Inducing cytotoxic T lymphocyte responses

Details Inducing cytotoxic T lymphocyte responses Inducing cytotoxic T lymphocyte responses

1995-09-15

1999-07-27

Wortman, Donna C.

Drug, bio-affecting and body treating compositions

Antigen, epitope, or other immunospecific immunoeffector

Conjugate or complex

42419711, 4242041, 4242341, 424491, A61K 39385

Patent

active

059286474

DESCRIPTION:

BRIEF SUMMARY
FIELD OF THE INVENTION

This invention relates to compositions and methods for inducing class I major histocompatibility-restricted cytotoxic T lymphocyte responses in a mammal by immunization with particulate protein antigen complexes comprising non-replicating protein antigen. The invention also relates to vaccine development for cytotoxic T lymphocyte immunity and methods of treating infectious diseases.


BACKGROUND OF THE INVENTION

One of the major immune responses that protects a host from disease, especially from intracellular infection, is the generation of cytotoxic T lymphocytes (CTLs). CTLs kill host cells that are infected and thereby eliminate the production and/or reservoir of the pathogen. CTLs may also control secondary pathogenic effects induced by infectious organisms, for example, the growth of transformed cells. There is abundant evidence that CTLs are critical components in the defense of the host against several viral pathogens, including influenza, POX and Herpes (Blanden, Transplant Rev., 19:56 (1975); Yap et al., Nature, 273:238 (1978). Furthermore, CTLs can provide immunity in vivo to retrovirally-induced diseases (Earl et al., Science, 234:728 (1986)). There is increasing evidence that CTLs may play a role in protection from human immunodeficiency virus (HIV). For example, CTLs from infected humans and apes can lyse infected cells and inhibit virus production in vitro.
One of the most efficacious and cost effective therapies for the prevention of infectious diseases is the stimulation of specific immune response through vaccination. The need for an effective HIV vaccine is tragically apparent.
Historically, vaccines have been prepared by killing or attenuating a pathogen, such as a virus or bacterium, and then injecting the resulting particles into a patient or host animal. Vaccines have also been prepared by using only a portion of the pathogenic organism, such as a predominantly important protein subunit from a bacterium or virus. While non-living virus particles and subunit vaccines can prime for a class-II restricted antibody response, such non-living vaccines typically do not prime for cytotoxic T lymphocyte immunity.
It is now well established that the tight segregation of the MHC class I pathway of antigen presentation accounts for the failure of most protein-based vaccines to prime CTL responses and is a major obstacle to using such vaccines. Specifically, from the published literature it is known that most antigens in the extracellular fluid are taken up by specialized antigen presenting cells (APCs), processed in an endosomal compartment, and subsequently displayed in association with class II MHC molecules, which elicits an antibody response. In contrast, most exogenous antigens are not presented in association with class I MHC molecules, which is necessary for a class I-restricted CTL response. However, exogenous antigens are presented in association with class I molecules if they are introduced, via experimental manipulations, into the cytoplasm ("cytosol") of cells. It is thought that the antigenic peptides that arise from processing in the cytosol are transported to the endoplasmic reticulum where they associate with class I MHC molecules. The failure of exogenous proteins to be presented in association with class I molecules reflects the inability of these proteins and their degraded endosomal products, to communicate with the appropriate cytosolic compartment, under physiological conditions. As a consequence of this segregation between MHC-class I and class II antigen-presentation pathways, CTLs are selectively targeted to pathologically-affected cells (ie. cells synthesizing abnormal proteins). Uninfected, healthy cells are not at risk of elimination when they encounter antigens in the extracellular fluids.
Despite the generally recognized inability of most antigens to prime CTL response, there have been reports in literature of inducing MHC class I-restricted CTLs with non-replicating antigen in vivo. For example, Zhou et al. have shown that allogeneic splenoc

REFERENCES:
patent: 5045320 (1991-09-01), Mescher
Remington's Pharmaceutical Sciences, 18.sup.th GD., p. 1280.

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