Chimeric protein in the treatment of amyloidosis
The present invention relates to a chimeric protein comprising at least one human amyloid P component and at least one fragment of an Fc region of a human antibody, the human amyloid P component and the fragment of an Fc region with which it is associated being bound to each other by means of a hinge region.
1. A method for treating systemic amyloidosis comprising administering an effective amount of a chimeric protein comprising one human serum amyloid P component (SAP), a first Fc region of a human antibody and a second Fc region of a human antibody,
wherein the human SAP and the first Fc region are bonded to each other by a first hinge region,
wherein the first and second Fc region are bonded to each other covalently by means of a bond formed from a spacer chain and a second hinge region, and wherein the first and second Fc region form a single polypeptide chain constituting a functional dimeric Fc region.
2. The method of claim 1 , wherein the human SAP comprises an amino acid sequence having at least 80% identity with SEQ ID NO: 1.
3. The method of claim 1 , wherein the first Fc region of a human antibody comprises at least one amino acid sequence having at least 80% identity with SEQ ID NO: 3.
4. The method of claim 1 , wherein the first Fc region comprises at least two modifications in its amino acid sequence selected from:
(i) a modification in the amino acid sequence selected from the group consisting of 378V, 378T, 434Y and 434S, and
(ii) at least one modification in the amino acid sequence selected from the group consisting of 226G, 230S, 230T, 230L, 241 L, 264E, 307P, 315D, 330V, 362R, 378V, 378T, 389T, 389K, 434Y and 434S,
wherein numbering of amino acids of the Fc region is that of the EU index proposed by Kabat, and wherein modification (i) does not occur at the same amino acid position as modification (ii).
5. The method of claim 1 , wherein the first hinge region comprises at least one amino acid sequence having at least 60% identity with a sequence selected from SEQ ID NOs: 13 and 15 to 18.
6. The method of claim 1 , wherein said chimeric protein further comprises at least one non-structuring peptide sequence between the first hinge region and the human SAP.
7. The method of claim 1 ,
wherein the first and the second Fc region are identical.
8. The method of claim 1 , wherein the spacer chain is represented by at least the amino acid sequence SEQ ID NO: 5.
9. The method of claim 1 , wherein the systemic amyloidosis is an amyloidosis of AL type.
10. The method of claim 1 , further comprising a step of administering a second active agent selected from the group consisting of 4-[bis(chloroethyl)amino]phenylalanine; 9-fluoro-1β,17,21-trihydroxy-16a-methylpregna-1,4-diene-3,20-dione; prednisone; dimethyl; sulfoxide; N [(7S)-5,6,7,9-tetrahydro-1,2,3,10-tetramethoxy-9-oxobenzo[a]heptalen-7-yl)acetamide]; (7S,9S)-7-[(2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-9-(2-hydroxyacetyl)-4-methoxy-8,10-dihydro-7H-tetracene-5,12-dione; bis-d-proline type; (R)-1-[6-[(R)-2-carboxypyrrolidin-I-yl]-6-oxohexanoyl]pyrrolidine-2-carboxylic acid; proteasome inhibitors; and mixtures thereof.
11. The method of claim 10 , wherein the proteasome inhibitors are bortezomib, carfilzomib, marizomib, ixazomib, delanzomib, ONX-912, or revlimid.
12. The method of claim 1 , wherein the chimeric protein is administered via intravenous, subcutaneous, or intramuscular route.
13. The method of claim 1 , wherein the first Fc and the second Fc region are not identical.
14. The method of claim 1 , wherein the first hinge and the second hinge region are identical.
15. The method of claim 1 , wherein the first hinge and the second hinge region are not identical.