Neoglycoproteins

Details Neoglycoproteins Neoglycoproteins

2002-04-16

2004-04-20

Russel, Jeffrey E. (Department: 1654)

Chemistry: natural resins or derivatives; peptides or proteins;

Peptides of 3 to 100 amino acid residues

Peptides containing saccharide radicals, e.g., bleomycins, etc.

C525S054200, C530S322000, C530S345000, C530S395000, C530S405000, C530S411000, C536S017600

Reexamination Certificate

active

06723831

ABSTRACT:

The present invention relates to novel polyamide conjugates, processes for their preparation and the use of these conjugates in therapeutic compositions.
The increased shortage of donor organs for transplantation from human to human has led to a great interest in the possibilities of xenotransplantation (transplantation from non-human to human). At present research is focused on easily accessible animals, such as pigs, as the source for organs. However, pig to human xenotransplantation has to over-come a series of obstacles the most immediate and striking of them being hyperacute rejection (HAR). HAR is caused by pre-formed ‘natural’ polyclonal antibodies which are mostly directed against carbohydrate cell surface epitopes containing terminal Gal &agr;1,3Gal structures (anti-&agr;Gal). In addition, other antibodies may also exist directed against N-glycolyl neuraminic acid structures also present on pig endothelium.
To achieve long term graft survival, strategies which address the xenoreactive antibodies are needed. One approach is removal of antibodies by injection of high affinity ligands which may act as inhibitors of antibody deposition on transplanted tissue. Another approach is immunoapheresis, a further development of plasmapheresis, a clinically established procedure similar to dialysis. Immunoapheresis involves the extracorporal treatment of blood by first separating the blood cells, then passage of plasma through immunoaffinity columns, re-mixing of blood cells with the antibody depleted plasma and reintroducing the blood into the patient.
Thus, there is a need for ligands able to bind intracorporally and for a column material able to bind extracorporally the polyclonal xenoreactive antibodies with improved affinity.
The present invention relates to a polyamide conjugate comprising
either (a)a xenoantigenic group;
or (b)a biologically active group and a macromolecular, macro- or microscopic entity; bound to a polyamide backbone
wherein the polyamide backbone comprises at least one structural element of formula I
and in case (b) additionally at least one structural element of formula II
in which
each of A and A′, independently, is a trivalent bridging group;
each of R
1
and R
1′
, independently, is a direct bond or C
1
-C
6
alkylene;
each of X
1
and X
1′
, independently, is —C(O)O—, —C(O)NR—, —NR—, —S— or —O—;
each of R
2
and R
2′
, independently, is a direct bond or a bivalent bridging group;
each of X
2
and X
2′
, independently, is a direct bond or —O— or —NR—; wherein R is hydrogen, OH, C
1
-C
12
alkyl, C
2
-C
12
alkenyl, C
3
-C
8
cycloalkyl, C
3
-C
8
cycloalkenyl, C
2
-C
7
heterocycloalkyl, C
2
-C
11
heterocycloalkenyl, C
6
- or C
10
aryl, C
5
-C
9
heteroaryl, C
7
-C
16
aralkyl, C
8
-C
16
aralkenyl with C
2
-C
6
alkenylene and C
6
- or C
10
aryl, or di-C
6
- or C
10
aryl-C
1
-C
6
alkyl; and
each of Y and Y′, independently, is a direct bond or a bivalent bridging group; with the proviso that X
1
or X
1′
is not —NR—, —S— or —O— when R
1
or R
1′
is a direct bond.
When the polyamide backbone of the invention comprises more than one structural element of formula I or II, these elements may be identical or different. It may be homopolymeric or copolymeric, or copolymeric additionally having comonomer units of e.g. other aminocarboxylic acids. The copolymeric backbones may be block or statistical polymers. When the trivalent bridging group is chiral, the polyamide backbones may homogeneously have the L- or D-configuration or contain structural elements of both configurations, as homogeneous blocks or as statistical mixtures including racemates (1:1 mixtures).
The average sum of structural elements of the polyamide backbone [n] may be in the range of from 10 to 10,000, preferably of from 50 to 1,500, more preferably of from 250 to 1,200, most preferably of from 900 to 1200. Polydispersity may range from 1.001 to 2.0, preferably from 1.1 to 1.5, more preferably from 1.15 to 1.2.
Any alkyl and alkylene radical or moiety may be linear or branched. Preferably alkyl is C
1
-C
18
alkyl, more preferably C
1
-C
4
alkyl, and may be e.g. methyl, ethyl, n- or i-propyl, or n-, i- or t-butyl. Preferably alkenyl may contain 2 to 7 C atoms. Aryl or heteroaryl may be a 5 or 6 membered ring or a bicyclic radical of two fused rings, one or more heteroatoms chosen from the group O—, N— and S-atom being present in the heteroaryl. Examples include phenyl, naphthyl, furanyl, pyrrolyl, etc. Aralkyl preferably has 7 to 12 C atoms and may be phenyl-C
1
-C
6
alkyl, e.g. benzyl or phenethyl. An example for aralkenyl is cinnamyl.
A or A′ may be a single atom with at least three valences, e.g. C, N or Si; in particular
wherein R
aa
is H, C
1
-C
6
alkyl, C
2
-C
6
alkenyl, C
3
-C
7
cycloalkyl, phenyl or benzyl.
R
2
or R
2′
as a bivalent bridging group may contain from 1 to 35, preferably from 1 to 20, particularly from 1 to 16 C atoms, e.g. C
1
-C
35
alkylene, C
2
-C
8
alkenylene, C
2
-C
8
alkynylene, C
3
-C
12
cycloalkylene, C
6
-C
10
arylene or C
7
-C
35
aralkylene wherein the alkylene, alkenylene and alkynylene radicals or moieties may be interrupted by one or more groups selected from —O—, —S—, —C(O)—, —SO
2
— and —HN—.
The bridging group R
2
or R
2′
may, for example, conform to formula III
—R
5
—X
5
—R
6
—X
4
—R
7
—  (III)
in which
each of X
5
and X
4
, independently, is a direct bond, —O—, —S—, —C(O)—, —C(O)O—, —OC(O)—, —OC(O)O—, —SO
2
O—, —OSO
2
—, —OSO
2
O—, —NH—, —NHC(O)—, —C(O)NH—, —NHC(O)O—, —OC(O)NH—, —NHC(O)NH—, —NHSO
2
—, —SO
2
NH—, —NHSO
2
O—, —OSO
2
NH— or —NHSO
2
NH—;
each of R
5
and R
7
, independently, is a direct bond, C
1
-C
20
alkylene, C
5
- or C
6
-cycloalkylene, C
6
-C
10
arylene or C
7
-C
12
aralkylene; and
R
6
is a direct bond or C
1
-C
20
alkylene which is optionally interrupted by one or more, preferably 2 O atoms;
with the proviso that when R
6
is a direct bond X
4
is also a direct bond.
Preferably R
2
or R
2′
may be oxyalkylene or polyoxyalkylene, more preferably having from 2 to 4 C atoms, particularly 2 or 3 C atoms, in the alkylene and from 2 to 20, preferably from 2 to 10, alkylene units, especially oxypropylene and polyoxypropylene, e.g. polyoxypropylene having from 2 to 20 preferably from 2 to 10, oxypropylene units.
A polyamide conjugate comprising a xenoantigenic group and no macromolecular, macro- or microscopic entity will hereinafter be referred to as “conjugate Type I” and a polyamide conjugate comprising a biologically active group and a macromolecular, macro- or micro-scopic entity will hereinafter be referred to as “conjugate Type II”.
In conjugates Type I the xenoantigenic group is conjugated to the polyamide backbone via Y of a structural element of formula I. The conjugates Type I may comprise one or more identical or different xenoantigenic groups.
A xenoantigenic group may be any group identifiable by known methods, e.g. as disclosed in U.S. Pat. No. 5,695,759 (the contents thereof with respect to the method being incorporated herein by reference), comprising isolating xenoantibodies from human blood by perfusing the blood over xenograft material, e.g. removing bound antibodies from the xenograft and using those antibodies to screen candidate epitopes, e.g. by a suitable immunoassay.
The xenoantigenic group may preferably be derived from an oligosaccharide terminating with an &agr;-linked D-galactopyranose or N-glycoyl-neuraminic acid at its reducing end.
Typically (and with respect to conjugates Type I and II) the oligosaccharide may consist of from 1 to 20, preferably 1 to 15, particularly 1 to 10 sugar monomers selected from naturally occurring and modified sugar monomers. The skilled person is familiar with naturally occurring and modified sugar monomers and oligosaccarides comprising these sugar monomers from the standard works of organic chemistry or biochemistry, for example the Specialist Periodical Reports edited at the beginning by The Chemical Society and now by The Royal Society of Chemistry London, e.g. Ferrier et al. Carbohy

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