VACCINES, VACCINE PRIMING, AND ANTIGEN DOSE SPARING
20230263886 · 2023-08-24
Inventors
Cpc classification
A61K39/215
HUMAN NECESSITIES
C12N2760/16134
CHEMISTRY; METALLURGY
A61K39/39
HUMAN NECESSITIES
C12N2770/20034
CHEMISTRY; METALLURGY
A61K31/704
HUMAN NECESSITIES
International classification
A61K39/39
HUMAN NECESSITIES
A61K39/215
HUMAN NECESSITIES
Abstract
The present application relates to new vaccines, improved vaccine priming, and antigen dose sparing in connection with triterpene glycoside saponin-derived adjuvants, salt forms thereof, and pharmaceutical compositions, as well as related methods.
Claims
1. A pharmaceutical composition for priming or antigen dose-sparing comprising an antigen, and a compound of Formula I ##STR00045## wherein is a single or double bond; W is CHO; V is hydrogen or ORx; Y is CH.sub.2, —O—, —NR—, or —NH—; Z is hydrogen; a cyclic or acyclic, optionally substituted moiety selected from the group consisting of acyl, aliphatic, heteroaliphatic, aryl, arylalkyl, heteroacyl, and heteroaryl; or a carbohydrate domain having the structure: 6 heteroaliphatic, 6-10-membered aryl, arylalkyl, 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, sulfur; 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; R2 is hydrogen, halogen, OH, OR, OC(O)R4, OC(O)OR4, OC(O)NHR4, OC(O)NRR4, OC(O)SR4, NHC(O)R4, NRC(O)R4, NHC(O)OR4, NHC(O)NHR4, NHC(O)NRR4, NHR4, N(R4).sub.2, NHR4, NRR4, N3, or an optionally substituted group selected from C1-10 aliphatic, C1-6 heteroaliphatic, 6-10-membered aryl, arylalkyl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; R3 is hydrogen, halogen, CH2OR1, or an optionally substituted group selected from the group consisting of acyl, C1-10 aliphatic, C1-6 heteroaliphatic, 6-10-membered aryl, arylalkyl, 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, R4 is -T-Rz, —C(O)-T-Rz, —NH-T-Rz, —O-T-Rz, —S-T-Rz, —C(O)NH-T-Rz, C(O)O-T-Rz, C(O)S-T-Rz, C(O)NH-T-O-T-Rz, —O-T-Rz, -T-O-T-Rz, -T-S-T-Rz, or ##STR00046## wherein X is —O—, —NR—, or T-Rz; T is a covalent bond or a bivalent C1-26 saturated or unsaturated, straight or branched, aliphatic or heteroaliphatic chain; and Rz is hydrogen, halogen, —OR, —ORx, —OR1, —SR, NR2, —C(O)OR, —C(O)R, —NHC(O)R, —NHC(O)OR, NC(O)OR, or an optionally substituted group selected from acyl, arylalkyl, heteroarylalkyl, C1-6 aliphatic, 6-10-membered aryl, 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; each occurrence of R.sup.x is independently hydrogen or an oxygen protecting group selected from the group consisting of alkyl ethers, benzyl ethers, silyl ethers, acetals, ketals, esters, carbamates, and carbonates; each occurrence of R is independently hydrogen, an optionally substituted group selected from acyl, arylalkyl, 6-10-membered aryl, C1-6 aliphatic, or C1-6 heteroaliphatic having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, or: two R on the same nitrogen atom are taken with the nitrogen atom to form a 4-7-membered heterocyclic ring having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. In one aspect, the present application provides compounds of Formula II: ##STR00047## or a pharmaceutically acceptable salt thereof, wherein
is a single or double bond; W is Me, —CHO, or ##STR00048## wherein each occurrence of R1 is Rx or a carbohydrate domain having the structure: ##STR00049## wherein: each occurrence of a, b, and c is independently 0, 1, or 2; d is an integer from 1-5, wherein each d bracketed structure may be the same or different; with the proviso that the d bracketed structure represents a furanose or a pyranose moiety, and the sum of b and c is 1 or 2; R0 is hydrogen; an oxygen protecting group selected from the group consisting of alkyl ethers, benzyl ethers, silyl ethers, acetals, ketals, esters, carbamates, and carbonates; or an optionally substituted moiety selected from the group consisting of acyl, C1-10 aliphatic, C1-6 heteroaliphatic, 6-10-membered aryl, arylalkyl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; each occurrence of Ra, Rb, Rc, and Rd is independently hydrogen, halogen, OH, OR, ORx, NR2, NHCOR, or an optionally substituted group selected from acyl, C1-10 aliphatic, C1- ##STR00050## V is hydrogen or ORx; Y is CH2, —O—, —NR—, or —NH—; Z is hydrogen; a cyclic or acyclic, optionally substituted moiety selected from the group consisting of acyl, aliphatic, heteroaliphatic, aryl, arylalkyl, heteroacyl, and heteroaryl; or a carbohydrate domain having the structure: ##STR00051## wherein each occurrence of R1 is Rx or a carbohydrate domain having the structure: ##STR00052## wherein: each occurrence of a, b, and c is independently 0, 1, or 2; d is an integer from 1-5, wherein each d bracketed structure may be the same or different; with the proviso that the d bracketed structure represents a furanose or a pyranose moiety, and the sum of b and c is 1 or 2; R0 is hydrogen; an oxygen protecting group selected from the group consisting of alkyl ethers, benzyl ethers, silyl ethers, acetals, ketals, esters, carbamates, and carbonates; or an optionally substituted moiety selected from the group consisting of acyl, C1-10 aliphatic, C1-6 heteroaliphatic, 6-10-membered aryl, arylalkyl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; each occurrence of Ra, Rb, Rc, and Rd is independently hydrogen, halogen, OH, OR, ORx, NR2, NHCOR, or an optionally substituted group selected from acyl, C1-10 aliphatic, C1-6 heteroaliphatic, 6-10-membered aryl, arylalkyl, 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, sulfur; 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; R2 is hydrogen, halogen, OH, OR, OC(O)R4, OC(O)OR4, OC(O)NHR4, OC(O)NRR4, OC(O)SR4, NHC(O)R4, NRC(O)R4, NHC(O)OR4, NHC(O)NHR4, NHC(O)NRR4, NHR4, N(R4).sub.2, NHR4, NRR4, N3, or an optionally substituted group selected from C1-10 aliphatic, C1-6 heteroaliphatic, 6-10-membered aryl, arylalkyl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; R3 is hydrogen, halogen, CH2OR1, or an optionally substituted group selected from the group consisting of acyl, C1-10 aliphatic, C1-6 heteroaliphatic, 6-10-membered aryl, arylalkyl, 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, R4 is -T-Rz, —C(O)-T-Rz, —NH-T-Rz, —O-T-Rz, —S-T-Rz, —C(O)NH-T-Rz, C(O)O-T-Rz, C(O)S-T-Rz, C(O)NH-T-O-T-Rz, —O-T-Rz, -T-O-T-Rz, -T-S-T-Rz, or ##STR00053## wherein X is —O—, —NR—, or T-Rz; T is a covalent bond or a bivalent C1-26 saturated or unsaturated, straight or branched, aliphatic or heteroaliphatic chain; and Rz is hydrogen, halogen, —OR, —ORx, —OR1, —SR, NR2, —C(O)OR, —C(O)R, —NHC(O)R, —NHC(O)OR, NC(O)OR, or an optionally substituted group selected from acyl, arylalkyl, heteroarylalkyl, C1-6 aliphatic, 6-10-membered aryl, 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; each occurrence of R.sup.x is independently hydrogen or an oxygen protecting group selected from the group consisting of alkyl ethers, benzyl ethers, silyl ethers, acetals, ketals, esters, carbamates, and carbonates; Ry is —OH, —OR, or a carboxyl protecting group selected from the group consisting of ester, amides, and hydrazides; Rs is ##STR00054## each occurrence of Rx′ is independently an optionally substituted group selected from 6-10-membered aryl, C1-6 aliphatic, or C1-6 heteroaliphatic having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; or: two Rx′ are taken together to form a 5-7-membered heterocyclic ring having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; each occurrence of R is independently hydrogen, an optionally substituted group selected from acyl, arylalkyl, 6-10-membered aryl, C1-6 aliphatic, or C1-6 heteroaliphatic having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, or: two R on the same nitrogen atom are taken with the nitrogen atom to form a 4-7-membered heterocyclic ring having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.
2. The pharmaceutical composition of claim 1, wherein the compound of Formula I is: ##STR00055##
3. The pharmaceutical composition of claim 1, wherein the amount of antigen provided is less than the amount of antigen required in the absence of the compound of Formula I.
4. The pharmaceutical composition of claim 1, wherein the amount of antigen provided is about 95%, 90%, 85%, 80%, 75%, 70%, 67%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 33%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.1% the amount of antigen required in the absence of the compound of Formula I.
5. The pharmaceutical composition of claim 1, wherein the antigen is associated with a bacteria or virus.
6. The pharmaceutical composition of claim 5, wherein the antigen is associated with influenza.
7. The pharmaceutical composition of claim 5, wherein the antigen is associated with SARS-CoV-2 virus.
8. The pharmaceutical composition of claim 5, wherein the antigen is associated with Varicella Zoster.
9. The pharmaceutical composition of claim 5, wherein the antigen is a combination of an antigen associated with influenza and an antigen associated with SARS-CoV-2 virus.
10. A method of providing a dose sparing effect, comprising providing a pharmaceutical composition according to claim 1.
11. A method of providing a vaccine priming effect, comprising providing a pharmaceutical composition according to claim 1.
12. A method of conferring resistance to an infection, the method comprising administering a pharmaceutical composition according to claim 1.
Description
BRIEF DESCRIPTION OF THE DRAWINGS
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DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS
[0139] Compounds
[0140] Compounds of this invention include those described generally above, and are further illustrated by the classes, subclasses, and species disclosed herein. In some embodiments, provided compounds are analogs of naturally occurring triterpene glycoside saponins and intermediates thereto. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. Additionally, general principles of organic chemistry are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito: 1999, and March's Advanced Organic Chemistry, 5th Ed., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.
[0141] In some embodiments, provided compounds are analogs of Quillaja saponins. In some embodiments, provided compounds are prosapogenins. In certain embodiments, provided compounds are analogs of QS-7 and QS-21 and possess potent adjuvant activity.
[0142] In one aspect, the present application provides compounds of Formula I:
##STR00012## [0143] or a pharmaceutically acceptable salt thereof, wherein [0144] is a single or double bond; [0145] W is —CHO; [0146] V is hydrogen or OR.sup.x; [0147] Y is CH.sub.2, —O—, —NR—, or —NH—; [0148] Z is hydrogen; a cyclic or acyclic, optionally substituted moiety selected from the group consisting of acyl, aliphatic, heteroaliphatic, aryl, arylalkyl, heteroacyl, and heteroaryl; or a carbohydrate domain having the structure:
##STR00013## [0149] wherein each occurrence of R.sup.1 is R.sup.x or a carbohydrate domain having the structure:
##STR00014## [0150] wherein: [0151] each occurrence of a, b, and c is independently 0, 1, or 2; [0152] d is an integer from 1-5, wherein each d bracketed structure may be the same or different; with the proviso that the d bracketed structure represents a furanose or a pyranose moiety, and the sum of b and c is 1 or 2; [0153] R.sup.0 is hydrogen; an oxygen protecting group selected from the group consisting of alkyl ethers, benzyl ethers, silyl ethers, acetals, ketals, esters, carbamates, and carbonates; or an optionally substituted moiety selected from the group consisting of acyl, C.sub.1-10 aliphatic, C.sub.1-6 heteroaliphatic, 6-10-membered aryl, arylalkyl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; [0154] each occurrence of R.sup.a, R.sup.b, R.sup.c, and R.sup.d is independently hydrogen, halogen, OH, OR, OR.sup.x, NR.sub.2, NHCOR, or an optionally substituted group selected from acyl, C.sub.1-10 aliphatic, C.sub.1-6 heteroaliphatic, 6-10-membered aryl, arylalkyl, 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, sulfur; 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; [0155] R.sup.2 is hydrogen, halogen, OH, OR, OC(O)R.sup.4, OC(O)OR.sup.4, OC(O)NHR.sup.4, OC(O)NRR.sup.4, OC(O)SR.sup.4, NHC(O)R.sup.4, NRC(O)R.sup.4, NHC(O)OR.sup.4, NHC(O)NHR.sup.4, NHC(O)NRR.sup.4, NHR.sup.4, N(R.sup.4).sub.2, NHR.sup.4, NRR.sup.4, N.sub.3, or an optionally substituted group selected from C.sub.1-10 aliphatic, C.sub.1-6 heteroaliphatic, 6-10-membered aryl, arylalkyl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; [0156] R.sup.3 is hydrogen, halogen, CH.sub.2OR.sup.1, or an optionally substituted group selected from the group consisting of acyl, C.sub.1-10 aliphatic, C.sub.1-6 heteroaliphatic, 6-10-membered aryl, arylalkyl, 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, [0157] R.sup.4 is -T-R.sup.z, —C(O)-T-R.sup.z, —NH-T-R.sup.z, —O-T-R.sup.z, —S-T-R.sup.z, —C(O)NH-T-R.sup.z, C(O)O-T-R.sup.z, C(O)S-T-R.sup.z, C(O)NH-T-O-T-R.sup.z, —O-T-R.sup.z, -T-O-T-R.sup.z, -T-S-T-R.sup.z, or
##STR00015## [0158] wherein [0159] X is —O—, —NR—, or T-R.sup.z; [0160] T is a covalent bond or a bivalent C.sub.1-26 saturated or unsaturated, straight or branched, aliphatic or heteroaliphatic chain; and [0161] R.sup.z is hydrogen, halogen, —OR, —OR.sup.x, —OR.sup.1, —SR, NR.sub.2, —C(O)OR, —C(O)R, —NHC(O)R, —NHC(O)OR, NC(O)OR, or an optionally substituted group selected from acyl, arylalkyl, heteroarylalkyl, C.sub.1-6 aliphatic, 6-10-membered aryl, 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; [0162] each occurrence of R.sup.x is independently hydrogen or an oxygen protecting group selected from the group consisting of alkyl ethers, benzyl ethers, silyl ethers, acetals, ketals, esters, carbamates, and carbonates; [0163] each occurrence of R is independently hydrogen, an optionally substituted group selected from acyl, arylalkyl, 6-10-membered aryl, C.sub.1-6 aliphatic, or C.sub.1-6 heteroaliphatic having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, or: [0164] two R on the same nitrogen atom are taken with the nitrogen atom to form a 4-7-membered heterocyclic ring having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.
[0165] In one aspect, the present application provides compounds of Formula II:
##STR00016## [0166] or a pharmaceutically acceptable salt thereof, wherein [0167] a single or double bond; [0168] W is Me, —CHO, or
##STR00017## [0169] V is hydrogen or OR.sup.x; [0170] Y is CH.sub.2, —O—, —NR—, or —NH—; [0171] Z is hydrogen; a cyclic or acyclic, optionally substituted moiety selected from the group consisting of acyl, aliphatic, heteroaliphatic, aryl, arylalkyl, heteroacyl, and heteroaryl; or a carbohydrate domain having the structure:
##STR00018## [0172] wherein each occurrence of R.sup.1 is R.sup.x or a carbohydrate domain having the structure:
##STR00019## [0173] wherein: [0174] each occurrence of a, b, and c is independently 0, 1, or 2; [0175] d is an integer from 1-5, wherein each d bracketed structure may be the same or different; with the proviso that the d bracketed structure represents a furanose or a pyranose moiety, and the sum of b and c is 1 or 2; [0176] R.sup.0 is hydrogen; an oxygen protecting group selected from the group consisting of alkyl ethers, benzyl ethers, silyl ethers, acetals, ketals, esters, carbamates, and carbonates; or an optionally substituted moiety selected from the group consisting of acyl, C.sub.1-10 aliphatic, C.sub.1-6 heteroaliphatic, 6-10-membered aryl, arylalkyl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; [0177] each occurrence of R.sup.a, R.sup.b, R.sup.c, and R.sup.d is independently hydrogen, halogen, OH, OR, OR.sup.x, NR.sub.2, NHCOR, or an optionally substituted group selected from acyl, C.sub.1-10 aliphatic, C.sub.1-6 heteroaliphatic, 6-10-membered aryl, arylalkyl, 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, sulfur; 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; [0178] R.sup.2 is hydrogen, halogen, OH, OR, OC(O)R.sup.4, OC(O)OR.sup.4, OC(O)NHR.sup.4, OC(O)NRR.sup.4, OC(O)SR.sup.4, NHC(O)R.sup.4, NRC(O)R.sup.4, NHC(O)OR.sup.4, NHC(O)NHR.sup.4, NHC(O)NRR.sup.4, NHR.sup.4, N(R.sup.4).sub.2, NHR.sup.4, NRR.sup.4, N.sub.3, or an optionally substituted group selected from C.sub.1-10 aliphatic, C.sub.1-6 heteroaliphatic, 6-10-membered aryl, arylalkyl, 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; [0179] R.sup.3 is hydrogen, halogen, CH.sub.2OR.sup.1, or an optionally substituted group selected from the group consisting of acyl, C.sub.1-10 aliphatic, C.sub.1-6 heteroaliphatic, 6-10-membered aryl, arylalkyl, 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, [0180] R.sup.4 is -T-R.sup.z, —C(O)-T-R.sup.z, —NH-T-R.sup.z, —O-T-R.sup.z, —S-T-R.sup.z, —C(O)NH-T-R.sup.z, C(O)O-T-R.sup.1, C(O)S-T-R.sup.z, C(O)NH-T-O-T-R.sup.z, —O-T-R.sup.z, -T-O-T-R.sup.z, -T-S-T-R.sup.z, or
##STR00020## [0181] wherein [0182] X is —O—, —NR—, or T-R.sup.z; [0183] T is a covalent bond or a bivalent C.sub.1-26 saturated or unsaturated, straight or branched, aliphatic or heteroaliphatic chain; and [0184] R.sup.z is hydrogen, halogen, —OR, —OR.sup.x, —OR.sup.1, —SR, NR.sub.2, —C(O)OR, —C(O)R, —NHC(O)R, —NHC(O)OR, NC(O)OR, or an optionally substituted group selected from acyl, arylalkyl, heteroarylalkyl, C.sub.1-6 aliphatic, 6-10-membered aryl, 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; [0185] each occurrence of R.sup.x is independently hydrogen or an oxygen protecting group selected from the group consisting of alkyl ethers, benzyl ethers, silyl ethers, acetals, ketals, esters, carbamates, and carbonates; [0186] R.sup.y is —OH, —OR, or a carboxyl protecting group selected from the group consisting of ester, amides, and hydrazides; [0187] R.sup.s is
##STR00021## [0188] each occurrence of R.sup.x′ is independently an optionally substituted group selected from 6-10-membered aryl, C.sub.1-6 aliphatic, or C.sub.1-6 heteroaliphatic having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; or: [0189] two R.sup.x′ are taken together to form a 5-7-membered heterocyclic ring having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; [0190] each occurrence of R is independently hydrogen, an optionally substituted group selected from acyl, arylalkyl, 6-10-membered aryl, C.sub.1-6 aliphatic, or C.sub.1-6 heteroaliphatic having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, or: [0191] two R on the same nitrogen atom are taken with the nitrogen atom to form a 4-7-membered heterocyclic ring having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.
[0192] In one aspect, the present application provides compounds of Formula I:
##STR00022##
or a pharmaceutically acceptable salt thereof, wherein [0193] is a single or double bond; [0194] W is —CHO; [0195] V is —OH; [0196] Y is —O—; [0197] wherein Z is a carbohydrate domain having the structure:
##STR00023## [0198] wherein: [0199] R.sup.1 is independently H or
##STR00024## [0200] R.sup.2 is NHR.sup.4; [0201] R.sup.3 is CH.sub.2OH; and [0202] R.sup.4 is -T-R.sup.z, —C(O)-T-R.sup.z, —NH-T-R.sup.z, —O-T-R.sup.z, —S-T-R.sup.z, —C(O)NH-T-R.sup.z, C(O)O-T-R.sup.z, C(O)S-T-R.sup.z, C(O)NH-T-O-T-R.sup.z, —O-T-R.sup.z, -T-O-T-R.sup.z, -T-S-T-R.sup.z, or
##STR00025## [0203] wherein: [0204] X is —O—, —NR—, or T-R.sup.z; [0205] T is a covalent bond or a bivalent C.sub.1-26 saturated or unsaturated, straight or branched, aliphatic or heteroaliphatic chain; and [0206] R.sup.z is hydrogen, halogen, —OR, —OR.sup.x, —OR.sup.1, —SR, NR.sub.2, —C(O)OR, —C(O)R, —NHC(O)R, —NHC(O)OR, NC(O)OR, or an optionally substituted group selected from acyl, arylalkyl, heteroarylalkyl, C.sub.1-6 aliphatic, 6-10-membered aryl, 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.
[0207] It will be appreciated by one of ordinary skill in the art that the compounds of the present application include but are not necessarily limited to those compounds encompassed in the genus definitions set forth as part of the present section. The compounds encompassed by this application include at least all of the compounds disclosed in the entire specification as a whole, including all individual species within each genus.
[0208] In certain embodiments, V is OR.sup.x. In certain embodiments V is OH. In certain embodiments, V is H.
[0209] In certain embodiments, Y is —O—. In certain embodiments, Y is —NH—. In certain embodiments, Y is —NR—. In certain embodiments, Y is CH.sub.2.
[0210] In certain embodiments, Z is hydrogen. In certain embodiments, Z is a cyclic or acyclic, optionally substituted moiety. In certain embodiments, Z is an acyl. In certain embodiments, Z is an aliphatic. In certain embodiments, Z is a heteroaliphatic. In certain embodiments, Z is aryl. In certain embodiments Z is arylalkyl. In certain embodiments, Z is heteroacyl. In certain embodiments, Z is heteroaryl. In certain embodiments, Z is a carbohydrate domain having the structure:
##STR00026##
[0211] In some embodiments Z is a carbohydrate domain having the structure:
##STR00027## [0212] wherein: [0213] R.sup.1 is independently H or
##STR00028## [0214] R.sup.2 is NHR.sup.4, [0215] R.sup.3 is CH.sub.2OH, and [0216] R.sup.4 is selected from:
##STR00029##
[0217] In some embodiments, R.sup.1 is R.sup.x. In other embodiments, R.sup.1 a carbohydrate domain having the structure:
##STR00030##
[0218] In some aspects, each occurrence of a, b, and c is independently 0, 1, or 2. In some embodiments, d is an integer from 1-5. In some embodiments, each d bracketed structure may be the same. In some embodiments, each d bracketed structure may be different. In some embodiments, the d bracketed structure represents a furanose or a pyranose moiety. In some embodiments, and the sum of b and c is 1 or 2.
[0219] In some embodiments, R.sup.0 is hydrogen. In some embodiments, R.sup.0 is an oxygen protecting group selected from the group. In some embodiments, R.sup.0 is an alkyl ether. In some embodiments, R.sup.0 is a benzyl ether. In some embodiments, R.sup.0 is a silyl ether. In some embodiments, R.sup.0 is an acetal. In some embodiments, R.sup.0 is ketal. In some embodiments, R.sup.0 is an ester. In some embodiments, R.sup.0 is a carbamate. In some embodiments, R.sup.0 is a carbonate. In some embodiments, R.sup.0 is an optionally substituted moiety. In some embodiments, R.sup.0 is an acyl. In some embodiments, R.sup.0 is a C.sub.1-10 aliphatic. In some embodiments, R.sup.0 is a C.sub.1-6 heteroaliphatic. In some embodiments, R.sup.0 is a 6-10-membered aryl. In some embodiments, R.sup.0 is an arylalkyl. In some embodiments, R.sup.0 is a 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R.sup.0 is a 4-7 membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.
[0220] In some embodiments, R.sup.a is hydrogen. In some embodiments, R.sup.a is a halogen. In some embodiments, R.sup.a is OH. In some embodiments, R.sup.a is OR. In some embodiments, R.sup.a is OR.sup.x. In some embodiments, R.sup.a is NR.sub.2. In some embodiments, R.sup.a is NHCOR. In some embodiments, R.sup.a an acyl. In some embodiments, R.sup.a is C.sub.1-10 aliphatic. In some embodiments, R.sup.a is C.sub.1-6 heteroaliphatic. In some embodiments, R.sup.a is 6-10-membered aryl. In some embodiments, R.sup.a is arylalkyl. In some embodiments, R.sup.a is 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, sulfur. In some embodiments, R.sup.a is 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.
[0221] In some embodiments, R.sup.b is hydrogen. In some embodiments, R.sup.b is a halogen. In some embodiments, R.sup.b is OH. In some embodiments, R.sup.b is OR. In some embodiments, R.sup.b is OR.sup.x. In some embodiments, R.sup.b is NR.sub.2. In some embodiments, R.sup.b is NHCOR. In some embodiments, R.sup.b an acyl. In some embodiments, R.sup.b is C.sub.1-10 aliphatic. In some embodiments, R.sup.b is C.sub.1-6 heteroaliphatic. In some embodiments, R.sup.b is 6-10-membered aryl. In some embodiments, R.sup.b is arylalkyl. In some embodiments, R.sup.b is 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, sulfur. In some embodiments, R.sup.b is 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.
[0222] In some embodiments, R.sup.b is hydrogen. In some embodiments, R.sup.b is a halogen. In some embodiments, R.sup.b is OH. In some embodiments, R.sup.b is OR. In some embodiments, R.sup.b is OR.sup.x. In some embodiments, R.sup.b is NR.sub.2. In some embodiments, R.sup.b is NHCOR. In some embodiments, R.sup.b an acyl. In some embodiments, R.sup.b is C.sub.1-10 aliphatic. In some embodiments, R.sup.b is C.sub.1-6 heteroaliphatic. In some embodiments, R.sup.b is 6-10-membered aryl. In some embodiments, R.sup.b is arylalkyl. In some embodiments, R.sup.b is 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, sulfur. In some embodiments, R.sup.b is 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.
[0223] In some embodiments, R.sup.c is hydrogen. In some embodiments, R.sup.c is a halogen. In some embodiments, R.sup.c is OH. In some embodiments, R.sup.c is OR. In some embodiments, R.sup.c is OR.sup.x. In some embodiments, R.sup.c is NR.sub.2. In some embodiments, R.sup.c is NHCOR. In some embodiments, R.sup.c an acyl. In some embodiments, R.sup.c is C.sub.1-10 aliphatic. In some embodiments, R.sup.c is C.sub.1-6 heteroaliphatic. In some embodiments, R.sup.c is 6-10-membered aryl. In some embodiments, R.sup.c is arylalkyl. In some embodiments, R.sup.c is 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, sulfur. In some embodiments, R.sup.c is 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.
[0224] In some embodiments, R.sup.d is hydrogen. In some embodiments, R.sup.d is a halogen. In some embodiments, R.sup.d is OH. In some embodiments, R.sup.d is OR. In some embodiments, R.sup.d is OR.sup.x. In some embodiments, R.sup.d is NR.sub.2. In some embodiments, R.sup.d is NHCOR. In some embodiments, R.sup.d an acyl. In some embodiments, R.sup.d is C.sub.1-10 aliphatic. In some embodiments, R.sup.d is C.sub.1-6 heteroaliphatic. In some embodiments, R.sup.d is 6-10-membered aryl. In some embodiments, R.sup.d is arylalkyl. In some embodiments, R.sup.d is 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, sulfur. In some embodiments, R.sup.d is 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.
[0225] In some embodiments, R.sup.2 is hydrogen. In some embodiments, R.sup.2 is a halogen. In some embodiments, R.sup.2 is OH. In some embodiments, R.sup.2 is OR. In some embodiments, R.sup.2 is OC(O)R.sup.4. In some embodiments, R.sup.2 is OC(O)OR.sup.4. In some embodiments, R.sup.2 is OC(O)NHR.sup.4. In some embodiments, R.sup.2 is OC(O)NRR.sup.4. In some embodiments, R.sup.2 is OC(O)SR.sup.4. In some embodiments, R.sup.2 is NHC(O)R.sup.4. In some embodiments, R.sup.2 is NRC(O)R.sup.4. In some embodiments, R.sup.2 is NHC(O)OR.sup.4. In some embodiments, R.sup.2 is NHC(O)NHR.sup.4. In some embodiments, R.sup.2 is NHC(O)NRR.sup.4. In some embodiments, R.sup.2 is NHR.sup.4. In some embodiments, R.sup.2 is N(R.sup.4).sub.2. In some embodiments, R.sup.2 is NHR.sup.4, In some embodiments, R.sup.2 is NRR.sup.4. In some embodiments, R.sup.2 is N.sub.3. In some embodiments, R.sup.2 is C.sub.1-10 aliphatic. In some embodiments, R.sup.2 is C.sub.1-6 heteroaliphatic. In some embodiments, R.sup.2 is 6-10-membered aryl. In some embodiments, R.sup.2 is arylalkyl. In some embodiments, R.sup.2 is 5-10 membered heteroaryl having 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, R.sup.2 is 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.
[0226] In some embodiments, R.sup.3 is hydrogen. In some embodiments, R.sup.3 is a halogen. In some embodiments, R.sup.3 is CH.sub.2OR.sup.1. In some embodiments, R.sup.3 is an acyl. In some embodiments, R.sup.3 is C.sub.1-10 aliphatic. In some embodiments, R.sup.3 is C.sub.1-6 heteroaliphatic. In some embodiments, R.sup.3 is 6-10-membered aryl. In some embodiments, R.sup.3 is arylalkyl. In some embodiments, R.sup.3 is 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, R.sup.3 is 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.
[0227] In some embodiments, R.sup.4 is -T-R.sup.z. In some embodiments, R.sup.4 is —C(O)-T-R.sup.z. In some embodiments, R.sup.4 is —NH-T-R.sup.z. In some embodiments, R.sup.4 is —O-T-R.sup.z. In some embodiments, R.sup.4 is —S-T-R.sup.z. In some embodiments, R.sup.4 is —C(O)NH-T-R.sup.z. In some embodiments, R.sup.4 is C(O)O-T-R.sup.z. In some embodiments, R.sup.4 is C(O)S-T-R.sup.z. In some embodiments, R.sup.4 is C(O)NH-T-O-T-R.sup.z. In some embodiments, R.sup.4 is —O-T-R.sup.z. In some embodiments, R.sup.4 is -T-O-T-R.sup.z. In some embodiments, R.sup.4 is -T-S-T-R.sup.z. In some embodiments, R.sup.4 is
##STR00031##
[0228] In some embodiments, X is —O—. In some embodiments, X is —NR—. In some embodiments, X is T-R.sup.z.
[0229] In some embodiments, T is a covalent bond or a bivalent C.sub.1-26 saturated or unsaturated, straight or branched, aliphatic or heteroaliphatic chain.
[0230] In some embodiments, R.sup.z is hydrogen. In some embodiments, R.sup.z is a halogen. In some embodiments, R.sup.z is —OR. In some embodiments, R.sup.z is —OR.sup.x. In some embodiments, R.sup.z is —OR.sup.1. In some embodiments, R.sup.z is —OR.sup.1′. In some embodiments, R.sup.z is —SR. In some embodiments, R.sup.z is NR.sub.2. In some embodiments, R.sup.z is —C(O)OR. In some embodiments, R.sup.z is —C(O)R. In some embodiments, R.sup.z is —NHC(O)R. In some embodiments, R.sup.z is —NHC(O)OR. In some embodiments, R.sup.z is NC(O)OR. In some embodiments, R.sup.z is an acyl. In some embodiments, R.sup.z is arylalkyl. In some embodiments, R.sup.z is heteroarylalkyl. In some embodiments, R.sup.z is C.sub.1-6 aliphatic. In some embodiments, R.sup.z is 6-10-membered aryl. In some embodiments, R.sup.z is 5-10-membered heteroaryl having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In some embodiments, R.sup.z is 4-7-membered heterocyclyl having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.
[0231] In some embodiments, R.sup.x is hydrogen. In some embodiments, R.sup.x is an oxygen protecting group. In some embodiments, R.sup.x is an alkyl ether. In some embodiments, R.sup.x is a benzyl ether. In some embodiments, R.sup.x is silyl ether. In some embodiments, R.sup.x is an acetal. In some embodiments, R.sup.x is ketal. In some embodiments, R.sup.x is ester. In some embodiments, R.sup.x is carbamate. In some embodiments, R.sup.x is carbonate.
[0232] In some embodiments, R.sup.y is —OH. In some embodiments, R.sup.y is —OR. In some embodiments, R.sup.y is a carboxyl protecting group. In some embodiments, R.sup.y is an ester. In some embodiments, R.sup.y is an amide. In some embodiments, R.sup.y is a hydrazide.
[0233] In some embodiments, R.sup.s is
##STR00032##
[0234] In some embodiments, R.sup.x is optionally substituted 6-10-membered aryl. In some embodiments, R.sup.x′ is optionally substituted C.sub.1-6 aliphatic. In some embodiments, R.sup.x′ is optionally substituted or C.sub.1-6 heteroaliphatic having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, two R.sup.x′ are taken together to form a 5-7-membered heterocyclic ring having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.
[0235] In some embodiments, R is hydrogen. In some embodiments, R is an acyl. In some embodiments, R is arylalkyl. In some embodiments, R is 6-10-membered aryl. In some embodiments, R is C.sub.1-6 aliphatic. In some embodiments, R is C.sub.1-6 heteroaliphatic having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, two R on the same nitrogen atom are taken with the nitrogen atom to form a 4-7-membered heterocyclic ring having 1-2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur.
[0236] In some embodiments, R.sup.1′ has the same embodiments as R.sup.1.
[0237] Exemplary compounds of Formula I are set forth in Table 1 below:
TABLE-US-00001 TABLE 1 EXEMPLARY COMPOUNDS OF FORMULA I
[0238] It will be appreciated that it is not an object of the present subject matter to claim compounds disclosed in the prior art that are the result of isolation or degradation studies on naturally occurring prosapogenins or saponins.
[0239] Synthesis
[0240] The compounds of the present application may be synthesized as provided in PCT/US2009/039954, PCT/US2015/33567, PCT/US2016/67530, PCT/US2016/60564, and/or PCT/US2018/027462.
[0241] Adjuvants
[0242] The present application encompasses the recognition that synthetic access to and structural modification of QS-21 and related Quillaja saponins may afford compounds with high adjuvant potency and low toxicity, as well as having more stability and being more cost effective. Accordingly, compounds of the present application, including TQL-1055, have industrial applicability and are useful as adjuvants, in free form acid or base form or in pharmaceutically acceptable salt form.
[0243] Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.
[0244] In other cases, the compounds of the present invention may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically-acceptable salts with pharmaceutically acceptable bases. The term “pharmaceutically acceptable salts” in these instances refers to the relatively non-toxic, inorganic and organic base addition salts of compounds of the present invention. These salts can likewise be prepared in situ in the administration vehicle or the dosage form manufacturing process, or by separately reacting the purified compound in its free acid form with a suitable base, such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C.sub.1-4alkyl).sub.4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate. Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like.
[0245] Further pharmaceutically acceptable salts include, when appropriate, choline, L-lysine, magnesium, meglumine, potassium, sodium, and TEA.
[0246] Certain embodiments of the present application include salt forms of synthetic saponin-derived adjuvants. In some embodiments, the adjuvants are compounds of Formula I as described herein. In some embodiments, the adjuvant is the compound TQL-1055.
Vaccines
[0247] Compositions in this application and their pharmaceutically acceptable salts are useful as vaccines to induce active immunity towards antigens in subjects. Any animal that may experience the beneficial effects of the compositions of the present application is within the scope of subjects that may be treated. In some embodiments, the subjects are mammals. In some embodiments, the subjects are humans.
[0248] The vaccines of the present application may be used to confer resistance to infection by either passive or active immunization. When the vaccines of the present application are used to confer resistance through active immunization, a vaccine of the present application is administered to an animal to elicit a protective immune response which either prevents or attenuates a proliferative or infectious disease. When the vaccines of the present application are used to confer resistance to infection through passive immunization, the vaccine is provided to a host animal (e.g., human, dog, or mouse), and the antisera elicited by this vaccine is recovered and directly provided to a recipient suspected of having an infection or disease or exposed to a causative organism.
[0249] The present application thus concerns and provides a means for preventing or attenuating a proliferative disease resulting from organisms which have antigens that are recognized and bound by antisera produced in response to the immunogenic antigens included in vaccines of the present application. As used herein, a vaccine is said to prevent or attenuate a disease if its administration to an animal results either in the total or partial attenuation (i.e., suppression) of a symptom or condition of the disease, or in the total or partial immunity of the animal to the disease.
[0250] The administration of the vaccine (or the antisera which it elicits) may be for either a “prophylactic” or “therapeutic” purpose. When provided prophylactically, the vaccine(s) are provided in advance of any symptoms of proliferative disease. The prophylactic administration of the vaccine(s) serves to prevent or attenuate any subsequent presentation of the disease. When provided therapeutically, the vaccine(s) is provided upon or after the detection of symptoms which indicate that an animal may be infected with a pathogen. The therapeutic administration of the vaccine(s) serves to attenuate any actual disease presentation. Thus, the vaccines may be provided either prior to the onset of disease proliferation (so as to prevent or attenuate an anticipated infection) or after the initiation of an actual proliferation.
[0251] One of ordinary skill in the art will appreciate that vaccines may optionally include a pharmaceutically acceptable excipient or carrier. Thus, according to another aspect, provided vaccines may comprise one or more antigens that are optionally conjugated to a pharmaceutically acceptable excipient or carrier. In some embodiments, said one or more antigens are conjugated covalently to a pharmaceutically acceptable excipient. In other embodiments, said one or more antigens are non-covalently associated with a pharmaceutically acceptable excipient.
[0252] As described above, adjuvants may be used to increase the immune response to an antigen. According to the present application, provided vaccines may be used to invoke an immune response when administered to a subject. In certain embodiments, an immune response to an antigen may be potentiated by administering to a subject a provided vaccine in an effective amount to potentiate the immune response of said subject to said antigen.
Formulations
[0253] The compounds of the present application and/or their salts may be combined with a pharmaceutically acceptable excipient to form a pharmaceutical composition. In certain embodiments, formulations of the present application include injectable formulations. In certain embodiments, the pharmaceutical composition includes a pharmaceutically acceptable amount of a compound of the present application. In certain embodiments, the compounds of the application and an antigen form an active ingredient. In certain embodiments, the compound of the present application alone forms an active ingredient. The amount of active ingredient(s) which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, and the particular mode of administration. The amount of active ingredient(s) that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, this amount will range from about 1% to about 99% of active ingredient, preferably from about 5% to about 70%, most preferably from about 10% to about 30%, or from about 1% to 99%, preferably from 10% to 90%, 20% to 80%, 30% to 70%, 40% to 60%, 45% to 55%, or about 50%.
[0254] Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
[0255] Thus, in one aspect the present application provides formulations comprising a liposome formulation of MPL and Compound 1-4. In another aspect the present application provides formulations comprising MPL, Compound 1-4, and a squalene emulsion. In another aspect the present application provides formulations comprising MPL, Compound 1-4, and CpG 7909 or CpG 1018. MPL is a heterogeneous mixture of molecules from a biological source including both agonists and antagonists for TLR4. CpG 7909 is an immunomodulating synthetic oligonucleotide designed to specifically agonise the Toll-like receptor 9 (TLR9).
[0256] Liposomal formulations of MPL and naturally occurring QS-21 are formulated, for example, by first producing liposomes by mixing methanol and a cholesterol. Liposomes are closed bilayer membranes containing an entrapped aqueous volume. Liposomes may also be uni-lamellar vesicles possessing a single membrane bilayer or multi-lamellar vesicles with multiple membrane bilayers, each separated from the next by an aqueous layer. The structure of the resulting membrane bilayer is such that the hydrophobic (non-polar) tails of the lipid are oriented toward the center of the bilayer while the hydrophilic (polar) heads orient towards the aqueous phase. Suitable hydrophilic polymers for surrounding the liposomes include, without limitation, PEG, polyvinylpyrrolidone, polyvinylmethylether, polymethyloxazoline, polyethyloxazoline, polyhydroxypropyloxazoline, polyhydroxypropylmethacrylamide, polymethacrylamide, polydimethylacrylamide, polyhydroxypropylmethacrylate, polyhydroxethylacrylate, hydroxymethylcellulose, hydroxyethylcellulose, polyethyleneglycol, polyaspartamide and hydrophilic peptide sequences as described in U.S. Pat. Nos. 6,316,024; 6, 126,966; 6,056,973; and 6,043,094. Liposomes can be made without hydrophilic polymers. Therefore, liposome formulations may or may not contain hydrophilic polymers.
[0257] Liposomes may be comprised of any lipid or lipid combination known in the art. For example, the vesicle-forming lipids may be naturally-occurring or synthetic lipids, including phospholipids, such as phosphatidylcholine, phosphatidylethanolamine, phosphatide acid, phosphatidylserine, phosphatidylglycerol, phosphatidylinositol, and sphingomyelin as disclosed in U.S. Pat. Nos. 6,056,973 and 5,874,104.
[0258] The vesicle-forming lipids may also be glycolipids, cerebrosides, or cationic lipids, such as I,2-dioleyloxy-3-(trimethylamino)propane (DOTAP); N-[I-(2,3,-ditetradecyloxy)propyl]-N,N-dimethyl-N-hydroxyethylammonium bromide (DMRIE); N-[I [(2,3,-dioleyloxy)propyl]-N,N-dimethyl-N-hydroxy ethylammonium bromide (DORIE); N-[I-(2,3-dioleyloxy)propyl]-N,N,N-trimethylammonium chloride (DOTMA); 3 [N-(N′,N′-dimethylaminoethane) carbamoly] cholesterol (DCChol); or dimethyldioctadecylammonium (DDAB) also as disclosed in U.S. Pat. No. 6,056,973. Cholesterol may also be present in the proper range to impart stability to the liposome vesicle, as disclosed in U.S. Pat. Nos. 5,916,588 and 5,874,104. Additional liposomal technologies are described in U.S. Pat. Nos. 6,759,057; 6,406,713; 6,352,716; 6,316,024; 6,294,191; 6,126,966; 6,056,973; 6,043,094; 5,965,156; 5,916,588; 5,874,104; 5,215,680; and 4,684,479. These described liposomes and lipid-coated microbubbles, and methods for their manufacture. Thus, one skilled in the art, considering both the present disclosure and the disclosures of these other patents could produce a liposome for the purposes of the present embodiments. Liposomes may comprise phospholipid or nonphospholipid bilayers. Phospholipid bilayers may comprise hydrocarbon chains, optionally having a melting temperature in water of at least 23° C. Such phospholipids may comprise, for example, dimyristoyl phosphatidylcholine (DMPC), dimyristoyl phosphatidylglycerol (DMPG), cholesterol (Chol), or similar molecules, and mixtures thereof. The liposome may optionally comprise a neutral lipid that is non-crystalline at room temperature, such as dioleoyl phosphatidylcholine or similar compounds. See U.S. Published Patent Application No. 2011/0206758.
[0259] During manufacture of liposomal formulations containing, for example, QS-21, small unicellular liposomal vesicles (SUV) are first created. The SUV is then added to an aqueous environment having QS-21 or another saponin and the SUV takes up QS-21 or the saponin from the aqueous environment. The liposomal composition also may have certain optional ingredients, such as for example MPL, synthetic MPL such as MPLA, CpG 7909 or CpG 1018, or similar substances.
[0260] However, formulation of liposomal formulations containing other saponin derivatives such as Compound 1-4 surprisingly cannot be accomplished using procedures known in the art, because the SUV or liposomal formulations do not take up such saponin derivatives, resulting in SUV or liposomes without the saponin derivative molecule Thus, another aspect of the present application provides a novel method of producing liposomal formulations of saponin derivates that cannot be formulated using traditional methods. In such a method, the SUVs or liposomes are first formulated with the presence of a saponin derivative such as Compound 1-4. For example, the SUV may be formulated by combining a lipid such as a cholesterol and methanol in the presence of Compound 1-4. The SUV may also be formulated according to the traditional method as set forth above; however, the SUV is formulated in the presence of a saponin derivative such as QS-21. These SUV or liposomes form with Compound 1-4 incorporated therein. Such SUV or liposomes are then added to an aqueous environment having, for example, MPL or other compositions as set forth above.
[0261] Non-limiting examples of pharmaceutically-acceptable antioxidants include: water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
[0262] Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
[0263] Non-limiting examples of suitable aqueous and nonaqueous carriers, which may be employed in the pharmaceutical compositions of the present application include water, alcohols (including but not limited to methanol, ethanol, butanol, etc.), polyols (including but not limited to glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
[0264] These compositions may also contain additives such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms upon the subject compounds may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
[0265] In some cases, in order to prolong the effect of a formulation, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which in turn, may depend upon crystal size and crystalline form.
[0266] Regardless of the route of administration selected, the compounds of the present application, which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present application, are formulated into pharmaceutically-acceptable dosage forms by conventional methods known to those of skill in the art.
[0267] Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present application may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
[0268] The selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present application employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
[0269] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds of the present application employed in the pharmaceutical composition at levels lower than that required to achieve the desired therapeutic effect and then gradually increasing the dosage until the desired effect is achieved.
[0270] In some embodiments, a compound or pharmaceutical composition of the present application is provided to a subject chronically. Chronic treatments include any form of repeated administration for an extended period of time, such as repeated administrations for one or more months, between a month and a year, one or more years, or longer. In many embodiments, a chronic treatment involves administering a compound or pharmaceutical composition of the present application repeatedly over the life of the subject. Preferred chronic treatments involve regular administrations, for example one or more times a day, one or more times a week, or one or more times a month. In general, a suitable dose, such as a daily dose of a compound of the present application, will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.
[0271] Generally, doses of the compounds of the present application for a patient, when used for the indicated effects, will range from about 0.0001 to about 100 mg per kg of body weight per day. Preferably the daily dosage will range from 0.001 to 50 mg of compound per kg of body weight, and even more preferably from 0.01 to 10 mg of compound per kg of body weight. However, lower or higher doses can be used. In some embodiments, the dose administered to a subject may be modified as the physiology of the subject changes due to age, disease progression, weight, or other factors.
[0272] In some embodiments, provided adjuvant compounds of the present application are administered as pharmaceutical compositions or vaccines. In certain embodiments, it is contemplated that the amount of adjuvant compound administered will be 1-2000 μg. In certain embodiments, it is contemplated that the amount of adjuvant compound administered will be 1-1000 μg. In certain embodiments, it is contemplated that the amount of adjuvant compound administered will be 1-500 μg. In certain embodiments, it is contemplated that the amount of adjuvant compound administered will be 1-250 μg. In certain embodiments, it is contemplated that the amount of adjuvant compound administered will be 100-1000 μg. In certain embodiments, it is contemplated that the amount of adjuvant compound administered will be 100-500 μg. In certain embodiments, it is contemplated that the amount of adjuvant compound administered will be 100-200 μg. In certain embodiments, it is contemplated that the amount of adjuvant compound administered will be 250-500 μg. In certain embodiments, it is contemplated that the amount of adjuvant compound administered will be 10-1000 μg. In certain embodiments, it is contemplated that the amount of adjuvant compound administered will be 500-1000 μg. In certain embodiments, it is contemplated that the amount of adjuvant compound administered will be 50-250 μg. In certain embodiments, it is contemplated that the amount of adjuvant compound administered will be 50-500 μg.
[0273] In some embodiments, provided adjuvant compounds of the present application are administered as pharmaceutical compositions or vaccines. In certain embodiments, it is contemplated that the amount of adjuvant compound administered will be 1-2000 mg. In certain embodiments, it is contemplated that the amount of adjuvant compound administered will be 1-1000 mg. In certain embodiments, it is contemplated that the amount of adjuvant compound administered will be 1-500 mg. In certain embodiments, it is contemplated that the amount of adjuvant compound administered will be 1-250 mg. In certain embodiments, it is contemplated that the amount of adjuvant compound administered will be 100-1000 mg. In certain embodiments, it is contemplated that the amount of adjuvant compound administered will be 100-500 mg. In certain embodiments, it is contemplated that the amount of adjuvant compound administered will be 100-200 mg. In certain embodiments, it is contemplated that the amount of adjuvant compound administered will be 250-500 mg. In certain embodiments, it is contemplated that the amount of adjuvant compound administered will be 10-1000 mg. In certain embodiments, it is contemplated that the amount of adjuvant compound administered will be 500-1000 mg. In certain embodiments, it is contemplated that the amount of adjuvant compound administered will be 50-250 mg. In certain embodiments, it is contemplated that the amount of adjuvant compound administered will be 50-500 mg. In certain embodiments, it is contemplated that the amount of adjuvant compound administered will be 0.01-215.4 mg.
[0274] In certain embodiments, it is contemplated that the amount of adjuvant administered will be 1000-5000 μg/kg. In certain embodiments, it is contemplated that the amount of adjuvant administered will be 1000-4000 μg/kg. In certain embodiments, it is contemplated that the amount of adjuvant administered will be 1000-3000 μg/kg. In certain embodiments, it is contemplated that the amount of adjuvant administered will be 1000-2000 μg/kg. In certain embodiments, it is contemplated that the amount of adjuvant administered will be 2000-5000 μg/kg. In certain embodiments, it is contemplated that the amount of adjuvant administered will be 2000-4000 μg/kg. In certain embodiments, it is contemplated that the amount of adjuvant administered will be 2000-3000 μg/kg. In certain embodiments, it is contemplated that the amount of adjuvant administered will be 3000-5000 μg/kg. In certain embodiments, it is contemplated that the amount of adjuvant administered will be 3000-4000 μg/kg. In certain embodiments, it is contemplated that the amount of adjuvant administered will be 4000-5000 μg/kg. In certain embodiments, it is contemplated that the amount of adjuvant administered will be 1-500 μg/kg. In certain embodiments, it is contemplated that the amount of adjuvant administered will be 500-1000 μg/kg. In certain embodiments, it is contemplated that the amount of adjuvant administered will be 1000-1500 μg/kg. In certain embodiments, it is contemplated that the amount of adjuvant administered will be 1 mg/kg. In certain embodiments, it is contemplated that the amount of adjuvant administered will be 2 mg/kg. In certain embodiments, it is contemplated that the amount of adjuvant administered will be 3 mg/kg. In certain embodiments, it is contemplated that the amount of adjuvant administered will be 4 mg/kg. In certain embodiments, it is contemplated that the amount of adjuvant administered will be 5 mg/kg. In certain embodiments, it is contemplated that the amount of adjuvant administered will be 0.0029-5 mg/kg. In certain embodiments, the amount of adjuvant administered in females is less than the amount of adjuvant administered in males. In certain embodiments, the amount of adjuvant administered to infants is less than the amount of adjuvant administered to adults. In certain embodiments, the amount of adjuvant administered to pediatric recipients is less than the amount of adjuvant administered to adults. In certain embodiments, the amount of adjuvant administered to immunocompromised recipients is more than the amount of adjuvant administered to healthy recipients. In certain embodiments, the amount of adjuvant administered to elderly recipients is more than the amount of adjuvant administered to non-elderly recipients.
[0275] If desired, the effective dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms.
[0276] While it is possible for a compound of the present application to be administered alone, in certain embodiments the compound is administered as a pharmaceutical formulation or composition as described above.
[0277] The compounds according to the present application may be formulated for administration in any convenient way for use in human or veterinary medicine, by analogy with other pharmaceuticals.
[0278] The present application provides kits comprising pharmaceutical formulations or compositions of a compound of the present application. In certain embodiments, such kits include the combination of a compound of formulae I and/or II and an antigen. The agents may be packaged separately or together. The kit optionally includes instructions for prescribing the medication. In certain embodiments, the kit includes multiple doses of each agent. The kit may include sufficient quantities of each component to treat one or more subject for a week, two weeks, three weeks, four weeks, or multiple months. The kit may include a full cycle of immunotherapy. In some embodiments, the kit includes a vaccine comprising one or more bacterial or viral-associated antigens, and one or more provided compounds.
[0279] Antigen Dose-Sparing
[0280] The present application also provides pharmaceutical compositions that demonstrate an antigen dose-sparing effect. Such pharmaceutical compositions may include the compounds or compositions of the present application in combination with an antigen. Preferably, the pharmaceutical compositions include TQL-1055:
##STR00043##
[0281] In some embodiments, the amount of antigen provided is less than the amount of antigen required in the absence of the compound of Formula I. In some embodiments, the amount of antigen provided is about 95%, 90%, 85%, 80%, 75%, 70%, 67%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 33%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.1% the amount of antigen required in the absence of the compound of Formula I.
[0282] In some embodiments, the antigen is associated with a bacteria or virus. In some embodiments, the antigen is associated with influenza. In some embodiments, the antigen is associated with SARS-CoV-2 virus. In some embodiments, the antigen is associated with Varicella Zoster.
[0283] In some embodiments, the antigen associated with influenza is associated with influenza A. In some embodiments, the antigen associated with influenza is associated with influenza B. In some embodiments, the antigen associated with influenza is associated with influenza C. In some embodiments, the antigen associated with influenza is associated with influenza D. In some embodiments, the antigen associated with influenza is associated with any one of the 18 different hemagglutinin subtypes (H1 through H18). In some embodiments, the antigen associated with influenza is associated with any one of the 11 different neuraminidase subtypes (N1 through N11). In some embodiments, the antigen associated with influenza is associated with H3N2. In some embodiments, the antigen associated with influenza is associated with H1N1. In some embodiments, the antigen associated with influenza is associated with B/Phuket. In some embodiments, the antigen associated with influenza is associated with B/Victoria. In some embodiments, the antigen associated with influenza is associated with B/Yamagata. In some embodiments, the antigen associated with influenza is associated with the 6B.1, 3C.2, 3C.3a, V1A, Y1, Y2, or Y3 clades.
[0284] In some embodiments, the antigen associated with SARS-CoV-2 is associated with the SARS-CoV-2 spike protein. In some embodiments, the antigen associated with SARS-CoV-2 is associated with the SARS-CoV-2 nucleocapsid protein. In some embodiments, the antigen associated with SARS-CoV-2 is associated with the SARS-CoV-2 envelope protein. In some embodiments, the antigen associated with SARS-CoV-2 is associated with aSARS-CoV-2 non-structural protein, including the papain-like protease, the 3C-like proteinase, NSP1, NSP2, NSP3, NSP4, NSP5, NSP6, NSP7, NSP8, NSP9, NSP10, NSP11, NSP12, NSP13, NSP14, NSP15, and NSP16. In some embodiments, the antigen associated with SARS-CoV-2 is a recombinant SARS-CoV-2 protein, including a recombinant version of any of the foregoing. In some embodiments, the antigen associated with SARS-CoV-2 is an mRNA or DNA version of any of the foregoing. In some embodiments, the antigen associated with SARS-CoV-2 is viral vector incorporating the foregoing. In some embodiments, the antigen associated with SARS-CoV-2 is a live attenuated virus or an inactivated virus. In some embodiments, the vaccine comprises an antigen selected from the group consisting of mRNA-1273, Ad5-nCoV, INO-4800, LV-SMENP-DC, Pathogen-specific aAPC, AZD1222, VPM1002, NVX-CoV2373, and ChAdOx1 nCoV-19.
[0285] In some embodiments, vaccines of the present application includes a combination of two different antigens in one vaccine. Preferably, a vaccine of the present application includes a combination of an influenza antigen and a SARS-CoV-2 antigen together with TQL-1055.
[0286] Priming
[0287] The present application also provides pharmaceutical compositions that demonstrate a substantial priming effect. Such pharmaceutical compositions may include the compounds or compositions of the present application in combination with an antigen. Preferably, the pharmaceutical compositions include TQL-1055:
##STR00044##
[0288] In some embodiments, the amount of antigen provided is less than the amount of antigen required in the absence of the compound of Formula I. In some embodiments, the amount of antigen provided is about 95%, 90%, 85%, 80%, 75%, 70%, 67%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 33%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.1% the amount of antigen required in the absence of the compound of Formula I.
[0289] In some embodiments, the antigen is associated with a bacteria or virus. In some embodiments, the antigen is associated with influenza. In some embodiments, the antigen is associated with SARS-CoV-2 virus. In some embodiments, the antigen is associated with Varicella Zoster.
[0290] In some embodiments, the antigen associated with influenza is associated with influenza A. In some embodiments, the antigen associated with influenza is associated with influenza B. In some embodiments, the antigen associated with influenza is associated with influenza C. In some embodiments, the antigen associated with influenza is associated with influenza D. In some embodiments, the antigen associated with influenza is associated with any one of the 18 different hemagglutinin subtypes (H1 through H18). In some embodiments, the antigen associated with influenza is associated with any one of the 11 different neuraminidase subtypes (N1 through N11). In some embodiments, the antigen associated with influenza is associated with H3N2. In some embodiments, the antigen associated with influenza is associated with H1N1. In some embodiments, the antigen associated with influenza is associated with B/Phuket. In some embodiments, the antigen associated with influenza is associated with B/Victoria. In some embodiments, the antigen associated with influenza is associated with B/Yamagata. In some embodiments, the antigen associated with influenza is associated with the 6B.1, 3C.2, 3C.3a, V1A, Y1, Y2, or Y3 clades.
[0291] In some embodiments, the antigen associated with SARS-CoV-2 is associated with the SARS-CoV-2 spike protein. In some embodiments, the antigen associated with SARS-CoV-2 is associated with the SARS-CoV-2 nucleocapsid protein. In some embodiments, the antigen associated with SARS-CoV-2 is associated with the SARS-CoV-2 envelope protein. In some embodiments, the antigen associated with SARS-CoV-2 is associated with aSARS-CoV-2 non-structural protein, including the papain-like protease, the 3C-like proteinase, NSP1, NSP2, NSP3, NSP4, NSP5, NSP6, NSP7, NSP8, NSP9, NSP10, NSP11, NSP12, NSP13, NSP14, NSP15, and NSP16. In some embodiments, the antigen associated with SARS-CoV-2 is a recombinant SARS-CoV-2 protein, including a recombinant version of any of the foregoing. In some embodiments, the antigen associated with SARS-CoV-2 is an mRNA or DNA version of any of the foregoing. In some embodiments, the antigen associated with SARS-CoV-2 is viral vector incorporating the foregoing. In some embodiments, the antigen associated with SARS-CoV-2 is a live attenuated virus or an inactivated virus. In some embodiments, the vaccine comprises an antigen selected from the group consisting of mRNA-1273, Ad5-nCoV, INO-4800, LV-SMENP-DC, Pathogen-specific aAPC, AZD1222, VPM1002, NVX-CoV2373, and ChAdOx1 nCoV-19.
[0292] In some embodiments, vaccines of the present application includes a combination of two different antigens in one vaccine. Preferably, a vaccine of the present application includes a combination of an influenza antigen and a SARS-CoV-2 antigen together with TQL-1055.
[0293] Methods
[0294] The present application also encompasses methods of conferring immune resistance to an individual. Such methods include administering to an individual a vaccine comprising a therapeutically effective amount of a compound of Formula I, in free form or in pharmaceutically acceptable salt form, together with an antigen or a combination of antigens. In particular, the compound of Formula I may be TQL-1055. In particular, the antigen(s) may be associated with influenza and/or SARS-CoV-2.
[0295] The present application also encompasses methods of providing antigen dose sparing effect. Such methods include providing an antigen and a compound of Formula I, wherein the amount of antigen provided is less than the amount of antigen required in the absence of the compound of Formula I.
[0296] The present application also encompasses methods of providing vaccine priming effect. Such methods include providing an antigen and a compound of Formula I, wherein the amount of antigen provided is less than the amount of antigen required in the absence of the compound of Formula I to generate the same priming effect.
[0297] In particular, the compound of Formula I may be TQL-1055.
[0298] The amount of antigen provided may be about 95%, 90%, 85%, 80%, 75%, 70%, 67%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 33%, 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.1% the amount of antigen required in the absence of the compound of Formula I.
[0299] In some embodiments, the antigen is associated with a bacteria or virus. In some embodiments, the antigen is associated with influenza. In some embodiments, the antigen is associated with SARS-CoV-2 virus. In some embodiments, the antigen is associated with Varicella Zoster.
EXAMPLES
Example 1—Evaluation of Priming and Dose-Sparing Effect for Recombinant Influenza Vaccine (H3N2, H1N1, B/Phuket)
[0300] Vaccination against both seasonal and pandemic pathogens, e.g. SARS-CoV-2 and influenza, requires effective adjuvants to maximize the utility of limited antigen and to enhance immunogenicity in hyporesponsive at-risk populations. First-generation natural saponins are potent immuno-enhancers but are reactogenic and have supply constraints. As part of a NIH-funded project, the novel semisynthetic saponin TQL-1055 was evaluated for its potential to augment the immunogenicity of influenza antigens.
[0301] Methods:
[0302] Groups of 10 C57BL/6J mice were immunized subcutaneously (SC) with FLUBLOK® (H3N2 antigen, H1N1 antigen, B/Phuket antigen) alone at either a 4.5 mcg or 1.125 mcg dose, or with 30 mcg dose of TQL-1055 choline salt in combination with either a 1.125 mcg, 0.56 mcg, 0.28 mcg, or 0.14 mcg dose of FLUBLOK® on Days 0 and 21. Sera were analyzed at days 0, 14, and 28 by ELISA for H3N2-specific IgG titers and HI (hemagglutination inhibition) titers, H1N1-specific IgG titers and HI titers, and B/Phuket-specific IgG titers and HI titers. All mice were previously naïve to human influenza.
TABLE-US-00002 TABLE 1-1 Adjuvant Administration Dosing Grp Mice Antigen Formulation Route Day Serology 1 10 4.5 mcg — Subcutaneous D 0, D 14 D 0, D 14, FLUBLOK D 28 2 10 1.125 mcg — Subcutaneous D 0, D 14 D 0, D 14, FLUBLOK D 28 3 10 1.125 mcg 30 mcg TQL- Subcutaneous D 0, D 14 D 0, D 14, FLUBLOK 1055 choline D 28 salt 4 10 0.56 mcg 30 mcg TQL- Subcutaneous D 0, D 14 D 0, D 14, FLUBLOK 1055 choline D 28 salt 5 10 0.28 mcg 30 mcg TQL- Subcutaneous D 0, D 14 D 0, D 14, FLUBLOK 1055 choline D 28 salt 6 10 0.14 mcg 30 mcg TQL- Subcutaneous D 0, D 14 D 0, D 14, FLUBLOK 1055 choline D 28 salt
[0303] Results:
[0304] H3N2
[0305] A 2-dose series of 1.125 mcg, 0.56 mcg, 0.28 mcg, and 0.14 mcg FLUBLOK® in combination with 30 mcg of TQL-1055 choline salt elicited anti-H3N2 antibodies in mice at greater levels than a 2-dose series of 4.5 mcg or 1.125 mcg FLUBLOK® alone. Additionally, a single dose of 1.125 mcg, 0.56 mcg, 0.28 mcg, and 0.14 mcg FLUBLOK® in combination with 30 mcg of TQL-1055 choline salt elicited anti-H3N2 antibodies in mice at greater levels than a 2-dose series of 4.5 mcg or 1.125 mcg FLUBLOK® alone. See
[0306] A 2-dose series of 1.125 mcg, 0.56 mcg, 0.28 mcg, and 0.14 mcg FLUBLOK® in combination with 30 mcg of TQL-1055 choline salt elicited H3N2 HI titers in mice at equal or greater levels than a 2-dose series of 4.5 mcg or 1.125 mcg FLUBLOK® alone. See
[0307] Low dose FLUBLOK (0.14 mcg)+30 mcg 1055 salt induces significantly higher anti-H3N2 IgG titers after 1 dose compared to high dose (4.5 mcg) FLUBLOK alone after 2 doses. See
[0308] Statistical analysis of the post dose 1 (day 14) anti-H3N2 IgG titers demonstrates the following:
TABLE-US-00003 TABLE 1-2 1.125 mcg 0.56 mcg 0.28 mcg 0.14 mcg FLUBLOK + FLUBLOK + FLUBLOK + FLUBLOK + 30 mcg 30 mcg 30 mcg 30 mcg 4.5 mcg TQL-1055 TQL-1055 TQL-1055 TQL-1055 FLUBLOK Choline Salt Choline Salt Choline Salt Choline Salt Geometric 50 1559 1740 1251 1005 Mean Geometric 1 1.784 1.764 1.7 1.866 SD factor
TABLE-US-00004 TABLE 1-3 Welch's ANOVA with Dunnett's T3 multiple Adjusted comparisons test P-Value 4.5 mcg FLUBLOK vs. 1.125 mcg FLUBLOK >0.9999 4.5 mcg FLUBLOK vs. 1.125 mcg FLUBLOK + 30 mcg <0.0001 TQL-1055 choline salt 4.5 mcg FLUBLOK vs. 0.56 mcg FLUBLOK + 30 mcg <0.0001 TQL-1055 choline salt 4.5 mcg FLUBLOK vs. 0.28 mcg FLUBLOK + 30 mcg <0.0001 TQL-1055 choline salt 4.5 mcg FLUBLOK vs. 0.14 mcg FLUBLOK + 30 mcg 0.0001 TQL-1055 choline salt 1.125 mcg FLUBLOK vs. 1.125 mcg FLUBLOK + 30 mcg <0.0001 TQL-1055 choline salt 1.125 mcg FLUBLOK vs. 0.56 mcg FLUBLOK + 30 mcg <0.0001 TQL-1055 choline salt 1.125 mcg FLUBLOK vs. 0.28 mcg FLUBLOK + 30 mcg <0.0001 TQL-1055 choline salt 1.125 mcg FLUBLOK vs. 0.14 mcg FLUBLOK + 30 mcg 0.0001 TQL-1055 choline salt 1.125 mcg FLUBLOK + 30 mcg TQL-1055 choline salt vs. 0.9532 0.56 mcg FLUBLOK + 30 mcg TQL-1055 choline salt 1.125 mcg FLUBLOK + 30 mcg TQL-1055 choline salt vs. 0.978 0.28 mcg FLUBLOK + 30 mcg TQL-1055 choline salt 1.125 mcg FLUBLOK + 30 mcg TQL-1055 choline salt vs. 0.2285 0.14 mcg FLUBLOK + 30 mcg TQL-1055 choline salt 0.56 mcg FLUBLOK + 30 mcg TQL-1055 choline salt vs. >0.9999 0.28 mcg FLUBLOK + 30 mcg TQL-1055 choline salt 0.56 mcg FLUBLOK + 30 mcg TQL-1055 choline salt vs. 0.7098 0.14 mcg FLUBLOK + 30 mcg TQL-1055 choline salt 0.28 mcg FLUBLOK + 30 mcg TQL-1055 choline salt vs. 0.78 0.14 mcg FLUBLOK + 30 mcg TQL-1055 choline salt
[0309] Statistical analysis of the post dose 2 (day 28) anti-H3N2 IgG titers demonstrates the following:
TABLE-US-00005 TABLE 1-4 1.125 mcg 0.56 mcg 0.28 mcg 0.14 mcg FLUBLOK + FLUBLOK + FLUBLOK + FLUBLOK + 30 mcg 30 mcg 30 mcg 30 mcg TQL-1055 TQL-1055 TQL-1055 TQL-1055 4.5 mcg 1.125 mcg Choline Choline Choline Choline FLUBLOK FLUBLOK Salt Salt Salt Salt Number of 10 10 9 10 10 9 Values Geometric 132.0 107.2 43891 38802 29407 20319 Mean Geometric 1.430 1.245 1.587 1.794 2.046 2.000 SD factor Lower 95% 102.1 91.62 30769 25543 17621 11926 CI of geo. mean Upper 95% 170.5 125.4 62609 58946 49074 34617 CI of geo. mean
TABLE-US-00006 TABLE 1-5 Welch's ANOVA with Dunnett's T3 multiple Adjusted comparisons test P-Value 4.5 mcg FLUBLOK vs. 1.125 mcg FLUBLOK 0.8188 4.5 mcg FLUBLOK vs. 1.125 mcg FLUBLOK + 30 mcg <0.0001 TQL-1055 choline salt 4.5 mcg FLUBLOK vs. 0.56 mcg FLUBLOK + 30 mcg <0.0001 TQL-1055 choline salt 4.5 mcg FLUBLOK vs. 0.28 mcg FLUBLOK + 30 mcg <0.0001 TQL-1055 choline salt 4.5 mcg FLUBLOK vs. 0.14 mcg FLUBLOK + 30 mcg <0.0001 TQL-1055 choline salt 1.125 mcg FLUBLOK vs. 1.125 mcg FLUBLOK + 30 mcg <0.0001 TQL-1055 choline salt 1.125 mcg FLUBLOK vs. 0.56 mcg FLUBLOK + 30 mcg <0.0001 TQL-1055 choline salt 1.125 mcg FLUBLOK vs. 0.28 mcg FLUBLOK + 30 mcg <0.0001 TQL-1055 choline salt 1.125 mcg FLUBLOK vs. 0.14 mcg FLUBLOK + 30 mcg <0.0001 TQL-1055 choline salt 1.125 mcg FLUBLOK + 30 mcg TQL-1055 choline salt vs. >0.9999 0.56 mcg FLUBLOK + 30 mcg TQL-1055 choline salt 1.125 mcg FLUBLOK + 30 mcg TQL-1055 choline salt vs. 0.8741 0.28 mcg FLUBLOK + 30 mcg TQL-1055 choline salt 1.125 mcg FLUBLOK + 30 mcg TQL-1055 choline salt vs. 0.1692 0.14 mcg FLUBLOK + 30 mcg TQL-1055 choline salt 0.56 mcg FLUBLOK + 30 mcg TQL-1055 choline salt vs. 0.9951 0.28 mcg FLUBLOK + 30 mcg TQL-1055 choline salt 0.56 mcg FLUBLOK + 30 mcg TQL-1055 choline salt vs. 0.4187 0.14 mcg FLUBLOK + 30 mcg TQL-1055 choline salt 0.28 mcg FLUBLOK + 30 mcg TQL-1055 choline salt vs. 0.976 0.14 mcg FLUBLOK + 30 mcg TQL-1055 choline salt 4.5 mcg FLUBLOK post dose 2 vs 0.14 mcg FLUBLOK + <0.0001 30 mcg TQL-1055 choline salt post dose 1
[0310] Statistical analysis of the post dose 2 (day 28) H3N2 Hemagglutination Inhibition (HI) titers demonstrates the following:
TABLE-US-00007 TABLE 1-6 1.125 mcg 0.56 mcg 0.28 mcg 0.14 mcg FLUBLOK + FLUBLOK + FLUBLOK + FLUBLOK + 30 mcg 30 mcg 30 mcg 30 mcg TQL-1055 TQL-1055 TQL-1055 TQL-1055 4.5 mcg 1.125 mcg Choline Choline Choline Choline FLUBLOK FLUBLOK Salt Salt Salt Salt Number of 9 9 10 10 10 10 Values Geometric 5.000 5.000 640.0 844.5 320.0 226.3 Mean Geometric 1.000 1.000 5.653 2.985 9.394 5.854 SD factor Lower 95% 5.000 5.000 185.8 386.2 64.45 63.92 CI of geo. mean Upper 95% 5.000 5.000 2205 1846 1589 801.0 CI of geo. mean
TABLE-US-00008 TABLE 1-7 Welch's ANOVA with Dunnett's T3 multiple Adjusted comparisons test P-Value 4.5 mcg FLUBLOK vs. 1.125 mcg FLUBLOK >0.9999 4.5 mcg FLUBLOK vs. 1.125 mcg FLUBLOK + 30 mcg 0.0008 TQL-1055 choline salt 4.5 mcg FLUBLOK vs. 0.56 mcg FLUBLOK + 30 mcg 0.0003 TQL-1055 choline salt 4.5 mcg FLUBLOK vs. 0.28 mcg FLUBLOK + 30 mcg 0.0203 TQL-1055 choline salt 4.5 mcg FLUBLOK vs. 0.14 mcg FLUBLOK + 30 mcg 0.1198 TQL-1055 choline salt 1.125 mcg FLUBLOK vs. 1.125 mcg FLUBLOK + 30 mcg 0.0008 TQL-1055 choline salt 1.125 mcg FLUBLOK vs. 0.56 mcg FLUBLOK + 30 mcg 0.0003 TQL-1055 choline salt 1.125 mcg FLUBLOK vs. 0.28 mcg FLUBLOK + 30 mcg 0.0203 TQL-1055 choline salt 1.125 mcg FLUBLOK vs. 0.14 mcg FLUBLOK + 30 mcg 0.1198 TQL-1055 choline salt 1.125 mcg FLUBLOK + 30 mcg TQL-1055 choline salt vs. >0.9999 0.56 mcg FLUBLOK + 30 mcg TQL-1055 choline salt 1.125 mcg FLUBLOK + 30 mcg TQL-1055 choline salt vs. 0.9982 0.28 mcg FLUBLOK + 30 mcg TQL-1055 choline salt 1.125 mcg FLUBLOK + 30 mcg TQL-1055 choline salt vs. 0.3175 0.14 mcg FLUBLOK + 30 mcg TQL-1055 choline salt 0.56 mcg FLUBLOK + 30 mcg TQL-1055 choline salt vs. 0.9673 0.28 mcg FLUBLOK + 30 mcg TQL-1055 choline salt 0.56 mcg FLUBLOK + 30 mcg TQL-1055 choline salt vs. 0.1556 0.14 mcg FLUBLOK + 30 mcg TQL-1055 choline salt 0.28 mcg FLUBLOK + 30 mcg TQL-1055 choline salt vs. 0.9787 0.14 mcg FLUBLOK + 30 mcg TQL-1055 choline salt
[0311] A 2-dose series of 1.125 mcg, 0.56 mcg, 0.28 mcg, and 0.14 mcg FLUBLOK® in combination with 30 mcg of TQL-1055 choline salt elicited anti-H1N1 antibodies in all mice at greater levels than a 2-dose series of 4.5 mcg or 1.125 mcg FLUBLOK® alone. Additionally, a single dose of 1.125 mcg, 0.56 mcg, 0.28 mcg, and 0.14 mcg FLUBLOK® in combination with 30 mcg of TQL-1055 choline salt elicited anti-H1N1 antibodies in all mice at equal or greater levels than a 2-dose series of 4.5 mcg or 1.125 mcg FLUBLOK® alone.
[0312] A 2-dose series of 1.125 mcg, 0.56 mcg, 0.28 mcg, and 0.14 mcg FLUBLOK® in combination with 30 mcg of TQL-1055 choline salt elicited H1N1 HI titers in all mice at equal or greater levels than a 2-dose series of 4.5 mcg or 1.125 mcg FLUBLOK® alone. See
[0313] Low dose FLUBLOK (0.14 mcg)+30 mcg TQL-1055 choline salt induces similar anti-H1N1 IgG titers after 1 dose compared to high dose (4.5 mcg) FLUBLOK alone after 2 doses. See
[0314] Statistical analysis of the post dose 1 (day 14) anti-H1N1 IgG titers demonstrates the following:
TABLE-US-00009 TABLE 1-8 1.125 mcg 0.56 mcg 0.28 mcg 0.14 mcg FLUBLOK + FLUBLOK + FLUBLOK + FLUBLOK + 30 mcg 30 mcg 30 mcg 30 mcg TQL-1055 TQL-1055 TQL-1055 TQL-1055 4.5 mcg 1.125 mcg Choline Choline Choline Choline FLUBLOK FLUBLOK Salt Salt Salt Salt Number of 10 10 10 10 10 10 Values Geometric 100.0 100.0 162.5 186.6 373.2 214.4 Mean Geometric 1.000 1.000 1.769 1.992 2.293 1.668 SD factor Lower 95% 100.0 100.0 108.0 114.0 206.1 148.7 CI of geo. mean Upper 95% 100.0 100.0 244.3 305.5 675.7 309.0 CI of geo. mean
TABLE-US-00010 TABLE 1-9 Welch's ANOVA with Dunnett's T3 multiple Adjusted comparisons test P-Value 4.5 mcg FLUBLOK vs. 1.125 mcg FLUBLOK >0.9999 4.5 mcg FLUBLOK vs. 1.125 mcg FLUBLOK + 30 mcg 0.219 TQL-1055 choline salt 4.5 mcg FLUBLOK vs. 0.56 mcg FLUBLOK + 30 mcg 0.1739 TQL-1055 choline salt 4.5 mcg FLUBLOK vs. 0.28 mcg FLUBLOK + 30 mcg 0.0084 TQL-1055 choline salt 4.5 mcg FLUBLOK vs. 0.14 mcg FLUBLOK + 30 mcg 0.0123 TQL-1055 choline salt 1.125 mcg FLUBLOK vs. 1.125 mcg FLUBLOK + 30 mcg 0.219 TQL-1055 choline salt 1.125 mcg FLUBLOK vs. 0.56 mcg FLUBLOK + 30 mcg 0.1739 TQL-1055 choline salt 1.125 mcg FLUBLOK vs. 0.28 mcg FLUBLOK + 30 mcg 0.0084 TQL-1055 choline salt 1.125 mcg FLUBLOK vs. 0.14 mcg FLUBLOK + 30 mcg 0.0123 TQL-1055 choline salt 1.125 mcg FLUBLOK + 30 mcg TQL-1055 choline salt vs. >0.9999 0.56 mcg FLUBLOK + 30 mcg TQL-1055 choline salt 1.125 mcg FLUBLOK + 30 mcg TQL-1055 choline salt vs. 0.2123 0.28 mcg FLUBLOK + 30 mcg TQL-1055 choline salt 1.125 mcg FLUBLOK + 30 mcg TQL-1055 choline salt vs. 0.9764 0.14 mcg FLUBLOK + 30 mcg TQL-1055 choline salt 0.56 mcg FLUBLOK + 30 mcg TQL-1055 choline salt vs. 0.5145 0.28 mcg FLUBLOK + 30 mcg TQL-1055 choline salt 0.56 mcg FLUBLOK + 30 mcg TQL-1055 choline salt vs. >0.9999 0.14 mcg FLUBLOK + 30 mcg TQL-1055 choline salt 0.28 mcg FLUBLOK + 30 mcg TQL-1055 choline salt vs. 0.6739 0.14 mcg FLUBLOK + 30 mcg TQL-1055 choline salt
[0315] Statistical analysis of the post dose 2 (day 38) anti-H1N1 IgG titers demonstrates the following:
TABLE-US-00011 TABLE 1-10 1.125 mcg 0.56 mcg 0.28 mcg 0.14 mcg FLUBLOK + FLUBLOK + FLUBLOK + FLUBLOK + 30 mcg 30 mcg 30 mcg 30 mcg TQL-1055 TQL-1055 TQL-1055 TQL-1055 4.5 mcg 1.125 mcg Choline Choline Choline Choline FLUBLOK FLUBLOK Salt Salt Salt Salt Number of 10 10 9 9 10 9 Values Geometric 188.2 99.90 12172 14678 13427 10224 Mean Geometric 2.366 1.003 2.084 1.626 1.918 1.889 SD factor Lower 95% 101.6 99.67 6923 10100 8428 6271 CI of geo. mean Upper 95% 384.4 100.1 21401 21330 21393 16668 CI of geo. mean
TABLE-US-00012 TABLE 1-11 Welch's ANOVA with Dunnett's T3 multiple Adjusted comparisons test P-Value 4.5 mcg FLUBLOK vs. 1.125 mcg FLUBLOK 0.4812 4.5 mcg FLUBLOK vs. 1.125 mcg FLUBLOK + 30 mcg 0.1066 TQL-1055 choline salt 4.5 mcg FLUBLOK vs. 0.56 mcg FLUBLOK + 30 mcg 0.0032 TQL-1055 choline salt 4.5 mcg FLUBLOK vs. 0.28 mcg FLUBLOK + 30 mcg 0.0050 TQL-1055 choline salt 4.5 mcg FLUBLOK vs. 0.14 mcg FLUBLOK + 30 mcg 0.0382 TQL-1055 choline salt 1.125 mcg FLUBLOK vs. 1.125 mcg FLUBLOK + 30 mcg 0.1014 TQL-1055 choline salt 1.125 mcg FLUBLOK vs. 0.56 mcg FLUBLOK + 30 mcg 0.0029 TQL-1055 choline salt 1.125 mcg FLUBLOK vs. 0.28 mcg FLUBLOK + 30 mcg 0.0046 TQL-1055 choline salt 1.125 mcg FLUBLOK vs. 0.14 mcg FLUBLOK + 30 mcg 0.0353 TQL-1055 choline salt 1.125 mcg FLUBLOK + 30 mcg TQL-1055 choline salt vs. >0.9999 0.56 mcg FLUBLOK + 30 mcg TQL-1055 choline salt 1.125 mcg FLUBLOK + 30 mcg TQL-1055 choline salt vs. >0.9999 0.28 mcg FLUBLOK + 30 mcg TQL-1055 choline salt 1.125 mcg FLUBLOK + 30 mcg TQL-1055 choline salt vs. >0.9999 0.14 mcg FLUBLOK + 30 mcg TQL-1055 choline salt 0.56 mcg FLUBLOK + 30 mcg TQL-1055 choline salt vs. >0.9999 0.28 mcg FLUBLOK + 30 mcg TQL-1055 choline salt 0.56 mcg FLUBLOK + 30 mcg TQL-1055 choline salt vs. 0.9921 0.14 mcg FLUBLOK + 30 mcg TQL-1055 choline salt 0.28 mcg FLUBLOK + 30 mcg TQL-1055 choline salt vs. 0.9981 0.14 mcg FLUBLOK + 30 mcg TQL-1055 choline salt 4.5 mcg FLUBLOK post dose 2 vs 0.14 mcg FLUBLOK + 0.7404 30 mcg TQL-1055 choline salt post dose 1
[0316] Statistical analysis of the post dose 2 (day 28) H1N1 Hemagglutination Inhibition (HI) titers demonstrates the following:
TABLE-US-00013 TABLE 1-12 1.125 mcg 0.56 mcg 0.28 mcg 0.14 mcg FLUBLOK + FLUBLOK + FLUBLOK + FLUBLOK + 30 mcg 30 mcg 30 mcg 30 mcg TQL-1055 TQL-1055 TQL-1055 TQL-1055 4.5 mcg 1.125 mcg Choline Choline Choline Choline FLUBLOK FLUBLOK Salt Salt Salt Salt Number of 10 10 10 10 10 10 Values Geometric 5.359 5.359 121.3 278.6 85.74 79.54 Mean Geometric 1.245 1.245 9.665 4.438 7.585 5.781 SD factor Lower 95% 4.581 4.581 23.93 95.93 20.12 22.67 CI of geo. mean Upper 95% 6.269 6.269 614.4 808.9 365.3 279.1 CI of geo. mean
TABLE-US-00014 TABLE 1-13 Welch's ANOVA with Dunnett's T3 multiple Adjusted comparisons test P-Value 4.5 mcg FLUBLOK vs. 1.125 mcg FLUBLOK >0.9999 4.5 mcg FLUBLOK vs. 1.125 mcg FLUBLOK + 30 mcg 0.1701 TQL-1055 choline salt 4.5 mcg FLUBLOK vs. 0.56 mcg FLUBLOK + 30 mcg 0.0415 TQL-1055 choline salt 4.5 mcg FLUBLOK vs. 0.28 mcg FLUBLOK + 30 mcg 0.1632 TQL-1055 choline salt 4.5 mcg FLUBLOK vs. 0.14 mcg FLUBLOK + 30 mcg 0.2188 TQL-1055 choline salt 1.125 mcg FLUBLOK vs. 1.125 mcg FLUBLOK + 30 mcg 0.1701 TQL-1055 choline salt 1.125 mcg FLUBLOK vs. 0.56 mcg FLUBLOK + 30 mcg 0.0415 TQL-1055 choline salt 1.125 mcg FLUBLOK vs. 0.28 mcg FLUBLOK + 30 mcg 0.1632 TQL-1055 choline salt 1.125 mcg FLUBLOK vs. 0.14 mcg FLUBLOK + 30 mcg 0.2188 TQL-1055 choline salt 1.125 mcg FLUBLOK + 30 mcg TQL-1055 choline salt vs. >0.9999 0.56 mcg FLUBLOK + 30 mcg TQL-1055 choline salt 1.125 mcg FLUBLOK + 30 mcg TQL-1055 choline salt vs. 0.9954 0.28 mcg FLUBLOK + 30 mcg TQL-1055 choline salt 1.125 mcg FLUBLOK + 30 mcg TQL-1055 choline salt vs. 0.9298 0.14 mcg FLUBLOK + 30 mcg TQL-1055 choline salt 0.56 mcg FLUBLOK + 30 mcg TQL-1055 choline salt vs. 0.8924 0.28 mcg FLUBLOK + 30 mcg TQL-1055 choline salt 0.56 mcg FLUBLOK + 30 mcg TQL-1055 choline salt vs. 0.6169 0.14 mcg FLUBLOK + 30 mcg TQL-1055 choline salt 0.28 mcg FLUBLOK + 30 mcg TQL-1055 choline salt vs. >0.9999 0.14 mcg FLUBLOK + 30 mcg TQL-1055 choline salt
[0317] B/Phuket
[0318] A 2-dose series of 1.125 mcg, 0.56 mcg, 0.28 mcg, and 0.14 mcg FLUBLOK® in combination with 30 mcg of TQL-1055 choline salt elicited anti-B/Phuket antibodies in all mice at greater levels than a 2-dose series of 4.5 mcg or 1.125 mcg FLUBLOK® alone. Additionally, a single dose of 1.125 mcg, 0.56 mcg, 0.28 mcg, and 0.14 mcg FLUBLOK® in combination with 30 mcg of TQL-1055 choline salt elicited anti-B/Phuket antibodies in all mice on average at equal or greater levels than a 2-dose series of 4.5 mcg or 1.125 mcg FLUBLOK® alone. See
[0319] A 2-dose series of 1.125 mcg, 0.56 mcg, 0.28 mcg, and 0.14 mcg FLUBLOK® in combination with 30 mcg of TQL-1055 choline salt elicited B/Phuket HI titers in all mice at equal or greater levels than a 2-dose series of 4.5 mcg or 1.125 mcg FLUBLOK® alone. See
[0320] Low dose (0.14 mcg) FLUBLOK+30 mcg TQL-1055 choline salt induces similar anti-B/Phuket IgG titers after 1 dose compared to high dose (4.5 mcg) FLUBLOK alone after 2 doses. See
[0321] Statistical analysis of the post dose 1 (day 14) anti-B/Phuket IgG titers demonstrates the following:
TABLE-US-00015 TABLE 1-14 1.125 mcg 0.56 mcg 0.28 mcg 0.14 mcg FLUBLOK + FLUBLOK + FLUBLOK + FLUBLOK + 30 mcg 30 mcg 30 mcg 30 mcg TQL-1055 TQL-1055 TQL-1055 TQL-1055 4.5 mcg 1.125 mcg Choline Choline Choline Choline FLUBLOK FLUBLOK Salt Salt Salt Salt Number of 9 9 10 10 10 10 Values Geometric 108.0 100.0 1213 1056 984.9 1056 Mean Geometric 1.260 1.000 1.624 1.624 2.234 1.954 SD factor Lower 95% 90.43 100.0 857.3 746.3 554.3 653.8 CI of geo. mean Upper 95% 129.0 100.0 1715 1493 1750 1704 CI of geo. mean
TABLE-US-00016 TABLE 1-15 Welch's ANOVA with Dunnett's T3 multiple Adjusted comparisons test P-Value 4.5 mcg FLUBLOK vs. 1.125 mcg FLUBLOK 0.9908 4.5 mcg FLUBLOK vs. 1.125 mcg FLUBLOK + 30 mcg <0.0001 TQL-1055 choline salt 4.5 mcg FLUBLOK vs. 0.56 mcg FLUBLOK + 30 mcg <0.0001 TQL-1055 choline salt 4.5 mcg FLUBLOK vs. 0.28 mcg FLUBLOK + 30 mcg <0.0001 TQL-1055 choline salt 4.5 mcg FLUBLOK vs. 0.14 mcg FLUBLOK + 30 mcg <0.0001 TQL-1055 choline salt 1.125 mcg FLUBLOK vs. 1.125 mcg FLUBLOK + 30 mcg <0.0001 TQL-1055 choline salt 1.125 mcg FLUBLOK vs. 0.56 mcg FLUBLOK + 30 mcg <0.0001 TQL-1055 choline salt 1.125 mcg FLUBLOK vs. 0.28 mcg FLUBLOK + 30 mcg 0.0001 TQL-1055 choline salt 1.125 mcg FLUBLOK vs. 0.14 mcg FLUBLOK + 30 mcg <0.0001 TQL-1055 choline salt 1.125 mcg FLUBLOK + 30 mcg TQL-1055 choline salt vs. >0.9999 0.56 mcg FLUBLOK + 30 mcg TQL-1055 choline salt 1.125 mcg FLUBLOK + 30 mcg TQL-1055 choline salt vs. 0.9998 0.28 mcg FLUBLOK + 30 mcg TQL-1055 choline salt 1.125 mcg FLUBLOK + 30 mcg TQL-1055 choline salt vs. >0.9999 0.14 mcg FLUBLOK + 30 mcg TQL-1055 choline salt 0.56 mcg FLUBLOK + 30 mcg TQL-1055 choline salt vs. >0.9999 0.28 mcg FLUBLOK + 30 mcg TQL-1055 choline salt 0.56 mcg FLUBLOK + 30 mcg TQL-1055 choline salt vs. >0.9999 0.14 mcg FLUBLOK + 30 mcg TQL-1055 choline salt 0.28 mcg FLUBLOK + 30 mcg TQL-1055 choline salt vs. >0.9999 0.14 mcg FLUBLOK + 30 mcg TQL-1055 choline salt
[0322] Statistical analysis of the post dose 2 (day 38) anti-B/Phuket IgG titers demonstrates the following:
TABLE-US-00017 TABLE 1-16 1.125 mcg 0.56 mcg 0.28 mcg 0.14 mcg FLUBLOK + FLUBLOK + FLUBLOK + FLUBLOK + 30 mcg 30 mcg 30 mcg 30 mcg TQL-1055 TQL-1055 TQL-1055 TQL-1055 4.5 mcg 1.125 mcg Choline Choline Choline Choline FLUBLOK FLUBLOK Salt Salt Salt Salt Number of 10 10 9 9 10 9 Values Geometric 625.6 131.8 36494 38247 29174 26180 Mean Geometric 4.599 1.794 1.305 1.499 1.595 1.610 SD factor Lower 95% 210.0 86.77 29742 28014 20894 18151 CI of geo. mean Upper 95% 1863 200.2 44780 52218 40735 37760 CI of geo. mean
TABLE-US-00018 TABLE 1-17 Welch's ANOVA with Dunnett's T3 multiple Adjusted comparisons test P-Value 4.5 mcg FLUBLOK vs. 1.125 mcg FLUBLOK 0.7899 4.5 mcg FLUBLOK vs. 1.125 mcg FLUBLOK + 30 mcg <0.0001 TQL-1055 choline salt 4.5 mcg FLUBLOK vs. 0.56 mcg FLUBLOK + 30 mcg 0.0001 TQL-1055 choline salt 4.5 mcg FLUBLOK vs. 0.28 mcg FLUBLOK + 30 mcg 0.0024 TQL-1055 choline salt 4.5 mcg FLUBLOK vs. 0.14 mcg FLUBLOK + 30 mcg 0.0017 TQL-1055 choline salt 1.125 mcg FLUBLOK vs. 1.125 mcg FLUBLOK + 30 mcg <0.0001 TQL-1055 choline salt 1.125 mcg FLUBLOK vs. 0.56 mcg FLUBLOK + 30 mcg 0.0001 TQL-1055 choline salt 1.125 mcg FLUBLOK vs. 0.28 mcg FLUBLOK + 30 mcg 0.0019 TQL-1055 choline salt 1.125 mcg FLUBLOK vs. 0.14 mcg FLUBLOK + 30 mcg 0.0014 TQL-1055 choline salt 1.125 mcg FLUBLOK + 30 mcg TQL-1055 choline salt vs. >0.9999 0.56 mcg FLUBLOK + 30 mcg TQL-1055 choline salt 1.125 mcg FLUBLOK + 30 mcg TQL-1055 choline salt vs. 0.9978 0.28 mcg FLUBLOK + 30 mcg TQL-1055 choline salt 1.125 mcg FLUBLOK + 30 mcg TQL-1055 choline salt vs. 0.7448 0.14 mcg FLUBLOK + 30 mcg TQL-1055 choline salt 0.56 mcg FLUBLOK + 30 mcg TQL-1055 choline salt vs. 0.9556 0.28 mcg FLUBLOK + 30 mcg TQL-1055 choline salt 0.56 mcg FLUBLOK + 30 mcg TQL-1055 choline salt vs. 0.5195 0.14 mcg FLUBLOK + 30 mcg TQL-1055 choline salt 0.28 mcg FLUBLOK + 30 mcg TQL-1055 choline salt vs. >0.9999 0.14 mcg FLUBLOK + 30 mcg TQL-1055 choline salt 4.5 mcg FLUBLOK post dose 2 vs 0.14 mcg FLUBLOK + 0.3398 30 mcg TQL-1055 choline salt post dose 1
[0323] Statistical analysis of the post dose 2 (day 28) B/Phuket Hemagglutination Inhibition (HI) titers demonstrates the following:
TABLE-US-00019 TABLE 1-18 1.125 mcg 0.56 mcg 0.28 mcg 0.14 mcg FLUBLOK + FLUBLOK + FLUBLOK + FLUBLOK + 30 mcg 30 mcg 30 mcg 30 mcg TQL-1055 TQL-1055 TQL-1055 TQL-1055 4.5 mcg 1.125 mcg Choline Choline Choline Choline FLUBLOK FLUBLOK Salt Salt Salt Salt Number of 10 10 10 10 10 10 Values Geometric 7.579 5.359 127.1 259.9 211.1 149.3 Mean Geometric 3.725 1.245 4.951 1.398 2.403 2.876 SD factor Lower 95% −34.76 4.369 89.67 216.7 119.0 89.42 CI of geo. mean Upper 95% 107.8 6.631 426.5 327.3 473.0 354.6 CI of geo. mean
TABLE-US-00020 TABLE 1-19 Welch's ANOVA with Dunnett's T3 multiple Adjusted comparisons test P-Value 4.5 mcg FLUBLOK vs. 1.125 mcg FLUBLOK 0.9966 4.5 mcg FLUBLOK vs. 1.125 mcg FLUBLOK + 30 mcg 0.2417 TQL-1055 choline salt 4.5 mcg FLUBLOK vs. 0.56 mcg FLUBLOK + 30 mcg 0.0003 TQL-1055 choline salt 4.5 mcg FLUBLOK vs. 0.28 mcg FLUBLOK + 30 mcg 0.1422 TQL-1055 choline salt 4.5 mcg FLUBLOK vs. 0.14 mcg FLUBLOK + 30 mcg 0.211 TQL-1055 choline salt 1.125 mcg FLUBLOK vs. 1.125 mcg FLUBLOK + 30 mcg 0.11 TQL-1055 choline salt 1.125 mcg FLUBLOK vs. 0.56 mcg FLUBLOK + 30 mcg <0.0001 TQL-1055 choline salt 1.125 mcg FLUBLOK vs. 0.28 mcg FLUBLOK + 30 mcg 0.0699 TQL-1055 choline salt 1.125 mcg FLUBLOK vs. 0.14 mcg FLUBLOK + 30 mcg 0.0717 TQL-1055 choline salt 1.125 mcg FLUBLOK + 30 mcg TQL-1055 choline salt vs. >0.9999 0.56 mcg FLUBLOK + 30 mcg TQL-1055 choline salt 1.125 mcg FLUBLOK + 30 mcg TQL-1055 choline salt vs. >0.9999 0.28 mcg FLUBLOK + 30 mcg TQL-1055 choline salt 1.125 mcg FLUBLOK + 30 mcg TQL-1055 choline salt vs. >0.9999 0.14 mcg FLUBLOK + 30 mcg TQL-1055 choline salt 0.56 mcg FLUBLOK + 30 mcg TQL-1055 choline salt vs. >0.9999 0.28 mcg FLUBLOK + 30 mcg TQL-1055 choline salt 0.56 mcg FLUBLOK + 30 mcg TQL-1055 choline salt vs. 0.9998 0.14 mcg FLUBLOK + 30 mcg TQL-1055 choline salt 0.28 mcg FLUBLOK + 30 mcg TQL-1055 choline salt vs. >0.9999 0.14 mcg FLUBLOK + 30 mcg TQL-1055 choline salt
[0324] Discussion:
[0325] As shown in the foregoing results and in
Example 2—Evaluating Antibody Response of TQL-1055 Choline Salt (C.S.) and TQL-1055 Free Acid (F.A.) with SARS-CoV-2 Receptor Binding Domain (RBD)
[0326] Methods:
[0327] Mice were vaccinated subcutaneously (S.C.) or intramuscularly (I.M.) with 1 mcg SARS-CoV-2 receptor binding domain (RBD) antigen. In addition to the antigen, mice received TQL-1055 C.S. or TQL-1055 F.A. at various doses (10 mcg, 30 mcg, 100 mcg). Control groups with antigen alone and antigen with 10 mcg QS-21 were used. Thirteen days after Dose 1, sera was collected and analyzed for total anti-RBD IgG. On D14, a second dose identical to the first dose was administered. Twenty-eight days after Dose 1, sera was collected and analyzed for total anti-RBD IgG.
[0328] Results:
[0329] IgG Endpoint Titer Data—Subcutaneous Injection—Post Dose 1
[0330] The IgG endpoint titer data for subcutaneous injection post dose 1 is depicted in
TABLE-US-00021 TABLE 2-1 1 μg 1 μg 1 μg 1 μg 1 μg 1 μg SARS- SARS- SARS- SARS- SARS- SARS- 1 μg 1 μg CoV-2 CoV-2 CoV-2 CoV-2 CoV-2 CoV-2 SARS- SARS- RBD + RBD + RBD + RBD + RBD + RBD + CoV-2 CoV-2 10 μg 30 μg 100 μg 10 μg 30 μg 100 μg RBD + RBD 1055 1055 1055 1055 1055 1055 10 μg alone F.A F.A F.A C.S C.S C.S QS-21 S.C. S.C. S.C. S.C. S.C. S.C. S.C. S.C. Number of 8 8 10 10 9 10 10 6 values Geometric 272.6 297.3 415.3 1043 250.0 522.8 406.1 250.0 mean Geometric 1.278 1.378 2.052 2.571 1.000 2.428 1.398 1.000 SD factor Lower 95% 222.1 227.4 248.4 530.9 250.0 277.2 319.6 250.0 CI of geo. mean Upper 95% 334.6 388.8 694.4 2050 250.0 986.2 516.0 250.0 CI of geo. mean
[0331] IgG Endpoint Titer Data—Subcutaneous Injection—Post Dose 1
[0332] The IgG endpoint titer data for subcutaneous injection post dose 1 is depicted in
TABLE-US-00022 TABLE 2-2 1 μg 1 μg 1 μg 1 μg 1 μg 1 μg SARS- SARS- SARS- SARS- SARS- SARS- 1 μg 1 μg CoV-2 CoV-2 CoV-2 CoV-2 CoV-2 CoV-2 SARS- SARS- RBD + RBD + RBD + RBD + RBD + RBD + CoV-2 CoV-2 10 μg 30 μg 100 μg 10 μg 30 μg 100 μg RBD + RBD 1055 1055 1055 1055 1055 1055 10 μg alone F.A F.A F.A C.S C.S C.S QS-21 I.M. I.M. I.M. I.M. I.M. I.M. I.M. I.M. Number of 8 8 10 10 9 10 10 5 values Geometric 250.0 250.0 250.0 250.0 291.6 361.5 287.2 250.0 mean Geometric 1.000 1.000 1.000 1.000 1.358 2.092 1.339 1.000 SD factor Lower 95% 250.0 250.0 250.0 250.0 230.6 213.2 233.0 250.0 CI of geo. mean Upper 95% 250.0 250.0 250.0 250.0 368.9 613.0 354.0 250.0 CI of geo. mean
[0333] IgG Endpoint Titer Data—Subcutaneous Injection—Post Dose 2
[0334] The IgG endpoint titer data for subcutaneous injection post dose 2 is depicted in
TABLE-US-00023 TABLE 2-3 1 μg 1 μg 1 μg 1 μg 1 μg 1 μg SARS- SARS- SARS- SARS- SARS- SARS- 1 μg 1 μg CoV-2 CoV-2 CoV-2 CoV-2 CoV-2 CoV-2 SARS- SARS- RBD + RBD + RBD + RBD + RBD + RBD + CoV-2 CoV-2 10 μg 30 μg 100 μg 10 μg 30 μg 100 μg RBD + RBD 1055 1055 1055 1055 1055 1055 10 μg alone F.A F.A F.A C.S C.S C.S QS-21 S.C. S.C. S.C. S.C. S.C. S.C. S.C. S.C. Number of 8 8 10 10 9 10 10 5 values Geometric 707.1 1677 5000 40829 12226 22572 21283 18119 mean Geometric 1.448 2.546 2.135 5.255 2.336 5.281 2.493 2.054 SD factor Lower 95% 518.8 767.7 2906 12460 6370 6864 11072 7413 CI of geo. mean Upper 95% 963.8 3663 8604 133792 23467 74229 40914 44287 CI of geo. mean
[0335] IgG Endpoint Titer Data—Intramuscular Injection—Post Dose 2
[0336] The IgG endpoint titer data for intramuscular injection post dose 2 is depicted in
TABLE-US-00024 TABLE 2-4 1 μg 1 μg 1 μg 1 μg 1 μg 1 μg SARS- SARS- SARS- SARS- SARS- SARS- 1 μg 1 μg CoV-2 CoV-2 CoV-2 CoV-2 CoV-2 CoV-2 SARS- SARS- RBD + RBD + RBD + RBD + RBD + RBD + CoV-2 CoV-2 10 μg 30 μg 100 μg 10 μg 30 μg 100 μg RBD + RBD 1055 1055 1055 1055 1055 1055 10 μg alone F.A F.A F.A C.S C.S C.S QS-21 I.M. I.M. I.M. I.M. I.M. I.M. I.M. I.M. Number of 8 8 10 10 9 10 10 5 values Geometric 2299 840.9 1512 6899 5979 20224 23755 9518 mean Geometric 2.984 2.938 3.131 4.388 1.710 3.582 3.248 2.415 SD factor Lower 95% 921.9 341.5 668.4 2395 3959 8117 10228 3186 CI of geo. mean Upper 95% 5735 2071 3421 19872 9031 50385 55171 28439 CI of geo. mean
[0337] Discussion:
[0338] As shown in the foregoing results and in
Example 3—Evaluating Antibody Response of TQL-1055 Choline Salt (C.S.) Adjuvanted H1N1 Influenza A Virus/SARS-CoV-2 Combined Vaccine
[0339] Methods:
[0340] Mice were vaccinated intramuscularly (I.M.) with 0.1 or 1 mcg PR8 HA antigen (Influenza), 0.3 or 3 mcg FL-S (full-length S protein) antigen (SARS-CoV-2), 30 mcg TQL-1055 in situ salt (choline salt), 1 mcg PHAD (in DOPC liposomes), and combinations thereof as shown in Table 3-1 below. Control groups with antigen alone or a combination of antigens were used. Serology was performed at D1, D13, and D28 and samples were analyzed for anti-PR8 HA IgG and anti-SARS-CoV-2 FL-S IgG.
TABLE-US-00025 TABLE 3-1 Grp Mice PR8 HA Antigen FL-S Antigen TQL-1055 in situ salt PHAD 1 10 1 mcg PR8 HA — — — 2 10 — 3 mcg FL-S — — 3 10 1 mcg PR8 HA 3 mcg FL-S 30 mcg TQL-1055 — 4 10 0.1 mcg PR8 HA — 30 mcg TQL-1055 — 5 10 1 mcg PR8 HA — 30 mcg TQL-1055 — 6 10 — 0.3 mcg FL-S 30 mcg TQL-1055 — 7 10 — 3 mcg FL-S 30 mcg TQL-1055 — 8 10 0.1 mcg PR8 HA 0.3 mcg FL-S 30 mcg TQL-1055 — 9 10 0.1 mcg PR8 HA 3 mcg FL-S 30 mcg TQL-1055 — 10 10 1 mcg PR8 HA 0.3 mcg FL-S 30 mcg TQL-1055 — 11 10 1 mcg PR8 HA 3 mcg FL-S 30 mcg TQL-1055 — 12 10 0.1 mcg PR8 HA 0.3 mcg FL-S 30 mcg TQL-1055 1 mcg PHAD 13 10 0.1 mcg PR8 HA 3 mcg FL-S 30 mcg TQL-1055 1 mcg PHAD 14 10 1 mcg PR8 HA 0.3 mcg FL-S 30 mcg TQL-1055 1 mcg PHAD 15 10 1 mcg PR8 HA 3 mcg FL-S 30 mcg TQL-1055 1 mcg PHAD
[0341] Results:
[0342] TQL-1055 allows for vaccination with combined Influenza/SARS-CoV-2 antigens using PR8 HA and FL-S without loss of antigen-specific IgG titers. Specifically: [0343] As shown in
[0347] Statistical analysis of the post dose 1 (D13) anti-PR8 HA IgG titers demonstrates the following:
TABLE-US-00026 TABLE 3-2 Adjusted Dunnett's multiple comparisons test Summary P Value 1 μg PR8 + 30 μg TQL1055 in situ salt vs. 1 μg PR8 Alone * 0.0324 1 μg PR8 + 30 μg TQL1055 in situ salt vs. 1 μg PR8 Alone + * 0.0324 3 μg Fl-S Alone 1 μg PR8 + 30 μg TQL1055 in situ salt vs. 1 μg PR8 + ns 0.0764 0.3 μg Fl-S + 30 μg TQL1055 in situ salt 1 μg PR8 + 30 μg TQL1055 in situ salt vs. 1 μg PR8 + ns 0.3484 3 μg Fl-S + 30 μg TQL1055 in situ salt 1 μg PR8 + 30 μg TQL1055 in situ salt vs. 1 μg PR8 + ns 0.9996 0.3 μg Fl-S + 30 μg TQL1055 in situ salt + 1 μg PHAD 1 μg PR8 + 30 μg TQL1055 in situ salt vs. 1 μg PR8 + ns 0.1207 3 μg Fl-S + 30 μg TQL1055 in situ salt + 1 μg PHAD
TABLE-US-00027 TABLE 3-3 Adjusted Dunnett's multiple comparisons test Summary P Value 0.1 μg PR8 + 30 μg TQL1055 in situ salt vs. 0.1 μg PR8 + ns 0.9999 0.3 μg Fl-S + 30 μg TQL1055 in situ salt 0.1 μg PR8 + 30 μg TQL1055 in situ salt vs. 0.1 μg PR8 + ns 0.8305 3 μg Fl-S + 30 μg TQL1055 in situ salt 0.1 μg PR8 + 30 μg TQL1055 in situ salt vs. 0.1 μg PR8 + ns 0.0601 0.3 μg Fl-S + 30 μg TQL1055 in situ salt + 1 μg PHAD 0.1 μg PR8 + 30 μg TQL1055 in situ salt vs. 0.1 μg PR8 + * 0.0144 3 μg Fl-S + 30 μg TQL1055 in situ salt + 1 μg PHAD
[0348] Statistical analysis of the post dose 1 (D13) anti-SARS-CoV-2 FL-S IgG titers demonstrates the following:
TABLE-US-00028 TABLE 3-4 Adjusted Dunnett's multiple comparisons test Summary P Value 3 μg Fl-S + 30 μg TQL1055 in situ salt vs. 3 μg Fl-S Alone ns 0.9962 3 μg Fl-S + 30 μg TQL1055 in situ salt vs. 1 μg PR8 Alone + ns 0.9997 3 μg Fl-S Alone 3 μg Fl-S + 30 μg TQL1055 in situ salt vs. 0.1 μg PR8 + ns 0.9997 3 μg Fl-S + 30 μg TQL1055 in situ salt 3 μg Fl-S + 30 μg TQL1055 in situ salt vs. 1 μg PR8 + ns 0.9997 3 μg Fl-S + 30 μg TQL1055 in situ salt 3 μg Fl-S + 30 μg TQL1055 in situ salt vs. 0.1 μg PR8 + ns 0.4043 3 μg Fl-S + 30 μg TQL1055 in situ salt + 1 μg PHAD 3 μg Fl-S + 30 μg TQL1055 in situ salt vs. 1 μg PR8 + ** 0.0049 3 μg Fl-S + 30 μg TQL1055 in situ salt + 1 μg PHAD
TABLE-US-00029 TABLE 3-5 Adjusted Dunnett's multiple comparisons test Summary P Value 0.3 μg Fl-S + 30 μg TQL1055 in situ salt vs. 0.1 μg PR8 + ns 0.4163 0.3 μg Fl-S + 30 μg TQL1055 in situ salt 0.3 μg Fl-S + 30 μg TQL1055 in situ salt vs. 1 μg PR8 + ns 0.3367 0.3 μg Fl-S + 30 μg TQL1055 in situ salt 0.3 μg Fl-S + 30 μg TQL1055 in situ salt vs. 0.1 μg PR8 + ns 0.6013 0.3 μg Fl-S + 30 μg TQL1055 in situ salt + 1 μg PHAD 0.3 μg Fl-S + 30 μg TQL1055 in situ salt vs. 1 μg PR8 + ns 0.6716 0.3 μg Fl-S + 30 μg TQL1055 in situ salt + 1 μg PHAD
[0349] Statistical analysis of the post dose 2 (D28) anti-PR8 HA IgG titers demonstrates the following: Table 3-6
TABLE-US-00030 TABLE 3-6 Adjusted Dunnett's multiple comparisons test Summary P Value 1 μg PR8 + 30 μg TQL1055 in situ salt vs. 1 μg PR8 Alone ** 0.0026 1 μg PR8 + 30 μg TQL1055 in situ salt vs. 1 μg PR8 Alone + ** 0.0012 3 μg Fl-S Alone 1 μg PR8 + 30 μg TQL1055 in situ salt vs. 1 μg PR8 + ns 0.0571 0.3 μg Fl-S + 30 μg TQL1055 in situ salt 1 μg PR8 + 30 μg TQL1055 in situ salt vs. 1 μg PR8 + ns 0.8591 3 μg Fl-S + 30 μg TQL1055 in situ salt 1 μg PR8 + 30 μg TQL1055 in situ salt vs. 1 μg PR8 + ns 0.6015 0.3 μg Fl-S + 30 μg TQL1055 in situ salt + 1 μg PHAD 1 μg PR8 + 30 μg TQL1055 in situ salt vs. 1 μg PR8 + ns >0.9999 3 μg Fl-S + 30 μg TQL1055 in situ salt + 1 μg PHAD
TABLE-US-00031 TABLE 3-7 Adjusted Dunnett's multiple comparisons test Summary P Value 0.1 μg PR8 + 30 μg TQL1055 in situ salt vs. 0.1 μg PR8 + ns 0.7748 0.3 μg Fl-S + 30 μg TQL1055 in situ salt 0.1 μg PR8 + 30 μg TQL1055 in situ salt vs. 0.1 μg PR8 + ns 0.9551 3 μg Fl-S + 30 μg TQL1055 in situ salt 0.1 μg PR8 + 30 μg TQL1055 in situ salt vs. 0.1 μg PR8 + * 0.0464 0.3 μg Fl-S + 30 μg TQL1055 in situ salt + 1 μg PHAD 0.1 μg PR8 + 30 μg TQL1055 in situ salt vs. 0.1 μg PR8 + ns 0.7963 3 μg Fl-S + 30 μg TQL1055 in situ salt + 1 μg PHAD
[0350] Statistical analysis of the post dose 2 (D28) anti-SARS-CoV-2 FL-S IgG titers demonstrates the following:
TABLE-US-00032 TABLE 3-8 Adjusted Dunnett's multiple comparisons test Summary P Value 3 μg Fl-S + 30 μg TQL1055 in situ salt vs. 3 μg Fl-S Alone ns 0.0996 3 μg Fl-S + 30 μg TQL1055 in situ salt vs. 1 μg PR8 Alone + ns 0.0995 3 μg Fl-S Alone 3 μg Fl-S + 30 μg TQL1055 in situ salt vs. 0.1 μg PR8 + ns 0.345 3 μg Fl-S + 30 μg TQL1055 in situ salt 3 μg Fl-S + 30 μg TQL1055 in situ salt vs. 1 μg PR8 + ns 0.8952 3 μg Fl-S + 30 μg TQL1055 in situ salt 3 μg Fl-S + 30 μg TQL1055 in situ salt vs. 0.1 μg PR8 + *** 0.0006 3 μg Fl-S + 30 μg TQL1055 in situ salt + 1 μg PHAD 3 μg Fl-S + 30 μg TQL1055 in situ salt vs. 1 μg PR8 + ns 0.2054 3 μg Fl-S + 30 μg TQL1055 in situ salt + 1 μg PHAD
TABLE-US-00033 TABLE 3-9 Adjusted Dunnett's multiple comparisons test Summary P Value 0.3 μg Fl-S + 30 μg TQL1055 in situ salt vs. 0.1 μg PR8 + ns >0.9999 0.3 μg Fl-S + 30 μg TQL1055 in situ salt 0.3 μg Fl-S + 30 μg TQL1055 in situ salt vs. 1 μg PR8 + ns 0.9954 0.3 μg Fl-S + 30 μg TQL1055 in situ salt 0.3 μg Fl-S + 30 μg TQL1055 in situ salt vs. 0.1 μg PR8 + *** 0.0005 0.3 μg Fl-S + 30 μg TQL1055 in situ salt + 1 μg PHAD 0.3 μg Fl-S + 30 μg TQL1055 in situ salt vs. 1 μg PR8 + * 0.0281 0.3 μg Fl-S + 30 μg TQL1055 in situ salt + 1 μg PHAD
[0351] Discussion:
[0352] As shown in the foregoing results and in
Example 4—Evaluation of Dose-Sparing Effect for Influenza Vaccine
[0353] Vaccination against both seasonal and pandemic influenza requires effective adjuvants to maximize the utility of limited antigen and to enhance immunogenicity in hyporesponsive at-risk populations. First-generation natural saponins are potent immuno-enhancers but are reactogenic and have supply constraints. As part of a NIH-funded project, the novel semisynthetic saponin TQL-1055 was evaluated for its potential to augment the immunogenicity of influenza antigens.
[0354] Methods:
[0355] Groups of 10 C57BL/6J mice were immunized subcutaneously (SC) with FLUBLOK® (H3N2 antigen) alone at either a 4.5 mcg or 1.1 mcg dose, or at a 1.1 mcg dose in combination with 10, 30 or 100 mcg TQL-1055 on Days 0 and 21. Sera were analyzed at days 0, 21 and 42 by ELISA for H3N2-specific IgG. Body weights were measured serially.
[0356] Results:
[0357] A 2-dose series of 1.1 mcg FLUBLOK with TQL-1055 elicited anti-H3N2 antibodies in all mice. This effect was TQL-1055 dose-dependent, with GMTs of 2178 in the 10 mcg group, 13674 in the 30 mcg group, and 48959 in the 100 mcg group. The GMT in all TQL-1055 groups were higher than the GMT of 176 in the group receiving 4.5 mcg of FLUBLOK alone. See
[0358] Discussion:
[0359] As show in