Drug – bio-affecting and body treating compositions – Whole live micro-organism – cell – or virus containing
Reexamination Certificate
1999-06-24
2002-06-11
Bansal, Geetha P. (Department: 1642)
Drug, bio-affecting and body treating compositions
Whole live micro-organism, cell, or virus containing
C424S093200, C424S093210, C424S093700, C424S093710, C424S136100, C435S325000, C514S002600, C514S012200, C530S387300
Reexamination Certificate
active
06403080
ABSTRACT:
FIELD OF THE INVENTION
The invention relates in general to the immune system, and in particular to compositions and methods of modulating an immune response to an antigen.
BACKGROUND OF THE INVENTION
Opsonins are molecules which are capable, by virtue of being contemporaneously bound or attached to both an antigen and an antigen-presenting cell (APC), of acting as a coupling agent between the antigen and the APC to allow more efficient binding, engulfment, and internalization of the antigen by the APC. This is believed to facilitate generation of an immune response, since APCs present antigen to T cells. Naturally occurring opsonins can be categorized as belonging to the innate immune system (innate opsonins), which provides first line defense against foreign antigens and an antigen recognition repertoire which does not diversify during the ontogeny of the individual, or to the acquired immune system, which provides later phase defense mechanisms based on a repertoire of antigen-specific molecules, e.g., immunoglobulins, that diversify over the ontogeny of the individual.
Families of opsonins include fragments of complement components C3 and C4, collecting, and immunoglobulins. Other opsonins include fibronectin, alpha-2-macroglobulin (a2m), and C reactive protein (CRP).
It is an object of the invention to provide compositions and methods for improved vaccines by improving the uptake of antigen by antigen presenting cells.
The invention is based, at least in part, on the discovery that opsonin-enhanced cells, that is, cells which have been 1) modified so as to express an opsonin from a recombinant nucleic acid, 2) modified so as to express higher levels of an endogenous opsonin, or 3) mixed with an exogenous opsonin can, when administered to a subject, modulate the immune response in the recipient to a selected antigen or antigens contained in or attached to the cells.
The invention therefore encompasses a method of vaccinating a mammal to a selected antigen, the method comprising administering to the mammal a vaccine composition comprising an opsonin-enhanced cell, wherein the opsonin-enhanced cell comprises the selected antigen and a nucleic acid encoding an opsonin and expresses the nucleic acid encoding the opsonin.
The invention also encompasses a method of vaccinating a mammal to a selected antigen, the method comprising administering to the mammal a vaccine composition comprising an opsonin-enhanced cell, wherein the opsonin-enhanced cell comprises the selected antigen and is admixed with an exogenous opsonin.
Preferably, the exogenous opsonin is an engineered opsonin.
The invention also encompasses a method of vaccinating a mammal to a selected antigen, the method comprising contacting an APC in vitro with an opsonin-enhanced cell comprising a selected antigen and an opsonin, for a time sufficient to permit internalization of the selected antigen by the APC, and administering the contacted APC to a mammal.
Preferably, the opsonin-enhanced cell comprises the selected antigen and a nucleic acid encoding the opsonin. It also is preferred that the opsonin is an exogenous opsonin and/or an engineered opsonin.
Preferably, in the inventive methods and compositions, the opsonin-enhanced cell is substantially unable to divide in vitro. “Substantially unable to divide in vitro” means that opsonin-enhanced cells divide at a rate that is less than about 50% with respect to corresponding cells which are not treated to prevent cell division.
It also is preferred that the vaccine composition is attenuated, and therefore is unable to cause a disease that the cells cause in their pathogenic form.
Preferably, the opsonin is one of alpha′ chain of C3b or mannose binding protein.
Preferably, the antigen is a pathogenic cell, which may be a tumor cell which is malignant.
The invention also encompasses a pathogenic cell containing a selected antigen and a recombinant nucleic acid encoding an opsonin, wherein the cell expresses the encoded opsonin, wherein the opsonin is selected from the group consisting of: fibronectin, complement components C1q, C1qA chain, C1qB chain, C1qC chain, complement fragments C3b, C3bi, C3d, C3dg and C4b, mannose binding protein, conglutinin, surfactant proteins A and D, alpha-2-macroglobulin, and immunoglobulins and engineered opsonins.
Preferably, the pathogenic cell is a tumor cell which may be malignant.
It is preferred that the pathogenic cell is selected from the group consisting of: a pathogenic bacterium, a pathogenic fungus, a pathogenic virus, a cell of a pathogenic parasite. Where the invention comprises an opsonin-enhanced bacterial pathogen, it is preferred that the administered cells comprise opsonin bound to the cells.
The invention also encompasses a host cell containing and expressing a recombinant nucleic acid encoding an opsonin and a recombinant nucleic acid encoding an antigen.
Preferably, the host cell is any host cell which is able to act as a carrier for the opsonin and the antigen, and thus may be a nucleated cell or a procaryotic cell. In this aspect of the invention, the host cell need not be pathogenic, but may be any cell into which nucleic acid is introduced artificially. Such cells include but are not limited to a fibroblast, including a specialized mesenchymal cell such as a synoviocyte, a keratinocyte, an epithelial cell, an endothelial cell, a leukocyte, a tumor cell, a bacterial cell, a cell of a fungus, a cell of a parasite.
The invention also encompasses a composition comprising a cell admixed with an engineered opsonin.
Preferably, the cell is a pathogenic cell.
The invention also encompasses a composition comprising a cell admixed with an opsonin, wherein the cell is substantially unable to divide in vitro.
Preferably, the cell is a pathogenic cell.
Preferably, the composition is substantially free of culture medium. As used herein, “culture medium” refers to medium that is used in cell culture containing at least 2% animal serum, such as fetal calf serum.
The invention also encompasses a composition comprising a cell comprising a heterologous antigen, admixed with an innate opsonin, wherein the cell is substantially unable to divide in vitro.
Preferably, the composition is substantially free of culture medium.
The invention also encompasses a composition comprising a cell comprising a heterologous antigen, admixed with an exogenous engineered opsonin which is able to bind to the cell either via covalent bonding or via a receptor-ligand binding interaction, e.g., an interaction between a lectin domain of a collectin opsonin and a carbohydrate on the surface of an antigen-containing cell.
Preferably, the cell is unable to divide in a mammalian host.
The invention also encompasses a composition consisting essentially of a cell and an opsonin.
Preferably, the composition further comprises a physiologically compatible buffer, and also further comprises a cytokine, which cytokine may be expressed by the cell.
The invention also encompasses a composition consisting essentially of a cell and an opsonin, wherein the cell is substantially unable to divide in vitro.
Preferably, the composition further comprises a physiologically compatible buffer.
Compositions of the invention also may further include a cytokine, which is preferably expressed by the cell.
The invention also encompasses a vaccine composition comprising opsonin-enhanced cells and a pharmaceutically acceptable carrier.
The invention also encompasses a nucleic acid encoding a chimeric protein comprising first and second ends, wherein the chimeric protein binds via the first end to a first cell which is an APC and binds via the second end to a second cell containing a selected antigen, wherein the first end comprises an APC binding sequence (moiety or domain) from an opsonin.
Preferably, the nucleic acid also encodes a GPI-modification signal sequence.
It also is preferred that the fusion protein contains a transmembrane sequence.
The invention also encompasses an engineered opsonin, which opsonin comprises an APC binding moiety of a naturally occurring opsonin, and
Bansal Geetha P.
Palmer & Dodge LLP
Whitehead Institute for Biomedical Research
Williams Kathleen Madden
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