US2007254851A1PendingUtilityA1
Chemically-defined non-polymeric valency platform molecules and conjugates thereof
Individually held — no corporate assignee on recordPriority: Jan 15, 1991Filed: Oct 2, 2006Published: Nov 1, 2007
Est. expiryJan 15, 2011(expired)· nominal 20-yr term from priority
A61P 37/06A61P 37/00A61P 29/00A61K 2039/6093A61K 47/645A61K 47/60A61K 47/59A61K 47/54A61P 17/00A61K 39/35C07K 14/003A61K 38/00A61K 47/595C07H 21/00A61K 39/0008
60
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Claims
Abstract
Chemically-defined, non-polymeric valency platform molecules and conjugates comprising chemically-defined valency platform molecules and biological or chemical molecules including polynucleotide duplexes of at least 20 base pairs that have significant binding activity for human lupus anti-dsDNA autoantibodies.
Claims
exact text as granted — not AI-modified1 . A conjugate comprising (a) biological or chemical molecules reacted with (b) a chemically-defined, non-polymeric valency platform molecule of the formula:
G
[
1
]
{
T
[
1
]
}
n
[
1
]
Formula
1
or
G
[
2
]
{
L
[
2
]
-
J
[
2
]
-
Z
[
2
]
(
T
[
2
]
)
p
[
2
]
}
n
[
2
]
Formula
2
wherein
each of G [1] and G [2] , if present, is independently a linear, branched or multiply-branched chain comprising 1-2000 chain atoms selected from the group C, N, O, Si, P and S;
each of the n [1] moieties shown as T [1] and each of the p [2] ×n [2] moieties shown as T [2] is independently chosen from the group NHR SUB (amine), C(═O)NHNHR SUB (hydrazide), NHNHR SUB (hydrazine), C(═O)OH (carboxylic acid), C(═O)OR ESTER (activated ester), C(═O)OC(═O)R B (anhydride), C(═O)X (acid halide), S(═O) 2 X (sulfonyl halide), C(═NR SUB )OR SUB (imidate ester), NCO (isocyanate), NCS (isothiocyanate), OC(═O)X (haloformate), C(═O)OC(═NR SUB )NHR SUB (carbodiimide adduct), C(═O)H (aldehyde), C(═O)R B (ketone), SH (sulfhydryl or thiol), OH (alcohol), C(═O)CH 2 X (haloacetyl), R ALK X (alkyl halide), S(═O) 2 OR ALK X (alkyl sulfonate), NR 1 R 2 wherein R 1 R 2 is —C(═O)CH═CHC(═O)— (maleimide), C(═O)CR B ═CR B 2 (α,β-unsaturated carbonyl), R ALK —Hg—X (alkyl mercurial), and S(═O)CR B ═CR B 2 (α,β-unsaturated sulfone);
wherein
each X is independently a halogen of atomic number greater than 16 and less than 54 or other good leaving group;
each R ALK is independently a linear, branched, or cyclic alkyl (1-20C) group;
each R SUB is independently H, linear, branched, or cyclic alkyl (1-20C), aryl (6-20C), or alkaryl (7-30C);
each R ESTER is independently N-hydroxysuccinimidyl, p-nitrophenoxy, pentafluorophenoxy, or other activating group;
each R B is independently a radical comprising 1-50 atoms selected from the group C, H, N, O, Si, P and S;
each of the n [2] moieties shown as L [2] , if present, is independently chosen from the group O, NR SUB and S;
each of the n [2] moieties shown as J [2] , if present, is independently chosen from the group C(═O) and C(═S);
n [1] =1 to 32;
n [2] =1 to 32;
p [2] =1 to 8;
with the proviso that the product n [2] ×p [2] be greater than 1 and less than 33;
each of the n [2] moieties shown as Z [2] is independently a radical comprising 1-200 atoms selected from the group C, H, N, O, Si, P and S, containing attachment sites for at least p [2] functional groups on alkyl, alkenyl, or aromatic carbon atoms.
2 . A conjugate according to claim 1 , wherein the biological molecules comprise polynucleotide duplexes of at least about 20 base pairs each bound to the valency platform molecule, the duplexes each having a significant binding activity for human systemic lupus erythematosus anti-dsDNA autoantibodies.
3 . A conjugate according to claim 1 , wherein the biological or chemical molecules are selected from the group consisting of carbohydrates, lipid, lipopolysaccharides, peptides, proteins, glycoproteins, single-stranded or double-stranded oligonucleotides, haptens, or chemical analogs thereof such as mimotopes, aptamers.
4 . A conjugate according to claim 1 , wherein the biological or chemical molecules are analogs of immunogens wherein (a) the analog binds specifically to B cells to which the immunogen binds specifically and (b) the conjugate lacks a T cell epitope.
5 . The conjugate of claim 1 , wherein the valency platform molecule is derivatized by a reagent selected from the group consisting of DABA, BAHA, BAHA ox , and AHAB.
6 . The conjugate of claim 2 , wherein a linker molecule couples the duplexes to the valency platform molecule.
7 . The conjugate of claim 6 , wherein the linker molecule is selected from the group consisting of HAD and HAD p S.
8 . The conjugate of claim 2 , wherein the duplexes are substantially homogeneous in length.
9 . The conjugate of claim 2 , wherein the duplexes are substantially homogeneous in nucleotide composition.
10 . The conjugate of claim 2 , wherein the duplexes are 20 to 50-bp in length.
11 . The conjugate of claim 2 , wherein the duplexes are bound to the valency platform molecule at or proximate one of their ends.
12 . The conjugate of claim 2 , wherein the conjugate is a tolerogen for human systemic lupus erythematosus.
13 . A conjugate according to claim 2 , wherein the polynucleotide duplexes have a B-DNA type helical structure and a significant binding activity for human systemic lupus erythematosus anti-dsDNA autoantibodies.
14 . A pharmaceutical composition for treating lupus comprising the conjugate of claim 2 formulated with a pharmaceutically acceptable injectable vehicle.
15 . A method for treating an individual for lupus comprising administering a therapeutically effective amount of the composition claim 14 to an individual in need of such treatment.
16 . A method for making the conjugate of claim 2 , comprising:
(a) bonding a multiplicity of single-stranded polynucleotides of at least about 20 base pairs each on the valency platform molecule; and (b) annealing complementary single-stranded polynucleotides to the single-stranded polynucleotides conjugated to the valency platform molecule to form said duplexes.
17 . A pharmaceutical composition for treating an antibody-mediated pathology comprising a therapeutically effective amount of the conjugate of claim 2 , combined with a pharmaceutically acceptable carrier.
18 . A method of inducing specific B cell anergy to an immunogen in an individual comprising administering to the individual an effective amount of the conjugate of claim 17 .
19 . A method of treating an individual for an antibody-mediated pathology in which undesired antibodies are produced in response to an immunogen comprising administering a therapeutically effective amount of the conjugate of claim 17 to the individual.
20 . A method for making a conjugate according to claim, 2, comprising
(a) covalently bonding the analog of the immunogen lacking T cell epitopes to the chemically-defined valency platform molecule to form a conjugate; and (b) recovering the conjugate from the reaction mixture.
21 . A chemically-defined, non-polymeric valency platform molecule of the formula:
G
[
6
]
{
O
-
C
(
=
O
)
-
NR
SUB
-
Q
[
6
]
(
T
[
6
]
)
p
[
6
]
}
n
[
6
]
Formula
6
or
G
[
7
]
{
O
-
C
(
=
O
)
-
N
[
Q
[
7
]
(
T
[
7
]
)
p
[
7
]
/
2
]
2
}
n
[
7
]
Formula
7
wherein
each of G [6] and G [7] , if present, is independently a linear, branched or multiply-branched chain comprising 1-2000 chain atoms selected from the group C, N, O, Si, P and S;
each of the n [6] ×p [6] moieties shown as T [6] and each of the n [7] ×p [7] moieties shown as T [7] is independently chosen from the group NHR SUB (amine), C(═O)NHNHR SUB (hydrazide), NHNHR SUB (hydrazine), C(═O)OH (carboxylic acid), C(═O)OR ESTER (activated ester), C(═O)OC(═O)R B (anhydride), C(═O)X (acid halide), S(═O) 2 X (sulfonyl halide), C(═NR SUB )OR SUB (imidate ester), NCO (isocyanate), NCS (isothiocyanate), OC(═O)X (haloformate), C(═O)OC(═NR SUB )NHR SUB (carbodiimide adduct), C(═O)H (aldehyde), C(═O)R B (ketone), SH (sulfhydryl or thiol), OH (alcohol), C(═O)CH 2 X (haloacetyl), R ALK X (alkyl halide), S(═O) 2 OR ALK X (alkyl sulfonate), NR 1 R 2 wherein R 1 R 2 is —C(═O)CH═CHC(═O)— (maleimide), C(═O)CR B ═CR B 2 (α,β-unsaturated carbonyl), R ALK —Hg—X (alkyl mercurial), and S(═O)CR B ═CR B 2 (α,β-unsaturated sulfone);
wherein
each X is independently a halogen of atomic number greater than 16 and less than 54 or other good leaving group;
each R ALK is independently a linear, branched, or cyclic alkyl (1-20C) group;
each R SUB is independently H, linear, branched, or cyclic alkyl (1-20C), aryl (1-20C), or alkaryl (1-30C);
each R ESTER is independently N-hydroxysuccinimidyl, p-nitrophenoxy, pentafluorophenoxy, or other activating group;
each R B is independently a radical comprising 1-50 atoms selected from the group C, H, N, O, Si, P and S;
n [6] =1 to 32;
p [6] =1 to 8;
with the proviso that the product n [6] ×p [6] be greater than 1 and less than 33;
n [7] =1 to 32;
p [7] =2, 4, 6 or 8;
with the proviso that the product n [7] ×p [7] be greater than 1 and less than 33;
each of the n [6] moieties shown as Q [6] and each of the 2×n [7] moieties shown as Q [7] is independently a radical comprising 1-100 atoms selected from the group C, H, N, O, Si, P and S, containing attachment sites for at least p [6] (for Q [6] ) or p [7] /2 (for Q [7] , where p [7] /2 is an integer) functional groups on alkyl, alkenyl, or aromatic carbon atoms.Join the waitlist — get patent alerts
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