Drug – bio-affecting and body treating compositions – Nonspecific immunoeffector – per se ; or nonspecific...
Reexamination Certificate
1999-02-23
2001-11-06
Gambel, Phillip (Department: 1644)
Drug, bio-affecting and body treating compositions
Nonspecific immunoeffector, per se ; or nonspecific...
C424S134100, C424S192100, C424S204100, C424S234100, C424S277100, C530S350000, C530S351000, C530S387100, C530S387300
Reexamination Certificate
active
06312700
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to methods and compositions for generating enhanced immune responses in animals, particularly in human and non-human mammals. The invention also relates to production of compositions and materials for use in the methods, for example to related vaccines, cells, plasmids, viral and other vectors, and preparations derived therefrom. Other aspects of the invention will be apparent from the following description.
BACKGROUND OF THE INVENTION
It is known that many receptor-ligand interactions are involved in the induction, establishment and modulation of immune responses directed against antigens. At least two signals are necessary to activate a CD4 or CD8 T-cell response to antigen (Lenschow et al., 1996). The first signal is delivered through the T-cell receptor (TCR) by an antigen (typically a peptide) bound to a major histocompatibility (MHC) class I or II molecule present on the surface of an antigen presenting cell (APC). The second signal involves the binding of a ligand present on the surface of the APC to a second receptor molecule on the surface of the T-cell. This second signal is termed co-stimulation, and the APC ligand is often referred to as a co-stimulatory molecule. The best characterized second signal is delivered via an interaction between the CD28 receptor on the T-cell, and its ligands B7.1 or B7.2 on the APC, although a number of other examples of receptor/co-stimulatory molecule interactions have been described.
In combination, the two signals activate the T-cell, which in turn secretes cytokines and proliferates. In the case of CD4 T-cells, the activated cells (designated CD4
+
) produce cytokines, including IL-2 and IFN&ggr;, which activate killer (CD8
+
) T-cells at the site of inflammation. Once CD4 T-cells are activated, another receptor, CTLA-4 is expressed, which is homologous to CD28 and binds B7 molecules with a higher affinity than CD28. The B7/CTLA-4 interaction inhibits the activation signal of CD28 and delivers a negative signal that may down-regulate T-cell responses (Krummel et al., 1996; Walunas et al., 1996). This down-regulation mechanism may serve to prevent excessive immune system responses, for example by decreasing the amount of cytokines produced during an inflammatory event. Concurrently, however, it may also down-regulate the number of T-cells that go on to become “memory cells”. Reducing the number of memory cells means that fewer such cells will be available to respond to the same antigen the next time it is encountered. However, there are a number of situations where it would be advantageous to maintain, rather than down-regulate, an active T-cell response. Cancer patients, for example, would benefit from maintaining an active T-cell response against tumor cells. The concept of vaccination requires that a population of memory T-cells which recognized the administered antigen be maintained.
Another receptor/ligand combination that has been proposed to play a role in co-stimulation of CD4 T-cells is the OX-40 receptor/OX-40 ligand pairing. While the CD28 receptor is present on the surface of many sub-classes of T-celis (irrespective of whether they are activated or not), the OX-40 receptor (“OX-40”) (Paterson et al. 1987; Calderhead et al., 1993) has been shown to be present only on antigen activated CD4
+
T-cells in vivo (Weinberg et al., 1994; 1996). Thus, it has been shown that OX-40 is present on activated CD4
+
T-cells that recognize autoantigen at the site of inflammation in autoimmune disease, but not in the peripheral blood system (Weinberg et al, 1994; 1996). OX-40 has also been shown to be present on the surface a percentage of CD4
+
T-cells isolated from tumor infiltrating lymphocytes and draining lymph node cells removed from patients with squamous cell tumors of the head and neck and melanomas (Vetto et al., 1997). The OX-40 ligand, a member of the tumor necrosis factor (TNF) superfamily, has been shown to co-stimulate T-cells which have been activated with an anti-CD-3 antibody (i.e., in a nonantigen-specific manner) (Godfrey et al., 1994). Beyond its general co-stimulatory function however, the biological role of the OX-40 receptor/OX-40 ligand interaction in the immune response pathway is, to date, unknown.
SUMMARY OF THE INVENTION
This invention provides in certain of its aspects compositions and methods which can be used to enhance and maintain the immune response of a mammal towards a chosen antigen. While prior procedures have attempted to boost the immune response generally, compositions and methods disclosed herein are specifically targeted to T-cells which have recently been activated in response to a particular antigen (so-called “memory cells”) or T-cells which are in the process of such priming. In particular, the effects of the methods disclosed herein are believed to include increasing the number of memory T-cells, thereby enhancing the response of the immune system to a specific (chosen) antigen.
Underlying the invention are findings (1) that engagement of the OX-40 receptor on CD4
+
T-cells especially for example during, or shortly after, priming of such cells by antigen, can result in an increased response of the CD4
+
T-cells to that antigen and (2) that the elevated response to that antigen can be maintained for a period of time substantially longer than in the absence of such an engagement. As a result, increasing the immune response by providing molecules which engage the OX-40 receptor, e.g. during T-cell priming, can markedly increase the resistance of an animal to disease, by boosting T-cell recognition of antigens presented by infectious agents, such as bacteria and viruses, as well as tumor cells.
Accordingly, the present invention provides among other things the use of an OX-40 receptor binding agent, or of a nucleic acid encoding an OX-40 receptor binding agent, in the manufacture of a pharmaceutical composition for enhancing immune response against an antigen in a mammal, which is either a tumour antigen, or an antigen for which the composition is administered so as to present the OX-40 receptor binding agent to T-cells of the mammal during or shortly after priming of the T-cells by the antigen.
The OX-40 receptor binding agent can be selected from OX-40L, anti-OX-40 antibodies (e.g. a monoclonal antibody such as a humanized monoclonal antibody), and immunologically effective portions of anti-OX-40 antibodies.
The antigen can be selected from viral antigens, bacterial antigens and tumor antigens.
Also according to the invention, a purified OX-40 receptor binding agent and a pharmaceutically acceptable carrier can be used in the manufacture of a pharmaceutical composition for enhancing the immune response of a mammal to an antigen by administering the composition to the mammal to present the OX-40 receptor binding agent to T-cells of the mammal during or shortly after priming of the T-cells by the antigen, e.g. about 3-7 days after administration of the antigen.
The technique can be applied to enhancing the immune response of a mammal to a tumour cell in the mammal.
One form in which the invention can be carried out is by the use of a nucleic acid encoding an OX-40 receptor binding agent that is localised on the surface of a cell (e.g. by possessing a suitable transmembrane sequence), in the manufacture of a composition for introducing the nucleic acid into a cell and enhancing the immunogenicity of the cell, e.g. a tumor cell.
The nucleic acid can if desired further encode a second protein, e.g. one selected from major histocompatibility complex proteins, cytokines, interferons and immune-system co-stimulatory molecules.
The nucleic acid encoding the OX-40 receptor binding agent can be made part of a viral or plasmid vector, e.g. a viral vector based on an adenovirus, retrovirus or herpesvirus. The viral vector can be an attenuated or disabled virus.
According to a further aspect of the invention a nucleic acid which encodes an OX-40 receptor binding agent that is localised on the surface of a cell, along wi
Gambel Phillip
Klarquist & Sparkman, LLP
Roark Jessica H.
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