Immunological adjuvant compounds compositions and methods of...

Details Immunological adjuvant compounds compositions and methods of... Immunological adjuvant compounds compositions and methods of...

2001-07-30

2003-02-18

McKane, Joseph K. (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Phosphorus esters

C424S184100, C424S278100

Reexamination Certificate

active

06521776

ABSTRACT:

BACKGROUND OF THE INVENTION
Vaccines have proven to be successful, highly acceptable methods for the prevention of infectious diseases. They are cost effective, and do not induce antibiotic resistance to the target pathogen or affect normal flora present in the host. In many cases, such as when inducing antiviral immunity, vaccines can prevent a disease for which there are no viable curative or ameliorative treatments available.
Vaccines function by triggering the immune system to mount a response to an agent, or antigen, typically an infectious organism or a portion thereof that is introduced into the body in a non-infectious or non-pathogenic form. Once the immune system has been “primed” or sensitized to the organism, later exposure of the immune system to this organism as an infectious pathogen results in a rapid and robust immune response that destroys the pathogen before it can multiply and infect enough cells in the host organism to cause disease symptoms.
The agent, or antigen, used to prime the immune system can be the entire organism in a less infectious state, known as an attenuated organism, or in some cases, components of the organism such as carbohydrates, proteins or peptides representing various structural components of the organism, or nucleic acids encoding such components.
In many cases, it is necessary to enhance the immune response to the antigens present in a vaccine in order to stimulate the immune system to a sufficient extent to make a vaccine effective, i.e., to confer immunity. Many protein and most peptide and carbohydrate antigens, administered alone, do not elicit a sufficient antibody response to confer immunity. Such antigens need to be presented to the immune system in such a way that they will be recognized as foreign and will elicit an immune response. To this end, additives (adjuvants) have been devised which enhance the immune response.
The best known adjuvant, Freund's complete adjuvant, consists of a mixture of mycobacteria in an oil/water emulsion. Freund's adjuvant works in two ways: first, by enhancing cell and humoral-mediated immunity, and second, by blocking rapid dispersal of the antigen challenge (the “depot effect”). However, due to frequent toxic physiological and immunological reactions to this material, Freund's adjuvant cannot be used in humans.
Another molecule that has been shown to have immunostimulatory or adjuvant activity is endotoxin, also known as lipopolysaccharide (LPS). LPS stimulates the immune system by triggering an “innate” immune response—a response that has evolved to enable an organism to recognize endotoxin (and the invading bacteria of which it is a component) without the need for the organism to have been previously exposed. While LPS is too toxic to be a viable adjuvant, molecules that are structurally related to endotoxin, such as monophosphoryl lipid A (“MPL”) are being tested as adjuvants in clinical trials. Currently, however, the only FDA-approved adjuvant for use in humans is aluminum salts (Alum) which are used to “depot” antigens by precipitation of the antigens. Alum also stimulates the immune response to antigens.
Thus, there is a recognized need in the art for compounds which can be co-administered with antigens in order to stimulate the immune system to generate a more robust response to the antigen than would be seen if the antigen were injected alone or with Alum.
SUMMARY OF THE INVENTION
In one aspect, the invention provides novel compounds that are capable of enhancing an immune response in an animal when administered to the animal. In one embodiment, the compounds of the invention function as immunological adjuvants when co-administered with antigens, including antigens used as vaccines for any disease or condition amenable to vaccination. The novel adjuvant compounds of the invention have the formula I.
wherein
R
1
is selected from the group consisting of
(a) —C(O)—;
(b) —C(O)—C
1-14
alkylene-C(O)— or —C(O)—C
1-14
alkenylene-C(O)—, wherein the C
1-14
alkylene or C
1-14
alkenylene is optionally substituted with hydroxy, C
1-6
alkoxy, C
1-6
alkylenedioxy, carboxy, C
1-6
alkoxycarbonyl, C
1-6
carbamoyl, C
1-6
acylamino, C
1-6
alkylamino, or (aryl)C
1-6
alkyl, wherein said aryl moiety of said (aryl)C
1-6
alkyl is optionally substituted with C
1-6
alkyl, C
1-6
alkoxy, C
1-6
alkylamino, (C
1-6
alkoxy)C
1-6
alkylamino, (C
1-6
alkylamino)C
1-6
alkoxy, —O—C
1-6
alkylene-NH—C
1-6
alkylene-O—C
1-6
alkyl, —O—C
1-6
alkylene-NH—C(O)—C
1-6
alkylene-C(O)OH, or —O—C
1-6
alkylene-NH—C(O)—C
1-6
alkylene-C(O)—C
1-6
alkyl;
(c) C
2
to C
15
straight or branched chain alkyl optionally substituted with hydroxy or alkoxy; and
(d) —C(O)—C
6-12
arylene-C(O)— wherein said arylene is optionally substituted with C
1-6
alkyl, hydroxy, C
1-6
alkoxy, halogen, nitro or amino;
a and b are independently an integer from 0 to about 4;
d and e are independently an integer from 1 to about 6;
d′ and e′ are independently an integer from 0 to about 2;
X
1
and Y
1
are independently selected from the group consisting of a null, oxygen, —NH—, —N(C(O)C
1-4
alkyl)-, and —N(C
1-4
alkyl)-;
G
1
, G
2
, G
3
, and G
4
are independently selected from the group consisting of oxygen, methylene, —NH—, —N(C
1-4
alkyl)-, —N[C(O)—C
1-4
alkyl]-, —NH—C(O)—, —NH—SO
2
—, —C(O)—O—, —C(O)—NH—, —O—C(O)—, —O—C(O)—NH—, —O—C(O)—O—, —NH—C(O)—NH—, —C(O)NH—, C(O)N(C
1-4
alkyl), and —S(O)
n
—, where n is 0, 1, or 2;
R
2
, R
3
, R
4
, R
5
, R
6
, and R
7
are independently selected from the group consisting of:
(a) C
1
to C
20
straight chain or branched chain alkyl which is optionally substituted with halo, oxo, hydroxy or alkoxy;
(b) C
2
to C
20
straight chain or branched chain alkenyl, alkynyl, or dialkenyl which is optionally substituted with halo, oxo, hydroxy or alkoxy; and
 wherein
R
8
is C
1-6
straight or branched chain alkyl or C
2-6
straight or branched chain alkenyl, alkynyl, or dialkenyl;
G
5
is selected from the group consisting of oxygen, methylene, arylene, —NH—, —N(C
1-4
alkyl)-, —N(C(O)—C
1-4
alkyl)-, —NH—C(O)—, —NH—SO
2
—, —C(O)—O—, —C(O)—NH—, —O—C(O)—, —O—C(O)—NH—, —O—C(O)—O—, —NH—C(O)—NH—, and —S(O)
n
—, where n is 0, 1, or 2;
R
9
and R
10
are independently selected from the group consisting of
(i) C
1
to C
20
straight chain or branched chain alkyl which is optionally substituted with halo, oxo, hydroxy or alkoxy; and
(ii) C
2
to C
20
straight chain or branched chain alkenyl, alkynyl, or dialkenyl which is optionally substituted with halo, oxo, hydroxy or alkoxy;
 or any one or two of G
1
R
2
, G
2
R
4
, G
3
R
5
, and G
4
R
7
may together be a hydrogen atom or hydroxyl;
or a pharmaceutically acceptable salt thereof.
In a second aspect, the present invention is directed to novel immunological formulations which comprise at least one of the adjuvant compounds of the invention.
In a third aspect, the invention is directed to novel immunological compositions which comprise an antigen and at least one of the adjuvant compounds of the invention.
In another aspect, the present invention is directed to methods for enhancing an immune response in an animal, comprising administering to the animal a compound of the invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The invention provides novel compounds that are capable of enhancing an immune response in an animal when administered to the animal. In certain preferred embodiments, the compounds of the invention are capable of producing in immunological effect when administered alone. In certain other preferred embodiments, the compounds of the invention function as immunological adjuvants when co-administered with antigens, including antigens used as vaccines for any disease or condition amenable to vaccination. The invention also provides immunological compositions comprising the novel compounds of the invention and methods for immunizing humans and non-human animals.
The patent and scientific literature referred to herein establishes knowledge that is available to those with skill in the

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