Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1999-04-01
2001-05-01
Huff, Sheela (Department: 1642)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C424S130100
Reexamination Certificate
active
06225286
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a cell surface protein expressed on human cortical thymocytes and its use. More particulary, the present invention relates to a novel protein (called “JL1” hereinafter) having molecular weight of about 120,000 dalton expressed exclusively on cortical thymocytes and on malignant cells of T lymphoblastic leukemia, T lymphoblastic lymphoma originated from cortical thymocytes and about 50% of all kinds of leukemia, which are identified by immunohistochemical and flow cytometric analysis, and to its diagnostic an clinical application on leukemia and T lymphoblastic lymphoma.
2. Description of Related Art
Human body shows the specific responses to foreign substances exposed after birth, and T. and B. lymphocytes and antigen presenting cells are involved in immune responses to protect human body, Lymphocytes are the major components of lymphoid organ cells and have an important role in the specific immune response during circulation through blood and lymph. The major role of B-lymphocytes is to produce antibodies against foreign substances. T lymphocytes are classified into two types, one of which has the function to help the specific immune response and the other has the function of killing cells infected by pathogens. And the role of antigen presenting cells is to engulf infecting antigens non-specifically, and to process them by cleaving into small peptides and provide their information to T lymphocytes.
Intrathymic T cell development entails complex series of proliferation, differentiation, and selection stages. T cells are originated from hematopoietic stem cells produced in embryonic liver and postnatal bone marrow. They move into thymus, differentiates, become mature, and after this, move out through blood vessel and become mature T cells. After rearrangement of T cell receptor germline gene in the thymus, thymocytes express T cell receptor complexes on their cell surfaces. The gene rearrangement process requires enzymatic system including RAG-1RAG-2. As a result, extreme T cell receptor diversity can be produced in the course of this complicated process. However, all the T cell receptors produced cannot carry out their appropriated functions in the periphery. The cells which cannot recognize the antigens provided by major histocompatibilty complex (MHC) class I and class II, and cells which show strong response to self antigen are removed. These processes are called positive and negative selection, respectively. T cell receptors can accomplish their appropriate function when they recognize foreign antigen bound to their won MHC molecule on the cell surface. This educational process takes place in the thymus.
T cells express not only T cell receptors but also various cell surface proteins. These proteins are also important in T cell function. Most of these T cell surface proteins are expressed in 2 broad range of T cell subsets. However, some of them are expressed only at 2 specific stage and these proteins can be used as T cell surface markers for the determination of T cell maturation stage. Generally, the classification system by Renherz et al, using T cell surface molecules as markers, has been used for determining the differentiation stages of thymocytes. According to this classification, thymocytes are classified into (a) early thymocyte, DF4
·
/CD8
·
double negative, (b) common thymocyte, CD4
+
/CD8
+
double positive, and (c) mature thymocyte, CD4
+
or CD8
−
single positive. Early thymocytes express CD7, CD38 and CD71 proteins. They are the cells which recently arrive at the thymus from bone marrow and actively divide. The rearrangement of T cell receptor gene. −TCR&bgr;− occurs at this stage. Common thymocytes occupy the largest protein of the thymus and begin to express CD1, CD2, CD3, CD4, CD5, CD8 and the like on cell surfaces, and TCR&agr; genes are rearranged. Thereafter, mature thymocytes express T cell receptors on the cell surface. Only some of them can survive and move to the next stage, and most of them die (Nikolis-Zugic, 1991
, Immunol. Today,
12, 65-70). The cell surface molecules in T cells and thymocytes can be used to determine the stage of differentiation and the classification of subsets. In addition, they can be used for the diagnosis and treatment of tumors originated form T cells. These cell surface proteins have an important role in function and development of T cell.
A thymocyte should die unless its T cell receptor is appropriate. And the death is not simply passive death but an active death requiring certain proteins or the synthesis of certain metabolic produces (Rothenberg, 1990
, Immunol. today,
11, 116-119). This cell death may require the specific stimulating signals from the outside. And the cell surface proteins may be involved in the signal pathway. However, identification of cell surface molecules involved has not been possible until now. If common thymocytes express the specific proteins to transmit the signals for the selection of T cell receptor and programmed cell death, these proteins would be the intrinsic proteins at that stage. Even though a few cortical thymocyte antigens such as CD1a, b and c have been known to be expressed on thymic cortex, they are also expressed on various types of cells such as dendritic cells, brain astrocytes and B lymphocytes.
SUMMARY OF THE INVENTION
An object of the present invention is to provide a novel protein which is expressed on cortical thymocytes which can be used to classify the developmental stage of cell.
Another object of the present invention is to provide a protein whose expression is restricted on thymocytes and tumor cells originated from hematopoietic system.
A third object of the present invention is to provide material to determine the developmental stage of thymocytes and diagnose the tumors originated from hematopoietic system.
A fourth object of the present invention is to provide therapeutic material which can kill tumor cells originated form hematopoietic system.
In addition, the present invention is to provide a method for treatment by use of the therapeutic material of the present invention.
The present invention provides a cell surface protein expressed on human cortical thymocytes, “JL-1”. The cell surface protein above is a single chain glycoprotein with a approximately 120,000 dalton of molecular weight.
the protein of the present invention is expressed on human cortical thymocytes, and it is also expressed on cells of T lymphoblastic leukemia and lymphoma originated from human cortex thymocytes, and cells of about 50% of various types of leukemia.
Also, the present invention provides material is selected from the group consisting if antibodies and ligands, and the antibody is preferably selected from the group consisting of monoclonal antibody and polyclonal antibody, and more preferably it is originated from human or animal. The antibody mentioned above comprise parts of antibody including antigen recognition region (V
E
and V
L
), so has the capacity to recognize antigen specifically. And it also includes antibody fragment, such as F(ab′)2, Fab and Fv. Preferably the antibody fragment (Fv) comprises a single chain polypeptide fragment of antigen, so called single chain Fv, which is prepared by inserting a linking peptide between two polypeptides, V
E
and V
L
to increase heat stability. The material above may comprise labelling material which is selected from the group consisting of radioisotope, fluorescent material and staining material.
The present invention also provides a method for producing the material above, and it provides a cell producing the material above and a method for producing the cell.
Further, the present invention provides a method for the diagnosis of T leukemia and T lymphoblastic lymphoma using the material above.
In addition, the present invention provides a method for the treatment of leukemia and T lymphoblastic lymphoma using the material above, which is selected from the group consisting of antibody, antibod
Bae Young Mee
Park Seong Hoe
Finnegan Henderson Farabow Garrett & Dunner L.L.P.
Huff Sheela
Park Seong Hoe
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