Fc fusion high affinity IgE receptor α-chain
Inventors
Sakamoto, Takashi • Inada, Yoichi • Yokoyama, Kazumasa
Assignees
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Publication Number
US-10077297-B2
Publication Date
2018-09-18
Expiration Date
Abstract
Provided is an Fc fusion high affinity IgE receptor α-chain having excellent stability at low pH.An Fc fusion protein comprising: (i) a high affinity IgE receptor α-chain; and(ii) an Fc region of IgG1, whereina linker fragment region between the (i) and the (ii) is the amino acid sequence shown in SEQ ID NO: 2.
Core Innovation
The invention relates to an Fc fusion protein comprising a high affinity IgE receptor alpha-chain (FCER1A) and an Fc region of IgG1 that are linked by a linker fragment region corresponding to an amino acid sequence shown in SEQ ID NO: 2. The Fc fusion protein further comprises an amino acid sequence shown in SEQ ID NO: 3, or an amino acid sequence comprising a deletion of lysine (K) at the C-terminus of the amino acid sequence shown in SEQ ID NO: 3.
The linker fragment region of SEQ ID NO: 2 contains three cysteines that form three disulfide bonds to stabilize an Fc-fusion dimer. The resulting Fc fusion dimer shows improved stability under low-pH conditions and after heat challenge compared with a prior fusion using a two-cysteine linker, while maintaining IgE binding inhibition.
The document reports supportive experimental results indicating concentration-dependent IgE binding inhibition and reduced aggregate formation under low-pH conditions and after incubation at 37°C. The invention is stated to be useful as an IgE-neutralizing protein pharmaceutical for type I allergic diseases, with optional pharmaceutical composition, formulation, and administration routes also described.
Claims Coverage
The independent claims recite 1 core structural definition of an Fc fusion protein, specifying the high affinity IgE receptor alpha-chain, the IgG1 Fc region, the linker fragment region, and the specific fused amino acid sequence (SEQ ID NO: 3) with an optional C-terminal lysine deletion. Dependent claims further specify dimer formation, disulfide bond formation by three linker cysteines, and a pharmaceutical composition aspect.
An Fc fusion protein with FCER1A linked to an IgG1 Fc region by SEQ ID NO: 2 and SEQ ID NO: 3
An Fc fusion protein comprising a high affinity IgE receptor alpha-chain, an Fc region of IgG1, and an amino acid sequence shown in SEQ ID NO: 3 or an amino acid sequence comprising a deletion of lysine (K) at the C-terminus of SEQ ID NO: 3, wherein a linker fragment region between the high affinity IgE receptor alpha-chain and the IgG1 Fc region is the amino acid sequence shown in SEQ ID NO: 2.
The claim coverage centers on the defined Fc fusion architecture linking FCER1A and an IgG1 Fc region through the SEQ ID NO: 2 linker, with the fused sequence defined by SEQ ID NO: 3 and optionally lacking C-terminal lysine, further narrowed by dependent features specifying dimerization and three disulfide bonds in the linker.
Stated Advantages
Improved stability under low-pH conditions compared with a prior fusion with a two-cysteine linker.
Improved stability after heat challenge compared with a prior fusion with a two-cysteine linker.
Reduced aggregate formation under low-pH conditions and after 37°C incubation.
Maintains IgE binding inhibitory activity while providing improved stability.
Documented Applications
IgE-neutralizing protein pharmaceutical for type I allergic diseases (type I allergy), including bronchial asthma, allergic rhinitis, and allergic conjunctivitis.
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