BETA-1,6-GLUCAN CETUXIMAB ANTIBODY CONJUGATES
The present invention encompasses embodiments in which cetuximab or a related cetuximab antibody is conjugated to β-1,6-glucan oligomers. Thus, the present invention includes, among other things, compositions including cetuximab conjugated to one or more β-1,6-glucan oligomers. The present invention further includes, among other things, methods of making and/or using such β-1,6-glucan conjugates. In certain embodiments, a β-1,6-glucan conjugate of the present invention is useful as a therapeutic or in a method of therapy.
1 . A composition comprising a cetuximab antibody conjugated to between 1 and 6 β-1,6-glucan oligomers, wherein each β-1,6-glucan oligomer is independently comprised of between 2 and 10 glucose monomer units.
2 . The composition of any preceding claim, wherein the β-1,6-glucan oligomers are independently comprised of between 3 and 7 glucose monomer units.
3 . The composition of any preceding claim, wherein the β-1,6-glucan oligomers are independently comprised of between 3 and 5 glucose monomer units.
4 . The composition of any preceding claim, wherein the β-1,6-glucan oligomers are each comprised of 4 glucose monomer units.
5 . The composition of any preceding claim, wherein the antibody is conjugated to between 2 and 4 β-1,6-glucan oligomers.
6 . The composition of any preceding claim, wherein the antibody is conjugated to 3 β-1,6-glucan oligomers.
7 . The composition of any preceding claim, wherein the antibody is conjugated to between 2 and 4 β-1,6-glucan oligomers, and the β-1,6-glucan oligomers are independently comprised of between 3 and 7 glucose monomer units.
8 . The composition of any preceding claim, wherein the antibody is conjugated to between 2 and 4 β-1,6-glucan oligomers, and the β-1,6-glucan oligomers are independently comprised of between 3 and 5 glucose monomer units.
9 . The composition of any preceding claim, wherein the antibody is conjugated to between 2 and 4 β-1,6-glucan oligomers, and the β-1,6-glucan oligomers are each comprised of 4 glucose monomer units.
10 . The composition of any preceding claim, wherein the antibody is conjugated to 3 β-1,6-glucan oligomers, and the β-1,6-glucan oligomers are independently comprised of between 3 and 7 glucose monomer units.
11 . The composition of any preceding claim, wherein the antibody is conjugated to 3 β-1,6-glucan oligomers, and the β-1,6-glucan oligomers are independently comprised of between 3 and 5 glucose monomer units.
12 . The composition of any preceding claim, wherein the antibody is conjugated to 3 β-1,6-glucan oligomers, and the β-1,6-glucan oligomers are each comprised of 4 glucose monomer units.
13 . The composition of any preceding claim, wherein the antibody is conjugated to the β-1,6-glucan oligomers according to Formula II:
wherein:
Lys is a lysine residue;
b is between 1 and 6; and
is a compound of Formula I:
wherein:
a is between 1 and 9;
L is a linker; and
“ ” represents a point of attachment between two atoms.
14 . The composition of claim 13 , wherein is a compound of Formula Ia:
wherein:
a 1 is between 1 and 9; and
“ ” represents a point of attachment between two atoms.
15 . The composition any one of the preceding claims, wherein the antibody comprises a variable domain having at least 80% identity with SEQ ID NO: 4 or SEQ ID NO: 5.
16 . The composition any one of the preceding claims, wherein the antibody comprises a heavy chain variable domain having at least 80% identity with SEQ ID NO: 4.
17 . The composition any one of the preceding claims, wherein the antibody comprises a heavy chain having at least 80% identity with SEQ ID NO: 1.
18 . The composition any one of the preceding claims, wherein the antibody comprises a light chain variable domain having at least 80% identity with SEQ ID NO: 5.
19 . The composition any one of the preceding claims, wherein the antibody comprises a light chain having at least 80% identity with SEQ ID NO: 2.
20 . The composition of any one of the preceding claims, wherein the antibody is cetuximab.
21 . The composition of any one of the preceding claims, wherein the antibody competes with cetuximab for binding to EGFR.
22 . The composition of any one of the preceding claims, wherein the β-1,6-glucan oligomers are chemically synthesized.
23 . The composition of any one of the preceding claims, wherein at least 90% of the dry weight of glucan contained in the composition is β-1,6-glucan.
24 . The composition of any one of the preceding claims, wherein less than 10% of the dry weight of glucan contained in the composition is β-1,3-glucan.
25 . The composition of any one of the preceding claims, wherein the composition is substantially free of β-1,3-glucan.
26 . A method of treating a cancer associated with expression of EGFR in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a composition of any one of the preceding claims.
27 . The method of claim 26 , wherein the cancer is a colorectal cancer.
28 . The method of claim 26 , wherein the cancer is a KRAS wild-type EGFR-expressing colorectal cancer.
29 . The method of claim 26 , wherein the cancer is a KRAS mutant EGFR-expressing colorectal cancer.
30 . The method of claim 26 , wherein the cancer is a BRAF mutant EGFR-expressing colorectal cancer.
31 . The method of claim 26 , wherein the cancer is a squamous cell carcinoma.
32 . The method of claim 26 , wherein the cancer is a squamous cell carcinoma of the head and neck.
33 . The method of claim 26 , wherein the cancer is a lung cancer.
34 . The method of claim 26 , wherein the cancer is a triple negative breast cancer.