Antigenic complexes and methods

Details Antigenic complexes and methods Antigenic complexes and methods

2000-07-17

2004-06-29

Housel, James (Department: 1648)

Drug, bio-affecting and body treating compositions

Nonspecific immunoeffector, per se ; or nonspecific...

Virus

C424S144100, C424S184100, C424S233100, C424S278100, C435S235100, C530S388200

Reexamination Certificate

active

06756044

ABSTRACT:

TECHNICAL FIELD OF THE INVENTION
The present invention pertains to antigenic complexes and methods of inoculating and immunizing animals.
BACKGROUND OF THE INVENTION
The identification of pathogenic organisms and viruses has led to the development of successful protocols for immunizing healthy individuals against such organisms. Early protocols involved exposing healthy individuals to live or attenuated pathogens to induce immune responses against the pathogens. With respect to many pathogens, such live or attenuated vaccines remain superior to other vaccines because of their tendency to elicit a broad level protective response. Other disorders, however, are caused or spread by pathogens less amenable to this approach. For example, it has proven difficult to develop or store live or attenuated vaccines derived from several common pathogens. Still other pathogens simply are not sufficiently antigenic to generate a sufficient (or even any) response in a host animal to be useful as a vaccine, whether through evolved stealthing defenses (e.g., HIV, herpes, etc.), limited presentation of antigen, genetic drift (e.g., influenza), or other proclivities. Of course, the possibility of actually causing the disease against which protection is intended (e.g., polio, measles, etc.) remains a major concern associated with this approach.
An alternative to the use of live/attenuated pathogen vaccines is to use antibodies raised against antigens associated only with an identified pathogen. Such approaches can be effective in some instances. However, no assurance can be had that any antibodies raised against a putative antigen will effectively protect against the pathogen providing the antigen. Thus, it is frequently necessary to test a large number of putative antigens isolated from a pathogen, rendering such approaches relatively costly and time consuming. Also, such approaches generally do not elicit the broad level of protective response associated with live vaccines.
Genetic or peptide immunization has emerged as an alternative to conventional vaccines. This technology involves inoculating DNA encoding a pathogen protein, or an isolated pathogen protein, into the host. Risk of infection is greatly reduced, and the DNA or protein vaccines can be delivered to cells not normally infected by the pathogen. Compared to conventional vaccines, the production of DNA or peptide vaccines is straightforward, and DNA and protein are considerably more stable than live/attenuated vaccines. However, some DNA or protein vaccines are not effective against certain pathogens. Indeed, vaccine approaches that deliver entire proteins may direct the immune response against immunodominant epitopes only, and not against subdominant epitopes (e.g., EBV latent membrane protein). Alternatively, such approaches can direct an immune response against epitopes subject to antigenic variation, and in some instances, such approaches can actually result in tolerance to the pathogen (e.g., a tumor or a microbe), rather than immunity (see, e.g., Toes et al.,
Proc. Nat. Acad. Sci
. (
USA
) 94, 14660-65 (1997); Toes et al.,
Proc. Nat. Acad. Sci
. (
USA
), 93, 7855-60 (1996); Toes et al.,
J. Immunol
., 156, 3911-18 (1996); Aichele et al.,
Proc. Nat. Acad. Sci
. (
USA
), 91, 444-48 (1994); Aichele et al.,
J. Exp. Med
., 182, 261-66 (1995)).
Other recent advances in vaccine technology have focused on the manner in which cellular immunity is acquired in the first instance. Recognition and destruction of at least some pathogens is performed principally by CD8
+
cytotoxic T lymphocytes (CTLs). The mounting of a CTL immune response requires that “foreign” proteins undergo intracellular processing to peptide fragments, a function performed with high efficiency by professional antigen presenting cells (APCs), such as B-cells, dendritic cells, lymphoid fibroblasts, Langerhans cells, macrophages, monocytes, peripheral blood fibrocytes, etc., and potentially other cells such as cortical thymus epithelial cells, Ia-Thy 1-cells, peritoneal exudate cells, and the like. The processed peptide fragments ultimately are presented at the cell surface complexed with major histocompatability complex (MHC) class I molecules, which constitute the first stimulatory signals recognized by a CTL.
Processing of antigens presented by class I MHC generally involves endogenous synthesis and cytoplasmic processing not involving endosomes. While, under some circumstances, exogenous antigens can enter the cytoplasm for processing by the nonendosomal pathway and presentation by class I MHC, typically, exogenous antigens are internalized and processed through endosomes for presentation by class II MHC. To exploit this biology, APCs pulsed with proteins or DNA have been employed in vaccines. Typically, dendritic cells are harvested and pulsed with the protein or DNA and then cultured to activate MHC-I or MHC-II responses. These cells can be used subsequently in vivo or in vitro to present the antigens to CTLs. While these approaches may prove promising, a matter of concern when using APCs as carriers is that isolating even limited amounts of such cells is labor-intensive. Moreover, MHC class II-deficient APCs, expressing only MHC-I often fail to induce protection (Schnell et al.,
J. Immunol
., 164(3), 1243-50 (2000)). This demonstrates the desirability of achieving both types of response.
In addition to the limitations of current vaccine technologies, the identification of suitably antigenic proteins, peptides, or other moieties from many species of pathogen remains elusive. Considering these, and other, drawbacks, a need remains for improved strategies for identifying suitable antigens and for using them to inoculate animals.
BRIEF SUMMARY OF THE INVENTION
The present invention provides a complex that includes a virion having a ligand that recognizes an epitope present on an immune effector cell surface and at least a first nucleic acid encoding a first non-native antigen. The invention also provides a library including a plurality of such complexes, in which antigens of at least two of the plurality are different.
Such reagents are useful both in research and in the clinic. Thus, for example, the invention provides a method of precipitating an immune response within an immune effector cell, wherein such a complex is delivered to the cell under conditions sufficient for the cell to mount an immune response to the antigen. When applied in vivo, the method can serve to immunize an animal from the pathogen. Moreover, using a library including a plurality of complexes, which contains at least one test antigen, the invention provides a method of assessing the antigenicity of the test antigen. These and other aspects of the present invention, as well as additional inventive features, will be apparent upon reading the following detailed description.
DETAILED DESCRIPTION OF THE INVENTION
Within the inventive complex, the ligand on the virion typically (but need not be) proteinaceous. Examples of suitable ligands include (but are not limited to) short (e.g., about 6 amino acids or less) linear stretches of amino acids recognized by integrins, as well as polyamino acid sequences such as polylysine, polyarginine, etc. Inserting multiple lysines and/or arginines provides for recognition of heparin and DNA, and an RGD sequence can be used as a ligand to bind integrins, such as are present on immune effector cells. Tandem repeats of lysine, arginine, and/or histidine residues (e.g., three or more, five or more, or even as many as ten or more tandem lysine residues, tandem arginine residues, tandem histidine residues, or tandem mixtures of lysine or histidine) can be similarly employed. Other ligands can be specific for particular substrates, such as, for example, immunoglobulin-like molecules (e.g., FABs, ScABs, etc.), or known specific ligands (e.g., CD40L that recognizes the CD40 antigen). Thus, it will be apparent that, in some embodiments, the ligand is native to the virion (i.e., being present in a wild-type virus from which the virion is derived), but in other e

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