colon cancer
EP1953229A2 (en) 1998-10-15 2008-08-06 Novartis Vaccines and Diagnostics, Inc. Metastatic breast and colon cancer regulated genes
EP1961813A2 (en) 1998-12-16 2008-08-27 Novartis Vaccines and Diagnostics, Inc. Human cyclin-dependent kinase (hPNQALRE)
EP1967525A2 (en) 2001-05-08 2008-09-10 Darwin Molecular Corporation A method for regulating immune function in primates using the foxp3 protein
WO2008124176A2 (en) 2007-04-10 2008-10-16 The Administrators Of The Tulane Educational Fund Soluble and membrane-anchored forms of lassa virus subunit proteins
US7442520B2 (en) 2001-04-06 2008-10-28 Georgetown University Gene BRCC-3 and diagnostic and therapeutic uses thereof
US7462698B2 (en) 2005-07-22 2008-12-09 Y's Therapeutics Co., Ltd. Anti-CD26 antibodies and methods of use thereof
US7498407B2 (en) 2001-11-09 2009-03-03 Georgetown University Vascular endothelial cell growth inhibitor, VEGI-192a
EP2039768A1 (en) 1996-11-13 2009-03-25 Novartis Vaccines and Diagnostics, Inc. Mutant forms of Fas ligand and uses thereof
EP2058408A2 (en) 2003-02-14 2009-05-13 Sagres Discovery, Inc. Therapeutic GPCR targets in cancer
EP2062591A1 (en) 2005-04-07 2009-05-27 Novartis Vaccines and Diagnostics, Inc. CACNA1E in cancer diagnosis detection and treatment
US7541512B2 (en) 2001-03-30 2009-06-02 Synageva Biopharma Corp. Avians containing a lysozyme promoter transgene
US7550650B2 (en) 2001-09-18 2009-06-23 Synageva Biopharma Corp. Production of a transgenic avian by cytoplasmic injection
WO2009079649A1 (en) 2007-12-18 2009-06-25 Bioalliance C.V. Antibodies recognizing a carbohydrate containing epitope on cd-43 and cea expressed on cancer cells and methods using same
EP2075346A2 (en) 2002-01-08 2009-07-01 Novartis Vaccines and Diagnostics, Inc. Gene products differentially expressed in cancerous breast cells and their methods of use
EP2075255A1 (en) 2000-03-08 2009-07-01 Novartis Vaccines and Diagnostics, Inc. Human FGF-23 gene and gene expression products
EP2083088A2 (en) 2005-04-07 2009-07-29 Novartis Vaccines and Diagnostics, Inc. Cancer-related genes
EP2093233A1 (en) 2002-03-21 2009-08-26 Sagres Discovery, Inc. Novel compositions and methods in cancer
EP2100902A1 (en) 2002-10-08 2009-09-16 Rinat Neuroscience Corp. Methods for treating pain by administering an antagonist antibody against the nerve growth factor and an opioid analgesic, and compositions containing the same
US7615229B2 (en) 2002-03-15 2009-11-10 Wyeth Holdings Corporation Mutants of the P4 protein of nontypable Haemophilus influenzae with reduced enzymatic activity
US7674605B2 (en) 2006-06-07 2010-03-09 Bioalliance C.V. Antibodies recognizing a carbohydrate containing epitope on CD-43 and CEA expressed on cancer cells and methods using same
EP2163626A1 (en) 1999-11-18 2010-03-17 Novartis Vaccines and Diagnostics, Inc. Human FGF-21 gene and gene expression products
WO2010029513A2 (en) 2008-09-12 2010-03-18 Rinat Neuroscience Corporation Pcsk9 antagonists
WO2010039536A2 (en) 2008-09-23 2010-04-08 President And Fellows Of Harvard College Sirt4 and uses thereof
US7700359B2 (en) 2000-06-02 2010-04-20 Novartis Vaccines And Diagnostics, Inc. Gene products differentially expressed in cancerous cells
EP2191846A1 (en) 2003-02-19 2010-06-02 Rinat Neuroscience Corp. Method for treating pain by administering a nerve growth factor antagonist and an NSAID and composition containing the same
EP2204376A2 (en) 2004-07-20 2010-07-07 Sagres Discovery, Inc. Novel therapeutic targets in cancer
EP2206785A1 (en) 1998-12-31 2010-07-14 Novartis Vaccines and Diagnostics, Inc. Improved expression of HIV polypeptides and production of virus-like particles
EP2206728A1 (en) 2004-04-07 2010-07-14 Rinat Neuroscience Corp. Methods for treating bone cancer pain by administering a nerve growth factor antagonistic antibody
WO2010080985A1 (en) 2009-01-08 2010-07-15 Dana-Farber Cancer Institute, Inc. Compositions and methods for induced brown fat differentiation
EP2210945A2 (en) 1998-01-14 2010-07-28 Novartis Vaccines and Diagnostics S.r.l. Neisseria meningitidis antigens
WO2010084488A1 (en) 2009-01-20 2010-07-29 Ramot At Tel-Aviv University Ltd. Mir-21 promoter driven targeted cancer therapy
US7767387B2 (en) 2003-06-13 2010-08-03 Sagres Discovery, Inc. Therapeutic targets in cancer
WO2010086828A2 (en) 2009-02-02 2010-08-05 Rinat Neuroscience Corporation Agonist anti-trkb monoclonal antibodies
US7776523B2 (en) 2000-12-07 2010-08-17 Novartis Vaccines And Diagnostics, Inc. Endogenous retroviruses up-regulated in prostate cancer
WO2010100632A2 (en) 2009-03-06 2010-09-10 Novartis Ag Chlamydia antigens
WO2010118243A2 (en) 2009-04-08 2010-10-14 Genentech, Inc. Use of il-27 antagonists to treat lupus
US7816076B2 (en) 2003-02-14 2010-10-19 Sagres Discovery, Inc. Therapeutic targets in cancer
WO2010124365A1 (en) 2009-04-27 2010-11-04 Ottawa Hospital Research Institute Compositions and methods for modulating stem cells and uses thereof
EP2251424A1 (en) 1999-05-19 2010-11-17 Novartis Vaccines and Diagnostics S.r.l. Antigenic neisserial peptides
WO2010141861A1 (en) 2009-06-05 2010-12-09 Infectious Disease Research Institute Synthetic glucopyranosyl lipid adjuvants
EP2261342A2 (en) 1998-05-01 2010-12-15 Novartis Vaccines and Diagnostics, Inc. Neisseria meningitidis antigens and compositions
EP2263692A1 (en) 2002-12-24 2010-12-22 Rinat Neuroscience Corp. Anti-NGF antibodies and methods using same
WO2010146511A1 (en) 2009-06-17 2010-12-23 Pfizer Limited Treatment of overactive bladder
EP2267005A1 (en) 2003-04-09 2010-12-29 Novartis Vaccines and Diagnostics S.r.l. ADP-ribosylating toxin from Listeria monocytogenes
EP2270177A1 (en) 2001-03-27 2011-01-05 Novartis Vaccines and Diagnostics S.r.l. Streptococcus pneumoniae proteins and nucleic acids
EP2275554A2 (en) 1999-10-29 2011-01-19 Novartis Vaccines and Diagnostics S.r.l. Neisserial antigenic peptides
EP2275129A2 (en) 2000-01-17 2011-01-19 Novartis Vaccines and Diagnostics S.r.l. Outer membrane vesicle (OMV) vaccine comprising N. meningitidis serogroup B outer membrane proteins
WO2011007257A1 (en) 2009-07-16 2011-01-20 Novartis Ag Detoxified escherichia coli immunogens
US7875275B2 (en) 2004-06-16 2011-01-25 The General Hospital Corporation Use of Bridge-1 and activators and inhibitors thereof in the treatment of insulin deficiency and diabetes
EP2278006A2 (en) 1997-11-06 2011-01-26 Novartis Vaccines and Diagnostics S.r.l. Neisserial antigens
EP2277895A1 (en) 2000-10-27 2011-01-26 Novartis Vaccines and Diagnostics S.r.l. Nucleic acids and proteins from streptococcus groups A & B
EP2278007A1 (en) 1999-04-30 2011-01-26 Novartis Vaccines and Diagnostics S.r.l. Conserved neisserial antigens
EP2281832A2 (en) 2000-07-05 2011-02-09 Novartis Vaccines and Diagnostics, Inc. Polynucleotides encoding antigenic HIV type C polypeptides, polypeptides and uses thereof
EP2292772A1 (en) 2001-07-05 2011-03-09 Novartis Vaccines and Diagnostics, Inc. HIV vaccination with a DNA encoding a HIV polypeptide and a HIV polypeptide
EP2298796A2 (en) 2001-03-27 2011-03-23 Novartis Vaccines and Diagnostics S.r.l. Staphylococcus aureus proteins and nucleic acids
EP2298795A1 (en) 2005-02-18 2011-03-23 Novartis Vaccines and Diagnostics, Inc. Immunogens from uropathogenic escherichia coli
EP2298900A1 (en) 1996-09-17 2011-03-23 Novartis Vaccines and Diagnostics, Inc. Compositions and methods for treating intracellular diseases
EP2298807A2 (en) 2004-07-30 2011-03-23 Rinat Neuroscience Corp. Antibodies directed against amyloid-beta peptide and methods using same
EP2302039A1 (en) 2002-06-13 2011-03-30 Novartis Vaccines and Diagnostics, Inc. Virus-like particles comprising HML-2 gag polypeptide
WO2011038063A1 (en) 2009-09-28 2011-03-31 The Trustees Of The University Of Pennsylvania Method of diagnosing and treating interstitial cystitis
EP2305711A2 (en) 2005-04-11 2011-04-06 Rinat Neuroscience Corp. Methods for treating osteoarthitis pain by administering a nerve growth factor antagonist and compositions containing the same
US7928189B2 (en) 2008-05-05 2011-04-19 Ottawa Health Research Institute PCSK9 polypeptide fragment
US7935342B2 (en) 2006-02-02 2011-05-03 Rinat Neuroscience Corp. Methods for treating obesity by administering a trkB antagonist
EP2316951A1 (en) 2001-01-17 2011-05-04 Trubion Pharmaceuticals, Inc. Binding domain-immunoglobulin fusion proteins
WO2011058302A1 (en) 2009-11-10 2011-05-19 Guy's And St Thomas's Nhs Foundation Trust Bacteremia-associated antigen from staphylococcus aureus
EP2335723A1 (en) 2001-12-12 2011-06-22 Novartis Vaccines and Diagnostics S.r.l. Immunisation against chlamydia trachomatis
US7968690B2 (en) 2003-12-23 2011-06-28 Rinat Neuroscience Corp. Agonist anti-trkC antibodies and methods using same
EP2338906A1 (en) 2003-06-16 2011-06-29 UCB Manufacturing, Inc. Compostion and methods for increasing bone mineralization
WO2011091272A1 (en) 2010-01-21 2011-07-28 Dana-Farber Cancer Institute, Inc. Context specific genetic screen platform to aid in gene discovery and target validation
EP2353389A1 (en) 2003-04-21 2011-08-10 Epeius Biotechnologies Corporation Methods and compositions for treating disorders
EP2359842A1 (en) 2004-07-14 2011-08-24 University of Utah Research Foundation Netrin-related compositions and uses
EP2362226A1 (en) 2005-03-07 2011-08-31 The President and Fellows of Harvard College Diagnostic method for neurodegenerative diseases based on measurement of SIRT1 levels or activity
WO2011104632A1 (en) 2010-02-26 2011-09-01 Novartis Ag Immunogenic proteins and compositions
WO2011104687A1 (en) 2010-02-24 2011-09-01 Rinat Neuroscience Corporation Antagonist anti-il-7 receptor antibodies and methods
WO2011111007A2 (en) 2010-03-11 2011-09-15 Rinat Neuroscience Corporation ANTIBODIES WITH pH DEPENDENT ANTIGEN BINDING
WO2011121576A2 (en) 2010-04-01 2011-10-06 Novartis Ag Immunogenic proteins and compositions
EP2380592A2 (en) 2005-11-14 2011-10-26 Rinat Neuroscience Corp. Antagonist antibodies directed against calcitonin gene-related peptide and methods using same
WO2011133931A1 (en) 2010-04-22 2011-10-27 Genentech, Inc. Use of il-27 antagonists for treating inflammatory bowel disease
EP2386630A1 (en) 1997-10-14 2011-11-16 Darwin Molecular Corporation Thymidine kinase mutants and fusion proteins having thymidine kinase and guanylate kinase activities
EP2412242A2 (en) 2001-07-05 2012-02-01 Novartis Vaccines and Diagnostics, Inc. Polynucleotides encoding antigenic HIV Type C polypeptides, polypeptides and uses thereof
WO2012015758A2 (en) 2010-07-30 2012-02-02 Saint Louis University Methods of treating pain
EP2418223A2 (en) 2006-06-12 2012-02-15 Emergent Product Development Seattle, LLC Single-chain multivalent binding proteins with effector function
EP2431480A2 (en) 2002-08-09 2012-03-21 The President and Fellows of Harvard College Methods and compositions for increasing the stress resistance of cells and organisms
US8168178B2 (en) 1999-11-30 2012-05-01 Curis, Inc. Methods and compositions for regulating lymphocyte activity
WO2012075243A2 (en) 2010-12-01 2012-06-07 The University Of North Carolina At Chapel Hill Methods and compositions for targeting sites of neovascular growth
WO2012072769A1 (en) 2010-12-01 2012-06-07 Novartis Ag Pneumococcal rrgb epitopes and clade combinations
EP2486938A1 (en) 2006-09-26 2012-08-15 Infectious Disease Research Institute Vaccine composition containing synthetic adjuvant
EP2510947A1 (en) 2009-04-14 2012-10-17 Novartis AG Compositions for immunising against Staphylococcus aureus
WO2013028527A1 (en) 2011-08-23 2013-02-28 Indiana University Research And Technology Corporation Compositions and methods for treating cancer
WO2013028740A1 (en) 2011-08-22 2013-02-28 Saint Louis University Compositions and methods for treating inflammation
WO2013039996A1 (en) 2011-09-13 2013-03-21 Dana-Farber Cancer Institute, Inc. Compositions and methods for brown fat induction and activity using fndc5
EP2572726A1 (en) 2007-08-01 2013-03-27 Novartis AG Compositions comprising pneumococcal antigens
WO2013055911A1 (en) 2011-10-14 2013-04-18 Dana-Farber Cancer Institute, Inc. Znf365/zfp365 biomarker predictive of anti-cancer response
EP2586790A2 (en) 2006-08-16 2013-05-01 Novartis AG Immunogens from uropathogenic Escherichia coli
WO2013068946A2 (en) 2011-11-11 2013-05-16 Rinat Neuroscience Corp. Antibodies specific for trop-2 and their uses
WO2013093693A1 (en) 2011-12-22 2013-06-27 Rinat Neuroscience Corp. Staphylococcus aureus specific antibodies and uses thereof
WO2013093707A1 (en) 2011-12-22 2013-06-27 Rinat Neuroscience Corp. Human growth hormone receptor antagonist antibodies and methods of use thereof
WO2013119856A1 (en) 2012-02-07 2013-08-15 Infectious Disease Research Institute Improved adjuvant formulations comprising tlr4 agonists and methods of using the same
EP2629094A1 (en) 2007-01-24 2013-08-21 Carnegie Mellon University Optical biosensors
WO2013164754A2 (en) 2012-05-04 2013-11-07 Pfizer Inc. Prostate-associated antigens and vaccine-based immunotherapy regimens
WO2014025767A1 (en) 2012-08-07 2014-02-13 National Cheng Kung University Use of il-20 antagonists for treating liver diseases
US8673859B2 (en) 2007-03-20 2014-03-18 New York University GM-CSF cosmeceutical compositions and methods of use thereof
WO2014072876A1 (en) 2012-11-09 2014-05-15 Pfizer Inc. Platelet-derived growth factor b specific antibodies and compositions and uses thereof
US8853366B2 (en) 2001-01-17 2014-10-07 Emergent Product Development Seattle, Llc Binding domain-immunoglobulin fusion proteins
WO2014181229A2 (en) 2013-05-07 2014-11-13 Rinat Neuroscience Corp. Anti-glucagon receptor antibodies and methods of use thereof
WO2015015401A2 (en) 2013-08-02 2015-02-05 Pfizer Inc. Anti-cxcr4 antibodies and antibody-drug conjugates
US8957047B2 (en) 2013-04-18 2015-02-17 Immune Design Corp. GLA monotherapy for use in cancer treatment
US9017659B2 (en) 2006-11-03 2015-04-28 Epeius Biotechnologies Corporation Pathotropic targeted gene delivery system for cancer and other disorders
WO2015073580A1 (en) 2013-11-13 2015-05-21 Pfizer Inc. Tumor necrosis factor-like ligand 1a specific antibodies and compositions and uses thereof
US9044420B2 (en) 2011-04-08 2015-06-02 Immune Design Corp. Immunogenic compositions and methods of using the compositions for inducing humoral and cellular immune responses
WO2015087187A1 (en) 2013-12-10 2015-06-18 Rinat Neuroscience Corp. Anti-sclerostin antibodies
WO2015109212A1 (en) 2014-01-17 2015-07-23 Pfizer Inc. Anti-il-2 antibodies and compositions and uses thereof
US9101609B2 (en) 2008-04-11 2015-08-11 Emergent Product Development Seattle, Llc CD37 immunotherapeutic and combination with bifunctional chemotherapeutic thereof
WO2016040441A1 (en) 2014-09-09 2016-03-17 Unum Therapeutics Chimeric receptors and uses thereof in immune therapy
EP3023502A1 (en) 2008-04-10 2016-05-25 Cell Signaling Technology, Inc. Compositions and methods for detecting egfr mutations in cancer
EP3026432A2 (en) 2010-12-27 2016-06-01 Brown University Method for predicting patient's response to biglycan treatment
WO2016092419A1 (en) 2014-12-09 2016-06-16 Rinat Neuroscience Corp. Anti-pd-1 antibodies and methods of use thereof
WO2016144917A1 (en) 2015-03-10 2016-09-15 University Of Massachusetts Targeting gdf6 and bmp signaling for anti-melanoma therapy
US9463198B2 (en) 2013-06-04 2016-10-11 Infectious Disease Research Institute Compositions and methods for reducing or preventing metastasis
WO2016166629A1 (en) 2015-04-13 2016-10-20 Pfizer Inc. Therapeutic antibodies and their uses
US9526737B2 (en) 2007-12-03 2016-12-27 The Regents Of The University Of California Oxysterols for activation of hedgehog signaling, osteoinduction, antiadipogenesis, and Wnt signaling
US9532994B2 (en) 2003-08-29 2017-01-03 The Regents Of The University Of California Agents and methods for enhancing bone formation by oxysterols in combination with bone morphogenic proteins
US9539427B2 (en) 2010-11-08 2017-01-10 The Johns Hopkins University Methods for improving heart function
WO2017015431A1 (en) 2015-07-21 2017-01-26 Dyax Corp. A monoclonal antibody inhibitor of factor xiia
WO2017029583A2 (en) 2015-08-19 2017-02-23 Pfizer Inc. Tissue factor pathway inhibitor antibodies and uses thereof
WO2017049011A1 (en) 2015-09-15 2017-03-23 Scholar Rock, Inc. Anti-pro/latent-myostatin antibodies and uses thereof
WO2017066561A2 (en) 2015-10-16 2017-04-20 President And Fellows Of Harvard College Regulatory t cell pd-1 modulation for regulating t cell effector immune responses
WO2017070561A1 (en) 2015-10-23 2017-04-27 Pfizer Inc. Anti-il-2 antibodies and compositions and uses thereof
WO2017075037A1 (en) 2015-10-27 2017-05-04 Scholar Rock, Inc. Primed growth factors and uses thereof
US9670244B2 (en) 2006-02-27 2017-06-06 The Regents Of The University Of California Oxysterol compounds and the hedgehog pathway
US9683009B2 (en) 2013-05-02 2017-06-20 The Regents Of The University Of California Bone-selective osteogenic oxysterol-bone targeting agents
WO2017125831A1 (en) 2016-01-21 2017-07-27 Pfizer Inc. Mono and bispecific antibodies for epidermal growth factor receptor variant iii and cd3 and their uses
US9717742B2 (en) 2012-05-07 2017-08-01 The Regents Of The University Of California Oxysterol analogue OXY133 induces osteogenesis and hedgehog signaling and inhibits adipogenesis
US9719069B2 (en) 2009-01-27 2017-08-01 University Of Utah Research Foundation Methods and compositions relating to viral latency
US9730928B2 (en) 2013-06-14 2017-08-15 Univeristy Of Utah Research Foundation Trizol-1-OL analogs anti-retroviral latency drugs
WO2017200852A1 (en) 2016-05-16 2017-11-23 Infectious Disease Research Institute Formulation containing tlr agonist and methods of use
EP3251680A1 (en) 2008-05-22 2017-12-06 Infectious Disease Research Institute Vaccine composition containing synthetic adjuvant
WO2017210364A1 (en) 2016-06-01 2017-12-07 Infectious Disease Research Institute Nanoalum particles containing a sizing agent
US9895435B2 (en) 2012-05-16 2018-02-20 Immune Design Corp. Vaccines for HSV-2
EP3293257A1 (en) 2009-03-20 2018-03-14 Mesoblast, Inc. Production of reprogrammed pluripotent cells
US9925276B2 (en) 2013-03-14 2018-03-27 Epeius Biotechnologies Corporation Thymidine kinase gene
WO2018080573A1 (en) 2016-10-28 2018-05-03 Massachusetts Institute Of Technology Crispr/cas global regulator screening platform
EP3321283A1 (en) 2008-06-13 2018-05-16 Pfizer Inc Treatment of chronic prostatitis
WO2018148246A1 (en) 2017-02-07 2018-08-16 Massachusetts Institute Of Technology Methods and compositions for rna-guided genetic circuits
WO2018158658A1 (en) 2017-03-03 2018-09-07 Rinat Neuroscience Corp. Anti-gitr antibodies and methods of use thereof
WO2018167621A1 (en) 2017-03-16 2018-09-20 Pfizer Inc. Tyrosine prototrophy
US10143748B2 (en) 2005-07-25 2018-12-04 Aptevo Research And Development Llc B-cell reduction using CD37-specific and CD20-specific binding molecules
WO2018220584A1 (en) 2017-06-02 2018-12-06 Pfizer Inc. Antibodies specific for flt3 and their uses
WO2018231772A1 (en) 2017-06-13 2018-12-20 Bostongene Corporation Systems and methods for identifying responders and non-responders to immune checkpoint blockade therapy
WO2019016784A1 (en) 2017-07-21 2019-01-24 Universidade De Coimbra Anti-nucleolin antibody
WO2019070161A2 (en) 2017-10-04 2019-04-11 Opko Pharmaceuticals, Llc Articles and methods directed to personalized therapy of cancer
US10323086B2 (en) 2002-12-24 2019-06-18 Rinat Neuroscience Corp. Methods for treating osteoarthritis pain by administering a nerve growth factor antagonist and compositions containing the same

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993000103A1 (en) * 1991-06-21 1993-01-07 The Wistar Institute Of Anatomy And Biology Chimeric envelope proteins for viral targeting
AU4259193A (en) * 1992-04-28 1993-11-29 Frank Andreas Harald Meyer Medicament for the gene-therapeutic treatment of human beings, animals and plants, especially to block virus multiplication and carcinogenes and process for producing the medicament

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
Nature, Volume 313, issued 28 February 1985, JACOBS et al., "Isolation and Characterization of Genomic and cDNA Clones of Human Erythropoietin", pages 806-810, especially pages 806-807. *
Nature, Volume 339, issued 01 June 1989, EVANS et al., "An Engineered Poliovirus Chimaera Elicits Broadly Reactive HIV-1 Neutralizing Antibodies", pages 385-388, see entire article. *
Proceedings National Academy of Sciences, Volume 82, issued November 1985, LIN et al., "Cloning and Expression of the Human Erythropoietin Gene", pages 7580-7584, especially page 7581. *
See also references of EP0650370A4 *

Cited By (309)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6503501B1 (en) 1992-11-09 2003-01-07 W. French Anderson Targetable vector particles
US5985655A (en) * 1992-11-09 1999-11-16 The United States Of America As Represented By The Department Of Health And Human Sevices Targetable vector particles
US5942434A (en) * 1994-02-15 1999-08-24 Oxford Biomedica (Uk) Limited Nucleic acid constructs comprising hypoxia response elements
US6265390B1 (en) 1994-02-15 2001-07-24 Oxford Biomedica (Uk) Limited Methods for expressing nucleic acid sequences using nucleic acid constructs comprising hypoxia response elements
EP1514931A1 (en) 1994-05-27 2005-03-16 Ariad Gene Therapeutics, Inc. Immunosuppressant target proteins
WO1996000294A1 (en) * 1994-06-27 1996-01-04 Medical Research Council Improvements in or relating to delivery of nucleic acids
US5858743A (en) * 1994-06-27 1999-01-12 Medical Research Council Delivery of nucleic acids
US6465253B1 (en) 1994-09-08 2002-10-15 Genvec, Inc. Vectors and methods for gene transfer to cells
US6951755B2 (en) 1994-09-08 2005-10-04 Genvec, Inc. Vectors and methods for gene transfer
US6153435A (en) * 1995-02-21 2000-11-28 Cornell Research Foundation, Inc. Nucleic acid that encodes a chimeric adenoviral coat protein
US6576456B2 (en) 1995-02-21 2003-06-10 Cornell Research Foundation, Inc. Chimeric adenovirus fiber protein
WO1997005266A1 (en) * 1995-07-25 1997-02-13 Introgene B.V. Methods and means for targeted gene delivery
WO1997012049A1 (en) * 1995-09-28 1997-04-03 Medical Research Council Materials and methods relating to the transfer of nucleic acid into quiescent cells
US6723561B2 (en) 1995-09-28 2004-04-20 Mayo Foundation For Medical Education And Research Materials and methods relating to the transfer of nucleic acid into quiescent cells
US6057155A (en) * 1995-11-28 2000-05-02 Genvec, Inc. Targeting adenovirus with use of constrained peptide motifs
US6649407B2 (en) 1995-11-28 2003-11-18 Genvec, Inc. Targeting adenovirus with use of constrained peptide motifs
US6329190B1 (en) 1995-11-28 2001-12-11 Genvec, Inc. Targetting adenovirus with use of constrained peptide motifs
WO1997024453A1 (en) * 1995-12-28 1997-07-10 Chiron Corporation Receptor specific chimeric viral surface polypeptides for viral and particle incorporation and internalization in target cells
DE19605279A1 (en) * 1996-02-13 1997-08-14 Hoechst Ag Target cell-specific vectors for the introduction of genes into cells, to medicaments containing such vectors and the use thereof
US5916803A (en) * 1996-02-13 1999-06-29 Hoechst Aktiengesellshaft Target cell-specific non-viral vectors for inserting genes into cells, pharmaceutical compositions comprising such vectors and their use
US6358524B1 (en) 1996-02-13 2002-03-19 Aventis Pharma Deutschland Gmbh Target cell-specific non-viral vectors for inserting genes into cells, pharmaceutical compositions comprising such vectors and their use
EP2298900A1 (en) 1996-09-17 2011-03-23 Novartis Vaccines and Diagnostics, Inc. Compositions and methods for treating intracellular diseases
EP2039768A1 (en) 1996-11-13 2009-03-25 Novartis Vaccines and Diagnostics, Inc. Mutant forms of Fas ligand and uses thereof
US6864082B2 (en) 1997-04-10 2005-03-08 University Of Southern California Modified viral surface proteins for binding to extracellular matrix components
US7347998B2 (en) 1997-04-10 2008-03-25 University Of Southern California Method of delivering therapeutic agents to site of tissue injury
US7820157B2 (en) 1997-04-10 2010-10-26 University Of Southern California Transgene delivering retrovirus targeting collagen exposed at site of tissue injury
US8871734B2 (en) 1997-04-10 2014-10-28 The University Of Southern California Transgene delivering retrovirus targeting collagen exposed at site of tissue injury
US8530441B2 (en) 1997-04-10 2013-09-10 University Of Southern California Transgene delivering retrovirus targeting collagen exposed at site of tissue injury
US8148509B2 (en) 1997-04-10 2012-04-03 University Of Southern California Transgene delivering retrovirus targeting collagen exposed at site of tissue injury
US6004798A (en) * 1997-05-14 1999-12-21 University Of Southern California Retroviral envelopes having modified hypervariable polyproline regions
US6162641A (en) * 1997-06-06 2000-12-19 The Regents Of The University Of Michigan Neuregulin response element and uses therefor
US6916918B2 (en) 1997-08-04 2005-07-12 Cell Genesys, Inc. Human glandular kallikrein enhancer, vectors comprising the enhancer and methods of use thereof
EP2386629A1 (en) 1997-10-14 2011-11-16 Darwin Molecular Corporation Thymidine kinase mutants and fusion proteins having thymidine kinase and guanylate kinase activities
EP2386630A1 (en) 1997-10-14 2011-11-16 Darwin Molecular Corporation Thymidine kinase mutants and fusion proteins having thymidine kinase and guanylate kinase activities
EP2278006A2 (en) 1997-11-06 2011-01-26 Novartis Vaccines and Diagnostics S.r.l. Neisserial antigens
EP2210945A2 (en) 1998-01-14 2010-07-28 Novartis Vaccines and Diagnostics S.r.l. Neisseria meningitidis antigens
EP2278011A2 (en) 1998-01-14 2011-01-26 Novartis Vaccines and Diagnostics S.r.l. Neisseria meningitidis antigens
US7078483B2 (en) 1998-04-29 2006-07-18 University Of Southern California Retroviral vectors including modified envelope escort proteins
EP2261344A2 (en) 1998-05-01 2010-12-15 Novartis Vaccines and Diagnostics, Inc. Neisseria meningitidis antigens and compositions
EP2261349A2 (en) 1998-05-01 2010-12-15 Novartis Vaccines and Diagnostics, Inc. Neisseria meningitidis antigens and compositions
EP2261341A2 (en) 1998-05-01 2010-12-15 Novartis Vaccines and Diagnostics, Inc. Neisseria meningitidis antigens and compositions
EP2261347A2 (en) 1998-05-01 2010-12-15 Novartis Vaccines and Diagnostics, Inc. Neisseria meningitidis antigens and compositions
EP2261354A2 (en) 1998-05-01 2010-12-15 Novartis Vaccines and Diagnostics, Inc. Neisseria meningitidis antigens and compositions
EP2261353A2 (en) 1998-05-01 2010-12-15 Novartis Vaccines and Diagnostics, Inc. Neisseria meningitidis antigens and compositions
EP2261348A2 (en) 1998-05-01 2010-12-15 Novartis Vaccines and Diagnostics, Inc. Neisseria meningitidis antigens and compositions
EP2261343A2 (en) 1998-05-01 2010-12-15 Novartis Vaccines and Diagnostics, Inc. Neisseria meningitidis antigens and compositions
EP2261357A2 (en) 1998-05-01 2010-12-15 Novartis Vaccines and Diagnostics, Inc. Neisseria meningitidis antigens and compositions
EP2261339A2 (en) 1998-05-01 2010-12-15 Novartis Vaccines and Diagnostics, Inc. Neisseria meningitidis antigens and compositions
EP2261338A2 (en) 1998-05-01 2010-12-15 Novartis Vaccines and Diagnostics, Inc. Neisseria meningitidis antigens and compositions
EP2261340A2 (en) 1998-05-01 2010-12-15 Novartis Vaccines and Diagnostics, Inc. Neisseria meningitidis antigens and compositions
EP2261350A2 (en) 1998-05-01 2010-12-15 Novartis Vaccines and Diagnostics, Inc. Neisseria meningitidis antigens and compositions
EP2261346A2 (en) 1998-05-01 2010-12-15 Novartis Vaccines and Diagnostics, Inc. Neisseria meningitidis antigens and compositions
EP2261351A2 (en) 1998-05-01 2010-12-15 Novartis Vaccines and Diagnostics, Inc. Neisseria meningitidis antigens and compositions
EP2261342A2 (en) 1998-05-01 2010-12-15 Novartis Vaccines and Diagnostics, Inc. Neisseria meningitidis antigens and compositions
EP2261352A2 (en) 1998-05-01 2010-12-15 Novartis Vaccines and Diagnostics, Inc. Neisseria meningitidis antigens and compositions
EP2261356A2 (en) 1998-05-01 2010-12-15 Novartis Vaccines and Diagnostics, Inc. Neisseria meningitidis antigens and compositions
EP2261355A2 (en) 1998-05-01 2010-12-15 Novartis Vaccines and Diagnostics, Inc. Neisseria meningitidis antigens and compositions
EP2261345A2 (en) 1998-05-01 2010-12-15 Novartis Vaccines and Diagnostics, Inc. Neisseria meningitidis antigens and compositions
WO1999060148A3 (en) * 1998-05-20 2000-01-13 Introgene Bv Display of viral proteins as ligands for cell-surface receptor
EP0960942A3 (en) * 1998-05-20 2000-01-12 Introgene B.V. Targeted delivery through a cationic amino acid transporter
EP0959136A1 (en) * 1998-05-20 1999-11-24 Introgene B.V. Targeted delivery through a cationic amino acid transporter
EP0960942A2 (en) * 1998-05-20 1999-12-01 Introgene B.V. Targeted delivery through a cationic amino acid transporter
WO1999060147A3 (en) * 1998-05-20 1999-12-29 Introgene Bv Targeted delivery through a cationic amino acid transporter
WO1999060147A2 (en) * 1998-05-20 1999-11-25 Introgene B.V. Targeted delivery through a cationic amino acid transporter
EP0972841A1 (en) * 1998-05-20 2000-01-19 Introgene B.V. Display of viral proteins as ligands for cell-surface receptor
EP0959135A1 (en) * 1998-05-20 1999-11-24 Introgene B.V. Display of viral proteins and targeted delivery to cellular receptor
WO1999060148A2 (en) * 1998-05-20 1999-11-25 Introgene B.V. Display of viral proteins as ligands for cell-surface receptor
EP1953229A2 (en) 1998-10-15 2008-08-06 Novartis Vaccines and Diagnostics, Inc. Metastatic breast and colon cancer regulated genes
EP2261335A1 (en) 1998-11-27 2010-12-15 UCB Pharma S.A. Compositions and methods for increasing bone mineralisation
WO2000032773A1 (en) 1998-11-27 2000-06-08 Darwin Discovery Ltd. Compositions and methods for increasing bone mineralization
EP1961813A2 (en) 1998-12-16 2008-08-27 Novartis Vaccines and Diagnostics, Inc. Human cyclin-dependent kinase (hPNQALRE)
US7063850B1 (en) 1998-12-22 2006-06-20 University Of Tennessee Research Foundation Protective antigen of group A Streptococci
EP2206785A1 (en) 1998-12-31 2010-07-14 Novartis Vaccines and Diagnostics, Inc. Improved expression of HIV polypeptides and production of virus-like particles
US6911429B2 (en) 1999-04-01 2005-06-28 Transition Therapeutics Inc. Compositions and methods for treating cellular response to injury and other proliferating cell disorders regulated by hyaladherin and hyaluronans
US6864235B1 (en) 1999-04-01 2005-03-08 Eva A. Turley Compositions and methods for treating cellular response to injury and other proliferating cell disorders regulated by hyaladherin and hyaluronans
EP2290083A1 (en) 1999-04-30 2011-03-02 Novartis Vaccines and Diagnostics S.r.l. Conserved neisserial antigens
EP2278007A1 (en) 1999-04-30 2011-01-26 Novartis Vaccines and Diagnostics S.r.l. Conserved neisserial antigens
EP2251424A1 (en) 1999-05-19 2010-11-17 Novartis Vaccines and Diagnostics S.r.l. Antigenic neisserial peptides
US7396905B1 (en) 1999-05-21 2008-07-08 Mckeon Frank Calcipressins: endogenous inhibitors of calcineurin, uses and reagents related thereto
EP1935979A2 (en) 1999-07-14 2008-06-25 Novartis Vaccines and Diagnostics S.r.l. Antigenic meningococcal peptides
EP2275553A2 (en) 1999-10-29 2011-01-19 Novartis Vaccines and Diagnostics S.r.l. Neisserial antigenic peptides
EP2275551A2 (en) 1999-10-29 2011-01-19 Novartis Vaccines and Diagnostics S.r.l. Neisserial antigenic peptides
EP2275552A2 (en) 1999-10-29 2011-01-19 Novartis Vaccines and Diagnostics S.r.l. Neisserial antigenic peptides
EP2275554A2 (en) 1999-10-29 2011-01-19 Novartis Vaccines and Diagnostics S.r.l. Neisserial antigenic peptides
EP2975127A1 (en) 1999-10-29 2016-01-20 GlaxoSmithKline Biologicals SA Neisserial antigenic peptides
EP2163626A1 (en) 1999-11-18 2010-03-17 Novartis Vaccines and Diagnostics, Inc. Human FGF-21 gene and gene expression products
US8168178B2 (en) 1999-11-30 2012-05-01 Curis, Inc. Methods and compositions for regulating lymphocyte activity
US6951839B1 (en) 1999-11-30 2005-10-04 Curis, Inc. Methods and compositions for regulating lymphocyte activity
EP2281571A2 (en) 2000-01-17 2011-02-09 Novartis Vaccines and Diagnostics S.r.l. Outer membrane vesicle (omv) vaccine comprising n. meningitidids serogroup b outer membrane proteins
EP2275129A2 (en) 2000-01-17 2011-01-19 Novartis Vaccines and Diagnostics S.r.l. Outer membrane vesicle (OMV) vaccine comprising N. meningitidis serogroup B outer membrane proteins
EP2289545A2 (en) 2000-01-17 2011-03-02 Novartis Vaccines and Diagnostics S.r.l. Supplemented OMV vaccine against meningococcus
EP2281570A2 (en) 2000-01-17 2011-02-09 Novartis Vaccines and Diagnostics S.r.l. Outer membrane vesicle (OMV) vaccine comprising n. meningitidis serogroup B outer membrane proteins
EP1854476A2 (en) 2000-02-09 2007-11-14 Bas Medical, Inc. Use of relaxin to treat diseases related to vasoconstriction
EP2075255A1 (en) 2000-03-08 2009-07-01 Novartis Vaccines and Diagnostics, Inc. Human FGF-23 gene and gene expression products
EP1950297A2 (en) 2000-05-31 2008-07-30 Novartis Vaccines and Diagnostics, Inc. Compositions and methods for treating neoplastic disease using chemotherapy and radiation sensitizers
US7700359B2 (en) 2000-06-02 2010-04-20 Novartis Vaccines And Diagnostics, Inc. Gene products differentially expressed in cancerous cells
US8221983B2 (en) 2000-06-02 2012-07-17 Novartis Vaccines And Diagnostics, Inc. Gene products differentially expressed in cancerous cells
EP1953243A2 (en) 2000-06-15 2008-08-06 Novartis Vaccines and Diagnostics, Inc. Polynucleotides related to colon cancer
EP2311958A2 (en) 2000-07-05 2011-04-20 Novartis Vaccines and Diagnostics, Inc. Polynucleotides encoding antigenic HIV type C polypeptides, polypeptides and uses thereof
EP2281832A2 (en) 2000-07-05 2011-02-09 Novartis Vaccines and Diagnostics, Inc. Polynucleotides encoding antigenic HIV type C polypeptides, polypeptides and uses thereof
EP2277896A1 (en) 2000-10-27 2011-01-26 Novartis Vaccines and Diagnostics S.r.l. Nucleic acids and proteins from streptococcus groups A & B
EP2277894A1 (en) 2000-10-27 2011-01-26 Novartis Vaccines and Diagnostics S.r.l. Nucleic acids and proteins from streptococcus groups A & B
EP2896629A1 (en) 2000-10-27 2015-07-22 Novartis Vaccines and Diagnostics S.r.l. Nucleic acids and proteins from streptococcus group A & B
EP2284183A1 (en) 2000-10-27 2011-02-16 Novartis Vaccines and Diagnostics S.r.l. Nucleic acids and proteins from streptococcus groups A and B
EP2277895A1 (en) 2000-10-27 2011-01-26 Novartis Vaccines and Diagnostics S.r.l. Nucleic acids and proteins from streptococcus groups A & B
EP2284182A1 (en) 2000-10-27 2011-02-16 Novartis Vaccines and Diagnostics S.r.l. Nucleic acids and proteins from streptococcus groups A and B
EP2284181A1 (en) 2000-10-27 2011-02-16 Novartis Vaccines and Diagnostics S.r.l. Nucleic acids and proteins from streptococcus groups A and B
US7776523B2 (en) 2000-12-07 2010-08-17 Novartis Vaccines And Diagnostics, Inc. Endogenous retroviruses up-regulated in prostate cancer
EP2339035A1 (en) 2000-12-07 2011-06-29 Novartis Vaccines and Diagnostics, Inc. Endogenous retroviruses up-regulated in prostate cancer
EP2336368A1 (en) 2000-12-07 2011-06-22 Novartis Vaccines and Diagnostics, Inc. Endogenous retroviruses up-regulated in prostate cancer
US8853366B2 (en) 2001-01-17 2014-10-07 Emergent Product Development Seattle, Llc Binding domain-immunoglobulin fusion proteins
EP2706116A1 (en) 2001-01-17 2014-03-12 Emergent Product Development Seattle, LLC Binding domain-immunoglobulin fusion proteins
EP2316951A1 (en) 2001-01-17 2011-05-04 Trubion Pharmaceuticals, Inc. Binding domain-immunoglobulin fusion proteins
EP2314697A1 (en) 2001-03-27 2011-04-27 Novartis Vaccines and Diagnostics S.r.l. Streptococcus pneumoniae proteins and nucleic acids
EP2270175A1 (en) 2001-03-27 2011-01-05 Novartis Vaccines and Diagnostics S.r.l. Streptococcus pneumoniae proteins and nucleic acids
EP2270177A1 (en) 2001-03-27 2011-01-05 Novartis Vaccines and Diagnostics S.r.l. Streptococcus pneumoniae proteins and nucleic acids
EP2298796A2 (en) 2001-03-27 2011-03-23 Novartis Vaccines and Diagnostics S.r.l. Staphylococcus aureus proteins and nucleic acids
EP2278008A2 (en) 2001-03-27 2011-01-26 Novartis Vaccines and Diagnostics S.r.l. Streptococcus pneumoniae proteins and nucleic acids
EP2270176A1 (en) 2001-03-27 2011-01-05 Novartis Vaccines and Diagnostics S.r.l. Streptococcus pneumoniae proteins and nucleic acids
EP2278009A1 (en) 2001-03-27 2011-01-26 Novartis Vaccines and Diagnostics S.r.l. Streptococcus pneumoniae proteins and nucleic acids
EP2278010A1 (en) 2001-03-27 2011-01-26 Novartis Vaccines and Diagnostics S.r.l. Streptococcus pneumoniae proteins and nucleic acids
US7176300B2 (en) 2001-03-30 2007-02-13 Avigenics, Inc. Avian lysozyme promoter
US7199279B2 (en) 2001-03-30 2007-04-03 Avigenics, Inc. Recombinant promoters in avian cells
US7541512B2 (en) 2001-03-30 2009-06-02 Synageva Biopharma Corp. Avians containing a lysozyme promoter transgene
US7351811B2 (en) 2001-04-06 2008-04-01 Georgetown University Gene SCC-112 and diagnostic and therapeutic uses thereof
US7442520B2 (en) 2001-04-06 2008-10-28 Georgetown University Gene BRCC-3 and diagnostic and therapeutic uses thereof
US7253272B2 (en) 2001-04-06 2007-08-07 Georgetown University Gene BRCC-2 and diagnostic and therapeutic uses thereof
EP1967525A2 (en) 2001-05-08 2008-09-10 Darwin Molecular Corporation A method for regulating immune function in primates using the foxp3 protein
EP2292772A1 (en) 2001-07-05 2011-03-09 Novartis Vaccines and Diagnostics, Inc. HIV vaccination with a DNA encoding a HIV polypeptide and a HIV polypeptide
EP2412242A2 (en) 2001-07-05 2012-02-01 Novartis Vaccines and Diagnostics, Inc. Polynucleotides encoding antigenic HIV Type C polypeptides, polypeptides and uses thereof
US6867189B2 (en) 2001-07-26 2005-03-15 Genset S.A. Use of adipsin/complement factor D in the treatment of metabolic related disorders
US7550650B2 (en) 2001-09-18 2009-06-23 Synageva Biopharma Corp. Production of a transgenic avian by cytoplasmic injection
US7270827B2 (en) 2001-10-26 2007-09-18 University Of Tennessee Research Foundation Multivalent streptococcal vaccine compositions and methods for use
US7498407B2 (en) 2001-11-09 2009-03-03 Georgetown University Vascular endothelial cell growth inhibitor, VEGI-192a
US7750133B2 (en) 2001-11-09 2010-07-06 Georgetown University Vascular endothelial cell growth inhibitor, VEGI-192a
US7812215B2 (en) 2001-11-30 2010-10-12 Synageva Biopharma Corp. Methods and protein production using ovomucoid promoters
US7294507B2 (en) 2001-11-30 2007-11-13 Avigenics, Inc. Ovomucoid promoters and methods of use
US7375258B2 (en) 2001-11-30 2008-05-20 Avigenics, Inc. Transgenic avians with an ovomucoid gene expression control region linked to a nucleotide sequence encoding a heterologous polypeptide
US6875588B2 (en) 2001-11-30 2005-04-05 Avigenics, Inc. Ovomucoid promoter and methods of use
US7335761B2 (en) 2001-11-30 2008-02-26 Avigenics, Inc. Avian gene expression controlling regions
US7507873B2 (en) 2001-11-30 2009-03-24 Avigenics, Inc. Transgenic avians containing recombinant ovomucoid promoters
EP2335723A1 (en) 2001-12-12 2011-06-22 Novartis Vaccines and Diagnostics S.r.l. Immunisation against chlamydia trachomatis
EP2335724A1 (en) 2001-12-12 2011-06-22 Novartis Vaccines and Diagnostics S.r.l. Immunisation against chlamydia trachomatis
EP2075346A2 (en) 2002-01-08 2009-07-01 Novartis Vaccines and Diagnostics, Inc. Gene products differentially expressed in cancerous breast cells and their methods of use
US7135562B2 (en) 2002-03-14 2006-11-14 University Of Cincinnati Avian iFABP gene expression controlling region
US7666626B2 (en) 2002-03-15 2010-02-23 Wyeth Holdings Corporation Mutants of the P4 protein of nontypable Haemophilus influenzae with reduced enzymatic activity
US7615229B2 (en) 2002-03-15 2009-11-10 Wyeth Holdings Corporation Mutants of the P4 protein of nontypable Haemophilus influenzae with reduced enzymatic activity
EP2093233A1 (en) 2002-03-21 2009-08-26 Sagres Discovery, Inc. Novel compositions and methods in cancer
US7244565B2 (en) 2002-04-10 2007-07-17 Georgetown University Gene shinc-3 and diagnostic and therapeutic uses thereof
EP2302039A1 (en) 2002-06-13 2011-03-30 Novartis Vaccines and Diagnostics, Inc. Virus-like particles comprising HML-2 gag polypeptide
US8518694B2 (en) 2002-06-13 2013-08-27 Novartis Vaccines And Diagnostics, Inc. Nucleic acid vector comprising a promoter and a sequence encoding a polypeptide from the endogenous retrovirus PCAV
EP2431480A2 (en) 2002-08-09 2012-03-21 The President and Fellows of Harvard College Methods and compositions for increasing the stress resistance of cells and organisms
EP2100902A1 (en) 2002-10-08 2009-09-16 Rinat Neuroscience Corp. Methods for treating pain by administering an antagonist antibody against the nerve growth factor and an opioid analgesic, and compositions containing the same
EP2263692A1 (en) 2002-12-24 2010-12-22 Rinat Neuroscience Corp. Anti-NGF antibodies and methods using same
EP2270048A2 (en) 2002-12-24 2011-01-05 Rinat Neuroscience Corp. Anti-NGF antibodies and methods using same
US10323086B2 (en) 2002-12-24 2019-06-18 Rinat Neuroscience Corp. Methods for treating osteoarthritis pain by administering a nerve growth factor antagonist and compositions containing the same
US7816076B2 (en) 2003-02-14 2010-10-19 Sagres Discovery, Inc. Therapeutic targets in cancer
EP2058408A2 (en) 2003-02-14 2009-05-13 Sagres Discovery, Inc. Therapeutic GPCR targets in cancer
EP2191846A1 (en) 2003-02-19 2010-06-02 Rinat Neuroscience Corp. Method for treating pain by administering a nerve growth factor antagonist and an NSAID and composition containing the same
EP2267005A1 (en) 2003-04-09 2010-12-29 Novartis Vaccines and Diagnostics S.r.l. ADP-ribosylating toxin from Listeria monocytogenes
EP2353389A1 (en) 2003-04-21 2011-08-10 Epeius Biotechnologies Corporation Methods and compositions for treating disorders
US7767387B2 (en) 2003-06-13 2010-08-03 Sagres Discovery, Inc. Therapeutic targets in cancer
EP2341071A1 (en) 2003-06-16 2011-07-06 UCB Manufacturing, Inc. Compostion and methods for increasing bone mineralization
EP2338906A1 (en) 2003-06-16 2011-06-29 UCB Manufacturing, Inc. Compostion and methods for increasing bone mineralization
WO2005017148A1 (en) 2003-07-26 2005-02-24 Trubion Pharmaceuticals, Inc. Binding constructs and methods for use thereof
US9532994B2 (en) 2003-08-29 2017-01-03 The Regents Of The University Of California Agents and methods for enhancing bone formation by oxysterols in combination with bone morphogenic proteins
EP2402756A2 (en) 2003-12-23 2012-01-04 Rinat Neuroscience Corp. Agonist anti-trkC antibodies and methods using same
US7968690B2 (en) 2003-12-23 2011-06-28 Rinat Neuroscience Corp. Agonist anti-trkC antibodies and methods using same
WO2005093064A1 (en) 2004-03-29 2005-10-06 Galpharma Co., Ltd. Novel galectin 9 modification protein and use thereof
EP2206728A1 (en) 2004-04-07 2010-07-14 Rinat Neuroscience Corp. Methods for treating bone cancer pain by administering a nerve growth factor antagonistic antibody
EP3372614A1 (en) 2004-04-07 2018-09-12 Rinat Neuroscience Corp. Methods for treating bone cancer pain by administering a nerve growth factor antagonist
US7875275B2 (en) 2004-06-16 2011-01-25 The General Hospital Corporation Use of Bridge-1 and activators and inhibitors thereof in the treatment of insulin deficiency and diabetes
WO2006085979A2 (en) 2004-07-09 2006-08-17 The Henry M. Jackson Foundation For The Advancement Of Military Medicine, Inc. Soluble forms of hendra and nipah virus g glycoprotein
EP2495252A2 (en) 2004-07-09 2012-09-05 The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. Soluble forms of hendra and nipah virus G glycoprotein
EP3381930A1 (en) 2004-07-09 2018-10-03 The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. Soluble forms of hendra and nipah virus g glycoprotein
EP2359842A1 (en) 2004-07-14 2011-08-24 University of Utah Research Foundation Netrin-related compositions and uses
EP2204376A2 (en) 2004-07-20 2010-07-07 Sagres Discovery, Inc. Novel therapeutic targets in cancer
EP2298807A2 (en) 2004-07-30 2011-03-23 Rinat Neuroscience Corp. Antibodies directed against amyloid-beta peptide and methods using same
EP2298795A1 (en) 2005-02-18 2011-03-23 Novartis Vaccines and Diagnostics, Inc. Immunogens from uropathogenic escherichia coli
EP2362226A1 (en) 2005-03-07 2011-08-31 The President and Fellows of Harvard College Diagnostic method for neurodegenerative diseases based on measurement of SIRT1 levels or activity
EP2083088A2 (en) 2005-04-07 2009-07-29 Novartis Vaccines and Diagnostics, Inc. Cancer-related genes
EP2062591A1 (en) 2005-04-07 2009-05-27 Novartis Vaccines and Diagnostics, Inc. CACNA1E in cancer diagnosis detection and treatment
EP3272358A1 (en) 2005-04-11 2018-01-24 Rinat Neuroscience Corporation Methods for treating osteoarthitis pain by administering a nerve growth factor antagonist and compositions containing the same
EP2305711A2 (en) 2005-04-11 2011-04-06 Rinat Neuroscience Corp. Methods for treating osteoarthitis pain by administering a nerve growth factor antagonist and compositions containing the same
US7462698B2 (en) 2005-07-22 2008-12-09 Y's Therapeutics Co., Ltd. Anti-CD26 antibodies and methods of use thereof
US8030469B2 (en) 2005-07-22 2011-10-04 Sbi Incubation Co., Ltd. Anti-CD26 antibodies and methods of use thereof
US10307481B2 (en) 2005-07-25 2019-06-04 Aptevo Research And Development Llc CD37 immunotherapeutics and uses thereof
US10143748B2 (en) 2005-07-25 2018-12-04 Aptevo Research And Development Llc B-cell reduction using CD37-specific and CD20-specific binding molecules
EP3178493A1 (en) 2005-11-14 2017-06-14 Labrys Biologics Inc. Antagonist antibodies directed against calcitonin gene-related peptide and methods using same
EP2380592A2 (en) 2005-11-14 2011-10-26 Rinat Neuroscience Corp. Antagonist antibodies directed against calcitonin gene-related peptide and methods using same
EP3045182A1 (en) 2005-11-14 2016-07-20 Labrys Biologics Inc. Antagonist antibodies directed against calcitonin gene-related peptide and methods using same
EP3069731A1 (en) 2005-11-14 2016-09-21 Labrys Biologics Inc. Antagonist antibodies directed against calcitonin gene-related peptide and methods using same
US7935342B2 (en) 2006-02-02 2011-05-03 Rinat Neuroscience Corp. Methods for treating obesity by administering a trkB antagonist
US9670244B2 (en) 2006-02-27 2017-06-06 The Regents Of The University Of California Oxysterol compounds and the hedgehog pathway
US7674605B2 (en) 2006-06-07 2010-03-09 Bioalliance C.V. Antibodies recognizing a carbohydrate containing epitope on CD-43 and CEA expressed on cancer cells and methods using same
US9193794B2 (en) 2006-06-07 2015-11-24 Bioalliance C.V. Antibodies recognizing a carbohydrate containing epitope on CD-43 and CEA expressed on cancer cells and methods using same
WO2008020335A2 (en) 2006-06-09 2008-02-21 Novartis Ag Immunogenic compositions for streptococcus agalactiae
EP2418223A2 (en) 2006-06-12 2012-02-15 Emergent Product Development Seattle, LLC Single-chain multivalent binding proteins with effector function
US8409577B2 (en) 2006-06-12 2013-04-02 Emergent Product Development Seattle, Llc Single chain multivalent binding proteins with effector function
EP2586790A2 (en) 2006-08-16 2013-05-01 Novartis AG Immunogens from uropathogenic Escherichia coli
US8840908B2 (en) 2006-09-26 2014-09-23 Infectious Disease Research Institute Vaccine composition containing synthetic adjuvant
US9987355B2 (en) 2006-09-26 2018-06-05 Infectious Disease Research Institute Vaccine composition containing synthetic adjuvant
EP3403667A1 (en) 2006-09-26 2018-11-21 Infectious Disease Research Institute Vaccine composition containing synthetic adjuvant
EP2486938A1 (en) 2006-09-26 2012-08-15 Infectious Disease Research Institute Vaccine composition containing synthetic adjuvant
US8273361B2 (en) 2006-09-26 2012-09-25 Infectious Disease Research Institute Vaccine composition containing synthetic adjuvant
US9907845B2 (en) 2006-09-26 2018-03-06 Infectious Disease Research Institute Methods of using a vaccine composition containing synthetic adjuvant
US9950063B2 (en) 2006-09-26 2018-04-24 Infectious Disease Research Institute Vaccine composition containing synthetic adjuvant
US9017659B2 (en) 2006-11-03 2015-04-28 Epeius Biotechnologies Corporation Pathotropic targeted gene delivery system for cancer and other disorders
EP2629094A1 (en) 2007-01-24 2013-08-21 Carnegie Mellon University Optical biosensors
US8673859B2 (en) 2007-03-20 2014-03-18 New York University GM-CSF cosmeceutical compositions and methods of use thereof
WO2008124176A2 (en) 2007-04-10 2008-10-16 The Administrators Of The Tulane Educational Fund Soluble and membrane-anchored forms of lassa virus subunit proteins
EP2572726A1 (en) 2007-08-01 2013-03-27 Novartis AG Compositions comprising pneumococcal antigens
US9526737B2 (en) 2007-12-03 2016-12-27 The Regents Of The University Of California Oxysterols for activation of hedgehog signaling, osteoinduction, antiadipogenesis, and Wnt signaling
US8568718B2 (en) 2007-12-18 2013-10-29 Bioalliance C.V. Antibodies recognizing a carbohydrate containing epitope on CD-43 and CEA expressed on cancer cells and methods using same
US7982017B2 (en) 2007-12-18 2011-07-19 Bioalliance C.V. Antibodies recognizing a carbohydrate containing epitope on CD-43 and CEA expressed on cancer cells and methods using same
WO2009079649A1 (en) 2007-12-18 2009-06-25 Bioalliance C.V. Antibodies recognizing a carbohydrate containing epitope on cd-43 and cea expressed on cancer cells and methods using same
US9334329B2 (en) 2007-12-18 2016-05-10 Bioalliance C.V. Antibodies recognizing a carbohydrate containing epitope on CD-43 and CEA expressed on cancer cells and methods using same
EP3023502A1 (en) 2008-04-10 2016-05-25 Cell Signaling Technology, Inc. Compositions and methods for detecting egfr mutations in cancer
US9101609B2 (en) 2008-04-11 2015-08-11 Emergent Product Development Seattle, Llc CD37 immunotherapeutic and combination with bifunctional chemotherapeutic thereof
US7928189B2 (en) 2008-05-05 2011-04-19 Ottawa Health Research Institute PCSK9 polypeptide fragment
EP3251680A1 (en) 2008-05-22 2017-12-06 Infectious Disease Research Institute Vaccine composition containing synthetic adjuvant
EP3321283A1 (en) 2008-06-13 2018-05-16 Pfizer Inc Treatment of chronic prostatitis
WO2010029513A2 (en) 2008-09-12 2010-03-18 Rinat Neuroscience Corporation Pcsk9 antagonists
WO2010039536A2 (en) 2008-09-23 2010-04-08 President And Fellows Of Harvard College Sirt4 and uses thereof
WO2010080985A1 (en) 2009-01-08 2010-07-15 Dana-Farber Cancer Institute, Inc. Compositions and methods for induced brown fat differentiation
WO2010084488A1 (en) 2009-01-20 2010-07-29 Ramot At Tel-Aviv University Ltd. Mir-21 promoter driven targeted cancer therapy
US9719069B2 (en) 2009-01-27 2017-08-01 University Of Utah Research Foundation Methods and compositions relating to viral latency
WO2010086828A2 (en) 2009-02-02 2010-08-05 Rinat Neuroscience Corporation Agonist anti-trkb monoclonal antibodies
WO2010100632A2 (en) 2009-03-06 2010-09-10 Novartis Ag Chlamydia antigens
EP3293257A1 (en) 2009-03-20 2018-03-14 Mesoblast, Inc. Production of reprogrammed pluripotent cells
WO2010118243A2 (en) 2009-04-08 2010-10-14 Genentech, Inc. Use of il-27 antagonists to treat lupus
EP3263128A2 (en) 2009-04-14 2018-01-03 GlaxoSmithKline Biologicals S.A. Compositions for immunising against staphylococcus aureus
EP2510947A1 (en) 2009-04-14 2012-10-17 Novartis AG Compositions for immunising against Staphylococcus aureus
WO2010124365A1 (en) 2009-04-27 2010-11-04 Ottawa Hospital Research Institute Compositions and methods for modulating stem cells and uses thereof
WO2010141861A1 (en) 2009-06-05 2010-12-09 Infectious Disease Research Institute Synthetic glucopyranosyl lipid adjuvants
US9480740B2 (en) 2009-06-05 2016-11-01 Infectious Disease Research Institute Synthetic glucopyranosyl lipid adjuvants
US8722064B2 (en) 2009-06-05 2014-05-13 Infectious Disease Research Institute Synthetic glucopyranosyl lipid adjuvants
EP3124491A1 (en) 2009-06-05 2017-02-01 Infectious Disease Research Institute Synthetic glucopyranosyl lipid adjuvants and vaccine compositions containing them
US9814772B2 (en) 2009-06-05 2017-11-14 Infectious Disease Research Institute Synthetic glucopyranosyl lipid adjuvants
WO2010146511A1 (en) 2009-06-17 2010-12-23 Pfizer Limited Treatment of overactive bladder
WO2011007257A1 (en) 2009-07-16 2011-01-20 Novartis Ag Detoxified escherichia coli immunogens
EP2837386A1 (en) 2009-07-16 2015-02-18 Novartis AG Detoxified Escherichia coli immunogens
WO2011038063A1 (en) 2009-09-28 2011-03-31 The Trustees Of The University Of Pennsylvania Method of diagnosing and treating interstitial cystitis
WO2011058302A1 (en) 2009-11-10 2011-05-19 Guy's And St Thomas's Nhs Foundation Trust Bacteremia-associated antigen from staphylococcus aureus
WO2011091272A1 (en) 2010-01-21 2011-07-28 Dana-Farber Cancer Institute, Inc. Context specific genetic screen platform to aid in gene discovery and target validation
WO2011104687A1 (en) 2010-02-24 2011-09-01 Rinat Neuroscience Corporation Antagonist anti-il-7 receptor antibodies and methods
WO2011104632A1 (en) 2010-02-26 2011-09-01 Novartis Ag Immunogenic proteins and compositions
WO2011111007A2 (en) 2010-03-11 2011-09-15 Rinat Neuroscience Corporation ANTIBODIES WITH pH DEPENDENT ANTIGEN BINDING
WO2011121576A2 (en) 2010-04-01 2011-10-06 Novartis Ag Immunogenic proteins and compositions
WO2011133931A1 (en) 2010-04-22 2011-10-27 Genentech, Inc. Use of il-27 antagonists for treating inflammatory bowel disease
WO2012015758A2 (en) 2010-07-30 2012-02-02 Saint Louis University Methods of treating pain
US9539427B2 (en) 2010-11-08 2017-01-10 The Johns Hopkins University Methods for improving heart function
WO2012075243A2 (en) 2010-12-01 2012-06-07 The University Of North Carolina At Chapel Hill Methods and compositions for targeting sites of neovascular growth
WO2012072769A1 (en) 2010-12-01 2012-06-07 Novartis Ag Pneumococcal rrgb epitopes and clade combinations
EP2698635A2 (en) 2010-12-01 2014-02-19 The University Of North Carolina At Chapel Hill Methods and compositions for targeting sites of neovascular growth
EP3026432A2 (en) 2010-12-27 2016-06-01 Brown University Method for predicting patient's response to biglycan treatment
US9044420B2 (en) 2011-04-08 2015-06-02 Immune Design Corp. Immunogenic compositions and methods of using the compositions for inducing humoral and cellular immune responses
WO2013028740A1 (en) 2011-08-22 2013-02-28 Saint Louis University Compositions and methods for treating inflammation
WO2013028527A1 (en) 2011-08-23 2013-02-28 Indiana University Research And Technology Corporation Compositions and methods for treating cancer
WO2013039996A1 (en) 2011-09-13 2013-03-21 Dana-Farber Cancer Institute, Inc. Compositions and methods for brown fat induction and activity using fndc5
WO2013055911A1 (en) 2011-10-14 2013-04-18 Dana-Farber Cancer Institute, Inc. Znf365/zfp365 biomarker predictive of anti-cancer response
WO2013068946A2 (en) 2011-11-11 2013-05-16 Rinat Neuroscience Corp. Antibodies specific for trop-2 and their uses
WO2013093707A1 (en) 2011-12-22 2013-06-27 Rinat Neuroscience Corp. Human growth hormone receptor antagonist antibodies and methods of use thereof
WO2013093693A1 (en) 2011-12-22 2013-06-27 Rinat Neuroscience Corp. Staphylococcus aureus specific antibodies and uses thereof
WO2013119856A1 (en) 2012-02-07 2013-08-15 Infectious Disease Research Institute Improved adjuvant formulations comprising tlr4 agonists and methods of using the same
WO2013164754A2 (en) 2012-05-04 2013-11-07 Pfizer Inc. Prostate-associated antigens and vaccine-based immunotherapy regimens
US9717742B2 (en) 2012-05-07 2017-08-01 The Regents Of The University Of California Oxysterol analogue OXY133 induces osteogenesis and hedgehog signaling and inhibits adipogenesis
US9895435B2 (en) 2012-05-16 2018-02-20 Immune Design Corp. Vaccines for HSV-2
WO2014025767A1 (en) 2012-08-07 2014-02-13 National Cheng Kung University Use of il-20 antagonists for treating liver diseases
WO2014072876A1 (en) 2012-11-09 2014-05-15 Pfizer Inc. Platelet-derived growth factor b specific antibodies and compositions and uses thereof
US9925276B2 (en) 2013-03-14 2018-03-27 Epeius Biotechnologies Corporation Thymidine kinase gene
US9999683B2 (en) 2013-03-14 2018-06-19 Epeius Biotechnologies Corporation Method for identifying and treating a patient having tumor lesions comprising administering a gene therapy retroviral vector particle comprising a mutated HSV-thymidine kinase (HSV-TK) polynucleotide
US10350302B2 (en) 2013-03-14 2019-07-16 Genvivo, Inc. Thymidine kinase diagnostic assay for gene therapy applications
US8957047B2 (en) 2013-04-18 2015-02-17 Immune Design Corp. GLA monotherapy for use in cancer treatment
US8962593B2 (en) 2013-04-18 2015-02-24 Immune Design Corp. GLA monotherapy for use in cancer treatment
US10342815B2 (en) 2013-04-18 2019-07-09 Immune Design Corp. GLA monotherapy for use in cancer treatment
US9683009B2 (en) 2013-05-02 2017-06-20 The Regents Of The University Of California Bone-selective osteogenic oxysterol-bone targeting agents
WO2014181229A2 (en) 2013-05-07 2014-11-13 Rinat Neuroscience Corp. Anti-glucagon receptor antibodies and methods of use thereof
US9463198B2 (en) 2013-06-04 2016-10-11 Infectious Disease Research Institute Compositions and methods for reducing or preventing metastasis
US9730928B2 (en) 2013-06-14 2017-08-15 Univeristy Of Utah Research Foundation Trizol-1-OL analogs anti-retroviral latency drugs
US10144781B2 (en) 2013-08-02 2018-12-04 Pfizer Inc. Anti-CXCR4 antibodies and antibody-drug conjugates
WO2015015401A2 (en) 2013-08-02 2015-02-05 Pfizer Inc. Anti-cxcr4 antibodies and antibody-drug conjugates
US9708405B2 (en) 2013-08-02 2017-07-18 Pfizer Inc. Anti-CXCR4 antibodies and antibody-drug conjugates
WO2015073580A1 (en) 2013-11-13 2015-05-21 Pfizer Inc. Tumor necrosis factor-like ligand 1a specific antibodies and compositions and uses thereof
WO2015087187A1 (en) 2013-12-10 2015-06-18 Rinat Neuroscience Corp. Anti-sclerostin antibodies
WO2015109212A1 (en) 2014-01-17 2015-07-23 Pfizer Inc. Anti-il-2 antibodies and compositions and uses thereof
WO2016040441A1 (en) 2014-09-09 2016-03-17 Unum Therapeutics Chimeric receptors and uses thereof in immune therapy
WO2016092419A1 (en) 2014-12-09 2016-06-16 Rinat Neuroscience Corp. Anti-pd-1 antibodies and methods of use thereof
WO2016144917A1 (en) 2015-03-10 2016-09-15 University Of Massachusetts Targeting gdf6 and bmp signaling for anti-melanoma therapy
WO2016166629A1 (en) 2015-04-13 2016-10-20 Pfizer Inc. Therapeutic antibodies and their uses
WO2017015431A1 (en) 2015-07-21 2017-01-26 Dyax Corp. A monoclonal antibody inhibitor of factor xiia
WO2017029583A2 (en) 2015-08-19 2017-02-23 Pfizer Inc. Tissue factor pathway inhibitor antibodies and uses thereof
WO2017049011A1 (en) 2015-09-15 2017-03-23 Scholar Rock, Inc. Anti-pro/latent-myostatin antibodies and uses thereof
WO2017066561A2 (en) 2015-10-16 2017-04-20 President And Fellows Of Harvard College Regulatory t cell pd-1 modulation for regulating t cell effector immune responses
WO2017070561A1 (en) 2015-10-23 2017-04-27 Pfizer Inc. Anti-il-2 antibodies and compositions and uses thereof
WO2017075037A1 (en) 2015-10-27 2017-05-04 Scholar Rock, Inc. Primed growth factors and uses thereof
WO2017125831A1 (en) 2016-01-21 2017-07-27 Pfizer Inc. Mono and bispecific antibodies for epidermal growth factor receptor variant iii and cd3 and their uses
WO2017200852A1 (en) 2016-05-16 2017-11-23 Infectious Disease Research Institute Formulation containing tlr agonist and methods of use
WO2017210364A1 (en) 2016-06-01 2017-12-07 Infectious Disease Research Institute Nanoalum particles containing a sizing agent
WO2018080573A1 (en) 2016-10-28 2018-05-03 Massachusetts Institute Of Technology Crispr/cas global regulator screening platform
WO2018148246A1 (en) 2017-02-07 2018-08-16 Massachusetts Institute Of Technology Methods and compositions for rna-guided genetic circuits
WO2018158658A1 (en) 2017-03-03 2018-09-07 Rinat Neuroscience Corp. Anti-gitr antibodies and methods of use thereof
WO2018167621A1 (en) 2017-03-16 2018-09-20 Pfizer Inc. Tyrosine prototrophy
WO2018220584A1 (en) 2017-06-02 2018-12-06 Pfizer Inc. Antibodies specific for flt3 and their uses
WO2018231772A1 (en) 2017-06-13 2018-12-20 Bostongene Corporation Systems and methods for identifying responders and non-responders to immune checkpoint blockade therapy
WO2018231771A1 (en) 2017-06-13 2018-12-20 Bostongene Corporation Systems and methods for generating, visualizing and classifying molecular functional profiles
WO2018231762A1 (en) 2017-06-13 2018-12-20 Bostongene, Corporation Systems and methods for identifying cancer treatments from normalized biomarker scores
WO2019016784A1 (en) 2017-07-21 2019-01-24 Universidade De Coimbra Anti-nucleolin antibody
WO2019070161A2 (en) 2017-10-04 2019-04-11 Opko Pharmaceuticals, Llc Articles and methods directed to personalized therapy of cancer

Also Published As

Publication number Publication date
EP0650370A1 (en) 1995-05-03
EP0650370A4 (en) 1995-11-22
JPH07507689A (en) 1995-08-31

Similar Documents

Publication Publication Date Title
Baum et al. Side effects of retroviral gene transfer into hematopoietic stem cells
Caruso et al. Regression of established macroscopic liver metastases after in situ transduction of a suicide gene
CA2164088C (en) Plasmids suitable for gene therapy
US6071533A (en) Preparation of stable formulations of lipid-nucleic acid complexes for efficient in vivo delivery
EP0689593B1 (en) Inhibition of selected tumor growth with recombinant viral vector
CA2104396C (en) Viral particles having altered host range
US5885808A (en) Adenovirus with modified binding moiety specific for the target cells
KR100445712B1 (en) Virus-mediated dna to increase the transfer constructs and culture media for this purpose
Cole et al. Tumor-targeted, systemic delivery of therapeutic viral vectors using hitchhiking on antigen-specific T cells
US6110490A (en) Liposomal delivery system for biologically active agents
AU676204B2 (en) Gene therapy by retroviral vector with tumor suppressive gene
Roux et al. A versatile and potentially general approach to the targeting of specific cell types by retroviruses: application to the infection of human cells by means of major histocompatibility complex class I and class II antigens by mouse ecotropic murine leukemia virus-derived viruses
US5766902A (en) Transfection process
Salmons et al. Targeting of retroviral vectors for gene therapy
US5861171A (en) Adeno-associated viral (AAV) liposomes and methods related thereto
Chu et al. Toward highly efficient cell-type-specific gene transfer with retroviral vectors displaying single-chain antibodies.
US5922685A (en) IL-12 gene therapy of tumors
US20040265300A1 (en) Chimeric molecules containing a module able to target specific cells and a module regulating the apoptogenic function of the permeability transition pore complex (PTPC)
Zhang et al. Generation of a syngeneic mouse model to study the effects of vascular endothelial growth factor in ovarian carcinoma
KR100947875B1 (en) Compositions And Methods For Identifying Antigens Which Elicit An Immune Response
US6555367B1 (en) Complex of biotinylated viral vector and ligand for targeted gene delivery
JP3941963B2 (en) Retroviral delivery of the full-length first viii factor
Bosch et al. Proliferation induced by keratinocyte growth factor enhances in vivo retroviral-mediated gene transfer to mouse hepatocytes.
JP3222461B2 (en) New protein - polycation conjugates
Han et al. Ligand-directed retroviral targeting of human breast cancer cells

Legal Events

Date Code Title Description
AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE

AK Designated states

Kind code of ref document: A1

Designated state(s): JP

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 1993914334

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1993914334

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1993914334

Country of ref document: EP