Title:  Method for inducing a systemic immune response to an HIV antigen

United States Patent:  6,207,185

Assignee:  Bio-Sphere Technology (Reno, NV)

Filed:  October 10, 1997

A method is provided for inducing a systemic immune response to an antigen selected from inactivated HIV I and HIV II antigens in a mammal. The method comprises orally administering lyophilized multilaminar liposomes containing the antigen. The liposomes have a size of from 20 nm to 20 microns. The antigen-containing liposomes are absorbed in the Peyer's patches of the gut. Sufficient antigen-containing liposomes are taken up by macrophages in the Peyer's patches to induce a systemic immune response to the antigen.

SUMMARY OF THE INVENTION

The present invention provides a method for inducing a systemic immune response to one or more antigens in a mammal and does not require the presence of an adjuvant. According to the present invention, the lyophilized antigen-containing liposomes do not directly target the CD4 cells and cytotoxic lymphocytes, but instead are taken up by the macrophages in the Peyer's patches. The macrophages express the antigen in conjunction with self major histocompatibility antigen I and II (SMH I and SMH II). The CD4 cells recognize the antigen expressed with SMH I, and the cytotoxic lymphocytes recognize the antigen expressed with SMH II. Accordingly, the present methods involve an intermediate step, being taken up by the macrophages, which is different from the process that occurs when an antigen/adjuvant combination is orally administered. Thus, the present invention involves a method whereby the antigen containing liposomes can be orally administered without an adjuvant to induce a systemic immune response. Moreover, the inventive methods do not generate an adjuvant effect, e.g., an inflammatory response or clumping of antigens.

The inventive method comprises first incorporating at least one antigen selected from inactivated HIV I and HIV II antigens into liposomes, preferably multilamellar liposomes having a size from about 20 nm to about 20 microns or greater, preferably from about 200 nm to about 10 microns and more preferably from about 1 micron to about 5 microns. The antigen-containing liposomes are then lyophilized and packaged in a suitable form, such as a pill or capsule, for oral ingestion. Means, such as an enteric coating are provided for preventing breakdown of the preparation in the stomach but allowing digestion in the gut, i.e., small intestine. Once orally ingested, the preparation passes through the stomach into the gut wherein antigen-containing liposomes are absorbed in the Peyer's patches of the gut. In the Peyer's patches, sufficient antigen-containing liposomes are taken up by macrophages to induce a systemic immune response and preferably a long-term systemic immune response to the antigen(s).

The invention further provides a preparation suitable for oral ingestion for inducing a systemic response, and preferably a long-term systemic immune response, to one or more antigens selected from inactivated HIV I and HIV II antigens. The composition comprises lyophilized, preferably multilamellar, liposomes that contain the antigen(s). The liposomes have a size, before lyophilization, of from about 20 nm to about 20 microns or greater, preferably from about 200 nm to about 10 microns, and more preferably from about one to about five microns. A particularly preferred composition comprises liposomes of varying sizes including small liposomes, i.e., about 20 mn to about 1 micron, medium liposomes, i.e., about 1 to about 3 microns, and large liposomes, i.e. about 3 to about 20 microns or greater and preferably about 3 to about 5 microns. It is presently preferred that such a composition comprise at least 5% by volume small liposomes, at least 10% by volume medium liposomes, and at least 20% by volume large liposomes. The composition preferably comprises means for preventing breakdown of the preparation in the stomach but for allowing digestion of the liposomes in the gut. In the gut, the liposomes are absorbed by Peyer's patches and sufficient liposomes are taken up by macrophages to stimulate a long term systemic immune response.

Claim 1 of 51 Claims

What is claimed is:

1. A method for stimulating a systemic immune response to an antigen selected from the group consisting of inactivated HIV I and HIV II antigens and combinations thereof in a mammal comprising:

providing a lipsomal preparation comprising lyophilized liposomes containing at least one antigen selected from the group consisting of inactivated HIV I and HIV II antigens, wherein the liposomes have at least three different sizes and consist essentially of:

at least 5% by volume, based on the total volume of liposomes in the preparation, small liposomes having a size, before lyophilization, of from about 20 nm to about 1 micron,

at least 5% by volume, based on the total volume of liposomes in the preparation, medium liposomes having a size, before lyophilization, of from about 1 micron to about 3 microns, and

at least 5% by volume, based on the total volume of liposomes in the preparation, large liposomes having a size, before lyophilization, of from about 3 microns to about 20 microns; and

orally administering an effective amount of the liposomal preparation to a mammal,

whereby sufficient antigen containing liposomes are absorbed in the Peyer's patches of the gut of the mammal and are taken up by macrophages in the Peyer's patches to stimulate a systemic immune response.

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