Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Reexamination Certificate
1997-04-17
2004-06-08
Zeman, Mary K. (Department: 1631)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
C424S147100, C424S149100, C435S005000, C435S007100, C435S069100, C530S350000, C530S380000, C530S387100
Reexamination Certificate
active
06747136
ABSTRACT:
TECHNICAL FIELD
The present invention relates to compositions derived from immunoglobulin molecules specific for the hepatitis C virus (HCV). More particularly, the invention is related to recombinant human monoclonal antibodies which are capable of specifically binding with HCV E2 antigen.
BACKGROUND
Hepatitis C virus (HCV) infection occurs throughout the world and is the major cause of transfusion-associated hepatitis. There are an estimated 150,000 new cases of HCV infection each year in the United States. The seroprevalence of anti-HCV antibodies in blood donors from around the world has been shown to vary between 0.02 and 1.23%, with rates in some countries as high as about 19%. In addition to being the predominate cause of transfusion-induced hepatitis, HCV is also a common cause of hepatitis in individuals exposed to blood or blood products. Thus, recipients of blood or blood products, intravenous drug users, renal dialysis patients and needle-stick victims represent high-risk groups for HCV infection. Alter et al. (1993)
Infect Agents Dis
2:155-166. Further, heterosexual transmission of HCV across the urogenital tract, and mother-to-baby transmission, has been well documented. Ohto et al. (1994)
N Engl J Med
330:744-750. Other risk factors associated with HCV infection include familial or household contact with an HCV-infected individual and health-care employment with occupational exposure to blood and hemodialysis. Alter et al. (1990)
JAMA
264:2231-2235. Chronic hepatitis develops in approximately 62% of infections. Alter et al. (1992)
N Engl J Med
327:1899-1905.
Most of the serious liver disease associated with HCV results from the high propensity of the agent to cause chronic, persistent infection. Cirrhosis occurs in approximately 20% of chronic cases, of which 20 to 25% will result in liver failure. Another serious sequela associated with HCV infection is primary hepatocellular carcinoma.
The viral genomic sequence of HCV is known, as are methods for obtaining the sequence. See, e.g., International Publication Nos. WO 89/04669; WO 90/11089; and WO 90/14436. HCV has a 9.5 kb positive-sense, single-stranded RNA genome and is a member of the Flaviridae family of viruses. Currently, there are 6 distinct, but related genotypes of HCV which have been identified based on phylogenetic analyses (Simmonds et al.,
J. Gen. Virol
. (1993) 74:2391-2399). The virus encodes a single polypeptide having more than 3000 amino acid residues (Choo et al. (1989)
Science
244:359-362; Choo et al. (1991)
Proc. Natl. Acad. Sci. USA
88:2451-2455; Han et al. (1991)
Proc. Natl. Acad. Sci. USA
88:1711-1715). The polypeptide is processed co- and post-translationally into both structural and non-structural (NS) proteins.
In particular, there are three putative HCV structural proteins, consisting of the N-terminal nucleocapsid protein (termed “core”) and two envelope glycoproteins, “E1” (also known as E) and “E2” (also known as E2/NS1). (See, Houghton et al. (1991)
Hepatology
14:381-388, for a discussion of HCV proteins, including E1 and E2.) E1 is detected as a 32-35 kDa species and is converted into a single endo H-sensitive band of approximately 18 Kda. By contrast, E2 displays a complex pattern upon immunoprecipitation consistent with the generation of multiple species (Grakoui et al. (1993)
J. Virol.
67:1385-1395; Tomei et al. (1993)
J. Virol.
67:4017-4026). The HCV envelope glycoproteins E1 and E2 form a stable complex that is coimmunoprecipitable (Grakoui et al. (1993)
J. Virol.
67:1385-1395; Lanford et al. (1993)
Virology
197:225-235; Ralston et al. (1993)
J. Virol.
67:6753-6761).
The only currently available treatment for chronic hepatitis C infection consists of &agr;-interferon (&agr;-IFN) therapy. However, long-term response to interferon therapy only occurs in 10% to 30% of treated individuals, and there is evidence that the different HCV strains vary greatly in their responsiveness to interferon therapy, with the type 1 viruses being the most refractive. Furthermore, flu-like side effects are commonly encountered with interferon therapy (occurring in approximately 60% to 80% of treated individuals), as well as other less common side effects such as nausea, depression, fatigue and thrombocytopenia. Interferon therapy is also not indicated for immunocompromised individuals. Accordingly, there exists a need for more effective therapeutic approaches in the treatment of chronic HCV infection. In this regard, some effect has been seen using ribivirin, or combination therapies with ursodiol and &agr;-IFN.
In particular, the HCV E1 and E2 proteins are of considerable interest because recombinant vaccines based on those molecules have been shown to be protective against experimental challenge with HCV in primate studies. (Choo et al. (1994)
Proc. Natl. Acad. Sci. USA
91:1294-1298). Hyperimmune globulin compositions of anti-HCV antibody molecules obtained from donor samples have been described for the treatment of HCV in infected individuals, and in the prevention of HCV infection in high-risk groups. European Patent Application Publication No. 447,984, published Sep. 25, 1991. Since these compositions are made from donor blood products, an inherent risk is associated with their use due to the possible presence of infectious against such as the Human Immunodeficiency Virus (HIV) and HCV. Accordingly, hyperimmune globulin preparations must be carefully screened, and all infectious agents inactivated prior to administration to human subjects.
It is known that the immune response to HCV in normal individuals includes both humoral and cell mediated components. Koziel et al. (1993)
J Virol
67:7522-7532, Alter et al. (1989)
N Engl J Med
321:1494-1500. Further, several reports have indicated that antibodies elicited to HCV may neutralize the infectivity of the virus. Shimizu et al. (1994)
J Virol
68:1494-1500, Farci et al. (1994)
Proc Natl Acad Sci USA
91:7792-7796. Such results provide hope that an effective antibody-based therapy can be developed. In this regard, the administration of a highly-reactive, neutralizing anti-HCV antibody preparation to an individual who is at risk of infection, or who has been recently exposed to the agent will provide immediate passive immunity to the individual. Such passive immunizations would likewise be expected to be successful in both normal and immunocompromised subjects. Preferably, the neutralizing antibodies would be broadly cross-reactive against different HCV strains, and would be monoclonal in order to control the effects of the use of the antibodies in vivo.
For a number of practical and economic reasons, murine monoclonal antibodies have been generally used in research and medicine. Murine antibodies can be raised against a wide variety of molecules, such as HCV antigens, and fused with a myeloma cell to yield hybridomas which can be grown in culture to produce monoclonal antibodies toward HCV antigens. Kohler et al. (1975)
Nature
256:495-497. Although such monoclonal antibodies may have antigen binding specificities of significant therapeutic value, the use of such murine antibodies in the treatment of human disease has been limited since those molecules are immunogenic to the human immune system. Thus, murine monoclonals have been most commonly used in immunodiagnostics. In this regard, murine monoclonal antibodies to putative HCV E2 envelope polypeptides have been described for use in the detection of HCV in biological samples. U.S. Pat. No. 5,308,750 to Mehta et al.
Accordingly, there remains a need in the art to provide human monoclonal antibodies toward HCV E2 antigen, wherein the monoclonals are broadly cross-reactive with heterologous HCV isolates.
SUMMARY OF THE INVENTION
The present invention is based on the discovery of human monoclonal antibody molecules which exhibit immunological binding affinity for HCV E2 polypeptide antigen, and which are cross-reactive against different HCV strains. The monoclonal antibody molecules were obtained from a combinatorial library that was constructed from a nonimmuni
Allander Tobias Erik
Persson Mats Axel Atterdag
Clow Lori A.
Karolinska Innovations AB
Robins & Pasternak LLP
Zeman Mary K.
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