Heterodimeric Relaxin Fusions and Uses Thereof
AssigneeMedImmune, LLC
InventorsISABELLE SERMADIRAS, MONIKA ANNA PAPWORTH, JUDY CHRISTIANE PATERSON, ESTHER MARIE MARTIN, PENG KE
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Abstract
The present invention relates to heterodimeric Relaxin fusion polypeptides, in particular to heterodimeric Relaxin 2 fusion polypeptides and uses thereof. Thus, the invention provides Relaxin fusion polypeptides, nucleic acid molecules, vectors, host cells, pharmaceutical compositions and kits comprising the same and uses of the same including methods of treatment. The polypeptides and compositions of the invention may be useful, in particular, in the treatment of cardiovascular diseases, for example for the treatment of heart failure.
Claims37
A heterodimeric fusion comprising:
- (i) a first heterodimerisation domain connected to at least one Relaxin A chain polypeptide or a variant thereof;
- and
- (ii) a second heterodimerisation domain connected to at least one Relaxin B chain polypeptide or a variant thereof,
- wherein the first heterodimerisation domain heterodimerises with the second heterodimerisation domain, and wherein the heterodimeric fusion has Relaxin activity.
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A heterodimeric fusion comprising:
- (i) an FcX-con-A fusion polypeptide;
- and
- (ii) an FcY-con-B fusion polypeptide,
- wherein:
- A is a Relaxin A chain or variant thereof, e.g. a Relaxin-2 A chain or variant thereof;
- B is a Relaxin B chain or variant thereof, e.g. Relaxin-2 B chain or variant thereof;
- FcY is an Fc region comprising the constant domains CH2 and CH3 of a human IgG1 immunoglobulin and comprises “Fc Hole” amino acid mutations and/or modifications, preferably the amino acid mutations Y349C:
- T366S:L368A:Y407V;
- FcX is an Fc region with “Fc Knob” amino acid mutations and/or modifications, preferably comprising the constant domains CH2 and CH3 of a human IgG1 immunoglobulin and comprises “Fc Knob” amino acid mutations and/or modifications, preferably the amino acid mutations S354C:T366W;
- and
- con is a connector polypeptide, preferably having the sequence GGGGSGGGGSGGGGSGGGGGS [SEQ ID NO:
- 5],
- wherein the amino acid numbering is according to the EU index as in Kabat, wherein FcX heterodimerises with FcY, and wherein the heterodimeric fusion has Relaxin activity.
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A heterodimeric fusion comprising:
- (i) FcX-B-L-A and FcY, optionally FcY-B-L-A;
- or
- (ii) FcY-B-L-A and FcX, optionally FcX-B-L-A;
- wherein:
- FcY is an immunoglobulin Fc region with “Fc Hole” amino acid mutations and/or modifications, preferably comprising a CH3 domain having the amino acid mutations Y349C:T366S :L368A:Y407V;
- FcX is an immunoglobulin Fc region with “Fc Knob” amino acid mutations and/or modifications, preferably comprising a CH3 domain having the amino acid mutations S354C:T366W;
- B is a Relaxin B chain or a variant thereof, e.g. a Relaxin 2 B chain or variant thereof;
- A is a Relaxin A chain or a variant thereof, e.g. a Relaxin 2 A chain or variant thereof;
- and
- L is a linker polypeptide, preferably having the amino acid sequence GGGSGGGSGG [SEQ ID NO:
- 60],
- wherein the amino acid numbering is according to the EU index as in Kabat, wherein FcX heterodimerises with FcY, and wherein the heterodimeric fusion has Relaxin activity.
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Dependencies are inferred from the claim text.