CD8 antagonists

Details CD8 antagonists CD8 antagonists

1997-11-26

2001-01-30

Saunders, David (Department: 1644)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S002600, C514S012200, C514S013800, C514S014800, C514S015800, C514S016700, C514S017400, C514S018700, C435S375000, C530S317000, C530S324000, C530S325000, C530S326000, C530S327000, C530S328000, C530S329000, C530S330000

Reexamination Certificate

active

06180600

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to molecules which interfere with CD8-mediated activity.
BACKGROUND OF THE INVENTION
Clinical allogenic bone marrow transplantation is an important therapeutic treatment for several diseases including high risk leukemia, aplastic anemia, and severe combined immunodeficiency. In addition, there is a wide range of metabolic and genetic disorders that can potentially be corrected by this approach. However, the usefulness of marrow transplantation is currently limited by several important risk factors, the principal one being graft-versus-host disease (GVHD), an often times lethal complication which occurs in a high proportion of transplants (see Korngold, R.,
Amer. J. Ped. Hematol. & Oncol
. 15:18 (1993)).
The risk of GVHD can be reduced by HLA matching of the marrow donor and recipient, with a matched sibling being the primary choice. Yet, less than 30% of the patients in North America have an HLA-matched sibling, and therefore must seek suitable unrelated HLA-matched donors from the National Marrow Donor Program. The probability of finding an unrelated HLA-matched donor is currently on the order of 30-40% and depend on the total number of donors registered. In both related and unrelated HLA-matched transplant situations, the risk of GVHD is still quite high due to disparity of non-HLA multiple minor histocompatibility (H) antigens. GVHD is somewhat higher in unrelated cases, as this increases the probability of differences at these loci.
Mature donor T cells contaminating the marrow inoculum are responsible for GVHD. Several studies have shown that depletion of these T cells significantly diminishes the incidence of disease. However, the elimination of donor T cells has also resulted in a greater incidence of leukemic relapse. It seems important to provide at least some level of T cell immunocompetency in these completely immunocompromised patients to not only combat residual leukemia cells but also to counter opportunistic infections. In this respect, the same GVHD-reactive donor T cells may be important for targeting leukemia cells expressing the same host allogeneic histocompatibility antigens. Therapeutic approaches that could ameliorate the pathogenic tissue destruction accompanying GVHD, particularly in the gut and skin, but that would allow for continued anti-leukemia activity would greatly benefit marrow transplant patients.
Other transplantation procedures involving the implantation of immunogenic tissue include but are not limited to, heart transplants, liver transplants, kidney transplants, lung transplants, islet transplants, cornea transplants and skin grafts. In such procedures, organ rejection is an obstacle to complete recovery. The individual's immune system recognizes antigens (HLA or minor H antigens) on the implanted tissue as foreign and mounts an immune response against it which injures and destroys the implanted tissue.
T cells act as effectors of the immune response. One of the most striking ways in which they do so is by targeting cells displaying foreign antigen. The subset of T cells that mediate this lytic function are designated as cytotoxic T lymphocytes (CTL). The highly specific nature of the CTL response is apparent in cell-mediated responses to viral infections and to allografts. This sub-population of lymphocytes is characterized by expression of the cell surface marker CD8. The CD8 protein has been shown to play a major role in both activation of mature T-cells and the thymic differentiation process that leads to expression of CD8. Classically, CD8 has been viewed as an accessory molecule involved in ligation of class I major histocompatibility complex (MHC) bearing antigen on an antigen presenting cell (APC). In recent years, accumulating evidence suggests that this model for the role of CD8 in T cell activation is not complete. It is now believed that CD8 plays a major role in signal pathways leading to T cell proliferation (for review, see Miceli and Parnes,
Adv. In Immuno
. 53:59-72 (1993)).
CD8 has been shown to physically associate with the T cell receptor complex (TCR), as demonstrated by co-immunoprecipitation and by co-capping experiments (Gallagher et al.,
PNAS
86:10044-10048 (1989)). TCR signalling and TCR mediated lymphokine production are markedly enhanced with CD8-TCR aggregation. Characterization of the CD8 structure by a panel of monoclonal antibodies directed against CD8 showed that MHC class I binding and TCR interaction are associated with distinct regions of the CD8 molecule (Eichmann et al.,
J. of Immuno
. 147:2075-2081 (1991). In addition, CD8 and the TCR recognize the same class I molecule (Connoly et al.,
PNAS
87:2137-2141 (1990)). The human CD8 molecule is expressed either as an &agr;/&agr; homodimer or as an &agr;/&bgr; heterodimer. Individual human peripheral T-cells can express varying amounts of CD8 &agr;/&agr; and &agr;/&bgr; complexes, and their relative ratios appear to be differentially regulated upon T-cell activation. The biological activity of CD8 has primarily been attributed to the &agr; chain, which enhances or reconstitutes T-cell responses in the homodimeric form. In contrast, until recently, no role had been ascribed to the &bgr; chain. Mice that were chimeric for the homozygous disruption of the CD8 &bgr; gene developed normally to the CD4+ CD8+ stage, but did not efficiently differentiate further, which results in a low number of peripheral CD8+ T-cells. The fact that the number of peripheral CD8+ T-cells was restored upon transfer of exogenous CD8 &bgr; gene indicates that CD8 &bgr; is necessary for the maturation of CD8+ T-cells. It has also been shown that CD8 &agr;/&bgr; transfectants produce more IL-2 than CD8 &agr;/&agr; transfectants in response to specific stimuli (Wheeler et al.,
Nature
357:247-249 (1992)). T-cell activation results in the physical modification of the mouse CD8 &bgr; chain shown by the reversible alteration in its sialic acid content (Casabo et al.,
J. of Immuno
. 152:397-404 (1994)). This modification may influence the physical structure of the CD8 complex and in turn the interaction with TCR and MHC class I. The gene encoding the CD8 molecule has been cloned for several species (human, rat, mouse) (Sukhame et al.,
Cell
40:591-597 (1985); Nakauchi et al,
PNAS
82:5126-5130 (1985)). The murine CD8 molecule is expressed as a heterodimeric structure consisting of two disulfide linked subunits; Lyt-2, which has a molecular weight of about 38 kDa and Lyt-3, which has a molecular weight of 30 kDa (Ledbetter et al.,
J. of Exp. Med
. 153:1503-1516 (1981)). The &agr; chain gene can also undergo an alternative mode of mRNA splicing resulting in expression of the &agr;′ form which is distinguishable from &agr; by its shorter cytoplasmic tail (Zamoyska et al.,
Nature
342:278 (1989); Giblin et al.,
PNAS
86:998-1002 (1989)).
Sequence analysis of CD8 indicates that it is a member of the immunoglobulin (Ig) superfamily. Members of the Ig-superfamily exhibit highly conserved hydrophobic cores. The CD8 molecule consists of an unique amino-terminal Ig-variable domain, an extracellular spacer which carries the structural features of Ig hinge-line region, a transmembrane domain and an intracellular cytoplasmic tail. The crystal structure of the extracellular Ig-like portion of the homodimeric human CD8&agr; has been recently solved [Leahy et al.,
Cell
68:1145-1162 (1992)]. The amino-terminal domain of the CD8&agr; chain was shown to closely resemble an Ig-variable region. The regions that are analogous to antigen-binding domains on an immunoglobulin protein are referred to as the complementarity determining regions (CDRs). Recent mutagenesis studies of the different domains of CD8 has indicated that CDR1 and CDR2 like domains are involved in MHC class I interactions (Sanders et al.,
J. of Exp. Med
. 174:371-379 (1991)).
Replacement of the human CD8&agr; CDR2-like loop by the homologous mouse sequences results in the loss of interaction of monoclonal antibodies (MAb) that are

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