Conjugates of an anti-TNF-α antibody
View Patent ↗Conjugates of an anti-TNF antibody and one or more nonpeptidic water soluble polymers are provided. Typically, the nonpeptidic water soluble polymer is poly(ethylene glycol) or a derivative thereof. Also provided, among other things, are compositions comprising conjugates, methods of making conjugates, and methods of administering compositions to a patient.
1. A conjugate comprising a single water-soluble polymer covalently attached, either directly or through a spacer moiety of one to twenty atoms, to an amino group of an amino acid side chain or an N-terminal amine of a residue of a full length anti-TNFα antibody, wherein: (i), the one to twenty atoms within the spacer moiety, when present, correspond to the covalent attachment to the amino group of the full length anti-TNFα antibody and atoms derived from a water-soluble polymeric reagent used to attach the water-soluble polymer; (ii) the anti-TNFα antibody is neither galactosylated nor glycosylated; (iii) the water-soluble polymer is a polyethylene glycol terminally capped with a methoxy; and (iv) the water-soluble polymer has a weight-average molecular weight in the range of from about 10,000 Daltons to about 100,000 Daltons.
2. The conjugate of claim 1 , having the following structure:
wherein:
POLY is a water-soluble polymer;
(a) is either zero or one;
X, when present, is a spacer moiety comprised of one to twenty atoms;
R 1 is H or an organic radical containing 1 to 3 carbon atoms; and
ATA is a residue of an anti-TNFα antibody.
3. The conjugate of claim 1 , having the following structure:
wherein:
POLY is a water-soluble polymer;
X, when present, is a spacer moiety comprised of one to twenty atoms;
(a) is either zero or one;
(j) is zero or an integer from 1 to about 20;
(b) is zero or an integer from 1 to about 10;
each R 2 , when present, is H or an organic radical;
each R 3 , when present, is H or an organic radical; and
ATA is a residue of an anti-TNFα antibody.
4. The conjugate of claim 1 , wherein the water-soluble polymer is branched.
5. The conjugate of claim 1 , wherein the water-soluble polymer is linear.
6. The conjugate of claim 1 , wherein the anti-TNFα antibody is not a dimer or trimer.
7. The conjugate of claim 1 , wherein the anti-TNFα antibody is monovalent.
8. The conjugate of claim 1 , wherein the anti-TNFα antibody is not CDR-grafted.
9. The conjugate of claim 2 , having the following structure:
wherein n ranges from about 225 to about 1930.
10. The conjugate of claim 2 , having the following structure:
wherein n ranges from about 225 to about 1930.
11. The conjugate of claim 1 , wherein the poly(ethylene glycol) has a weight-average molecular weight in the range of from about 10,000 Daltons to about 85,000 Daltons.
12. The conjugate of claim 11 , wherein the poly(ethylene glycol) has a weight-average molecular weight in the range of from about 20,000 Daltons to about 65,000 Daltons.
13. The conjugate of claim 1 , wherein the anti-TNFα antibody is either infliximab or adalimumab.
14. A composition comprising the conjugate of claim 1 and a pharmaceutically acceptable excipient.