USRE50282EActiveUtility
Specific modification of antibody with IgG-binding peptide
Est. expiryMay 20, 2035(~8.9 yrs left)· nominal 20-yr term from priority
Inventors:Yuji Ito
A61K 38/00A61K 47/64C07K 19/00C07K 16/00A61K 39/395A61K 47/62C07K 14/4748C07K 2319/00C07K 7/08A61K 47/68A61K 47/68031A61K 47/68033
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Cited by
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References
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Claims
Abstract
This invention relates to an IgG-binding peptide, an IgG-binding peptide modified with a cross-linking agent, a conjugate of the IgG-binding peptide modified with a cross-linking agent and IgG, and a method for producing the conjugate, etc.
Claims
exact text as granted — not AI-modifiedThe invention claimed is:
1. A peptide comprising the amino acid sequence of the following formula (I): (X) 1-3 -C-(X) 2 -H-Xaa1-G-Xaa2-L-V-W-C-(X) 1-3 (SEQ ID NO: 43) (I), wherein each X is independently any amino acid residue other than cysteine, C is a cysteine residue, H is a histidine residue, Xaa1 is a lysine residue, a cysteine residue, an aspartic acid residue, a glutamic acid residue, 2-aminosuberic acid, or diaminopropionic acid, wherein Xaa1 is modified with a cross-linking agent, G is a glycine residue, Xaa2 is a glutamic acid residue or an asparagine residue, L is a leucine residue, V is a valine residue, and W is a tryptophan residue, wherein the peptide is 13 to 17 amino acid residues in length; and wherein the peptide exhibits the activity of binding to human immunoglobulin G (IgG) and/or rabbit IgG, and optionally wherein the cysteine residue that is between two to four amino acids from the N-terminus of formula (I) and the cysteine residue that is between two to four amino acids from the C-terminus of formula (I) are linked via a linker.
2. The peptide according to claim 1 , wherein the peptide comprises the amino acid sequence of the following formula (II): (X) 1-3 -C-Xaa3-Xaa4-H-Xaa1-G-Xaa2-L-V-W-C-(X) 1-3 (SEQ ID NO: 44) (II), wherein each X is independently any amino acid residue other than cysteine, C is a cysteine residue, H is a histidine residue, Xaa1 is a lysine residue, a cysteine residue, an aspartic acid residue, a glutamic acid residue, 2-aminosuberic acid, or diaminopropionic acid, G is a glycine residue, Xaa2 is a glutamic acid residue or an asparagine residue, L is a leucine residue, V is a valine residue, W is a tryptophan residue, Xaa3 is an alanine residue, a serine residue or a threonine residue, and Xaa4 is a tyrosine residue or a tryptophan residue.
3. The peptide according to claim 1 , wherein the peptide comprises the amino acid sequence of the following formula (III): (X) 1-3 -C-A-Y-H-Xaa1-G-E-L-V-W-C-(X) 1-3 (SEQ ID NO: 45) (III) wherein each X is independently any amino acid residue other than cysteine, C is a cysteine residue, A is an alanine residue, Y is a tyrosine residue, H is a histidine residue, Xaa1 is a lysine residue, a cysteine residue, an aspartic acid residue, a glutamic acid residue, 2-aminosuberic acid, or diaminopropionic acid, G is a glycine residue, E is a glutamic acid residue, L is a leucine residue, V is a valine residue, and W is a tryptophan residue.
4. The peptide according to claim 1 , wherein
the peptide is 17 amino acid residues in length, and wherein the amino acid residues from the 1st to 3rd and the 15th to 17th positions from the N terminus of formula (I) are each as follows:
the 1st amino acid residue is S, G, F or absent,
the 2nd amino acid residue is D, G, A, S, P, homocysteine, or absent,
the 3rd amino acid residue is S, D, T, N, E or R,
the 15th amino acid residue is S, T or D,
the 16th amino acid residue is H, G, Y, T, N, D, F, homocysteine, or absent, and
the 17th amino acid residue is Y, F, H, M or absent.
5. The peptide according to claim 1 , wherein the peptide consists of any one of the following amino acid sequences 1) to 15):
1)
(SEQ ID NO: 1)
DCAYHXaa1GELVWCT,
2)
(SEQ ID NO: 2)
GPDCAYHXaa1GELVWCTFH,
3)
(SEQ ID NO: 3)
RCAYHXaa1GELVWCS,
4)
(SEQ ID NO: 4)
GPRCAYHXaa1GELVWCSFH,
5)
(SEQ ID NO: 5)
SPDCAYHXaa1GELVWCTFH,
6)
(SEQ ID NO: 6)
GDDCAYHXaa1GELVWCTFH,
7)
(SEQ ID NO: 7)
GPSCAYHXaa1GELVWCTFH,
8)
(SEQ ID NO: 8)
GPDCAYHXaa1GELVWCSFH,
9)
(SEQ ID NO: 9)
GPDCAYHXaa1GELVWCTHH,
10)
(SEQ ID NO: 10)
GPDCAYHXaa1GELVWCTFY,
11)
(SEQ ID NO: 11)
SPDCAYHXaa1GELVWCTFY,
12)
(SEQ ID NO: 12)
SDDCAYHXaa1GELVWCTFY,
13)
(SEQ ID NO: 13)
RGNCAYHXaa1GQLVWCTYH,
14)
(SEQ ID NO: 36)
GXaa2DCAYHXaa1GELVWCTXaa2H,
and
15)
(SEQ ID NO: 37)
RRGPDCAYHXaa1GELVWCTFH,
wherein Xaa1 is a lysine residue, a cysteine residue, an aspartic acid residue, a glutamic acid residue, 2-aminosuberic acid, or diaminopropionic acid, and Xaa2 is homocysteine.
6. The peptide according to claim 1 , wherein the peptide comprises the amino acid sequence of the following formula (IV): D-C-Xaa3-Xaa4-H-Xaa1-G-Xaa2-L-V-W-C-T (SEQ ID NO: 46) (IV), wherein D is an aspartic acid residue, C is a cysteine residue, H is a histidine residue, Xaa1 is a lysine residue, a cysteine residue, an aspartic acid residue, a glutamic acid residue, 2-aminosuberic acid, or diaminopropionic acid, G is a glycine residue, Xaa2 is a glutamic acid residue or an asparagine residue, L is a leucine residue, V is a valine residue, W is a tryptophan residue, T is a threonine residue, Xaa3 is an alanine residue or a threonine residue, and Xaa4 is a tyrosine residue or a tryptophan residue.
7. The peptide according to claim 6 , wherein the peptide consists of any one of the following amino acid sequences 1) to 4):
1)
(SEQ ID NO: 14)
DCTYHXaa1GNLVWCT,
2)
(SEQ ID NO: 15)
DCAYHXaa1GNLVWCT,
3)
(SEQ ID NO: 16)
DCTYHXaa1GELVWCT,
and
4)
(SEQ ID NO: 17)
DCAWHXaa1GELVWCT,
wherein Xaa1 is a lysine residue, a cysteine residue, an aspartic acid residue, a glutamic acid residue, 2-aminosuberic acid, or diaminopropionic acid.
8. The peptide according to claim 1 , wherein the peptide has a disulfide bond formed between the two cysteine residue that is between two to four amino acids from the N-terminus of formula (I) and the cysteine residue that is between two to four amino acids from the C-terminus of formula (I), or the sulfide groups in the cysteine residue that is between two to four amino acids from the N-terminus of formula (I) and the cysteine residue that is between two to four amino acids from the C-terminus of formula (I) are linked via a linker represented by the following formula:
9. The peptide according to claim 1 , wherein the peptide is labeled with a labeling agent.
10. The peptide according to claim 1 , wherein the peptide is bound with a drug.
11. The peptide according to claim 1 , wherein Xaa1 is a lysine residue.
12. The peptide according to claim 1 , wherein Xaa1 is modified with a cross-linking agent.
13. The peptide according to claim 12 1 , wherein the cross-linking agent is selected from the group consisting of DSG (disuccinimidyl glutarate), DSS (disuccinimidyl suberate), DMA (dimethyl adipimidate dihydrochloride), DMP (dimethyl pimelimidate dihydrochloride), DMS (dimethyl suberimidate dihydrochloride), DTBP (dimethyl 3,3′-dithiobispropionimidate dihydrochloride), and DSP (dithiobis(succinimidyl propionate)).
14. The peptide according to claim 13 1 , wherein the cross-linking agent is DSG (disuccinimidyl glutarate) or DSS (disuccinimidyl suberate).
15. A peptide comprising the amino acid sequence of the following formula (V): D-C-Xaa2-Xaa3-Xaa4-Xaa1-G-Xaa5-L-Xaa6-W-C-T (SEQ ID NO: 47) (V), wherein D is an aspartic acid residue, C is a cysteine residue, G is a glycine residue, L is a leucine residue, W is a tryptophan residue, T is a threonine residue, Xaa1 is a lysine residue, a cysteine residue, an aspartic acid residue, a glutamic acid residue, 2-aminosuberic acid, or diaminopropionic acid, wherein Xaa1 is modified with a cross-linking agent, Xaa2 is an alanine residue, a serine residue or a threonine residue, Xaa3 is a tryptophan residue or a tyrosine residue, Xaa4 is a histidine residue, an arginine residue, a serine residue or a threonine residue, Xaa5 is a glutamic acid residue, an asparagine residue, an arginine residue, or an aspartic acid residue, and Xaa6 is an isoleucine residue or a valine residue, wherein the peptide is 13 amino acid residues in length; and wherein the peptide exhibits the activity of binding to human IgG and/or rabbit IgG.
16. A conjugate comprising the peptide according to claim 12 1 and IgG, wherein the conjugate is formed through a cross-linking reaction of the modified peptide and the IgG.
17. A pharmaceutical composition comprising the peptide according to claim 1 or a conjugate comprising the peptide according to claim 1 and IgG, wherein Xaa1 in the peptide of the conjugate is modified with a cross-linking agent, and wherein the conjugate is formed through a cross-linking reaction of the modified peptide and the IgG.
18. A method for producing the conjugate according to claim 16 , wherein the method comprises: (a) modifying Xaa1 in the peptide with a cross-linking agent, and (b) mixing the modified peptide with IgG to cross-link the modified peptide and the IgG.
19. A method for producing a peptide having two or more cysteine residues linked via a linker, wherein the method comprises mixing the peptide according to claim 1 a peptide with a compound represented by the following formula:
wherein R 1 and R 2 are each independently any halogen atom, to obtain a peptide in which sulfide groups in the two or more cysteine residues are linked via a linker represented by the following formula:
wherein the peptide comprises the amino acid sequence of the following formula (I):
(X) 1-3 -C-(X) 2 -H-Xaa1-G-Xaa2-L-V-W-C-(X) 1-3 (SEQ ID NO: 43) (I)
wherein
each X is independently any amino acid residue other than cysteine,
C is a cysteine residue,
H is a histidine residue,
Xaa1 is a lysine residue, a cysteine residue, an aspartic acid residue, a glutamic acid residue, 2-aminosuberic acid, or diaminopropionic acid,
G is a glycine residue,
Xaa2 is a glutamic acid residue or an asparagine residue,
L is a leucine residue,
V is a valine residue, and
W is a tryptophan residue,
wherein the peptide is 13 to 17 amino acid residues in length; wherein the peptide exhibits the activity of binding to human immunoglobulin G (IgG) and/or rabbit IgG, and optionally wherein the cysteine residue that is between two to four amino acids from the N-terminus of formula (I) and the cysteine residue that is between two to four amino acids from the C-terminus of formula (I) are linked via a linker.
20. The method according to claim 19 , wherein R 1 and R 2 in the compound are the same and are Cl, Br, or I.
21. The conjugate of claim 16 , wherein Xaa1 of the peptide is a lysine residue, a cysteine residue, or diaminopropionic acid.
22. The conjugate of claim 21 , wherein the peptide is labeled with a chelate complex of a radioisotope metal ion.
23. The conjugate according to claim 22 , wherein the chelate complex is a chelate complex of DOTA.
24. The conjugate according to claim 23 , wherein the labeling of the peptide by the radioisotope is formed through the reaction between an azide group and dibenzocyclooctyne.
25. The conjugate according to claim 22 , wherein the IgG is an anti-HER2 human IgG antibody.
26. The conjugate according to claim 24 , wherein the IgG is an anti-HER2 human IgG antibody.
27. The conjugate according to claim 22 , wherein the peptide is selected from the group following (i) to (v):
(i) the peptide comprises the amino acid sequence of the following formula (II): (X) 1-3 -C-Xaa3-Xaa4-H-Xaa1-G-Xaa2-L-V-W-C-(X) 1-3 (II) (SEQ ID NO: 44), wherein each X is independently any amino acid residue other than cysteine, C is a cysteine residue, H is a histidine residue, G is a glycine residue, Xaa2 is a glutamic acid residue or an asparagine residue, L is a leucine residue, V is a valine residue, W is a tryptophan residue, Xaa3 is an alanine residue, a serine residue or a threonine residue, and Xaa4 is a tyrosine residue or a tryptophan residue; (ii) the peptide comprises the amino acid sequence of the following formula (III): (X) 1-3 -C-A-Y-H-Xaa1-G-E-L-V-W-C-(X) 1-3 (III) (SEQ ID NO: 45), wherein each X is independently any amino acid residue other than cysteine, C is a cysteine residue, A is an alanine residue, Y is a tyrosine residue, H is a histidine residue, G is a glycine residue, E is a glutamic acid residue, L is a leucine residue, V is a valine residue, and W is a tryptophan residue; (iii) the amino acid residues from the 1st to 3rd and the 15th to 17th positions of formula (I) are each as follows: the 1st amino acid residue is S, G, F or absent, the 2nd amino acid residue is D, G, A, S, P, homocysteine, or absent, the 3rd amino acid residue is S, D, T, N, E or R, the 15th amino acid residue is S, T or D, the 16th amino acid residue is H, G, Y, T, N, D, F, homocysteine, or absent, and the 17th amino acid residue is Y, F, H, M or absent; (iv) the peptide consists of any one of the following amino acid sequences 1) to 15):
1)
(SEQ ID NO: 1)
DCAYH(Xaa1)GELVWCT,
2)
(SEQ ID NO: 2)
GPDCAYH(Xaa1)GELVWCTFH,
3)
(SEQ ID NO: 3)
RCAYH(Xaa1)GELVWCS,
4)
(SEQ ID NO: 4)
GPRCAYH(Xaa1)GELVWCSFH,
5)
(SEQ ID NO: 5)
SPDCAYH(Xaa1)GELVWCTFH,
6)
(SEQ ID NO: 6)
GDDCAYH(Xaa1)GELVWCTFH,
7)
(SEQ ID NO: 7)
GPSCAYH(Xaa1)GELVWCTFH,
8)
(SEQ ID NO: 8)
GPDCAYH(Xaa1)GELVWCSFH,
9)
(SEQ ID NO: 9)
GPDCAYH(Xaa1)GELVWCTHH,
10)
(SEQ ID NO: 10)
GPDCAYH(Xaa1)GELVWCTFY,
11)
(SEQ ID NO: 11)
SPDCAYH(Xaa1)GELVWCTFY,
12)
(SEQ ID NO: 12)
SDDCAYH(Xaa1)GELVWCTFY,
13)
(SEQ ID NO: 13)
RGNCAYH(Xaa1)GQLVWCTYH,
14)
(SEQ ID NO: 36)
GXaa2DCAYH(Xaa1)GELVWCTXaa2H,
and
15)
(SEQ ID NO: 37)
RRGPDCAYH(Xaa1)GELVWCTFH;
(v) the peptide defined in any of (i) to (iv) has a disulfide bond formed between the two cysteine residue that is between two to four amino acids from the N-terminus of the peptide and the cysteine residue that is between two to four amino acids from the C-terminus of the peptide, or the sulfide groups in the cysteine residue that is between two to four amino acids from the N-terminus of the peptide and the cysteine residue that is between two to four amino acids from the C-terminus of the peptide are linked via a linker represented by the following formula:
and Xaa1 of the peptide is a lysine residue, a cysteine residue, or diaminopropionic acid and is modified with a cross-linking agent.
28. The conjugate according to claim 22 , wherein Xaa1 is a lysine residue.
29. The conjugate according to claim 28 , wherein the chelate complex is a chelate complex of DOTA.
30. The conjugate according to claim 29 , wherein the labeling of the peptide by the radioisotope is formed through the reaction between an azide group and dibenzocyclooctyne.
31. The conjugate according to claim 28 , wherein the IgG is an anti-HER2 human IgG antibody.
32. The conjugate according to claim 30 , wherein the IgG is an anti-HER2 human IgG antibody.
33. The conjugate according to claim 22 , wherein the conjugate has a cross-linking structure formed between the Xaa1 residue of the peptide and IgG Fc.
34. The conjugate according to claim 22 , wherein the conjugate has a cross-linking structure formed between the Xaa1 residue of the peptide and Lys248 or Lys246 according to the EU numbering in the IgG Fc.
35. The conjugate according to claim 22 , the cross-linking agent is selected from the group consisting of DSG (disuccinimidyl glutarate), DSS (disuccinimidyl suberate), DMA (dimethyl adipimidate dihydrochloride), DMP (dimethyl pimelimidate dihydrochloride), DMS (dimethyl suberimidate dihydrochloride), DTBP (dimethyl 3,3′-dithiobispropionimidate dihydrochloride), and DSP (dithiobis(succinimidyl propionate).
36. The conjugate according to claim 35 , the cross-linking agent is DSG (disuccinimidyl glutarate) or DSS (disuccinimidyl suberate).
37. The conjugate according to claim 36 , wherein the chelate complex is a chelate complex of DOTA.
38. The conjugate according to claim 37 , wherein the labeling of the peptide by the radioisotope is formed through the reaction between an azide group and dibenzocyclooctyne.
39. The conjugate according to claim 36 , wherein the IgG is an anti-HER2 human IgG antibody.
40. The conjugate according to claim 38 , wherein the IgG is an anti-HER2 human IgG antibody.
41. The conjugate according to claim 36 , wherein the peptide is selected from the group following (i) to (v):
(i) the peptide comprises the amino acid sequence of the following formula (II): (X) 1-3 -C-Xaa3-Xaa4-H-Xaa1-G-Xaa2-L-V-W-C-(X) 1-3 (II) (SEQ ID NO: 44), wherein each X is independently any amino acid residue other than cysteine, C is a cysteine residue, H is a histidine residue, G is a glycine residue, Xaa2 is a glutamic acid residue or an asparagine residue, L is a leucine residue, V is a valine residue, W is a tryptophan residue, Xaa3 is an alanine residue, a serine residue or a threonine residue, and Xaa4 is a tyrosine residue or a tryptophan residue; (ii) the peptide comprises the amino acid sequence of the following formula (III): (X) 1-3 -C-A-Y-H-Xaa1-G-E-L-V-W-C-(X) 1-3 (III) (SEQ ID NO: 45), wherein each X is independently any amino acid residue other than cysteine, C is a cysteine residue, A is an alanine residue, Y is a tyrosine residue, H is a histidine residue, G is a glycine residue, E is a glutamic acid residue, L is a leucine residue, V is a valine residue, and W is a tryptophan residue; (iii) the amino acid residues from the 1st to 3rd and the 15th to 17th positions of formula (I) are each as follows: the 1st amino acid residue is S, G, F or absent, the 2nd amino acid residue is D, G, A, S, P, homocysteine, or absent, the 3rd amino acid residue is S, D, T, N, E or R, the 15th amino acid residue is S, T or D, the 16th amino acid residue is H, G, Y, T, N, D, F, homocysteine, or absent, and the 17th amino acid residue is Y, F, H, M or absent; (iv) the peptide consists of any one of the following amino acid sequences 1) to 15):
1)
(SEQ ID NO: 1)
DCAYH(Xaa1)GELVWCT,
2)
(SEQ ID NO: 2)
GPDCAYH(Xaa1)GELVWCTFH,
3)
(SEQ ID NO: 3)
RCAYH(Xaa1)GELVWCS,
4)
(SEQ ID NO: 4)
GPRCAYH(Xaa1)GELVWCSFH,
5)
(SEQ ID NO: 5)
SPDCAYH(Xaa1)GELVWCTFH,
6)
(SEQ ID NO: 6)
GDDCAYH(Xaa1)GELVWCTFH,
7)
(SEQ ID NO: 7)
GPSCAYH(Xaa1)GELVWCTFH,
8)
(SEQ ID NO: 8)
GPDCAYH(Xaa1)GELVWCSFH,
9)
(SEQ ID NO: 9)
GPDCAYH(Xaa1)GELVWCTHH,
10)
(SEQ ID NO: 10)
GPDCAYH(Xaa1)GELVWCTFY,
11)
(SEQ ID NO: 11)
SPDCAYH(Xaa1)GELVWCTFY,
12)
(SEQ ID NO: 12)
SDDCAYH(Xaa1)GELVWCTFY,
13)
(SEQ ID NO: 13)
RGNCAYH(Xaa1)GQLVWCTYH,
14)
(SEQ ID NO: 36)
GXaa2DCAYH(Xaa1)GELVWCTXaa2H,
and
15)
(SEQ ID NO: 37)
RRGPDCAYH(Xaa1)GELVWCTFH;
(v) the peptide defined in any of (i) to (iv) has a disulfide bond formed between the two cysteine residue that is between two to four amino acids from the N-terminus of the peptide and the cysteine residue that is between two to four amino acids from the C-terminus of the peptide, or the sulfide groups in the cysteine residue that is between two to four amino acids from the N-terminus of the peptide and the cysteine residue that is between two to four amino acids from the C-terminus of the peptide are linked via a linker represented by the following formula:
and Xaa1 of the peptide is a lysine residue and is modified with a cross-linking agent.Cited by (0)
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