Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Recombinant dna technique included in method of making a...
Patent
1995-09-11
2000-09-05
Stucker, Jeffrey
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Recombinant dna technique included in method of making a...
435 691, 435 696, 4241301, 4241371, 4241391, 4241411, 4241471, 4241601, C12N 1509, C12P 2104, C12P 1100, A61K 39395
Patent
active
061141437
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to an immunological technique which provides a novel substance useful for prevention, treatment, diagnosis of viral infection, and for study of biochemistry and histology. More particularly, it relates to a monoclonal antibody having a broad neutralization spectrum against human immunodeficiency virus (HIV), a causative virus of acquired immunodeficiency syndrome (AIDS), a hybridoma secreting said antibody and a process for preparing the same.
The present invention further relates to a humanized recombinant monoclonal antibody for clinical application.
BACKGROUND ART
Human immunodeficiency virus (HIV) is a human retrovirus which causes a series of diseases such as acquired immunodeficiency syndrome (AIDS) and AIDS related complexes (ARC). Today, these diseases have become a serious problem in the world, but no vaccines or established therapies effective for these diseases have been provided.
As an anti-viral agent against HIV, reverse transcriptase inhibitors of nucleic acid analogues such as 3'-azido-2', 3'-dideoxythymidin (AZT) or 2',3'-dideoxyinosin (ddI) have been used, and thereby therapeutic efficacy such as inhibition of viral growth, increase in the number of CD4-positive cells and prolongation of life span has been observed. However, in most cases, therapeutic efficacy of these drugs to AIDS is partial or temporal, and in addition, these drugs exhibit toxicity or growth inhibition to hematopoietic cells, and thereby inhibit reconstruction of an immune system which has become deficient. From these points of view, development of more effective anti-HIV agents has been desired.
An antibody is an important protein which plays a role in an immune reaction in mammals including humans and has a function to neutralize and remove foreign substances invaded from outside or substances recognized as foreign substances by the living body. In this respect, an antibody is expected to be useful for treatment of infectious diseases.
Karpas et al. observed remission of clinical symptoms after administration of anti-HIV antibodies derived from healthy patients infected with HIV to AIDS patients (Proc. Natl. Acad. Sci. USA, 85, p.9234 (1989), Proc. Natl. Acad. Sci. USA, 87, p. 7613 (1990)). Jackson et al. also obtained similar results (Lancet, 2, p. 647 (1988)). These results show usefulness of an antibody therapy in AIDS.
Apart from such passive immunotherapy, an active immunization of patients with a component vaccine of HIV has also been attempted in order to enhance immune capacity (AIDS Res. Hum. Retroviruses, 8, P1051 (1992)). This treatment was found to be effective to patients who have not yet developed symptoms, but did not show significant effect in patients who developed AIDS with a decreased number of CD4-positive cells since they are deficient in active immune response. Accordingly, in case of those patients whose disease has progressed, one cannot but rely on passive immunotherapy, and hence, a neutralizing antibody has a great significance.
Epitopes recognized by an antibody neutralizing HIV are located in a glycoprotein antigen having a molecular weight of about 1.2.times.10.sup.5 daltons (gp120) present on a coating membrane of HIV, a transmembrane glycoprotein antigen having a molecular weight of about 4.1.times.10.sup.4 daltons (gp41) and a nuclear protein antigen having a molecular weight of about 1.7.times.10.sup.4 daltons (p17). Among these epitopes, that located in the third variable region (V3) of gp120(amino acid number 303-338), which is also referred to as Principal Neutralization Determinant (PND), can induce a potent neutralizing antibody, and hence, is a major target in developing medicaments or vaccines.
Although a correct role of PND region in viral infection remains still unknown, it is assumed to help invasion of viruses after binding between gp120 and CD4. PND region also plays an important role in formation of multinuclear giant cells by CD4-positive cells. Accordingly, if an antibody which binds to this region and inhibits infectio
REFERENCES:
Matsushita, et al. : Characterization of a mouse/human . . . : AIDS Res. Hum. Retro.: v. 8, No. 6: pp. 1107-1115, 1992.
Ohno, et al. : A broadly neutalizing monoclonal . . . : Proc. Natl. Acad. Sci. : V. 88: pp. 10726-10729, 1991.
Scott, et al. : Human monoclonal antibody that recognizes . . . : Proc. Natl. Acad. Sci. : V. 8: pp. 8597-8601, 1990.
Eda Yasuyuki
Higuchi Hirofumi
Kimachi Kazuhiko
Maeda Hiroaki
Makizumi Keiichi
Juridical Foundation The Chemo-Sero-Therapeutic Research Institu
Nelson Brett
Stucker Jeffrey
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