JPWO2021053589A5 - - Google Patents

Description

Some embodiments relate to antigen-specific tolerogenic compounds. In some embodiments, the compound has Formula 1
containing (or consisting essentially of)
In some embodiments, m is an integer from about 1 to 100. In some embodiments, X comprises an antigen. In some embodiments, Y is a linker moiety. In some embodiments, Y is
A linker portion having a formula selected from the group consisting of:
In some embodiments, q is an integer from 0 to 100. In some embodiments, k is an integer from 0 to 10. In some embodiments, R ₁ is -CH ₂ -, -(CH ₂ ) ₂ -C(CH ₃ )(CN)-, -(CH ₂ ) ₂ -C(CH ₃ )(CH ₃ )-, -(CH ₂ ) ₂ -CH(CH ₃ )- and -CH(CH ₃ )-. In some embodiments, X ¹ and X ² are independently selected from a direct bond, -NR ⁶ - and -O-. In some embodiments, v is an integer from 0 to 10. In some embodiments, d is an integer from 0 to 5. In some embodiments, d' is an integer from 0 to 50. In some embodiments, R ⁶ is H or optionally substituted C _1-6 alkyl. In some embodiments, Y' is a random, gradient or block copolymer of W ¹ and W ² or W ³ and W ⁴ , where W ¹ , W ² , W ³ and W ⁴ are That's right.
In some embodiments, the number of repeating units of W ¹ or W ³ in Y is designated as p. In some embodiments, p is an integer of at least about 1. In some embodiments, the number of repeating units of W ² or W ⁴ in Y is designated as r. In some embodiments, r is an integer of at least about 1. In some embodiments, the sum of p and r ranges from 100 to 200. In some embodiments, X ³ is selected from -C(O)-NH- or -C(O)O-. In some embodiments, X ⁴ is -C(O)-NH-, -C(O)O-, or -C(O)-OH. In some embodiments, R ⁹ is a direct bond (e.g., the bond between X ³ and Z) or -[((CH ₂ ) _h X ⁵ ) _t -((CH ₂ ) _h' X ⁶ ) _t' ]-. In some embodiments, X ⁵ and X ⁶ are independently selected from a direct bond, -CNR ^6'- , and -O-. In some embodiments, each R ^6' is independently H or optionally substituted -C _1-6 alkyl. In some embodiments, R ¹⁰ is absent or is H or -[((CH ₂ ) _h" X ⁷ ) _t" -((CH ₂ ) _h'" X ⁸ ) _t'" ]-H . In some embodiments, X ⁷ and X ⁸ are independently selected from a direct bond, -CNR ^6' '- and -O-. In some embodiments, each R ^6'' is independently H or optionally substituted -C _1-6 alkyl. In some embodiments, t, t', h, h', t'', t''', h'' and h''' are each independently equal or at least 0, 1, 2, 3, 4, is an integer of 5, 6, 7, 8, 9, 10 or 20. In some embodiments, each R ¹³ is independently H, methyl, or optionally substituted -C _1-6 alkyl. In some embodiments, the EU is a termination unit. In some embodiments, the EU includes a carbon atom that is bonded to a carbon of the linker, thereby forming a carbon-carbon bond between the linker and the termination unit. In some embodiments, Z includes a liver targeting moiety.

Some embodiments provide pharmaceutical treatments for inducing tolerance to therapeutic proteins in subjects deficient in the production of naturally occurring proteins with similar function, including the compounds disclosed above or elsewhere herein. The present invention relates to compositions that are acceptable to the public. In some embodiments, the pharmaceutically acceptable composition comprises (and/or consists of and/or consists essentially of) a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutically acceptable composition includes a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutically acceptable composition includes one or more of a dispersion medium, a coating, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. In some embodiments, the compound is provided as a pharmaceutically acceptable salt. In some embodiments, the pharmaceutically acceptable composition includes a compound that promotes uptake of the compound into cells or tissues. For example, and without limitation, dimethyl sulfoxide (DMSO) is a commonly used carrier that facilitates the uptake of many organic compounds into cells or tissues of interest. In some embodiments, the pharmaceutically acceptable composition includes a diluent. In some embodiments, the pharmaceutically acceptable composition comprises (and/or consists of and/or consists essentially of) a liquid for dissolution of the compound administered by injection, ingestion , or inhalation. consisting of it). In some embodiments, pharmaceutically acceptable compositions include buffered aqueous solutions, such as, but not limited to, phosphate buffered saline (PBS) that mimics the pH and isotonicity of human blood. and/or consisting of and/or consisting essentially of). In some embodiments, the pharmaceutically acceptable composition comprises (and/or consists of and/or consists essentially of) other buffers.

Example 8: Further synthesis method for DTB-free polymers Synthesis of Polymer I
IBN-pGal-DTB (Polymer I) A typical synthesis example of IBN-pGal-DTB with a target molecular weight of 20.0 kDa, a target degree of polymerization of approximately 80 monomers, and a target GalNAc:HEMA monomer ratio of 50:50 is as follows: PTFE A 100 mL single-necked Schlenk flask equipped with a valve and placed in a low-light area was purged with ultrapure argon (grade 6), placed in an ice bath, and equipped with a magnetic stir bar, containing compound 9 (15.0 g, 39.9 mmol, solid), compound 11 (5.1 g, 39.9 mmol, added as 5.0 mL neat oil), 2-cyano-2-propylbenzodithioate (176.4 mg, 0.8 mmol 25.0 mg/mL stock solution 7.0 mL) 2,2'-azobis(2-methylpropionitrile) (26.2 mg, 0.2 mmol, added as 5.2 mL of a 5.04 mg/mL stock solution) and N,N-dimethylformamide (28 mL). The flask was sealed with a rubber septum, the septum was reinforced with parafilm, and the solution was bubbled with ultra-high purity (grade 6) argon for 1 hour on ice. After venting, the solution is degassed by the following method. The flask is stirred at approximately 500 rpm and exposed to high vacuum for 2 minutes. The vacuum is then turned off and the flask is refilled with argon. Repeat this procedure 10 times. After the final pump cycle, the degassed solution is layered with argon and stirred at about 700 rpm for 6 hours at 75° C. in a preheated oil bath. RAFT polymerization was stopped by immersing the flask in an ice bath, exposing the solution to air, and stirring the solution on ice at 500 rpm for 15 minutes. The solution was then precipitated with 1000 mL 2-propanol at room temperature. The resulting precipitate was filtered through a disposable polyethylene frit funnel (40 microns, 2000 mL capacity), washed four times with 2-propanol, isolated and dried under vacuum to give a flaky light pink solid (11.1 g, 55. 05%) was obtained as IBN-pGal-DTB. GPC: M _p = 16.6kDa, D = 1.15. ¹ H-NMR (499.9 MHz, D ₂ O, 25℃, ppm): δ = 0.8 - 1.6 (m, 3H, main chain methyl), 1.6 - 2.3 (m , 2H, main chain methylene), 3.2 - 3.45 (br. s, 4H, ethoxymethylene), 3.5 - 4.1 (m, sugar ring proton), 4.45 - 4.6 (br. s, 1H, anomer), 7.0 - 8.6 ( m, 9H, terminal aromatic)

Furthermore, the term "consisting essentially of" is interpreted to include the specifically recited elements and additional elements that do not substantially affect the essential novel features of the claimed technology. The term "consisting of" excludes any element not specified.
Furthermore, the present invention includes the following aspects.
1. An antigen-specific tolerogenic compound for the induction of antigen-specific immune tolerance in a subject, the compound comprising:
An antigen for which tolerance is desired,
an antigen to which tolerance is desired that, when presented alone to a subject, is capable of inducing an unwanted immune response in the subject;
A polymer linker,
a copolymer comprising a first acrylyl unit comprising a first C-amide or C-carboxy functional group and a second acrylyl unit comprising a second C-amide or C-carboxy functional group;
the second C-amide or C-carboxy functionality is conjugated to an aliphatic group, an alcohol or an aliphatic alcohol;
a polymeric linker is attached to the antigen to which tolerance is desired via a disulfide bond or a disulfanylethyl ester;
a polymeric linker comprising a termination unit lacking each of a dithioester and a dithiobenzoate (DTB), which improves the stability of the compound when the termination unit is dissolved; and
a liver targeting portion,
A liver targeting moiety connected to a first acrylyl unit via a first C-amide or C-carboxy functionality and a polyether.
Compounds, including.
2. The compound of paragraph 1, wherein the compound has improved stability as compared to a compound containing a dithioester moiety that is a remnant of a chain transfer agent (CTA).
3. The compound of item 1, wherein the terminal unit is isobutyronitrile.
4. The compound of paragraph 1, wherein the disulfide bond or the disulfanyl ethyl ester is each positioned such that upon administration of the compound to the subject, it is cleaved and releases the antigen to which tolerance is desired from the polymeric linker.
5. A compound according to item 1, wherein the terminal unit lacks one or more of a trithiocarbonate and a xanthate.
6. The compound of paragraph 1, wherein the compound degrades by less than 5.0% over 28 days when dissolved in 10 mM sodium acetate and 274 mM sorbitol at a compound concentration of 1 mg/mL at a temperature of 23° C. to 27° C.
7. The compound of paragraph 1, wherein the terminal unit comprises a carbon atom bonded to a carbon of the polymeric linker, thereby providing a carbon-carbon bond between the polymeric linker and the terminal unit.
8. The termination unit is provided by carrying out a reaction between the azo compound and the azo compound of the polymeric linker and a precursor of the polymeric linker comprising a dithioester, dithiobenzoate, trithiocarbonate or xanthate ester. compound.
9. The compound of item 8, wherein the azo compound is azobisisobutyronitrile (AIBN).
10. The compound according to any one of Items 1 to 9, wherein the terminal unit is isobutyronitrile.
11. A compound according to any one of Items 1 to 9, wherein the terminal unit lacks one or more S atoms or aryl groups.
12. The compound according to any of Items 1 to 9, wherein the reaction between the azo compound and a precursor of the compound provides the compound with a terminal unit.
13. The compound of item 12, wherein the azo compound is azobisalkylnitrile.
14. The compound of item 13, wherein the azo compound is azobisisobutyronitrile (AIBN).
15. The compound of item 12, wherein the compound precursor comprises a dithioester.
16. The compound of any of paragraphs 1 to 9, wherein the first acrylyl unit comprises a first ethyl acetamide functional group and the second acrylyl unit comprises a second ethyl acetamide functional group.
17. The liver-targeting moiety is attached to the polymeric linker via the first ethyl acetamide functional group, and the liver-targeting moiety is attached to the first acrylyl unit either directly or through a connecting group comprising an aliphatic group, a polyether, or a polyamino group. The compound of Item 16.
18. The compound of paragraph 17, wherein the secondary ethyl acetamide functionality is connected to an aliphatic group, an alcohol or an aliphatic alcohol, and acts as a spacer.
19. A composition comprising the compound according to any one of Items 1 to 18.
20. The composition of paragraph 19, wherein the composition comprises a pharmaceutically acceptable carrier.
21. Use of a compound according to any of Items 1 to 18 for use in inducing tolerance to an antigen.
22. A method of inducing tolerance in a subject to an antigen capable of producing an unwanted immune response, the method comprising administering to the subject a compound of any of Items 1-18.
23. The method of paragraph 22, wherein the compound is administered before the subject is exposed to the antigen, after the subject is exposed to the antigen, or both.
24. Use of a compound according to any of paragraphs 1 to 18 in the manufacture of a medicament for inducing tolerance to an antigen or treating an unwanted immune response.
25. A compound for the induction of antigen-specific immune tolerance in a subject, the compound comprising an antigen, a linker comprising a polymer moiety, and a liver targeting moiety;
wherein the linker binds to the antigen via a disulfide bond or a disulfanylethyl ester;
wherein the disulfide bond or disulfanyl ethyl ester is each positioned such that upon administration of the compound to the subject, it is cleaved and releases the antigen from the polymeric linker;
wherein the polymeric linker comprises a termination unit lacking each of a dithioester and a dithiobenzoate (DTB) and which improves the stability of the compound when the termination unit is dissolved;
Compound.
26. The compound of paragraph 25, wherein the polymeric portion is a copolymer and comprises a first repeating unit and a second repeating unit.
27. The compound of paragraph 26, wherein the liver targeting moiety is connected to the first unit either directly or via a connecting group.
28. The compound of paragraph 27, wherein the first unit comprises a first C-amide or first C-carboxy functionality and the connecting group is an aliphatic group, polyether or polyamino group.
29. The compound of any of paragraphs 26 to 28, wherein the first repeating unit is a first acrylyl unit and the second repeating unit is a second acrylyl unit.
30. Formula 1
[During the ceremony,
m is an integer of about 1 to 100;
X contains an antigen;
Y is a linker moiety having a formula selected from the group consisting of;
here,
q is an integer from 0 to 100;
k is an integer from 0 to 10;
R ₁ is -CH ₂ -, -(CH ₂ ) ₂ -C(CH ₃ )(CN)-, -(CH ₂ ) ₂ -C(CH ₃ )(CH ₃ )-, -(CH ₂ ) ₂ - selected from the group consisting of CH(CH ₃ )- and -CH(CH ₃ )-;
X ¹ and X ² are independently selected from a direct bond, -NR ⁶ - and -O-;
v is an integer from 0 to 10;
d is an integer from 0 to 5;
d' is an integer from 0 to 50;
R ⁶ is H or optionally substituted C _1-6 alkyl;
Y' is a random, gradient or block copolymer of W ¹ and W ² or W ³ and W ⁴ , where W ¹ , W ² , W ³ and W ⁴ are shown below;
where the number of repeat units of W ¹ or W ³ in Y is denoted as p, p is an integer of at least about 1;
The number of repeating units of W ² or W ⁴ in Y is designated as r, where r is an integer of at least about 1;
The sum of p and r ranges from 100 to 200;
X ³ is selected from -C(O)-NH- or -C(O)O-;
X ⁴ is -C(O)-NH-, -C(O)O- or -C(O)-OH;
R ⁹ is a direct bond or -[((CH ₂ ) _h X ⁵ ) _t -((CH ₂ ) _h' X ⁶ ) _t' ]-;
where X ⁵ and X ⁶ are independently selected from a direct bond, -CNR ^6' - and -O-;
where each R ^6' is independently H or optionally substituted -C _1-6 alkyl;
R ¹⁰ is absent or is H or -[((CH ₂ ) _h" X ⁷ ) _t" -((CH ₂ ) _h'" X ⁸ ) _t'" ]-H;
where X ⁷ and X ⁸ are independently selected from a direct bond, -CNR ^6'' - and -O-;
each R ^6” is independently H or optionally substituted -C _1-6 alkyl;
t, t', h, h', t'', t''', h'' and h''' are each independently equal or at least 0, 1, 2, 3, 4, 5, 6, 7, 8, is an integer of 9, 10 or 20;
each R ¹³ is independently H, methyl or optionally substituted -C _1-6 alkyl;
EU is a terminating unit, where EU includes a carbon atom bonded to a carbon of the linker, thereby forming a carbon-carbon bond between the linker and the terminating unit; and
Z is the liver targeting moiety. ]
Antigen-specific tolerogenic compounds, including.
31. The EU:
[In the formula, R ¹⁴ is s optionally substituted C _1-11 alkyl; -CN; optionally substituted -C(=NH)NH ₂ ; optionally substituted heterocyclyl; optionally substituted optionally substituted heteroaryl; optionally substituted aralkyl; optionally substituted heteroaralkyl; C-carboxy(-C(O)OR), where R is -H, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 alkylenyl or optionally substituted phenyl); optionally substituted C-amide (-C(O) NR _A R _B ) (where R _A and R _B are independently -H or optionally substituted C _1-6 alkyl); optionally substituted succinimidyl ester; optionally substituted selected from isoindoline-1,3-diones; alkylsilanes;
wherein each R ¹² is independently C _1-10 alkyl optionally substituted with hydrogen, halogen, C-carboxy, -amino or -OH or each R ¹² together is optionally substituted C _3-6 cycloalkyl. ]
The compound of term 30, represented by
32. Each optional substitution of R ¹⁴ is C _1-3 alkyl, C _1-6 alkoxy, C _1-6 alkylenyl, hydroxyl, amino, halogen, C-carboxy (wherein R is -H, C _1-6 31. The compound of paragraph 30 is selected from the group consisting of alkyl or polyethylene glycol (PEG).
33. The compound of term 1, wherein EU is selected from the group consisting of:
34. The compound of any of paragraphs 30-33, wherein the p to r ratio is about 1:1.
35. The compound of any of paragraphs 30-33, wherein the p to r ratio is about 4:1.
36. Y is Ya':
k is 2;
R ¹ is -(CH ₂ ) ₂ -C(CH ₃ )(CN)-;
X ³ is -C(O)-NH-, h is 2, X ⁵ is -O-, t is 2, and t' is 0, so that X ³ and R ⁹ together are -C(O)-NH-CH ₂ -CH ₂ -O-CH ₂ -CH ₂ -O-,
The compound according to any one of Items 30 to 33.
37. Y is Ye':
q is 0;
k is 2;
R ¹ is -(CH ₂ ) ₂ -C(CH ₃ )(CN)-;
X ³ and R ⁹ together are -C(O)-NH- and (CH ₂ ) ₂ -(O-CH ₂ -CH ₂ ) _t -;
t is 1;
Z is one or more of galactose, glucose, galactosamine, glucosamine, N-acetylgalactosamine or N-acetylglucosamine,
The compound according to any one of Items 30 to 33.
38. The compound of term 36 or 37, wherein q is 0.
39. The compound of item 36 or 37, wherein q is 3.
40. Items 1-39, wherein the compound degrades by less than 2.0% over a period of 28 days when dissolved in 10 mM sodium acetate and 274 mM sorbitol at a compound concentration of 1 mg/mL at a temperature of 23°C to 27°C. any compound of
41. The compound of any of paragraphs 1 to 40, wherein the liver targeting moiety is galactose, glucose, galactosamine, glucosamine, N-acetylgalactosamine and/or N-acetylglucosamine.
42. The compound of item 41, wherein Z is bonded to Y at its C1, C2 or C6.
43. The compound of paragraph 42, wherein Z is N-acetylgalactosamine or N-acetylglucosamine.
44. A compound according to any of paragraphs 1 to 43, wherein the antigen is a tolerogenic portion of a full-length antigen.
45. The compound according to any of Items 1 to 44, wherein the antigen comprises a food antigen.
46. Food antigens include conarachin (Ara h 1), allergen II (Ara h 2), Arachis agglutinin, conglutin (Ara h 6), 31kda major allergen/disease resistance protein homologue (Mal d 2), lipid transport protein Precursor (Mal d 3), major allergen Mal d 1.03D (Mal d 1), a-lactalbumin (ALA), lactotransferrin, actinidin (Act c 1, Act d 1), phytocystatin, thaumatin-like protein (Act d 2), quiwerin (Act d 5), ovomucoid, ovalbumin, ovotransferrin and lysozyme, livetin, apovitillin, bosvetin, 2S albumin (Sin a 1), 11S globulin (Sin a 2), lipid transport protein (Sin a 3) ), profilin (Sin a 4), profilin (Api g 4), high molecular weight glycoprotein (Api g 5), Pen a 1 allergen (Pen a 1), allergen Pen m 2 (Pen m 2), tropomyosin immediate Isoforms, high molecular weight glutenin, low molecular weight glutenin, alpha-, gamma- and omega-gliadin, hordein, secalin, avenin, major strawberry allergy Fra a 1-E (Fra a 1), profilin (Mus xp 1), 46. A compound of paragraph 45 selected from the group consisting of any part of an antigen and any mimetic of said antigen.
47. The food antigen is from the group consisting of high molecular weight glutenin, low molecular weight glutenin, alpha-, gamma- and omega-gliadin, hordein, secalin, avenin, any part of said antigen and any mimetic of said antigen. A selected compound of paragraph 45.
48. Compounds of item 45 whose food antigens are associated with celiac disease.
49. A compound according to any of paragraphs 1 to 48, wherein the antigen is associated with an autoimmune disease.
50. Autoimmune diseases include type I diabetes, multiple sclerosis, rheumatoid arthritis, leukoplakia, uveitis, pemphigus vulgaris, neuromyelitis optica, Goodpasture's disease, Parkinson's disease, myasthenia gravis, celiac disease, and 49. A compound of item 49 selected from the group consisting of anti-neutrophil cytoplasmic antibody associated vasculitis.
51. The compound according to any one of Items 1 to 50, wherein the antigen includes an autoantigen.
52. The compound of paragraph 51, wherein the autoantigen is selected from myelin basic protein, myelin oligodendrocyte glycoprotein and proteolipid protein, a portion of any of said antigen and a mimetic of any of said antigen.
53. Self-antigens include insulin, proinsulin, preproinsulin, glutamate decarboxylase-65 (GAD-65), GAD-67, insulinoma-associated protein 2 (IA-2) and insulinoma-associated protein 213 (IA-213), ICA69, ICA12 (SOX-13), carboxypeptidase H, Imogen 38, GLIMA38, chromogranin-A, HSP-60, carboxypeptidase E, peripherin, glucose transporter 2, hepatocellular carcinoma-enteropancreas/pancreas-related protein, S100β, glia cellular fibrous acidic protein, regenerative gene II, pancreatic duodenal homeobox 1, myotonic dystrophy kinase, islet cell-specific glucose-6-phosphatase catalytic subunit-related protein, SST protein G-coupled receptor 1-5, bone marrow 52. A compound of paragraph 51 selected from peroxidase (MPO), proteinase-3/myeloblastic cells (PR3) and a portion of any of said antigens and a mimetic of any of said antigens.
54. The compound of any of paragraphs 1-53, wherein the antigen comprises a therapeutic agent.
55. Therapeutic agents include abciximab, adalimumab, agalsidase alpha, agalsidase beta, aldesleukin, Al glucosidase alpha, factor VIII, factor IX, infliximab, L-asparaginase, laronidase, natalizumab, octreotide, phenylalanine ammonia-lyase (PAL) ), rasburicase (uricase), gene therapy vectors or AAV, portions of any of said antigens and mimetics of any of said antigens.
56. The compound according to any of Items 1 to 55, wherein the antigen comprises a transplantation antigen.
57. The transplantation antigen is selected from the group consisting of subunits of MHC class I and MHC class II haplotype proteins and their complexes with presenting antigens and minor blood group antigens RhCE, Kell, Kidd, Duffy and Ss. 56 compounds.
58. A compound according to any of paragraphs 1 to 57, wherein the antigen or tolerogenic portion thereof is desmoglein-3, -1 and/or -4.
59. A compound according to any of paragraphs 1 to 58, wherein the antigen or tolerogenic portion thereof is associated with pemphigus vulgaris.
60. A composition comprising a compound according to any one of Items 1 to 59.
61. Use of a compound according to any of Items 1 to 59 for use in inducing tolerance to an antigen.
62. A method of inducing tolerance in a subject to an antigen capable of producing an unwanted immune response, the method comprising administering to the subject a compound of any of paragraphs 1-61.
63. The method of paragraph 62, wherein the compound is administered before the subject is exposed to the antigen, after the subject is exposed to the antigen, or both.
64. Use of a compound according to any of Items 1 to 63 for the manufacture of a medicament for inducing tolerance to an antigen.
65. A compound according to any of paragraphs 1 to 64, wherein the antigen comprises a foreign transplant antigen, a tolerogenic portion thereof, or a mimetic thereof that produces an undesired immune response in the transplant recipient.
66. Any of paragraphs 1 to 66, wherein the antigen contains a foreign food, animal, plant or environmental antigen, a tolerogenic portion of any of it, or a mimetic of any of it, which produces an unwanted immune response in the patient. compound or composition.
67. A compound or composition according to any of paragraphs 1-66, wherein the antigen comprises a foreign therapeutic agent, a tolerogenic portion thereof, or a mimetic thereof, which results in an immune response that is unwanted by the patient.
68. Any of paragraphs 1 to 6, wherein the antigen is a self-antigen, a tolerogenic part thereof, or a mimetic thereof, which causes the endogenous version to produce an unwanted immune response in the patient, or a tolerogenic part thereof. any compound or composition.
69. Antigens include antibodies, antibody fragments or ligands that specifically bind to circulating proteins or peptides or antibodies that are responsible for graft rejection, immune responses to therapeutic agents, autoimmune diseases, hypersensitivity and/or allergies; The compound or composition according to any one of Items 1 to 68.
70. A pharmaceutically acceptable composition for inducing tolerance to a therapeutic protein in a subject deficient in the production of a naturally occurring protein with similar function, comprising a compound of any of Items 1-69.
71. Use of a compound or composition of any of paragraphs 1 to 70 for the treatment of an unwanted immune response to an antigen.
72. Unwanted immune responses are associated with type I diabetes, multiple sclerosis, rheumatoid arthritis, vitiligo, uveitis, pemphigus vulgaris, neuromyelitis optica, Parkinson's disease, Goodpasture's disease, celiac disease, or myasthenia gravis. Use of section 71 in connection with.
73. A compound or composition according to any of paragraphs 1 to 72 for the manufacture of a medicament for use in the treatment of an unwanted immune response to an antigen.
74. A method of producing an antigen-specific tolerogenic compound, comprising:
Preparation of the polymeric portion of the polymeric linker using reversible addition-fragmentation chain transfer (RAFT);
transfer of chain transfer agent remnants from polymer moieties with terminal units; and
Conjugate antigen to polymer linker
including methods.
75. The following structure:
A method for producing a compound having
The following structure:
providing a dithiobenzoate-containing compound;
The following structure:
providing a termination unit;
mixing a termination unit reagent and a dithiobenzoate-containing compound to form a compound;
where T, when present, is PDS or a carboxylic acid;
X ¹ and X ² are independently selected from a direct bond, -NR ⁶ - and -O-;
R ⁶ is H or C _1-6 alkyl optionally substituted with halogen, C _1-3 alkyl or C-carboxy;
v is an integer from 0 to 10;
d is an integer from 0 to 5;
d' is an integer from 0 to 50;
where each R ¹² is independently hydrogen or optionally substituted alkyl;
R ₁ is -CH ₂ -, -(CH ₂ ) ₂ -C(CH ₃ )(CN)-, -(CH ₂ ) ₂ -C(CH ₃ )(CH ₃ )-, -(CH ₂ ) ₂ - selected from the group consisting of CH(CH ₃ )- and -CH(CH ₃ )-
When Y' is a random copolymer of W ¹ and W ² or W ³ and W ⁴ , it is a gradient copolymer or a block copolymer, where W ¹ , W ² , W ³ and W ⁴ are shown below.
where the number of repeat units of W ¹ or W ³ in Y is denoted as p, p is an integer of at least about 1;
where the number of repeating units of W ² or W ⁴ in Y' is denoted as r, and r is an integer of at least about 1;
X ³ is selected from -C(O)-NH- or -C(O)O-;
X ⁴ is -C(O)-NH-, -C(O)O- or -C(O)-OH;
R ⁹ is a direct bond or -[((CH ₂ ) _h X ⁵ ) _t -((CH ₂ ) _h' X ⁶ ) _t' ]-;
where X ⁵ and X ⁶ are independently selected from a direct bond, -CNR ^6' - and -O-;
C _1-6 alkyl, where each R ^6′ is independently optionally substituted with H or halogen, C _1-3 alkyl or C-carboxy ;
R ¹⁰ is absent or -[((CH ₂ ) _h" X ⁷ ) _t" -((CH ₂ ) _h'" X ⁸ ) _t'" ]-H;
X ⁷ and X ⁸ are independently selected from a direct bond, -CNR ^6'' - and -O-;
each R ^6” is independently H or C 1-6 alkyl optionally substituted with halogen, C _1-3 alkyl or C-carboxy _;
t, t', h and h' are each independently equal to or an integer of at least about 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20;
t", t'", h" and h'" are each independently equal or an integer of at least about 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20; ;
each R ¹³ is independently H, methyl or optionally substituted -C _1-6 alkyl;
Z comprises a liver targeting moiety;
Method.
76. A method of producing an antigen-specific tolerogenic compound, comprising:
coupling a liver targeting moiety to a first acrylyl monomer;
A reversible addition-fragmentation chain transfer reaction (RAFT) of at least a first acrylyl monomer and a second acrylyl monomer is used to prepare the polymer portion of the polymer linker, the polymer portion being a first C-amide or C-carboxy functional group. and a second acrylyl unit comprising a C-amide or C-carboxy functional group;
transfers chain transfer agent remnants from the polymer moiety having the termination unit, improving the stability of the compound when the termination unit is dissolved;
conjugating an antigen to a polymeric linker, wherein the antigen to which tolerance is desired is capable of inducing an unwanted immune response in the subject when presented alone to the subject;
Method.
77. The method of paragraph 76, wherein the termination unit is added to the polymer moiety by reaction using a bis-azo compound.
78. The method of paragraph 76 or 77, wherein the second acrylyl monomer is attached to an aliphatic group, an alcohol, or an aliphatic alcohol.
79. A compound for the induction of antigen-specific immune tolerance in a subject, the compound comprising an antigen, a linker comprising a polymer moiety, and a liver targeting moiety;
wherein the linker binds to the antigen via a disulfide bond or a disulfanylethyl ester;
wherein the disulfide bond or disulfanyl ethyl ester is each positioned such that upon administration of the compound to the subject, it is cleaved and releases the antigen from the polymeric linker;
the polymeric linker contains a termination unit that improves the stability of the compound when dissolved;
The terminal unit is not -H, a dithioester, a dithiobenzoate, a trithiocarbonate or a xanthate,
Compound.
80. A compound according to any of paragraphs 1-48, wherein the antigen comprises all or an immunogenic fragment of SEQ ID NO: 54, 55, 56, 57, 60 or 61.
81. A compound according to any of paragraphs 1-44 or 49-52, wherein the antigen comprises all or an immunogenic fragment of SEQ ID NO: 21, 27, 28, 30, 32, 43, 44 or 46.
82. The compound of any of paragraphs 1-44, 49-51 or 53, wherein the antigen comprises all of SEQ ID NO: 1 to SEQ ID NO: 19 or an immunogenic fragment.

Claims (31)

A pharmaceutical composition for inducing antigen-specific immune tolerance in a subject, comprising an antigen-specific tolerogenic compound, the compound being the antigen to which tolerance is desired;
an antigen to which tolerance is desired that, when presented alone to a subject, is capable of inducing an unwanted immune response in the subject;
A polymer linker,
a copolymer comprising a first acrylyl unit comprising a first C-amide or C-carboxy functional group and a second acrylyl unit comprising a second C-amide or C-carboxy functional group;
the second C-amide or C-carboxy functionality is conjugated to an aliphatic group, an alcohol or an aliphatic alcohol;
a polymeric linker is attached to the antigen to which tolerance is desired via a disulfide bond or a disulfanylethyl ester;
a polymeric linker comprising a termination unit lacking each of a dithioester and a dithiobenzoate (DTB), which improves the stability of the compound when the termination unit is dissolved; and a liver targeting moiety, comprising:
comprising a liver targeting moiety connected to a first acrylyl unit via a first C-amide or C-carboxy functional group and a polyether;
As used herein, the term "C-amide functional group" refers to the group -C(O)-NH-, and the term "C-carboxy functional group" refers to the group -C(O)O-, in a pharmaceutical composition. 2. The pharmaceutical composition of claim 1, wherein the antigen to which tolerance is desired is associated with a food allergy or autoimmune disease, and the liver targeting moiety comprises a galactosylated or glucosylated moiety. The food antigen is selected from the group consisting of high molecular weight glutenin, low molecular weight glutenin, alpha-, gamma- and omega-gliadin, hordein, secalin, avenin, a portion of any of said antigen and a mimetic of any of said antigen. 3. The pharmaceutical composition of claim 2 . Food antigens include conarachin (Ara h 1), allergen II (Ara h 2), Arachis agglutinin, conglutin (Ara h 6), 31kda major allergen/disease resistance protein homologue (Mal d 2), lipid transport protein precursor (Mal d 3), major allergen Mal d 1.03D (Mal d 1), a-lactalbumin (ALA), lactotransferrin, actinidin (Act c 1, Act d 1), phytocystatin, thaumatin-like protein (Act d 2) ), kiwerin (Act d 5), ovomucoid, ovalbumin, ovotransferrin and lysozyme, livetin, apovitillin, bosvetin, 2S albumin (Sin a 1), 11S globulin (Sin a 2), lipid transport protein (Sin a 3), Profilin (Sin A 4), Profilin (Api G 4), High Molecular Weight Glycoprotein (Api G 5), Pen A 1 Allergen (Pen A 1), Allergen Pen M 2 (Pen M 2), Tropomyosin Immediate Isoform , high molecular weight glutenin, low molecular weight glutenin, alpha-, gamma- and omega-gliadin, hordein, secalin, avenin, major strawberry allergy Fra a 1-E (Fra a 1), profilin (Mus xp 1), of the antigen. 3. The pharmaceutical composition of claim 2 , selected from the group consisting of any part and any mimetic of said antigen. 3. The pharmaceutical composition of claim 2 , wherein the antigen is associated with an autoimmune disease. Autoimmune diseases include multiple sclerosis, type I diabetes, rheumatoid arthritis, vitiligo, uveitis, pemphigus vulgaris, neuromyelitis optica, Goodpasture's disease, Parkinson's disease, myasthenia gravis , and antineutrophils. 6. The pharmaceutical composition of claim 5 , selected from the group consisting of cytoplasmic antibody-associated vasculitis. 7. The pharmaceutical composition of claim 6 , wherein the antigen comprises an autoantigen. self-antigen
associated with multiple sclerosis;
Associated with type I diabetes;
associated with pemphigus vulgaris;
associated with myasthenia gravis;
selected from myelin oligodendrocyte glycoprotein, myelin basic protein and proteolipid protein and the tolerable portion of any of said antigens; and/or
Contains the tolerative portion of myelin oligodendrocyte glycoprotein
8. The pharmaceutical composition of claim 7, which is at least one of : Autoantigens include insulin, proinsulin, preproinsulin, glutamate decarboxylase-65 (GAD-65), GAD-67, insulinoma-associated protein 2 (IA-2) and insulinoma-associated protein 213 (IA-213), ICA69, ICA12 ( SOX-13), carboxypeptidase H, Imogen 38, GLIMA38, chromogranin-A, HSP-60, carboxypeptidase E, peripherin, glucose transporter 2, hepatocellular carcinoma-enteropancreas/pancreas-related protein, S100β, glial cell fiber acidic protein, regenerative gene II, pancreatic duodenal homeobox 1, myotonic dystrophy kinase, islet cell-specific glucose-6-phosphatase catalytic subunit-related protein, SST protein G-coupled receptor 1-5, bone marrow peroxidase ( 9. The pharmaceutical composition of claim 7 or 8 , wherein the pharmaceutical composition is selected from the group consisting of proteinase-3/myeloblastic cells (PR3) and the tolerized portion of any of said antigens. A claim in which the autoantigen comprises one or more of the tolerized portion desmoglein-3, the tolerated portion of desmoglein -1, the tolerated portion desmoglein-4 , desmoglein-3, desmoglein-1, or desmoglein-4. The pharmaceutical composition of item 7 or 8 . The self-antigen is the tolerative part of the acetylcholine receptor, the tolerative part of MuSK (muscle-specific kinase), the tolerative part of LRP4 (lipoprotein receptor-related protein 4), the tolerative part of the acetylcholine receptor, MuSK or LRP4. 9. The pharmaceutical composition of claim 7 or 8, comprising one or more. A pharmaceutical composition according to any of claims 1 to 4 , wherein the antigen to which tolerance is desired is associated with celiac disease. 13. The pharmaceutical composition of claim 12 , wherein the antigen for which tolerance is desired comprises one or more of SEQ ID NO: 55 , SEQ ID NO: 54 , SEQ ID NO: 56 , or SEQ ID NO: 57. 14. The pharmaceutical composition of claim 13, wherein the antigen for which tolerance is desired comprises SEQ ID NO: 55. A pharmaceutical composition according to any of claims 1 to 8, wherein the antigen to which tolerance is desired is associated with multiple sclerosis . 16. The pharmaceutical composition of claim 15 , wherein the antigen for which tolerance is desired comprises one or more of SEQ ID NO: 27, SEQ ID NO : 28, SEQ ID NO : 30, SEQ ID NO : 43, SEQ ID NO: 44, SEQ ID NO: 45 , or SEQ ID NO: 46. A pharmaceutical composition according to any of claims 1 to 16 , wherein the liver targeting moiety is N - acetylgalactosamine . 18. A pharmaceutical composition according to any of claims 1 to 17, wherein the compound has improved stability compared to compounds comprising a dithioester moiety that is a remnant of a chain transfer agent (CTA). A pharmaceutical composition according to any of claims to 18 , wherein the terminating unit is isobutyronitrile. 20. The pharmaceutical composition of any of claims 1 to 19, wherein the disulfide bond or disulfanyl ethyl ester is each positioned such that it is cleaved upon administration of the compound to the subject and liberates the antigen to which tolerance is desired from the polymeric linker. . Pharmaceutical composition according to any of claims 1 to 20 , wherein the terminal unit lacks one or more of a trithiocarbonate , a xanthate , an S atom and an aryl group . Any of claims 1 to 21, wherein the compound has less than 5.0% degradation over 28 days when dissolved in 10 mM sodium acetate and 274 mM sorbitol at a compound concentration of 1 mg/mL at a temperature of 23°C to 27° C. Pharmaceutical composition . 23. The pharmaceutical composition of any of claims 1-22 , wherein the termination unit comprises a carbon atom bonded to a carbon of the polymeric linker, thereby providing a carbon-carbon bond between the polymeric linker and the termination unit. the first acrylyl unit comprises a first ethyl acetamide functional group, the second acrylyl unit comprises a second ethyl acetamide functional group, and the liver targeting moiety is attached to the polymer linker via the first ethyl acetamide functional group; 23. A pharmaceutical composition according to any of claims 1 to 22 , wherein the liver targeting moiety is connected to the first acrylyl unit directly or via a connecting group comprising an aliphatic group, a polyether or a polyamino group. 25. The pharmaceutical composition of claim 24 , wherein the second ethyl acetamide functional group is connected to an aliphatic group, an alcohol or an aliphatic alcohol, and acts as a spacer. A pharmaceutical composition according to any of claims 1 to 25 , wherein the composition comprises a pharmaceutically acceptable carrier. 28. The pharmaceutical composition of any of claims 1-27, which is administered before the subject is exposed to the antigen, after the subject is exposed to the antigen, or both. A pharmaceutical composition according to any of claims 1 to 27 for treating an unwanted immune response. 29. A method for producing an antigen-specific tolerogenic compound for use in a pharmaceutical composition according to any of claims 1 to 28, comprising :
coupling a liver targeting moiety to a first acrylyl monomer;
A reversible addition-fragmentation chain transfer reaction (RAFT) of at least a first acrylyl monomer and a second acrylyl monomer is used to prepare the polymer portion of the polymer linker, the polymer portion being a first C-amide or C-carboxy functional group. and a second acrylyl unit comprising a C-amide or C-carboxy functional group;
transfers chain transfer agent remnants from the polymer moiety having the termination unit, improving the stability of the compound when the termination unit is dissolved;
conjugating an antigen to a polymeric linker, wherein the antigen to which tolerance is desired is capable of inducing an unwanted immune response in the subject when presented alone to the subject;
Method. A pharmaceutical composition according to any one of claims 1 to 28 for inducing tolerance to an antigen, wherein the compound is administered before the subject is exposed to the antigen, after the subject is exposed to the antigen, or both. Use of compounds. Use of a compound comprised in a pharmaceutical composition according to any of claims 1 to 28 for the manufacture of a medicament for inducing tolerance to an antigen or for treating an unwanted immune response.