WO1994016730A1 - Human monoclonal antibodies to cytomegalovirus - Google Patents
Human monoclonal antibodies to cytomegalovirus Download PDFInfo
- Publication number
- WO1994016730A1 WO1994016730A1 PCT/US1994/001068 US9401068W WO9416730A1 WO 1994016730 A1 WO1994016730 A1 WO 1994016730A1 US 9401068 W US9401068 W US 9401068W WO 9416730 A1 WO9416730 A1 WO 9416730A1
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- WIPO (PCT)
- Prior art keywords
- cmv
- antibody
- human
- msl
- sequence
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K39/42—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum viral
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
- C07K16/081—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from DNA viruses
- C07K16/085—Herpetoviridae, e.g. pseudorabies virus, Epstein-Barr virus
- C07K16/089—Cytomegalovirus
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Definitions
- the present invention is related generally to methods and compositions for treating or preventing cytomegalovirus (CMV) infections, such as CMV retinitis and the like. More particularly, the present invention is related to methods and compositions for prophylaxis and therapy of human cytomegalovirus infection, including the use of a human monoclonal antibody that binds and neutralizes human cytomegalovirus.
- CMV cytomegalovirus
- Cytomegalovirus is a widespread herpesvirus in the human population, with between 0.2 and 2.2% of the infant population becoming infected in utero and another 8-60% becoming infected during the first six months of life (Reynolds et al. (1973) New En ⁇ l. J. Med. 289: 1). Although CMV infections are most commonly subclinical, CMV-induced sensorineural hearing loss and fatal cytomegalovirus infections ("cyto gratisic inclusion disease”) are important public health problems.
- CMV Cytomegalovirus
- CMV is also responsible for a great deal of disease among the immunosuppressed, producing general and often severe systemic effects in patients with Acquired Immunodeficiency Syndrome (AIDS) , in organ transplant recipients who have been iatrogenically immunosuppressed, and in bone marrow transplant patients.
- AIDS Acquired Immunodeficiency Syndrome
- organ transplant recipients who have been iatrogenically immunosuppressed, and in bone marrow transplant patients.
- cytomegalovirus infections are a significant human health problem. Therefore, it is desirable to develop therapeutic agents that prevent cytomegalovirus infection and/or inhibit recurrent infectious outbreaks from persistent latent infections, particularly for treating CMV retinitis in human patients.
- CMV viral DNA replication can frequently be inhibited by agents that inhibit virally-encoded DNA polymerase.
- inhibitors of viral DNA polymerase are acyclovir, ganciclovir, citrusine-I, and the acyclic guanosine phosphonate (R,S)-HPMPC (Terry et al. (1988) Antiviral Res. 10: 235; Yamamoto et al. (1989) Antiviral Res. 12: 21).
- R,S acyclic guanosine phosphonate
- these compounds are not completely selective for viral thymidylate synthetases or DNA polymerases and therefore can disadvantageously cause inhibition of host DNA replication at high doses.
- CMV infections such as CMV retinitis
- CMV retinitis can be initially treated with foscarnet and ganciclovir, after a period of time CMV replication and progression of the pathological viral infection recurs.
- Such recurrences and progression of viral pathology may be refractory to further therapy with foscarnet or ganciclovir, and are termed "breakthrough" events.
- foscarnet and ganciclovir therapy of CMV infection e.g., retinitis
- results in fairly short period of antiviral efficacy in one study, the median time from antiviral treatment to disease progression (i.e., breakthrough) was only 56 days for ganciclovir treatment and 59 days for foscarnet treatment (N. En ⁇ l. J. Med. 326: 213 (1992) ) .
- hybridomas and like technology has made it possible today to produce antibodies of desired specificity in . vitro, in large quantities and in invariable quality.
- Such antibodies are typically produced from hybridoma cells, which are obtained by fusing a myeloma cell with a lymphocyte which secretes antibodies of the desired specificity.
- Other expression systems can also be used to express monoclonal antibodies subsequent to the introduction of polynucleotide(s) encoding the monoclonal antibody's light and/or heavy chains.
- Monoclonal antibodies can be obtained by various techniques familiar to those skilled in the art. Briefly, an animal, preferably a human (for producing human monoclonal antibodies having a reduced antigenicity for human therapy) , is immunized with a desired antigen or infected with CMV, and spleen cells are removed and are immortalized, commonly by fusion with a myeloma cell (see, Kohler and Milstein (1976) Eur. J. Immunol. 6,: 511 and Ostberg L and Pursch E (1983)
- Hybridoma 2 361) .
- Alternative methods of immortalization include transformation with Epstein Barr Virus, oncogenes, or retroviruses, or other methods known in the art. Colonies arising from single immortalized cells are screened for production of antibodies of the desired specificity and affinity for the antigen, and yield of the monoclonal antibodies produced by such cells may be enhanced by various techniques, including injection into the peritoneal cavity of a vertebrate host.
- Hybridoma cell lines and methods for producing them, as well as their use for producing antibodies are described in U.S. Patent No. 4,634,664. These hybridoma cell lines are made by fusing a xenogeneic hybridoma cell to a genetically compatible substance producing cell.
- Other references describing monoclonal antibodies include U.S. Patent Nos. 4,574,116; 4,624,921; 4,491,632; 4,618,577; 4,608,377; 4,634,666; and 5,043,281; U.K. Patent Application 2,086,937A; European Patent Application 0,389,983; PCT Patent Application No. WO 91/14703; Maeder et al.
- This invention relates to human monoclonal antibodies effective against cytomegalovirus infection. It relates to the production of human neutralizing monoclonal antibodies to cytomegalovirus, characterized in that the myeloma cell SPAZ-4 is fused either with lymphocytes from human spleens, which already have an immune response to cytomegalovirus and have had secondary stimulation in vitro with a CMV antigen, or with peripheral blood lymphocytes from humans who have an increase in antibodies to cytomegalovirus.
- the desired hybrid is selected, the hybridoma cell line thus prepared, which was filed on October 9, 1985 at the National Collection of Animal Cell Cultures (NACC) under number 85 100 803 is cultured in an in vitro medium, and the monoclonal antibody SDZ MSL 109 is isolated from this medium.
- the monoclonal antibodies are useful in treating immune-suppressed patients, such as newborns and patients having cancer or organ transplants, AIDS, and the like. It is an object of the present invention to provide compositions and compounds, including monoclonal antibodies, that have antiviral activity against cytomegalovirus infection, particularly for treating retinitis produced by infection with human cytomegalovirus (e.g., hCMV) .
- the invention provides human monoclonal anti-CMV antibodies which possess therapeutic efficacy in inhibiting CMV infectivity and/or CMV-related pathology in a human patient.
- a human monoclonal anti-CMV antibody designated SDZ MSL 109 which neutralizes CMV and possesses efficacy for therapy of human CMV infections is provided.
- the invention also provides monoclonal antibodies, such as MSL 109, which bind to the CMV gH surface glycoprotein and inhibit CMV infectivity (e.g., by neutralizing the virus).
- a hybridoma cell line secreting the SDZ MSL 109 antibody is provided and is designated EV 2-7.
- an efficacious dosage of a human monoclonal anti-CMV antibody such as an antibody that binds to the CMV gH glycoprotein external domain, is administered to a human patient infected with CMV, either alone or in combination with at least one other antiviral agent, such as foscarnet and/or ganciclovir.
- the human monoclonal anti-CMV antibody does not elicit a significant antibody response against the human monoclonal anti-CMV antibody.
- the invention relates to a process for the production of human monoclonal antibodies to cytomegalovirus (CMV) , as well as these antibodies themselves and also the stable hybridoma line EV 2-7 used in this process, as well as its production.
- CMV cytomegalovirus
- compositions of therapeutic human anti-CMV monoclonal antibodies for treating hCMV infections in humans comprising a unit dosage of a human monoclonal anti-CMV antibody, or a mixture of therapeutic antibodies and viral inhibitory agents, having the biological activity of inhibiting the propagation of a herpesvirus, such as CMV.
- compositions useful in treating human CMV infections are provided.
- the therapeutic composition comprises a human monoclonal anti-CMV antibody and a non-immunoglobulin antiviral agent, preferably foscarnet, ganciclovir, or both foscarnet and ganciclovir.
- the invention also provides a hybridoma (trio a) designated EV 2-7, which can be cultured under suitable culture conditions and expresses the MSL 109 monoclonal antibody in the culture supernantant.
- FIG. 1 shows a Kaplan-Meier plot of the patient population treated with SDZ MSL 109 in conjunction with either foscarnet or ganciclovir; percentage of patients not progressing in development of CMV retinitis is plotted versus the number of days before detectable progression resumed. Median time to resumption of progression (breakthrough of retinitis) was 202 days.
- naturally-occurring refers to the fact that an object can be found in nature.
- a polypeptide or polynucleotide sequence that is present in an organism (including viruses) that can be isolated from a source in nature and which has not been intentionally modified by man in the laboratory is naturally-occurring.
- substantially pure means an object species is the predominant species present (i.e., on a molar basis it is more abundant than any other individual species in the composition) , and preferably a substantially purified fraction is a composition wherein the object species comprises at least about 50 percent (on a molar basis) of all macromolecular species present. Generally, a substantially pure composition will comprise more than about 80 to 90 percent of all macromolecular species present in the composition. Most preferably, the object species is purified to essential homogeneity (contaminant species cannot be detected in the composition by conventional detection methods) wherein the composition consists essentially of a single macromolecular species.
- immunoglobulin refers to a protein consisting of one or more polypeptides substantially encoded by immunoglobulin genes.
- the recognized immunoglobulin genes include the kappa, lambda, alpha, gamma, delta, epsilon and u constant region genes, as well as the myriad immunoglobulin variable region genes.
- the immunoglobulins may exist in a variety of forms besides antibodies; including, for example, Fv, Fab, and F(ab) 2 , as well as in single chains (e.g.. Huston, et al., Proc. Nat. Acad. Sci. U.S.A..
- antibody refers to an immunoglobulin comprising at least two light polypeptide chains and two heavy polypeptide chains. Each of the heavy and light polypeptide chains contains a variable region (generally the amino terminal portion of the polypeptide chain) which contains a binding domain which interacts with antigen.
- Each of the heavy and light polypeptide chains also comprises a constant region of the polypeptide chains (generally the carboxyl terminal portion) which may mediate the binding of the immunoglobulin to host tissues or factors including various cells of the immune system, some phagocytic cells and the first component (Clq) of the classical complement system.
- the light and heavy polypeptide chains are complete chains each consisting essentially of a variable region and a complete constant region.
- the variable region(s) of the anti-CMV antibodies of the invention can be grafted to constant regions of other isotypes.
- a polynucleotide encoding the variable region of a human anti-CMV heavy chain of the 7I isotype can be grafted to a polynucleotide encoding the constant region of another heavy chain class (or subclass), such as ⁇ , 72, 73, 74, S , e , ⁇ l, ⁇ 2, and ⁇ sec ; a ⁇ constant region can be substituted for a K constant region.
- another heavy chain class or subclass
- one to several amino acid substitutions generally can be made to the amino acid sequence of the heavy chain and/or light chain sequences of the present antibodies without substantially interfering with antigen binding, and in some embodiments without substantially increasing the antigenicity of the antibody when injected into a human patient.
- deletion or addition of one to several amino acids can be made.
- the amino acid substitutions, additions, or deletions are made to constant regions or variable region framework sequences, and less typically to complementarity-determining (CDR) sequences.
- Conservative amino acid substitution is a substitution of an amino acid by a replacement amino acid which has similar characteristics (e.g., those with acidic properties: Asp and Glu) .
- a conservative (or synonymous) amino acid substitution should not substantially change the structural characteristics of the parent sequence (e.g., a replacement amino acid should not tend to break a helix that occurs in the parent sequence, or disrupt other types of secondary structure that characterizes the parent sequence) . Examples of art-recognized polypeptide secondary and tertiary structures are described in Proteins, Structures and Molecular Principles. (1984) Creighton (ed.), W.H. Freeman and Company, New York; Introduction to Protein Structure, (1991) , C.
- single or multiple amino acid substitutions may be made in the naturally-occurring sequence (preferably in the portion of the polypeptide which do not directly contact antigen) .
- Muteins and other analogs generally possess biological activity (i.e., CMV binding and neutralization) .
- the human anti- cytomegalovirus monoclonal antibody SDZ MSL 109 had not been derived or characterized.
- NCACC National Collection of Animal Cell Cultures
- the monoclonal antibodies to CMV are obtained by using the SPAZ-4 cell as the myeloma cell, prepared from drug resistant cell line SP-2 obtainable, e.g., from the NIGMS Human Genetic Mutant Cell Repository Ref. GM35669A (see U.S. DHHS 1982 Catalog of Cell Lines) .
- SPAZ 4 Preparation of SPAZ 4 is summarized as follows.
- the SP-2 cell line is fused with normal human peripheral lymphocytes by conventional techniques. A large number of hybrids are obtained and, after approximately five weeks, clones are selected which show fast growth and no antibody production.
- the lymphocytes stem from human spleens, for example, which have been removed due to traumatic rupture. Single cell suspensions are obtained from these spleens (within 2-4 hours following extirpation) and the lymphocytes are preserved in an appropriate freezing medium at -70°C until fusion. Out of a number of spleens, those which stem from CMV-immune donors are chosen. This takes place by stimulating the cells with CMV- antigen, with subsequent measurement of the thymidine incorporation. Lymphocytes of spleens which are thus pre ⁇ selected are then stimulated in vitro over 7 to 14 days with CMV-antigen, and subsequently fused by known methods with the SPAZ-4 cell.
- the lymphocytes stem from blood samples taken from a human during a cytomegalovirus infection, if possible at the time of a titre increase of the cytomegalovirus antibodies.
- the lymphocytes are isolated from the blood by known methods and fused with SPAZ-4 cells. Hybrid cells were then selected by known methods (e.g. in HAT medium) .
- the cell line obtained is then tested for the production of neutralizing antibodies to CMV. Positive cultures are subcloned and developed by in vitro culture over long periods of time into a stable cell line which produces neutralizing antibodies.
- the stable hybridoma line, called EV 2-7 is thus obtained.
- This cell line was deposited on 9 October 1985 at the National Collection of Animal Cell Cultures (NCACC) under Number 85 100 803.]
- This cell line produces the neutralizing monoclonal antibody SDZ MSL-109, which may be obtained in any quantity, and, after purification by known methods, is available for the therapy and prophylaxis of CMV-infection in humans.
- the antibodies belong to the sub class IgGl and possess a kappa chain as the light chain.
- the antibodies neutralize n vitro a series of tested strains of cytomegalovirus, including 3 laboratory strains (Towne, AD 169, and Davis) , as well as a series of tested fresh clinical isolates.
- the antibodies bind protein A and may thus be purified from the culture supernatants by affinity chromatography on protein A sepharose.
- Polynucleotides of the invention and recombinantly produced human anti-CMV antibodies of the invention may be prepared on the basis of the sequence data provided herein according to methods known in the art and described in Maniatis et al., Molecular Cloning: A Laboratory Manual, 2nd Ed., (1989) , Cold Spring Harbor, N.Y. and Berger and Kimmel, Methods in Enzymology, Volume 152, Guide to Molecular Cloning Techniques (1987), Academic Press, Inc., San Diego, CA, which are incorporated herein by reference.
- Polynucleotides of the invention are preferably formed from synthetic oligonucleotides.
- Such recombinant polynucleotides can be expressed in eukaryotic or prokaryotic host cells according to standard methods known in the art, preferably mammalian cells such as lymphocyte cell lines may be used as host cells.
- mammalian cells such as lymphocyte cell lines may be used as host cells.
- polynucleotide constructs encode a complete human immunoglobulin heavy chain and/or a complete human immunoglobulin light chain having at least the amino acid sequences of SDZ MSL 109 heavy and/or light chain variable regions, respectively.
- Alternative human constant region sequences (heavy and/or light chain) other than those naturally associated with the SDZ MSL 109 immunoglobulin chains may be substituted, including human constant region isotypes; such alternative human constant region sequences can be selected by those of skill in the art from various reference sources, including but not limited to those listed in E.A. Kabat et al. Sequences of Proteins of Immunological Interest (1987) National Institutes of Health, Bethesda, MD. The variable region sequences shown below as Sequence No. 3 and Sequence No. 4 confer CMV-binding upon such antibodies.
- a polynucleotide sequence encoding an immunoglobulin light chain comprising a human light chain constant region with an amino- terminal peptide linkage (i.e., an in-frame fusion) to Sequence No. 4 and a polynucleotide sequence encoding a immunoglobulin heavy chain constant region with an amino-terminal peptide linkage to Sequence No. 3 are expressed and form heavy/light chain di ers and other antibody types.
- other non-immunogenic constant regions may be used (e.g., non-human primate sequences, sequence variants) . Sequence variations which do not substantially reduce the binding activity of the variable domain as compared to native MSL 109 may be made.
- prokaryotes can be used for cloning the DNA sequences encoding a human anti-CMV immunoglobulin chain.
- E. coli is one prokaryotic host particularly useful for cloning the DNA sequences of the present invention.
- oligonucleotides may be synthesized chemically by a variety of methods, including phosphoramidite synthesis.
- the polynucleotide constructs will typically include an expression control sequence operably linked to the coding sequences, including naturally-associated or heterologous promoter regions.
- the expression control sequences will be eukaryotic promoter systems in vectors capable of transforming or transfecting eukaryotic host cells. Once the vector has been incorporated into the appropriate host, the host is maintained under conditions suitable for high level expression of the nucleotide sequences, and the collection and purification of the human anti-CMV immunoglobulins.
- the DNA sequences can be expressed in hosts after the sequences have been operably linked to an expression control sequence (i.e., positioned to ensure the transcription and translation of the structural gene) .
- expression vectors are typically replicable in the host organisms either as episomes or as an integral part of the host chromosomal DNA.
- expression vectors will contain selection markers, e.g. f ampicillin-resistance or hygromycin-resistance, to permit detection of those cells transformed with the desired DNA sequences (s_ee, e.g.. U.S. Patent 4,704,362, which is incorporated herein by reference).
- Microbes, such as yeast may be used for expression.
- Saccharo vces is a preferred yeast host, with suitable vectors having expression control sequences, an origin of replication, termination sequences and the like as desired.
- Typical promoters include 3-phosphoglycerate kinase and other glycolytic enzymes.
- Inducible yeast promoters include, among others, promoters from alcohol dehydrogenase 2, isocytochrome C, and enzymes responsible for maltose and galactose utilization.
- mammalian tissue cell culture may also be used to produce the polypeptides of the present invention (see. Winnacker, "From Genes to Clones," VCH Publishers, N.Y. , N.Y. (1987) , which is incorporated herein by reference) .
- Mammalian cells are actually preferred, because a number of suitable host cell lines capable of secreting intact heterc " ⁇ gous proteins have been developed in the art, and include the CHO cell lines, various COS cell lines, HeLa cells, myeloma cell lines, etc.
- Expression vectors for these cells can include expression control sequences, such as an origin of replication, a promoter, an enhancer (Queen, C.
- Preferred expression control sequences are promoters derived from endogenous genes, cytomegalovirus, SV40, adenovirus, bovine papillomavirus, and the like. See, Co, M. et al. (1992) J. Immunol. 148: 1149, which is incorporated herein by reference.
- the vectors containing the DNA segments of interest can be transferred into the host cell by well-known methods, depending on the type of cellular host. For example, calcium chloride transfection is commonly utilized for prokaryotic cells, whereas calcium phosphate treatment, electroporation, lipofection, biolistics or viral-based transfection may be used for other cellular hosts. Other methods used to transform mammalian cells include the use of Polybrene, protoplast fusion, liposomes, electroporation, and microinjection (see, generally. Sambrook et al., supra).
- glycosylating cell is a cell capable of glycosylating proteins, particularly eukaryotic cells capable of adding an N-linked "core oligosaccharide” containing at least one mannose residue and/or capable of adding an O-linked sugar, to at least one glycosylation site sequence in at least one polypeptide expressed in said cell, particularly a secreted protein.
- a glycosylating cell contains at least one enzymatic activity that catalyzes the attachment of a sugar residue to a glycosylating site sequence in a protein or polypeptide, and the cell actually glycosylates at least one expressed polypeptide.
- mammalian cells are typically glycosylating cells.
- Other eukaryotic cells, such as insect cells and yeast, may be glycosylating cells.
- human anti-CMV immunoglobulins of the invention can be purified according to standard procedures of the art, including HPLC purification, fraction column chromatography, gel electrophoresis and the like (see, generally. Scopes, R. , Protein Purification, Springer-Verlag, N.Y. (1982)). Once purified, partially or to homogeneity as desired, the polypeptides may then be used therapeutically or in developing and performing assay procedures or as commercial laboratory reagents.
- the monoclonal antibodies produced form the hybridoma lines, especially SDZ MSL 109 have only slight or even no immunogenicity in humans and many non-human primates. This could be proved on monkeys, and subsequently in human clinical trials. Because of the great similarity between the immunoglobulins of rhesus monkeys and that of humans, the rhesus monkey is a good animal model.
- the antibodies remain in the blood stream for an extraordinarily long time: the half-life of the SDZ MSL 109 antibody measured in an ELISA test was 18 days ("Sandwich Assay": anti-SDZ MSL 109 idiotype goat immunoglobulin adsorbed onto synthetic material: detection of the bound SDZ MSL 109 antibody with rabbit-anti-SDZ MSL 109 idiotype with anti-rabbit goat-IgG, which is conjugated with horseradish peroxidase) .
- This should correspond in the case of humans to a half-life at least as longs Schoultze, H.E. and J.F. Heremans, Molecular Biology of Human Proteins with Special Reference to Plasma Proteins, Vol. I, Elsevier Publishing Co., New York, page 480 [1966]).
- the monoclonal antibodies according to the invention are therefore suitable for therapeutical application even in the case of chronic illness, or for prophylactic application.
- diseases suitable for treatment or prophylaxis with the monoclonal antibodies are CMV diseases including CMV retinitis and CMV pneumonitis in patients undergoing organ transplants (e.g., kidney, heart or liver) or bone marrow transplants or having AIPS, congenital CMV disease, and the like.
- compositions for therapeutic or prophylactic uses, a sterile composition containing a pharmacologically effective dosage of one or more human monoclonal anti-CMV antibodies is administered to a human patient or veterinary non-human patient for treatment of a cytomegalovirus infection.
- the composition will comprise a human monoclonal anti-CMV antibody that is identical to or substantially similar to SPZ MSL 109.
- SPZ MSL 109 For example, if a human patient is infected with hCMV, it is preferable to administer an effective dose of SPZ MSL 109.
- a pharmaceutically acceptable carrier or excipient is often employed in such sterile compositions.
- Routes of administration are typically intramuscular or intravenous injection, subcutaneous, or transdermal application.
- compositions comprising a human monoclonal anti-CMV antibody of the present invention are useful for topical and parenteral administration, i.e. , subcutaneously, intramuscularly, intraocularly, intravenously, or by iontophoresis (e.g., transdermal) .
- the compositions for parenteral administration will commonly comprise a solution of a human monoclonal anti-CMV antibody or a cocktail thereof dissolved in an acceptable carrier, preferably an aqueous carrier.
- an acceptable carrier preferably an aqueous carrier.
- aqueous carriers can be used, e.g.. water, buffered water, 0.4% saline, 0.3% glycine and the like. These solutions are sterile and generally free of particulate matter.
- compositions may be sterilized by conventional, well known sterilization techniques.
- the compositions may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pH adjusting and buffering agents, toxicity adjusting agents and the like, for example sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate, etc.
- concentration of the human monoclonal anti-CMV antibody(ies) in these formulations can vary widely, i.e. , from less than about 0.01%, usually at least about 0.1% to as much as 5% by weight and will be selected primarily based on fluid volumes, viscosities, etc., in accordance with the particular mode of administration selected.
- a typical pharmaceutical composition for intramuscular injection could be made up to contain 1 ml sterile buffered water, and about 1-50 mg of human monoclonal anti-CMV antibody.
- a typical composition for intravenous in- fusion can be made up to contain 250 ml of sterile Ringer's solution, and about 10-500 mg of human monoclonal anti-CMV antibody.
- Actual methods for preparing parenterally administrable compositions will be known or apparent to those skilled in the art and are described in more detail in, for example, Remington's Pharmaceutical Science. 15th Ed., Mack Publishing Company, Easton, Pennsylvania (1980) , which is incorporated herein by reference.
- a typical pharmaceutical composition for topical application can be made with suitable dermal ointments, creams, lotions, ophthalmic ointments and solutions, respiratory aerosols, and other excipients.
- Excipients should be chemically compatible with the human monoclonal anti-CMV antibody(ies) that are the active ingredient(s) of the preparation, and generally should not increase decomposition, denaturation, or aggregation of active ingredient(s) .
- the human monoclonal anti-CMV antibodies of this invention can be lyophilized for storage and reconstituted in a suitable carrier prior to use. This technique has been shown to be effective with conventional antibodies and art-known lyophilization and reconstitution techniques can be employed. It will be appreciated by those skilled in the art that lyophilization and reconstitution can lead to varying degrees of biological activity loss, and that use levels may have to be adjusted to compensate.
- a preferred composition comprises 20 mg to 200 mg of human monoclonal anti-CMV antibody (e.g., SPZ MSL 109) .
- SPZ MSL 109 will be suspended or dissolved in a sterile buffered aqueous solution, such as a sterile saline solution or the like, prior to infusion into a patient.
- a composition comprising a human monoclonal anti-CMV antibody (e.g; , SPZ MSL 109) is administered to a patient already affected by the particular CMV-related disease (e.g., retinitis) , in an amount sufficient to cure, partially arrest, or detectably slow the progression of the condition and its complications by inhibiting CMV infectivity and infection recrudescence.
- a human monoclonal anti-CMV antibody e.g; SPZ MSL 109
- Amounts effective for this use will depend upon the severity of the condition, the general state of the patient, and the route of administration, and combination with other antiviral drugs, if any, but generally range from about l mg to about 1 g of human anti-CMV antibody per dose, with single dosage units of from 10 mg to 100 mg per patient being more commonly used, and dosage units of from 20 mg to 80 mg per patient being typical.
- a human monoclonal anti-CMV antibody e.g., SPZ MSL 109
- Alternative dosage levels are generally from about 0.25 mg/kg patient bodyweight to approximately 5 mg/kg patient bodyweight, with larger doses occasionally employed.
- multiple dosage administrations are performed as a course of therapy, with a typical administration schedule comprising therapeutically effective dosages administered from about once per day to once per month, with biweekly administrations being typical.
- compositions containing the human monoclonal anti-CMV antibodies or cocktails thereof are administered to a patient not already in a CMV disease state to enhance the patient's resistance or to retard the progression of CMV-related disease (e.g., CMV retinitis).
- CMV-related disease e.g., CMV retinitis
- Such an amount is defined to be a "prophylactically effective dose.”
- the precise amounts again depend upon the patient's state of health and general level of immunity, but generally range from 1 mg to 1 g per dose, especially 10 mg to 100 mg per patient.
- a typical formulation of a human monoclonal anti-CMV antibody used to prevent CMV infection recrudescence, such as SPZ MSL 109 will contain between about 20 and 80 mg of the antibody in a unit dosage form.
- the pharmaceutical formulations should provide a quantity of the human monoclonal anti-CMV antibody (e.g., SPZ MSL 109) of this invention sufficient to effectively treat the patient.
- a human monoclonal anti-CMV antibody e.g., SPZ MSL 109 is administered as the sole active ingredient, or in combination with one or more other active ingredients (e.g., foscarnet, ganciclovir, or CMV inhibitory tail peptide (U.S.S.N. 07/867,831)) .
- a suitable effective dose of the human monoclonal anti-CMV antibody will be in the range of 0.01 to 100 milligram (mg) per kilogram (kg) of body weight of recipient per dose, preferably in the range of 0.1 to 5 mg per kg of body weight per dose.
- the desired dosage is preferably presented in one, two, three, four or more subdoses administered at appropriate intervals throughout the treatment protocol. These subdoses can be administered as unit dosage forms, for example, containing 5 to 200 mg, preferably 20 to 80 mg of active antibody per unit dosage form.
- a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, can be reduced, as a function of the symptoms, to a level at which the improved condition is retained. When the symptoms have been alleviated to the desired level, treatment can cease or be reduced to a prophylactically effective dosage level. Patients can, however, require intermittent treatment on a long-term basis upon any recurrence of the disease symptoms or as a prophylactic measure to prevent disease symptom recurrence.
- the composition used in these therapies can be in a variety of forms. The preferred form depends on the intended mode of administration and therapeutic application. Typically, a sterile solution of a human monoclonal anti-CMV antibody (e.g., SPZ MSL 109) in an aqueous solvent (e.g., saline) will be administered intravenously.
- the human monoclonal anti-CMV antibody is administered to a patient suffering from a CMV infection (e.g., CMV retinitis) , alone or in combination with foscarnet and/or ganciclovir or other anti-CMV agents such as HPMPC, to increase the time period during which progression of the CMV viral pathogenesis is slowed, arrested, or reversed.
- a CMV infection e.g., CMV retinitis
- foscarnet and/or ganciclovir or other anti-CMV agents such as HPMPC
- the parent myeloma cell line, SPAZ-4 is a mouse x human hybridoma. This cell was constructed by fusing the murine hybridoma SP2/0-Agl4 to peripheral blood lymphocytes obtained from a healthy adult human male.
- the SP2/0-Agl4 is isolated as a re-clone of SP2/HL-Ag which was derived from SP2/HLGK; the hybrid between a BALB/c spleen cell with anti- sheep red blood activity to the myeloma cell line P3X63Ag8.
- SP2/0-Agl4 does not synthesize or secrete any immunoglobulin chains, is resistant to 8-azaguanine at 20 ⁇ g/mL and does not survive in hypoxanthine, aminopterin, thymidine (HAT) containing media.
- This cell line is freely available and has the ATCC number CRL1581. The cell line used was obtained from the University of Er Weg, Er Weg, Germany, (Prof, Ober Hausen) .
- the SP2/0-Agl4 cells were fused to human peripheral blood lymphocytes (PBL) isolated from heparinized blood by centrifugation on Ficoll-Plaque (Pharmacia, Uppsala, Sweden) , by the following procedure: after washing in saline, the PBLs were fused to the 8-azaguanine resistant myeloma cell in a proportion of PBL:myeloma of 2:1.
- PBL peripheral blood lymphocytes
- the fusion was performed according to Galfre et al. (1977) Nature 266: 550 using as fusogen a 50% solution of PEG 4,000 (Roth, Düsseldorf, Germany) in serum free Pulbecco's MEM.
- the cells were seeded into flat-bottomed microtiter plates at a concentration equivalent to 10 6 myeloma cells per ml in HAT- containing culture medium.
- the culture medium was Pulbecco's MEM containing 20% heat-inactivated (55°C, 30 min.) fetal bovine serum (FBS) , 10% NCTC-109 and additional amino acids, insulin, pyruvate and oxaloacetic acid. After 4 days the medium was replaced with growth medium containing only HT and after 3 weeks the supernatants were tested by ELISA for the presence of human antibody.
- FBS fetal bovine serum
- Pilutions of supernatants and detergent-lysed cells were incubated in the wells and after washing again, incubated with polyvalent horseradish peroxidase-conjugated rabbit antibodies to mouse (or human) immunoglobulin (Miles-Yeda, Rehovot, Israel) . After incubation and washing, the bound enzyme was detected using 1,2-phenylenediamine dihydrochloride (Fluka, Buchs, Switzerland) . Standards of murine and human immunoglobulin showed this test to be sensitive into the low ng/ml range, but neither murine nor human immunoglobulin chains could be found in the SPAZ-4 materials.
- the SPAZ-4 cell line has been repeatedly shown to be free of mycoplasma contamination and is routinely being maintained in antibiotics-free medium to eliminate the risk of undetected contaminations.
- the immune cell was obtained m . vitro immunization of human spleen cells.
- the spleen was obtained from an otherwise healthy motor vehicle accident victim undergoing surgery at the Landerskrankenhaus (County Hospital) Eisenstadt, Eisenstadt, Austria.
- the spleen was brought to the Sandoz Laboratory in Vienna, Austria, within 4 hours after surgery and a single-cell suspension was cryopreserved in liquid nitrogen until used.
- the cells were shown to be stimulated in vitro by human cytomegalovirus (CMV) antigens.
- CMV antigen for n vitro stimulation was prepared from MRC-5 cells infected with the Towne strain of CMV.
- CPE cytopathic effect
- the cells were scraped into the medium with a rubber-policeman, separated from the medium by centrifugation and washed 3 times in PBS.
- the cells from a 175 cm 2 tissue culture flash were then suspended in 1 ml of 0.1M glycine-NaOH, pH 9.5 and homogenized in a Pounce homogenizer.
- An equal volume of PBS was added and the suspension further homogenized by sonication for 30 seconds.
- Cell debris was removed by low speed centrifugation and the supernatant filtered through a 0.45 ⁇ m filter. The material was heated for 1 hour at 56°C, to inactivate potential residual infectivity, and stored at -70°C until used.
- Human spleen cells (8xl0 7 ) were cultivated in 50 ml RPMI 1640 containing 5% heat inactivated human serum and 2.5 ⁇ g/ml cimetidine.
- the inclusion of cimetidine into the culture medium was based on suggestions in the scientific literature that cimetidine could inhibit the activity of T- suppressor cells, and should therefore be helpful in eliciting in vitro immune responses.
- After 3 days in culture the cells were centrifuged and resuspended in fresh medium containing CMV antigen at a final concentration of 1:100 (virus antigen batch VZ547) . This concentration of antigen had been found to give optimum stimulation in initial screening experiments.
- 2xl0 7 cells were harvested and fused with a similar number of SPAZ-4 cells using 50% PEG4000 as fusogen.
- the fused cells at a concentration of 10 6 cells/ml were seeded into flat-bottomed
- 96-well tissue culture microplates in the same culture medium, as described in Example I. In this case, however, only HT was in the medium and the aminopterin was added in an equal volume of medium after 24 hours.
- supernatants were assayed for human immunoglobulins by an ELISA-assay as described in Example I. Positive wells were then tested for neutralizing antibodies against CMV in a micro-neutralization assay. This test was performed by mixing 50 ⁇ l of the supernatant with 50 ⁇ l of a predetermined dilution of the virus for 1 hour at 37°C.
- the neutralization capacity is highly dependent on the quality of the virus stock (if the virus preparation contains large amounts of non-infectious virus, this will absorb antibody and give a lower neutralization titer) but typically the antibody is able to neutralize the virus when present at a concentration of 100 ng/ml.
- the antibody was identified by a neutralizing test using complement but later studies have shown that there is no requirement for complement for neutralization.
- the hybridoma cell has regularly been grown in bulk culture in a medium composed of Pulbecco's MEM containing 5% heat-inactivated (56°C, 30 min.) fetal bovine serum (FBS) .
- FBS heat-inactivated fetal bovine serum
- proteins e.g. transferrin, albumin and growth factors e.g. insulin.
- Such media offer limited advantages over serum containing media, particularly regarding purification, but they still require validated testing of the proteinaceous raw materials and tests proving that the proteins have been removed from the final product.
- antibody SPZ MSL 109 was primarily identified based on its capacity to neutralize cytomegalovirus activity .in vitro. A reason for using such a laborious method, rather than a simple binding assay, was our experience that antibodies binding strongly to cytomegalovirus infected cell lysates are primarily directed against the capsid protein and do not have any neutralizing capacity. Antibody SPZ MSL 109 has only a weak activity in ELISA tests on cytomegalovirus infected cell lysates.
- the antigen used in such a binding study is prepared essentially as the stimulation antigen preparation described above, except that the antigen preparation is solubilized by a detergent (TRITON X-100) .
- the antigen is adsorbed to an immunoplate and after washing away surplus antigen, dilutions of the antibody are incubated in the wells. After washing bound antibody is indicated by a horseradish peroxidase conjugated goat anti-human immunoglob ⁇ lin reagent.
- the antibody has also been tested on a mock-infected antigen preparation and is completely negative in such a system. Attempts have been made to identify the antigen recognized by antibody SPZ MSL 109.
- Methods used include Western blots under reduced and non-reduced conditions, im unoprecipitation of radiolabelled infected cells and affinity chromatography on columns with coupled antibody. We have been able to identify a 82,000 dalton component by immunoprecipitation from a lysate of 35 S-methionine labelled, CMV-infected MRC-5 fibroblasts. This protein can be identified as the previously described gH glycoprotein of CMV.
- the antibody SPZ MSL 109 is of the IgGl, Kappa type.
- the antibody is of Kappa type is achieved with a slight modification of the immunoglobulin-ELISA described above, by replacing the polyvalent horseradish peroxidase conjugated rabbit antibodies against human immunoglobulin with a reagent specifically identifying Kappa-chain determinants respectively.
- Very reliable reagents able to distinguish such sub-groups are commercially available, e.g. from Tago, Inc., Burlingame, California.
- the determination of the heavy chain subclass is easily achieved by using a panel of murine monoclonal antibodies identifying all four human IgG- subclasses.
- the reagents used are for IgGl: JPC1 (Southern Biotechnology Associates, Birmingham, Alabama), for IgG2: HP6002 and HP6014, for IgG3 : HP6047 and HP6050, for IgG4: H06023 and HP6025 (all from the University of Texas Health Science Center at Houston, Dr. Robert G. Hamilton) .
- the identification is done by adsorbing SDZ MSL 109 to an immunoplate, incubating with a suitable dilution of the anti- subclass monoclonal antibody, and detecting binding with a goat anti-mouse Ig reagent. In such an experimental setting, SDZ MSL 109 gives a strong reaction with the anti-IgGl reagent, but not with any of the others.
- Preparations of SDZ MSL 109 are definitively negative when tested in sensitive ELISA tests for human immunoglobulin heavy chain classes other than IgG (IgM, IgA, IgD, and IgE have been tested) or for ⁇ -chain determinants.
- the pattern on a reduced SDA-PAGE gel shows that both the heavy and light chains appear as narrow, homogenous bands on the high resolution silver stained gels.
- Isoelectric-focusing gels show 4 bands which is well in agreement with a homogenous immunoglobulin product, when one takes into consideration the micro- heterogeneity always seen in antibody preparations. This, taken together with the information on the parent myeloma cell line is proof that this hybridoma cell line has no concurrent production of additional light or heavy chains.
- the monoclonal antibody SDZ MSL 109 is produced in cell culture from a hybridoma cell line in the absence of serum. This means that we have a need to remove from the final product only components from the cellular material. As SDZ MSL 109 is a human monoclonal antibody, which is not in itself expected to be immunogenic, it becomes very important to remove all potentially immunogenic components. The goal of the purification procedures is a final product that is more than 99.9% pure.
- the supernatant is filtered through a polyvinylidene difluoride 0.65 ⁇ m Prostack/filter (Millipore) , immediately after removal from the harvest tank.
- This type of filter unit works in a tangential flow mode which allows filtration of large amount of particulate material without clogging the filter.
- the cleared medium is collected into a refrigerated stainless steel tank.
- the conditioned medium is concentrated using a nominal 30,000 dalton polysulfone spiral wound membrane supplied by Millipore Corporation. After concentration, the pH is set to 7.0 using 1M acetic acid.
- the material is sterile filtered through a Sartobran-PH 0.8/0.2 ⁇ m (Sartorius) filter (the 0.8 ⁇ m component is polyester, the 0.2 ⁇ m component is cellulose acetate) before being stored at 4°C.
- the material is microfiltered (0.22 ⁇ m, Millipore) and filled into polypropylene shipment vessels.
- the purification step utilizes the high affinity of the human IgGl antibody to Staphylococcus Aureus Protein A.
- the Protein A is purchased already coupled covalently by an amide bond to agarose.
- the column with its contents and attached tubing is sanitized by treatment with 70% ethanol in water for 24 hours (this may be changed to a 1.0N NaOH sanitization) .
- the column is then equilibrated with PBS, pH 7.0. This treatment does not in any way damage the Protein A or the agarose particles.
- Performing the affinity chromatography separation on the Protein A column involves the following sequential steps: A/Loading.
- the concentrated conditioned medium is loaded on the column with a pump.
- the effluent from the column is collected and monitored for the presence of antibody by the human immunoglobulin ELISA.
- the column is loaded to such a degree that a measurable amount of antibody-containing fluid passes through the column. This allows a maximum utilization of the column material.
- the overload fraction is separately recovered and recycled if it contains more than 20 mg/ l of SDZ MSL 109.
- B/Washing To remove unbound materials the column is extensively washed with phosphate buffered saline, pH 7 with sodium chloride added to a final concentration of 0.5M. This wash is followed by a second washing step using a buffer of 0.02M sodium citrate, pH 5.6, containing 0.5M sodium chloride. This wash releases small amounts of the human antibody.
- the bound monoclonal antibodies are eluted from the column using a buffer composed of a 0.02M sodium citrate, pH 3.0, containing 0.5M sodium chloride.
- the eluted material is continuously diluted into a volume of 1M Tris-HCl, pH 8.0 to rapidly restore near-neutral conditions.
- the Protein A purification is performed in a closed system utilizing a Waters 650 Protein Purification System which consists of the following equipment.
- the system is controlled by the Waters 600E System Controller.
- the pumping system consists of two 400 ⁇ l pump heads for flow rates up to 80 ml/min.
- the absorbance is monitored by a Waters 440 Absorbance Detector.
- An ISCO Model 2150 Peak Separator with Threshold can be used to detect and isolate peaks using a 6 port pneumatic valve for diversion of the fluid stream, alternately the separations can be performed by time based valve switching, controlled by the 600E Controller.
- the pH is monitored utilizing an in-line probe and a JENCO Model 6071 pH meter.
- the Protein A is packed in a Pharmacia BPG 100/500 Bioprocess column. All buffer changes, and redirectioning of the effluent from waste pool to wash pools and elution pool is controlled by solenoid valves.
- the gel is packed between two adjustable adaptors which allows the column to be used without any mixing volume on top of the gel. This means that the buffer changes occur very abruptly and with a minimal mixing between different buffers.
- the performance of the column is monitored by an UV-monitor directly in the effluent from the column.
- the column should be able to bind at least 10 mg of SDZ MSL 109 per ml of gel.
- the eluate from the Protein A column is concentrated to at least 5 mg/ml SDZ MSL 109 using the same type of Pyrosart unit described above.
- the concentrate is sterile filtered through a 0.2 ⁇ M filter (Nalgene or Corning) and the sterile concentrate is stored at 4°C until sufficient materials have been collected for the next purification step.
- the antibody preparation is run on a Sephacryl S-300
- this step is not principally additional purification, but buffer change.
- buffer change After the elution of the Protein A column the antibodies are in a complex, hypertonic buffer composed of sodium citrate, sodium chloride and Tris-HCl. This buffer mixture cannot be used directly as a vehicle for an intravenous injection.
- the buffer after this step is suitable both for intravenous injection and for long term refrigerated storage.
- the column was packed according to the manufacturer's suggestions. After decanting the 20% ethanol solution the gel is delivered in, 100 m of gel was suspended in 200 ml of Lactated Ringer's solution. The slurry is poured into a Pharmacia K50/30 column, and when the gel has packed itself to a constant volume, it is sanitized with 1 column volume of 0.5N sodium hydroxide, followed by 3 column volumes of Pulbecco's PBS, followed by 5 column volumes of Lactated Ringer's solution. Immediately prior to use the column was washed with an additional 5 column volumes of Lactated Ringer's solution. The sample is then passed through the column and the pass- through is collected in a sterile container. I will be understood that this purification scheme is given by way of example only, and many other purification methods well-known to those skilled in the art may be employed instead.
- SPZ MSL 109 was sequenced using standard techniques as follows: To sequence the PNA, a cPNA library was prepared, using standard methodology, from hybridoma mRNA, in phage ⁇ ZAP (Stratagene, Inc.) The cPNA library was screened with an isolated human kappa constant region, or a human IgGl constant region, probes. PNA fragments of an appropriate size were selected from Bam Hl-digested cPNA on an agarose gel and cloned into bacteriophage lambda EMBL4.
- Phage plaques were screened with the respective probes, and positive clones were cloned into bacteriophage M13mpl8 for nucleotide sequencing. Sequencing was done according to Maniatis et al. (Maniatis, T., Fritsch, E.F., and Sambrook, J. , Molecular Cloning: A
- MSL 109 are given below as Sequence No. 1 and Sequence No. 2, respectively.
- the peptide sequences for the mature V H and V L regions are given (infra) as Sequence No. 3 and Sequence No. 4, respectively.
- sequences and other published immunoglobulin sequences and cloned immunoglobulin encoding sequences a wide variety of human sequence antibodies comprising a heavy chain having a variable region consisting essentially of Sequence No. 3, and comprising a light chain having a variable region consisting essentially of Sequence No. 4.
- from one to several amino acid substitutions, deletions, or additions may be made to Sequence No. 3 and/or Sequence No. 4, so long as the property of CMV binding and neutralization is substantially retained; such changes are usually conservative substitutions and are preferably minimal sequence alterations.
- SPZ MSL 109 Seventeen male AIPS patients with a median age of 44 years of age diagnosed with CMV retinitis were selected for experimental administration of the human monoclonal anti-CMV antibody, SPZ MSL 109, for determining pharmacokinetics and tolerance to the antibody.
- PHPG or foscarnet was administered to each patient for initial treatment of their CMV retinitis.
- SPZ MSL 109 was administered to each patient every two weeks for a total of up to 16 weeks (8 administrations) as an intravenous infusion.
- Posages of SPZ MSL 109 for each administration were either 0.25 mg/kg per dose, 1 mg/kg per dose, 2 mg/kg per dose, 5 mg/kg per dose, 20 mg fixed dose, or 80 mg fixed dose, and were consistent for each patient.
- MOLECULE TYPE DNA (genomic)
- MOLECULE TYPE DNA (genomic)
- ORIGINAL SOURCE
- Ser Ser Ser lie Asn Ser Asp Ser Thr Tyr Lys Tyr Tyr Ala Asp Ser Val 50 55 60
- Glu Pro Ala Ser lie Ser Cys Arg Ser Ser Gin Ser Leu Leu His Thr 20 25 30
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Abstract
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Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU61677/94A AU695584B2 (en) | 1993-01-28 | 1994-01-28 | Human monoclonal antibodies to cytomegalovirus |
EP94908670A EP0683675A4 (en) | 1993-01-28 | 1994-01-28 | Human monoclonal antibodies to cytomegalovirus. |
JP6517375A JPH08506325A (en) | 1993-01-28 | 1994-01-28 | Human monoclonal antibody against cytomegalovirus |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US1022893A | 1993-01-28 | 1993-01-28 | |
US08/010,228 | 1993-01-28 | ||
US7380893A | 1993-06-09 | 1993-06-09 | |
US08/073,808 | 1993-06-09 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1994016730A1 true WO1994016730A1 (en) | 1994-08-04 |
Family
ID=26680936
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1994/001068 WO1994016730A1 (en) | 1993-01-28 | 1994-01-28 | Human monoclonal antibodies to cytomegalovirus |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP0683675A4 (en) |
JP (1) | JPH08506325A (en) |
AU (1) | AU695584B2 (en) |
CA (1) | CA2153790A1 (en) |
WO (1) | WO1994016730A1 (en) |
Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5750106A (en) * | 1993-01-28 | 1998-05-12 | Novartis Ag | Human monoclonal antibodies to cytomegalovirus |
WO2001082965A1 (en) * | 2000-05-03 | 2001-11-08 | Medimmune, Inc. | Combination therapy of respiratory diseases using antibodies |
WO2007094423A1 (en) * | 2006-02-15 | 2007-08-23 | Evec Incorporated | Human monoclonal antibody capable of binding to human cytomegalovirus, and antigen-binding domain of the antibody |
WO2009003975A1 (en) | 2007-07-04 | 2009-01-08 | Ribovax Biotechnologies Sa | Antibodies against human cytomegalovirus (hcmv) |
US7947274B2 (en) | 2007-01-04 | 2011-05-24 | Humabs, LLC. | Human cytomegalovirus neutralising antibodies and use thereof |
US7955599B2 (en) | 2007-01-04 | 2011-06-07 | Humabs, LLC | Human cytomegalovirus neutralizing antibodies and use thereof |
US8124093B2 (en) | 2008-07-16 | 2012-02-28 | Institute For Research In Biomedicine | Human cytomegalovirus neutralizing antibodies and use thereof |
AU2009259923B2 (en) * | 2008-06-20 | 2015-09-03 | Duke University | Compositions, methods and kits for eliciting an immune response |
CN104945505A (en) * | 2010-09-29 | 2015-09-30 | 弗·哈夫曼-拉罗切有限公司 | Antibody compositions and methods of use |
WO2019121906A1 (en) | 2017-12-19 | 2019-06-27 | F-Star Beta Limited | Specific pd-l1 binding sequences inserted in a ch3 domain |
WO2020011964A1 (en) | 2018-07-12 | 2020-01-16 | F-Star Beta Limited | Antibody molecules that bind pd-l1 and cd137 |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR101390015B1 (en) | 2009-04-01 | 2014-04-29 | 에베크 인코포레이티드 | Monoclonal antibody capable of binding to specific discontinuous epitope occurring in ad1 region of human cytomegalovirus gb glycoprotein, and antigen-binding fragment thereof |
-
1994
- 1994-01-28 WO PCT/US1994/001068 patent/WO1994016730A1/en not_active Application Discontinuation
- 1994-01-28 AU AU61677/94A patent/AU695584B2/en not_active Ceased
- 1994-01-28 CA CA002153790A patent/CA2153790A1/en not_active Abandoned
- 1994-01-28 JP JP6517375A patent/JPH08506325A/en active Pending
- 1994-01-28 EP EP94908670A patent/EP0683675A4/en not_active Withdrawn
Non-Patent Citations (6)
Title |
---|
Annals of Internal Medicine, Vol. 103, No. 6, Part 1, issued December 1985, SINGER et al., "Foscarnet for Cytomegalovirus Retinitis", page 962, see entire document. * |
Hybridoma, Vol. 6, No. 2, issued 1987, EHRLICH et al., "Rhesus Monkey Responses to Multiple Injections of Human Monoclonal Antibodies", pages 151-160, see entire document. * |
International Conference on Aids, Vol. 9, No. 1, issued 6-11 June 1993, TOLPIN et al., "Combination Therapy of Cytomegalovirus (CMV) Retinitis with a Human Monoclonal Anti-CMV Antibody (SDZ MSL 109) and either Ganciclovir (DHPG) or Foscarnet (PFA)", page 54, Abstract No. WS-B11-2, see Abstract. * |
Journal of Infectious Diseases, Vol. 163, issued 1991, AULITZKY et al., "Human Monoclonal Antibodies Neutralizing Cytomegalovirus (CMV) for Prophylaxis of CMV Disease: Report of a Phase I Trial in Bone Marrow Transplant Recipients", pages 1344-1347, see entire document. * |
See also references of EP0683675A4 * |
Transplantation, Vol. 51, No. 6, issued June 1991, DROBYSKI et al., "Phase I Study of Safety and Pharmacokinetics of a Human Anticytomegalovirus Monoclonal Antibody in Allogeneic Bone Marrow Transplant Recipients", pages 1190-1196, see entire document. * |
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US5750106A (en) * | 1993-01-28 | 1998-05-12 | Novartis Ag | Human monoclonal antibodies to cytomegalovirus |
WO2001082965A1 (en) * | 2000-05-03 | 2001-11-08 | Medimmune, Inc. | Combination therapy of respiratory diseases using antibodies |
AU2001259379B2 (en) * | 2000-05-03 | 2006-08-03 | Medimmune, Llc | Combination therapy of respiratory diseases using antibodies |
WO2007094423A1 (en) * | 2006-02-15 | 2007-08-23 | Evec Incorporated | Human monoclonal antibody capable of binding to human cytomegalovirus, and antigen-binding domain of the antibody |
US9149524B2 (en) | 2007-01-04 | 2015-10-06 | Institute For Research In Biomedicine | Human cytomegalovirus neutralising antibodies and use thereof |
US8545848B2 (en) | 2007-01-04 | 2013-10-01 | Institute For Research In Biomedicine | Human cytomegalovirus neutralising antibodies and use thereof |
US7955599B2 (en) | 2007-01-04 | 2011-06-07 | Humabs, LLC | Human cytomegalovirus neutralizing antibodies and use thereof |
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US7947274B2 (en) | 2007-01-04 | 2011-05-24 | Humabs, LLC. | Human cytomegalovirus neutralising antibodies and use thereof |
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US9217028B2 (en) | 2007-01-04 | 2015-12-22 | Institute For Research In Biomedicine | Human cytomegalovirus neutralising antibodies and use thereof |
US8309089B2 (en) | 2007-01-04 | 2012-11-13 | Institute For Research In Biomedicine | Human cytomegalovirus neutralising antibodies and use thereof |
US8202518B2 (en) | 2007-07-04 | 2012-06-19 | Ribovax Biotechnologies S.A. | Antibodies against human cytomegalovirus (HCMV) |
WO2009003975A1 (en) | 2007-07-04 | 2009-01-08 | Ribovax Biotechnologies Sa | Antibodies against human cytomegalovirus (hcmv) |
US10632190B2 (en) | 2008-06-20 | 2020-04-28 | Duke University | Compositions, methods and kits for eliciting an immune response |
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US11351248B2 (en) | 2008-06-20 | 2022-06-07 | Duke University | Compositions, methods and kits for eliciting an immune response |
AU2009259923B2 (en) * | 2008-06-20 | 2015-09-03 | Duke University | Compositions, methods and kits for eliciting an immune response |
US9725502B2 (en) | 2008-07-16 | 2017-08-08 | Institute For Research In Biomedicine | Human cytomegalovirus neutralizing antibodies and use thereof |
US9796771B2 (en) | 2008-07-16 | 2017-10-24 | Institute For Research In Biomedicine | Human cytomegalovirus neutralizing antibodies and use thereof |
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Also Published As
Publication number | Publication date |
---|---|
JPH08506325A (en) | 1996-07-09 |
AU6167794A (en) | 1994-08-15 |
EP0683675A4 (en) | 1997-05-21 |
AU695584B2 (en) | 1998-08-20 |
EP0683675A1 (en) | 1995-11-29 |
CA2153790A1 (en) | 1994-08-04 |
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