Soluble ACE2 protein, fusion proteins thereof with an FC domain, and methods of treatment of an ACE2-related disease

1 . An Fc fusion protein multimer ACE2-hFc(n) comprising n polypeptide monomer units, wherein each of the polypeptide monomer units is a dimer in which two soluble angiotensin-converting enzyme 2 (ACE2) truncated forms are linked to N-terminal ends of two heavy chain Fc domains of an antibody respectively,

wherein said n polypeptide monomer units are further assembled into the Fc fusion protein multimer ACE2-hFc(n) via a tail located at each C-terminal end of the two heavy chain Fc domains,

wherein each of the two ACE2 truncated forms comprises an extracellular domain of ACE2, and comprises the amino acid sequence as shown by SEQ ID NO: 1 or SEQ ID NO: 2,

wherein the tail is an IgM derived tail and comprises the sequence as shown by SEQ ID NO: 17,

wherein each of the two heavy chain Fc domains has a hinge region at its N-terminal, a CH2 domain and a CH3 domain of the antibody, wherein the antibody is an IgG1 antibody, and

wherein n is selected from 4, 5 or 6.

2 . The Fc fusion protein multimer according to claim 1 , wherein the C-terminal end of each of the two heavy chain Fc domains is linked to the tail, and the n polypeptide monomer units have a total of 2n tails, which are connected to each other to form the Fc fusion protein multimer.

3 . The Fc fusion protein multimer according to claim 1 , wherein the Fc fusion protein multimer comprises one or more selected from the following group:

ACE2-hFc4, being a tetramer assembled from 4 polypeptide monomer units via the tails located at the C-terminal ends of the Fc domains, wherein each of the polypeptide monomer units comprises a dimer composed of two ACE2 truncated forms and two heavy chain Fc domains, and wherein one ACE2 truncated form, and one heavy chain Fc domain along with the tail comprise an amino acid sequence as shown by SEQ ID NO: 7; or

ACE2-NN-hFc4, being a tetramer assembled from 4 polypeptide monomer units via the tails located at the C-terminal ends of the Fc domains, wherein each of the polypeptide monomer units comprises a dimer composed of two ACE2 truncated forms and two heavy chain Fc domains, and wherein one ACE2 truncated form, and one heavy chain Fc domain along with the tail comprise an amino acid sequence as shown by SEQ ID NO: 8; or

ACE2-NN-hFc4-L309C, being a tetramer assembled from 4 polypeptide monomer units via the tails located at the C-terminal ends of the Fc domains, wherein each of the polypeptide monomer units comprises a dimer composed of two ACE2 truncated forms and two heavy chain Fc domains, and wherein one ACE2 truncated form, and one heavy chain Fc domain along with the tail comprise an amino acid sequence as shown by SEQ ID NO: 18, and the heavy chain Fc domain has an L309C mutation at position 309; or

ACE2-hFc5, being a pentamer assembled from 5 polypeptide monomer units via the tails located at the C-terminal ends of the Fc domains, wherein each of the polypeptide monomer units comprises a dimer composed of two ACE2 truncated forms and two heavy chain Fc domains, and wherein one ACE2 truncated form, and one heavy chain Fc domain along with the tail comprise an amino acid sequence as shown by SEQ ID NO: 7; or

ACE2-NN-hFc5, being a pentamer assembled from 5 polypeptide monomer units via the tails located at the C-terminal ends of the Fc domains, wherein each of the polypeptide monomer units comprises a dimer composed of two ACE2 truncated forms and two heavy chain Fc domains, and wherein one ACE2 truncated form, and one heavy chain Fc domain along with the tail comprise an amino acid sequence as shown by SEQ ID NO: 8; or

ACE2-NN-hFc5-L309C, being a pentamer assembled from 5 polypeptide monomer units via the tails located at the C-terminal ends of the Fc domains, wherein each of the polypeptide monomer units comprises a dimer composed of two ACE2 truncated forms and two heavy chain Fc domains, and wherein one ACE2 truncated form, and one heavy chain Fc domain along with the tail comprise an amino acid sequence as shown by SEQ ID NO: 18, and wherein the heavy chain Fc domain comprises an L309C mutation at position 309; or

ACE2-hFc6, being a hexamer assembled from 6 polypeptide monomer units via the tails located at the C-terminal ends of the Fc domains, wherein each of the polypeptide monomer units comprises a dimer composed of two ACE2 truncated forms and two heavy chain Fc domains, and wherein one ACE2 truncated form, and one heavy chain Fc domain along with the tail comprise an amino acid sequence as shown by SEQ ID NO: 7; or

ACE2-NN-hFc6, being a hexamer assembled from 6 polypeptide monomer units via the tails located at the C-terminal ends of the Fc domains, wherein each of the polypeptide monomer units comprises a dimer composed of two ACE2 truncated forms and two heavy chain Fc domains, and wherein one ACE2 truncated form, and one heavy chain Fc domain along with the tail comprise an amino acid sequence as shown by SEQ ID NO: 8; or

ACE2-NN-hFc6-L309C, being a hexamer assembled from 6 polypeptide monomer units via the tails located at the C-terminal ends of the Fc domains, wherein each of the polypeptide monomer units comprises a dimer composed of two ACE2 truncated forms and two heavy chain Fc domains, and wherein one ACE2 truncated form, and one heavy chain Fc domain along with the tail comprise an amino acid sequence as shown by SEQ ID NO: 18.

4 . The Fc fusion protein multimer according to claim 1 , wherein the soluble ACE2 truncated forms are glycosylated.

5 . The Fc fusion protein multimer according to claim 1 , wherein each of the two soluble ACE2 truncated forms is glycosylated at position(s) 53, 90, 103, 322, 432, 546 and/or 690 of human ACE2.

6 . A pharmaceutical composition comprising: the Fc fusion protein multimer according to claim 1 ; and a pharmaceutically acceptable carrier.

7 . A method for treating or preventing an ACE2-related disease, comprising administrating to a subject a therapeutically effective amount of the pharmaceutical composition of claim 6 .

8 . The method according to claim 7 , wherein the disease is caused by an infection of a virus employing ACE2 as a receptor.

9 . The method according to claim 7 , wherein the disease is selected from pneumonia, severe acute respiratory infection, renal failure, heart failure, adult respiratory distress syndrome (ARDS), liver injury, intestinal disease, or severe acute respiratory syndrome.

10 . The method according to claim 7 , wherein the method is used for passive immunization of a medical worker or a person at risk of exposure to the virus.

11 . The method according to claim 7 , wherein the pharmaceutical composition is administered by inhalation, intranasal or airway instillation, ocular injection, middle ear injection, ear drops, topical injection, transdermal injection, parenteral injection, subcutaneous injection, intravenous injection, intradermal injection, intramuscular injection, intrapleural instillation, intraperitoneal injection, intralesional administration, application to mucosa, or transplantation of a sustained-release carrier.

12 . The method according to claim 7 , wherein the disease is caused by an infection of a virus comprising a coronavirus.

13 . The method according to claim 12 , wherein the virus is selected from the group consisting of SARS-COV, HCoV-NL63 and SARS-CoV2.