Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Reexamination Certificate
1995-05-25
2001-01-09
Allen, Marianne P. (Department: 1631)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
C436S503000, C436S548000, C436S063000, C436S804000, C436S811000
Reexamination Certificate
active
06171799
ABSTRACT:
1. INTRODUCTION
The present invention is directed to monoclonal antibodies, which recognize defined regions of the T cell antigen receptor. The monoclonal antibodies of the invention have value in diagnosis and therapy and are useful tools for study of the immune system.
2. BACKGROUND OF THE INVENTION
2.1. THE T CELL ANTIGEN RECEPTOR
T lymphocytes interact with antigens through the T cell antigen receptor (TCR) complex. The TCR is a clone-specific heterodimer on T cells, which recognizes its target antigen in association with a major histocompatiblity antigen. The TCR has been shown to be noncovalently associated with the CD3 complex. TCR is highly polymorphic between T cells of different specificities. Approximately 90 percent of peripheral blood T cells express a TCR consisting of an &agr; polypeptide and a &bgr; polypeptide. A small percentage of T cells have been shown to express a TCR consisting of a &ggr; polypeptide and a &dgr; polypeptide. (Regarding TCR molecules, see Davis and Bjorkman, 1988, Nature 334:395-402; Marrack and Kappler, 1986, Sci. Amer. 254: 36; Meuer et al., 1984, Ann. Rev. Immunol. 2:23-50; Brenner et al., 1986, Nature 322:145-159; Krangel et al., 1987, Science 237:1051-1055; Hata et al., 1987, Science 238:678-682; Hochstenbach et al., 1988, J. Exp. Med. 168:761-776). The chains of the T cell antigen receptor of a T cell clone are each composed of a unique combination of domains designatedvariable (V), [diversity (D),] joining (J), and constant (C) (Siu et al., 1984, Cell 37:393; Yanagi et al., 1985, Proc. Natl. Acad. Sci. USA 82:3430). Hypervariable regions have been identified (Patten et al., 1984, Nature 312:40; Becker et al., 1985, Nature 317:430). In each T cell clone, the combination of V, D and J domains of both the alpha and the beta chains or of both the delta and gamma chains participates in antigen recognition in a manner which is uniquely characteristic of that T cell clone and defines a unique binding site, also known as the idiotype of the T cell clone. In contrast, the C domain does not participate in antigen binding.
2.2. T CELL ANTIGEN RECEPTOR GENES
TCR genes, like immunoglobulin genes, consist of regions which rearrange during T cell ontogeny (Chien et al., 1984, Nature 312:31-35; Hedrick et al., 1984, Nature 308:149-153; Yanagi et al., 1984, Nature 308:145-149). In genomic DNA, each TCR gene has V, J, and C regions; TCR &bgr; and &dgr; polypeptides also have D regions. The V (variable), D (diversity), J (junctional) and C (constant) regions are separated from one another by spacer regions in the DNA. There are usually many variable region segments and somewhat fewer diversity, junctional, and constant region segments. As a lymphocyte matures, these various segments are spliced together to create a continuous gene sequence consisting of one V, (D), J, and C region. TCR diversity, and thereby T cell specificity, is derived from several sources (Barth et al., 1985, Nature 316:517-523; Fink et al., 1986, Nature 321:219-225): a multiplicity of germline gene segments (Chien et al., 1984, Nature 309:322-326; Malissen et al., 1984, Cell 37:1101-1110; Gascoigne et al., 1984, Nature 310:387-391; Kavaler et al., 1984, Nature 310: 421-423; Siu et al., 1984, Nature 311:344-349; Patten e al., 1984, Nature 312:40-46), combinatorial diversity through the assembly of different V, D, J, and C segments (Siu et al., 1984, Cell 37:393-401; Goverman et al., 1985, Cell 40:859-867), and junctional flexibility, N-region diversity and the use of either multiple D regions or any of the three translational reading frames for Dp segments. TCR diversity does not appear to arise from the somatic hypermutation mechanism observed for immunoglobulins (Barth et al., supra). As a result of these mechanisms, TCRs are generated which differ in their amino-terminal, or N-terminal, domains (called variable, or V regions, constructed from combinations of V, D, and J gene segments) but are the same elsewhere, including their carboxy-terminal, or C-terminal domains (called constant regions). Accordingly, an almost limitless repertoire of TCR is established.
The V&bgr; gene of the TCR appears to resemble most closely the immunoglobulin V gene in that it has three gene segments, V&bgr;, D&bgr;, and J&bgr;, which rearrange to form a contiguous V&bgr; gene (Siu et al., 1984, Cell 37:393-401). The &bgr; locus has been well characterized in mice, where it spans 700-800 kilobases of DNA and is comprised of two nearly identical C regions tandemly arranged with one D element and a cluster of 5-6 J elements 5′ to each (Kronenberg et al., 1986, Ann. Rev. Immunol. 3:537-560). Approximately twenty to thirty V&bgr; regions are located upstream (5′) to the D, J, and C elements (Behlke et al., 1985, Science 229:566-570) although V&bgr; genes may also be located 3′ to the murine C&bgr; genes (Malissen et al., 1986, Nature 319:28). Study of the structure and diversity of the human TCR &bgr;-chain variable region genes has led to the grouping of genes into distinct V&bgr; subfamilies (Tillinghast et al., 1986, Science 233:879-883; Concannon et al., 1986, Proc. Natl. Acad. Sci. USA 83:6598-6602; Borst et al., 1987, J. Immunol. 139:1952-1959).
The &ggr;-TCR gene was identified, first in mice (Saito et al., 1984, Nature 309:757-762; Kranz et al., 1985, Nature 313:762-755; Hayday et al., 1985, Cell 40:259-269) and then in humans (Lefranc et al., 1985, Nature 316:464-466; Murre et al., 1985, Nature 316:549-552). The human &ggr;TCR locus appears to consist of between five and ten variable, five joining, and two constant region genes (Dialynas et al., 1986, Proc. Natl. Acad. Sci. U.S.A. 83:2619). The TCR &agr; and &dgr; locus are next to one another on human chromosome 14. Many TCR &dgr; coding segments are located entirely within the a gene locus (Satyanarayana et al., 1988, Proc. Natl. Acad. Sci. USA 85:8166-8170 Chien et al., 1987, Nature 330:722-727; Elliot et al., 1988, Nature 331:627-631). It is estimated that there are a minimum of 45-50 V&agr; regions (Becker et al., Nature 317:430-434) whereas there are only approximately 10 V&dgr; regions (Chien et al., 1987, supra). In peripheral blood, two predominant V&dgr; genes appear to be expressed, namely, V&dgr;1 and V&dgr;2, identifiable by monoclonal antibodies, &dgr;TCS1 and BB3, respectively. Nucleic acid sequences of TCR &agr; genes have been reported (Sim et al., 1984, Nature 312:771-775; Yanagi et al., 1985, Proc. Natl. Acad. Sci. USA 82:3430-3434; Berkout et al., 1988, Nucl. Acids Res. 16:5208).
2.3. ANTIBODIES TO THE T CELL ANTIGEN RECEPTOR
Clonotypic antibodies react only with a particular clone of T cells. Acuto et al. produced clonotypic monoclonal antibodies against a human thymocyte cell line, and thereby identified the TCR in relatively undifferentiated T3
+
cells (1983, Cell 34:717-726). Meuer et al. showed that anti-TCR clonotypic monoclonal antibodies coupled to sepharose beads could induce production of interleukin-2(1984, Proc. Natl. Acad. Sci. 81:1509-1513). Anti-TCR clonotypic antibody directed toward the CT8 cell line could only block cytotoxic effector cell function of that T cell line (Meuer et al., 1984, Ann. Rev. Immunol. 2:23-50). Antibodies which recognize TCR from many T cell lines recognize shared epitopes, or framework regions, of TCR peptides. Brenner et al. found that different cloned T cell lines shared antigenic determinants, none of which appeared to be accessible at the cell surface (1984, J. Exp. Med. 160:541-551). &bgr;-Framework-1 (&bgr;F1) monoclonal antibody reacts with a “hidden determinant” on the surface of viable T cells, and recognizes the TCR &bgr; polypeptide in Western blots (Brenner et al., 1987, J. Immunol. 138:1502-1509). Another framework antibody, WT31, originally thought to be a framework reagent is useful in cell binding, but is inefficient in immunoprecipitation studies (Spits et al., 1985, J. Immunol. 135:1922-1928). WT31 now appears to recognize a CD3 determinant.
2.4. RHEUMATOID ARTHRITIS
Rheumatoid arthritis (RA), a chronic, recurrent, inflammatory dis
Henry Larry D.
Ip Stephen H.
Ko Jone-Long
Kung Patrick C.
Rittershaus Charles W.
Allen Marianne P.
Astra AB
Banner & Witcoff , Ltd.
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