Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Patent
1996-03-27
2000-08-01
Burke, Julie
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
536 231, 536 2351, 435 911, C07M 2104
Patent
active
060968788
DESCRIPTION:
BRIEF SUMMARY
This is a 371 national stage filing of International Application No. PCT/JP93/00603, with an international filing data of May 10, 1993, now abandoned.
TECHNICAL FIELD
This invention relates to novel human immunoglobulin V.sub.H gene segments and DNA fragments containing the same. The segments and DNA fragments according to this present invention are useful for producing human antibodies using a mammalian host by a genetic engineering process.
BACKGROUND ART
Immunoglobulins are composed of the L chains and H chains, each of which consists of a variable region (V region) and a constant region (C region) that has a structure common to immunoglobulin molecules. What determines the antigenic specificity of an antibody is the V region. The V region of the H chain is encoded by V, D (diversity) and J (joining) genes (The gene of the H chain is expressed by placing a suffix "H", like "V.sub.H "). One of the important reasons why the V regions of immunoglobulins are highly diverse and can provide antibodies which specifically binds to infinite number of antigens is the rearrangement of V, D and J genes. That is, there are a plurality of V genes, D genes and J genes, respectively and they are randomly combined in somatic cells to form a gene encoding a single mRNA. Since the combination is randomly selected, side variety of immunoglobulin V regions are provided.
On the other hand, antibodies currently employed for therapies of various diseases are those originated from animals other than human, such as mouse. However, if these antibodies are administered to human, since the antibodies are of exogenous origin, an immunological response occurs in the human body to present allergy and to neutralize the antibodies. To overcome this problem, it is desired to use antibodies originated from human for the therapies for human. Further, if a human antibody is industrially produced using human as the host and using a human-originated antigen, a problem of immunological tolerance is brought about, so that this approach employing the known method is very difficult. Thus, the production of human immunoglobulins by a genetic engineering process using an animal as a host is now being developed (for example, Japanese Laid-open PCT Application (Kohyo) No. 4-504365; Proc. Natl. Acad. Sci. USA, Vol. 86, pp.5898-5902, August 1989; Proc. Natl. Acad. Sci. USA, Vol. 87, pp.5109-5113, July 1990; Genomics 8, 742-750 (1991)). However, in the conventional methods in which human immunoglobulin genes are expressed in host animals other than human, there is a problem that the number of human V.sub.H segments provided for the genetic recombination is very small, so that the diversity of the expressed human immunoglobulins is limited. Even if only one V.sub.H segment is recombined, the diversity of the immunoglobulin is assured to some degree because of the combination with D and J genes. However, as mentioned above, since the diversity of immunoglobulins is determined by the rearrangement (random combination) of V gene segments, the more the human V.sub.H segments recombined, the higher the diversity of the immunoglobulins expressed. If the diversity of immunoglobulins is increased, not only antibodies against a number of antigens can be formed, but also the possibility of forming an antibody having a high specificity to a given antigen is promoted. Therefore, it is important for therapies and diagnoses to recombine V.sub.H segments as many as possible.
DISCLOSURE OF THE INVENTION
Accordingly, an object of the present invention is to provide a DNA fragment comprising a plurality of human immunoglobulin V.sub.H segments. Another object of the present invention is to provide a novel human immunoglobulin V.sub.H segments.
The present inventors intensively studied to succeed in determining human immunoglobulin H chain V region gene segments having a size of about 800 kb and in determining DNA sequences of 64 human V.sub.H segments contained therein. This made it possible to provide this DNA fragment of 800 kb and various DNA fragments contain
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"Chromosomal Organiza
Honjo Tasuku
Matsuda Fumihiko
Burke Julie
Japan Tobacco Inc.
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