Hybrid immunoglobulin containing non-peptidyl linkage

1. A compound having the structure:

wherein A is a first polypeptide component of the compound;

wherein C is a second polypeptide component of the compound, which polypeptide component has at its N-terminus a sequence of amino acids selected from the group consisting of a cysteine, selenocysteine, CP, CPXCP (where X=P, R, or S) (SEQ ID NOs: 128-130), CDKTHTCPPCP (SEQ ID NO: 131), CVECPPCP (SEQ ID NO: 132), CCVECPPCP (SEQ ID NO: 133) and CDTPPPCPRCP (SEQ ID NO: 134) and comprises consecutive amino acids which (i) are identical to a stretch of consecutive amino acids present in a chain of an F c domain of an antibody; and (ii) bind to an F c receptor,

wherein B is (a) an organic acid residue or (b) a stretch of consecutive amino acid residues which is, or is present in any of the following sequences: EPKSCDKTHTCPPCP (SEQ ID NO: 135), ERKCCVECPPCP (SEQ ID NO: 136), ELKTPLGDTTHTCPRCP(EPKSCDTPPPCPRCP)3 (SEQ ID NO: 137), or ESKYGPPCPSC (SEQ ID NO: 138);

wherein the dashed line between B and C represents a peptidyl linkage between B and the N-terminus of C;

wherein the solid line between A and B represents a nonpeptidyl linkage comprising the structure:

wherein R 1 is part of a cyclic structure, R 2 is an organic structure which is connected to A, and R 4 is an organic structure which is connected to B, wherein the cyclic structure comprises: the carbon attached to R 2 , R 1 , and may also comprise (a) R 2 , or (b) a portion of R 2 .

2. The compound according to claim 1 ,

wherein R 1 and R 2 are linked via at least one direct bond so as to form a cyclic structure comprising

i) R 1 ,

ii) a portion of R 2 ,

iii) the carbon attached to R 2 , and

iv) the alkene double bond in the nonpeptidyl structure.

3. The compound according to claim 2 , wherein R 1 is selected from the group consisting of:

which is optionally substituted at any position.

4. The compound according to claim 1 , wherein the carbon attached to R 2 is:

(i) directly bonded to R 2 via a single bond; or

(ii) directly bonded to R 2 via a double bond and a single bond.

5. The compound according to claim 4 , wherein the carbon attached to R 2 is substituted with two hydrogens and directly bonded to R 2 via a single bond.

6. The compound according to claim 4 , wherein the carbon attached to R 2 is directly bonded to R 2 via a double bond and a single bond.

7. The compound according to claim 5 , wherein R 2 is

wherein R 2 is attached to A via J, and

wherein J is a bond or an organic structure comprising a chain of 2 or more moieties selected from the group consisting of a [PEG(y)]z, polyalkylene glycol, polyoxyalkylated polyol, polyvinyl alcohol, polyvinyl alkyl ether, poly(lactic acid), poly(lactic-glycolic acid), polysaccharide, a branched residue, C 1 -C 4 alkyl, amine, sulfur, oxygen, succinimide, maleimide, glycerol, triazole, isoxazolidine, C 1 -C 4 acyl, succinyl, malonyl, glutaryl, phthalyl, adipoyl and an amino acid,

wherein [PEG(y)]z is:

wherein y=1-100 and z=1-10.

8. The compound according to claim 6 , wherein R 2 is

which is optionally substituted at any position,

wherein R 2 is attached to R 1 via the nitrogen atom of R 2 , and

wherein J is a bond or an organic structure comprising a chain of 2 or more moieties selected from the group consisting of [PEG(y)]z, polyalkylene glycol, polyoxyalkylated polyol, polyvinyl alcohol, polyvinyl alkyl ether, poly(lactic acid), poly(lactic-glycolic acid), polysaccharide, a branched residue, C 1 -C 4 alkyl, amine, sulfur, oxygen, succinimide, maleimide, glycerol, triazole, isoxazolidine, C 1 -C 4 acyl, succinyl, malonyl, glutaryl, phthalyl, adipoyl and an amino acid,

wherein [PEG(y)]z is:

wherein y=1-100 and z=1-10.

9. The compound according to claim 6 , wherein the cyclic structure comprises R 1 and R 2 and is:

which is optionally substituted at any position,

wherein J is a bond or an organic structure comprising a chain of 2 or more moieties selected from the group consisting of [PEG(y)]z, polyalkylene glycol, polyoxyalkylated polyol, polyvinyl alcohol, polyvinyl alkyl ether, poly(lactic acid), poly(lactic-glycolic acid), polysaccharide, a branched residue, C 1 -C 4 alkyl, amine, sulfur, oxygen, succinimide, maleimide, glycerol, triazole, isoxazolidine, C 1 -C 4 acyl, succinyl, malonyl, glutaryl, phthalyl, adipoyl and an amino acid,

wherein [PEG(y)]z is:

wherein y=1-100 and z=1-10.

10. The compound according to claim 1 , wherein the nonpeptidyl linkage comprises the structure:

which is optionally substituted at any position,

wherein J is a bond or an organic structure comprising a chain of 2, 3, 4, 5, 6, 7, 8, 9, 10 or more moieties selected from the group consisting of [PEG(y)]z, polyalkylene glycol, polyoxyalkylated polyol, polyvinyl alcohol, polyvinyl alkyl ether, poly(lactic acid), poly(lactic-glycolic acid), polysaccharide, a branched residue, C 1 -C 4 alkyl, amine, sulfur, oxygen, succinimide, maleimide, glycerol, triazole, isoxazolidine, C 1 -C 4 acyl, succinyl, malonyl, glutaryl, phthalyl, adipoyl and an amino acid,

wherein [PEG(y)]z is:

wherein y=1-100 and z=1-10.

11. The compound according to claim 1 , wherein C is a second polypeptide component of the compound, which polypeptide component has at its N-terminus a sequence of amino acids consisting of a naturally occurring cysteine selected from the group consisting of CP, CPXCP (where X=P, R, or S) (SEQ ID NOs: 128-130), CDKTHTCPPCP (SEQ ID NO: 131), CVECPPCP (SEQ ID NO: 132), CCVECPPCP (SEQ ID NO: 133) and CDTPPPCPRCP (SEQ ID NO: 134) and comprises consecutive amino acids which (i) are identical to a stretch of consecutive amino acids present in a chain of an F c domain of an antibody; and (ii) bind to an F c receptor.

12. The compound according to claim 1 , wherein C is a second polypeptide component of the compound, which polypeptide component has at its N-terminus a sequence consisting of a non-naturally occurring cysteine or selenocysteine and comprises consecutive amino acids which (i) are identical to a stretch of consecutive amino acids present in a chain of an F c domain of an antibody; and (ii) bind to an F c receptor.

13. The compound according to claim 1 , wherein A comprises a secreted protein.

14. The compound according to claim 1 , wherein A comprises an extracellular domain of a protein.

15. The compound according to claim 1 , wherein A has biological activity.

16. The compound according to claim 1 , wherein the A is an independently-folding protein or a portion thereof.

17. The compound according to claim 1 , wherein A is a glycosylated protein.

18. The compound according to claim 1 , wherein A comprises intra-chain disulfide bonds.

19. The compound according to claim 1 , wherein A comprises at least one stretch of consecutive amino acids which are identical to a stretch of consecutive amino acids present in the heavy chain of a Fab or a Fab′ of an antibody.

20. The compound according to claim 1 , wherein A comprises at least one stretch of consecutive amino acids which are identical to a stretch of consecutive amino acids present in the light chain of a Fab or a Fab′ of an antibody.

21. The compound according to claim 1 , wherein A comprises at least one Fab or Fab′ of an antibody, or a portion of the at least one Fab or Fab′.

22. The compound according to claim 1 , wherein A comprises at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 copies of the Fab or Fab′ or portion thereof.

23. The compound according to claim 1 , wherein A comprises at least one stretch of consecutive amino acids which are identical to a stretch of consecutive amino acids present in a single chain antibody.

24. The compound according to claim 1 , wherein A comprises at least one stretch of consecutive amino acids which are identical to a stretch of consecutive amino acids present in a TNFα receptor.

25. A homodimer comprising the compound according to claim 1 .

26. A heterodimer comprising the compound according to claim 1 , which forms part of a heterodimer.

27. A process for producing a compound having the structure:

wherein A is a first polypeptide component of the compound;

wherein C is a second polypeptide component of the compound, which polypeptide component has at its N-terminus a sequence selected from the group consisting of a cysteine, selenocysteine, CP, CPXCP (where X=P, R, or S) (SEQ ID NOs: 128-130), CDKTHTCPPCP (SEQ ID NO: 131), CVECPPCP (SEQ ID NO: 132), CCVECPPCP (SEQ ID NO: 133) and CDTPPPCPRCP (SEQ ID NO: 134) and comprises consecutive amino acids which (i) are identical to a stretch of consecutive amino acids present in a chain of an F c domain of an antibody; and (ii) bind to an F c receptor,

wherein B is (a) an organic acid residue or (b) a stretch of consecutive amino acid residues which is, or is present in any of the following sequences: EPKSCDKTHTCPPCP (SEQ ID NO: 135), ERKCCVECPPCP (SEQ ID NO: 136), ELKTPLGDTTHTCPRCP(EPKSCDTPPPCPRCP)3 (SEQ ID NO: 137), or ESKYGPPCPSC (SEQ ID NO: 138);

wherein the dashed line between B and C represents a peptidyl linkage between B and the N-terminus of C;

wherein the solid line between A and B represents a nonpeptidyl linkage comprising the structure:

wherein R 1 is part of a cyclic structure, R 2 is an organic structure which is connected to A, and R 4 is an organic structure which is connected to B, wherein the cyclic structure comprises: the carbon attached to R 2 , R 1 , and may also comprise (a) R 2 , or (b) a portion of R 2 ;

which comprises the following steps:

a) obtaining an A′ which comprises A or a derivative of A, and a first terminal reactive group which is an alkyne;

b) obtaining a B′ which comprises B or a derivative of B, a second terminal reactive group and a third terminal reactive group, wherein the second terminal reactive group is an azide capable of reacting with the first terminal reactive group to form a non-peptidyl linkage, and the third reactive group is a thioester;

c) obtaining a C′ which comprises C or a derivative of C, and a fourth terminal reactive group, wherein the fourth terminal reactive group is an amino acid or amino acid derivative capable of reacting with the third terminal reactive group to form a peptidyl linkage; and

d) reacting A′, B′ and C′ in any order to produce the compound.

28. The process according to claim 27 , wherein the fourth reactive group is cysteine, selenocysteine, homocysteine, or homoselenosysteine, or a derivative of cysteine, selenocysteine, homocysteine, or homoselenosysteine.

29. The compound according to claim 1 , wherein

R 4 is

wherein x is 1-100, and w is 0-5.