Tetrahedral Antibody

Abstract

The present invention provides a tetrahedral antibody comprising first, second, third and fourth domains, each of the first and second domains being selected from the group consisting of a Fab domain and an Fc domain, each of the first and second domains comprising a first polypeptide chain comprising a first N-terminus and a first C-terminus of the domain, and a second polypeptide chain comprising a second N-terminus and a second C-terminus of the domain, wherein the first domain and the second domain are spaced apart between the first N-terminus of the first domain and the first N-terminus of the second domain, between the first C-terminus of the first domain and the first C-terminus of the second domain, between the first N-terminus of the first domain and the first C-terminus of the second domain, or between the first C-terminus of the first domain and the first N-terminus of the second domain. They are linked to each other by non-peptidyl bonds.

Description

[Technical Field]

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 298,999, filed January 12, 2022, the contents of which are hereby incorporated by reference herein.

[0002] Throughout this application, various publications are cited, including those cited within parentheses. The disclosures of all publications mentioned in this application are hereby incorporated by reference in their entirety into this specification in order to provide further description of the art to which the invention pertains and features therein that may be used.

[0003] Sequence Listing Reference This application incorporates by reference the nucleotide sequence in the file entitled "230112_91300-D-PCT_SequenceListing_DH.xml", which is 11.3 megabytes in size and contained in an xml file created on January 9, 2022 in an IBM PC machine format with an MS-Windows® compatible operating system, and submitted as part of this application on January 12, 2023. [Background technology]

[0004] Antibodies are a diverse family of vertebrate proteins containing a Y-shaped structure consisting of two antigen-binding (Fab) domains and one effector cell-binding (Fc) domain. The arrangement of these three domains around a central hinge region closely resembles a planar triangular molecular structure (a central atom bound to three peripheral atoms located at each corner of the triangle). Such a planar configuration of the binding domain is sufficient for antibodies to achieve their normal functions. Therefore, efforts to date to engineer antibodies and antibody-like molecules have generally adopted the natural planar configuration of antibody binding domains. However, when the binding domains of engineered antibodies and antibody-like molecules are intended to engage multiple targets, the planar configuration of the binding domain is not ideally suited to enable simultaneous engagement of multiple targets by the binding domains. Summary of the Invention

[0005] The invention provides a tetrahedral antibody comprising a first, second, third and fourth domain, a) each of the first and second domains is selected from the group consisting of a Fab domain and an Fc domain; b) each of the first and second domains: i) a first polypeptide chain comprising a first N-terminus and a first C-terminus of the domain; and ii) a second polypeptide chain comprising a second N-terminus and a second C-terminus of said domain; Including, c) the first domain and the second domain are linked to each other by a non-peptidyl bond, wherein the non-peptidyl bond is i) (1) a covalent bond linking a first N-terminus of the first domain to a first N-terminus of the second domain; (2) a covalent bond linking the first C-terminus of the first domain to the first C-terminus of the second domain; (3) a covalent bond linking the first N-terminus of the first domain and the first C-terminus of the second domain; or (4) a covalent bond linking the first C-terminus of the first domain and the first N-terminus of the second domain; or ii) (1) a non-covalent bond between a first dimer-forming polypeptide attached to a first N-terminus of a first domain by a peptide bond or via a peptide linker and a second dimer-forming polypeptide attached to a first N-terminus of a second domain by a peptide bond or via a peptide linker; (2) a non-covalent bond between a first dimer-forming polypeptide attached to the first C-terminus of the first domain by a peptide bond or via a peptide linker and a second dimer-forming polypeptide attached to the first C-terminus of the second domain by a peptide bond or via a peptide linker; (3) a non-covalent bond between a first dimer-forming polypeptide attached to a first N-terminus of a first domain by a peptide bond or via a peptide linker and a second dimer-forming polypeptide attached to a first C-terminus of a second domain by a peptide bond or via a peptide linker; or (4) a non-covalent bond between a first dimer-forming polypeptide attached to a first C-terminus of the first domain by a peptide bond or via a peptide linker and a second dimer-forming polypeptide attached to a first N-terminus of the second domain by a peptide bond or via a peptide linker; and wherein the first and second dimer-forming polypeptides are not immunoglobulins, d) when the first domain is covalently linked at its first N-terminus to the second domain, the third domain is linked at its C-terminus to the second N-terminus of the first domain by a peptide bond or via a peptide linker; e) when a first domain is covalently linked at its first C-terminus to a second domain, said third domain is linked at its N-terminus to a second C-terminus of said first domain by a peptide bond or via a peptide linker; f) when the first domain is linked to the second domain via a first dimerization polypeptide linked to its first N-terminus, the third domain is linked at its C-terminus by a peptide bond or via a peptide linker, i) the N-terminus of the first dimer-forming polypeptide; ii) the second N-terminus of the first domain, or iii) the N-terminus of a third dimer-forming polypeptide, wherein the third dimer-forming polypeptide is linked at its C-terminus to the second N-terminus of the first domain by a peptide bond or via a peptide linker; binds to g) when the first domain is linked to the second domain via a first dimerization polypeptide linked to its first C-terminus, the third domain is linked at its N-terminus by a peptide bond or via a peptide linker, i) the C-terminus of the first dimer-forming polypeptide; ii) the second C-terminus of the first domain, or iii) the C-terminus of a third dimer-forming polypeptide, wherein the third dimer-forming polypeptide is linked at its N-terminus to the second C-terminus of the first domain by a peptide bond or via a peptide linker; binds to h) when the second domain is covalently linked at its first N-terminus to the first domain, the fourth domain is linked at its C-terminus to the second N-terminus of the second domain by a peptide bond or via a peptide linker; i) when the second domain is covalently linked at its first C-terminus to the first domain, the fourth domain is linked at its N-terminus to the second C-terminus of the second domain by a peptide bond or via a peptide linker; j) when the second domain is linked to the first domain via a second dimer-forming polypeptide linked to its first N-terminus, the fourth domain is linked at its C-terminus by a peptide bond or via a peptide linker, i) the N-terminus of the second dimer-forming polypeptide; ii) the second N-terminus of the second domain, or iii) the N-terminus of a fourth dimer-forming polypeptide, wherein the third dimer-forming polypeptide is linked at its C-terminus to the second N-terminus of the second domain by a peptide bond or via a peptide linker; binds to k) when the second domain is linked to the first domain via a second dimer-forming polypeptide linked to its first C-terminus, the fourth domain is linked at its N-terminus by a peptide bond or via a peptide linker, i) the C-terminus of the second dimer-forming polypeptide; ii) the second C-terminus of the second domain, or iii) the C-terminus of a fourth dimer-forming polypeptide, wherein the fourth dimer-forming polypeptide is linked at its N-terminus to the second C-terminus of the second domain by a peptide bond or via a peptide linker; is bonded to Tetrahedral antibodies are provided.

[0006] The invention provides a tetrahedral molecule comprising first, second, third and fourth domains, a) the first and second domains each independently: i) a first polypeptide chain comprising a first N-terminus and a first C-terminus of the domain; and ii) optionally a second polypeptide chain comprising a second N-terminus and a second C-terminus of said domain; Including, b) the first domain and the second domain are: (1) a non-covalent bond between a first dimer-forming polypeptide attached to a first N-terminus of a first domain by a peptide bond or via a peptide linker and a second dimer-forming polypeptide attached to a first N-terminus of a second domain by a peptide bond or via a peptide linker; (2) a non-covalent bond between a first dimer-forming polypeptide attached to the first C-terminus of the first domain by a peptide bond or via a peptide linker and a second dimer-forming polypeptide attached to the first C-terminus of the second domain by a peptide bond or via a peptide linker; (3) a non-covalent bond between a first dimer-forming polypeptide attached to a first N-terminus of a first domain by a peptide bond or via a peptide linker and a second dimer-forming polypeptide attached to a first C-terminus of a second domain by a peptide bond or via a peptide linker; or (4) a non-covalent bond between a first dimer-forming polypeptide attached to a first C-terminus of the first domain by a peptide bond or via a peptide linker and a second dimer-forming polypeptide attached to a first N-terminus of the second domain by a peptide bond or via a peptide linker; and are connected to each other by wherein the first and second dimer-forming polypeptides are not immunoglobulins, c) when the first domain is linked to the second domain via a first dimerization polypeptide linked to its first N-terminus, the third domain is linked at its C-terminus by a peptide bond or via a peptide linker, i) the N-terminus of the first dimer-forming polypeptide; ii) if present, the second N-terminus of the first domain; or iii) if present, the N-terminus of a third dimer-forming polypeptide, wherein said third dimer-forming polypeptide is linked at its C-terminus to the second N-terminus of said first domain by a peptide bond or via a peptide linker; binds to d) when the first domain is linked to the second domain via a first dimerization polypeptide linked to its first C-terminus, the third domain is linked at its N-terminus by a peptide bond or via a peptide linker, i) the C-terminus of the first dimer-forming polypeptide; ii) if present, the second C-terminus of the first domain; or iii) if present, the C-terminus of a third dimer-forming polypeptide, wherein said third dimer-forming polypeptide is linked at its N-terminus to the second C-terminus of said first domain by a peptide bond or via a peptide linker; binds to e) when the second domain is linked to the first domain via a second dimer-forming polypeptide linked to its first N-terminus, the fourth domain is linked at its C-terminus by a peptide bond or via a peptide linker, i) the N-terminus of the second dimer-forming polypeptide; ii) if present, the second N-terminus of the second domain; or iii) if present, the N-terminus of a fourth dimer-forming polypeptide, wherein the third dimer-forming polypeptide is linked at its C-terminus to the second N-terminus of the second domain by a peptide bond or via a peptide linker; binds to f) when the second domain is linked to the first domain via a second dimer-forming polypeptide linked to its first C-terminus, the fourth domain is linked at its N-terminus by a peptide bond or via a peptide linker, i) the C-terminus of the second dimer-forming polypeptide; ii) if present, the second C-terminus of the second domain; or iii) if present, the C-terminus of a fourth dimer-forming polypeptide, wherein said fourth dimer-forming polypeptide is linked at its N-terminus to the second C-terminus of said second domain by a peptide bond or via a peptide linker; is bonded to Tetrahedral molecules are also provided.

[0007] The present invention provides a non-natural fusion protein dimer comprising a dimer of a first dimerizing polypeptide and a second dimerizing polypeptide, a) the first dimer-forming polypeptide is linked at its N-terminus or C-terminus to the first domain by a peptide bond or via a peptide linker; b) the second dimer-forming polypeptide is optionally linked at its N-terminus or C-terminus to the second domain by a peptide bond or via a peptide linker; c) the first and second dimer-forming polypeptides are i) a collectrin-like domain (CLD), and ii) Collectrin domain (CD) selected from the group consisting of d) the first dimer-forming polypeptide is optionally linked at its remaining free N-terminus or C-terminus to a third domain by a peptide bond or via a peptide linker; e) the second dimer-forming polypeptide is optionally linked at its remaining free N-terminus or C-terminus to the fourth domain by a peptide bond or via a peptide linker; Non-natural fusion protein dimers are also provided.

[0008] The invention provides an octahedral antibody comprising a first, second, third, fourth, fifth and sixth domain, a) each of the first, second and third domains is selected from the group consisting of a Fab domain and an Fc domain; b) each of the first, second and third domains: i) a first polypeptide chain comprising a first N-terminus and a first C-terminus of the domain; and ii) a second polypeptide chain comprising a second N-terminus and a second C-terminus of said domain; Including, c) the first N-terminus of the first domain, the first N-terminus of the second domain, and the first N-terminus of the third domain are linked to each other by a non-peptidyl bond, wherein said non-peptidyl bond is i) a branched covalent bond, or ii) (1) a first trimerizing polypeptide attached to a first N-terminus of the first domain by a peptide bond or via a peptide linker; (2) a second trimerizing polypeptide linked to the first N-terminus of the second domain by a peptide bond or via a peptide linker; and (3) a third trimerizing polypeptide linked to the first N-terminus of the third domain by a peptide bond or via a peptide linker; is a non-covalent bond between wherein the first, second and third trimer-forming polypeptides are not immunoglobulins, d) the fourth domain is connected at its C-terminus by a peptide bond or via a peptide linker, i) the second N-terminus of the first domain, or ii) the N-terminus of the first trimer-forming polypeptide; binds to e) the fifth domain is connected at its C-terminus by a peptide bond or via a peptide linker, i) the second N-terminus of the second domain, or ii) the N-terminus of a second trimerizing polypeptide; binds to f) the sixth domain is connected at its C-terminus by a peptide bond or via a peptide linker, i) the second N-terminus of the third domain, or ii) the N-terminus of the third trimer-forming polypeptide binds to Octahedral antibodies are also provided. [Brief explanation of the drawings]

[0009] [Figure 1] FIG. 1 is a general schematic structure of a tetrahedral antibody showing the locations of domains D1, D2, D3, D4 (A-D) and D5 and D6 (D) as well as the locations of covalent (A) and non-covalent (B-D) bonds. [Figure 2]Figure 2 is a schematic structure of the tetrahedral antibody with covalent bonds shown in Figure 1A, where (A) D1, D2, D3, and D4 are all different, (B) D1 and D2 are different and D3 and D4 are identical, (C) D1 and D2 are identical and D3 and D4 are different, and (D) D1 and D2 are identical and D3 and D4 are identical. [Figure 3] 3 shows the schematic structure of the tetrahedral antibody having non-covalent bonds shown in FIG. 1B, where (A) D1, D2, D3, and D4 are all different, (B) D1 and D2 are different and D3 and D4 are identical, (C) D1 and D2 are identical and D3 and D4 are different, and (D) D1 and D2 are identical and D3 and D4 are identical. A single pair of dimer-forming polypeptides forms a heterodimer pair in (A-C) and a homodimer pair in (D). [Figure 4] 4 shows the schematic structure of the tetrahedral antibody having non-covalent bonds shown in FIG. 1C, where (A) D1, D2, D3, and D4 are all different, (B) D1 and D2 are different and D3 and D4 are identical, (C) D1 and D2 are identical and D3 and D4 are different, and (D) D1 and D2 are identical and D3 and D4 are identical. A single pair of dimer-forming polypeptides forms a heterodimer pair in (A-C) and a homodimer pair in (D). [Figure 5] Figure 5 shows a schematic structure of the tetrahedral antibody having non-covalent bonds shown in Figure 1D, in which D1 and D2 are different, and among the D3 to D6 domains, (A) D3 to D6 are all different, (B) D4 and D5 are identical and D3 and D6 are different, (C) D4 and D6 are identical and D3 and D5 are different, and (D) D3 and D4 are identical and D5 and D6 are different. A single pair of dimer-forming polypeptides forms a heterodimer pair in (A to D). [Figure 6]6 shows a schematic structure of the tetrahedral antibody having non-covalent bonds shown in FIG. 1D, in which D1 and D2 are different, and among the D3 to D6 domains, (A) D3 and D6 are identical, and D4 and D6 are identical, (B) D3 and D5 are identical, and D4 and D5 are identical, (C) D3 and D4 are identical, and D5 and D6 are identical, and (D) D3 to D6 are identical. A single pair of dimer-forming polypeptides forms a heterodimer pair in (A to D). [Figure 7] 7 shows a schematic structure of the tetrahedral antibody having non-covalent bonds shown in FIG. 1D, in which D1 and D2 are different, the D6 domain is absent, and among the D3 to D5 domains, (A) D3 to D5 are all different, (B) D4 and D5 are identical and D3 is different, (C) D3 and D5 are identical and D4 is different, and (D) D3 to D5 are all identical. A single pair of dimer-forming polypeptides forms a heterodimer pair in (A to D). [Figure 8A] 8A is a schematic structure of the tetrahedral antibody having non-covalent bonds shown in FIG. 1D, in which D1 and D2 are identical, and among the D3 to D6 domains, (A) D3 to D6 are all the same of a first type, (B) D3 to D6 are all the same of a second type, (C) D3 and D4 are of a first type, and D5 and D6 are of a second type, and (D) D3 and D5 are of a first type, and D4 and D6 are of a second type. A single pair of dimer-forming polypeptides forms a homodimer pair in (A to D). [Figure 8B] 8B is a schematic structure of the tetrahedral antibody having non-covalent bonds shown in FIG. 1D, in which D1 and D2 are identical, and among the D3 to D6 domains, (A) D3 to D6 are all the same and are of the first type, (B) D3 to D6 are all the same and are of the second type, (C) D3 and D4 are of the first type, and D5 and D6 are of the second type, and (D) D3 and D4 are of the second type, and D5 and D6 are of the first type. A single pair of dimer-forming polypeptides forms a homodimer pair in (A to D). [Figure 9]9 is a schematic structure of the tetrahedral antibody having non-covalent bonds shown in FIG. 1D, in which D1 and D2 are identical, and among the D3 to D5 domains, (A) D3 to D6 are all the same of the first type, (B) D3 to D6 are all the same of the second type, (C) D4 and D5 are of the first type and D3 and D6 are of the second type, and (D) D3 and D6 are of the first type and D4 and D5 are of the second type. Two pairs of dimer-forming polypeptides each form a heterodimer pair in (A to D). [Figure 10] 10 shows a schematic structure of the tetrahedral antibody having non-covalent bonds shown in FIG. 1D, in which (A-B) D1 and D2 are identical, and among the D3-D5 domains, (A) D3-D6 are all the same first type, and (B) D3-D6 are all the same second type; (C-D) D1 and D2 are different, and among the D3-D5 domains, (C) D3 and D4 are of the first type, and D5 and D6 are of the second type; and (D) D3 and D5 are of the first type, and D4 and D6 are of the second type. Each of the two pairs of dimer-forming polypeptides forms a homodimer pair in (A-B). Each of the two pairs of dimer-forming polypeptides forms a separate homodimer pair in (C-D). [Figure 11] Figure 11 shows the schematic structures of tetrahedral antibodies (A) Rc6-P4-Rc6, (B) Rc66SIDE-P4-Rc66SIDE, (C) Rc66SIDE-P16-Rc66SIDE, (D) Rc66SIDE-P28-Rc66SIDE, (E) B19c66-P4-Rc6m, (F) Soc66-P28-6Ec66, (G) HA9c66AAC9-P4-HA9c66AAC9, and (H) HA9c66AAC9-P4-IL15c6AAC9. [Figure 12] FIG. 12 shows the production of tetrahedral antibody Rc6-P4-Rc6. [Figure 13] FIG. 13 is the preparation of a tetrahedral antibody with non-covalent bonds as shown in FIG. 1B. [Figure 14] Figure 14: Preparation of tetrahedral antibody ACE2RQ740c60PG-ACE2RQ740c60PG. [Figure 15] Figure 15 is an analysis of the tetrahedral antibody ACE2RQ740c60PG-ACE2RQ740c60PG by SE-HPLC. [Figure 16] Figure 16 shows the results of SE-HPLC analysis of various peptide linkers: (L-1) ACE2RQ740c60PGRF-ACE2RQ740c60PGRF, (L-185) ACE2RQ740c60PGRF185-ACE2RQ740c60PGRF185, (L-198) ACE2RQ740c60PGRF198-ACE2RQ740c60PGRF198, (L-208) ACE2RQ740c60PG Analysis of tetrahedral antibodies with RF208-ACE2RQ740c60PGRF208, (L-212)ACE2RQ740c60PGRF235-ACE2RQ740c60PGRF235, (L-235)ACE2RQ740c60PGRF235-ACE2RQ740c60PGRF235, and (L-240)ACE2RQ740c60PGRF240-ACE2RQ740c60PGRF240. [Figure 17] Figure 17 is an analysis of the tetrahedral antibody ACE2RQ740c60PG-ACE2RQ740c60PG by SE-HPLC / MALS. [Figure 18] Figure 18 shows the stoichiometric binding analysis of a mixture of tetrahedral antibody ACE2RQ740c60PG-ACE2RQ740c60PG and ACE monomer ACE2RQ615c60PG. [Figure 19] FIG. 19. Production of tetrahedral antibody ACE2740FcG9-ACE2740FcG9. [Figure 20] FIG. 20 is an analysis of the tetrahedral antibody ACE2740FcG9-ACE2740FcG9 by SE-HPLC. [Figure 21] FIG. 21 is an analysis of the tetrahedral antibody ACE2740FcG9-ACE2740FcG9 by SE-HPLC / MALS. [Figure 22] Figure 22 shows the analysis of the tetrahedral antibody ACE2RQ740FcPG-ACE2RQ740FcPG by SE-HPLC / MALS. [Figure 23]FIG. 23 shows the stoichiometric binding analysis of crude tetrahedral antibody ACE2740FcG9-ACE2740FcG9 and ACE2 dimer ACE2740FcG9. [Figure 24] FIG. 24 shows the stoichiometric binding analysis of a mixture of tetrahedral antibody ACE2740FcG9-ACE2740FcG9 and ACE2 dimer ACE2-740Fc-G9. [Figure 25] Figure 25 shows the stoichiometric binding analysis of a mixture of tetrahedral antibody ACE2RQ740FcPG-ACE2RQ740FcPG and ACE2 dimer ACE2-740Fc-G9. [Figure 26] Figure 26 shows the stoichiometric binding analysis of a mixture of tetrahedral antibody ACE2740FcG9-ACE2740FcG9 and ACE2 dimer ACE2-615Fc-G9. [Figure 27] Figure 27. Inhibition of SARS-CoV-2-VSV pseudotyped virus infection by ACE2 tetrahedron antibodies ACE2740FcG9-ACE2740FcG9 and ACE2RQ740FcPG-ACE2RQ740FcPG, and by ACE2 dimers ACE2-615Fc-G9 and ACE2RQ615FcPG. [Figure 28] Figure 28. Inhibition of SARS-CoV-2-VSV pseudotyped virus infection by ACE2 tetrahedron antibodies ACE2740FcG9-ACE2740FcG9 and ACE2RQ740FcPG-ACE2RQ740FcPG, and by ACE2 dimers ACE2-740Fc-G9 and ACE2RQ740FcPG. [Figure 29A] Figure 29A shows a tetrahedral antibody comprising a first and a second dimer-forming polypeptide that form a non-covalent homodimer, where D1 and D2 are each heterodimeric Fc domains, and D3 and D4 are each Fab domains that specifically bind to a first target. [Figure 29B]Figure 29B: A tetrahedral antibody comprising a first and a second dimer-forming polypeptide that form a non-covalent homodimer, wherein D1 and D2 are each heterodimeric Fc domains, D3 and D4 are each Fab domains that specifically bind to a first target, and D5 and D6 are each variable region-exchanged Fab domains that specifically bind to a second target. [Figure 29C] Figure 29C shows a tetrahedral antibody comprising first and second dimerizing polypeptides that form a non-covalent homodimer, where D1 and D2 are each heterodimeric Fc domains, D3 and D4 are each Fab domains that specifically bind to a first target, and D7 and D8 are each domains that specifically bind to a second target. D7 and D8 are each depicted as single-chain TNFSF fusion polypeptides, but may be any domain. [Figure 29D] Figure 29D shows a tetrahedral antibody comprising first and second dimer-forming polypeptides that form a non-covalent homodimer, where D1 and D2 are each heterodimeric Fc domains, D3 and D4 are each Fab domains that specifically bind to a first target, D5 and D6 are each variable region-exchanged Fab domains that specifically bind to a second target, and D7 and D8 are each domains that specifically bind to a third target. D7 and D8 are depicted as single-chain TNFSF fusion polypeptides, but may be any domain. [Figure 30A] Figure 30A shows an octahedral antibody comprising first, second, and third trimerization polypeptides that form a homotrimeric non-covalent bond, where D1, D2, and D3 are each heterodimeric Fc domains, and D4, D5, and D6 are each Fab domains that specifically bind to a first target. [Figure 30B] Figure 30B is an octahedral antibody comprising first, second, and third trimerization polypeptides that form a homotrimeric non-covalent bond, wherein D1, D2, and D3 are each heterodimeric Fc domains, D4, D5, and D6 are each Fab domains that specifically bind to a first target, and D7, D8, and D9 are each variable region-exchanged Fab domains that specifically bind to a second target. [Figure 30C] Figure 30C shows an octahedral antibody comprising first, second, and third trimerization polypeptides that form a homotrimeric non-covalent bond, where D1, D2, and D3 are each heterodimeric Fc domains, D4, D5, and D6 are each Fab domains that specifically bind to a first target, and D10, D11, and D12 are each Fab domains that specifically bind to a second target. D10, D11, and D12 are each depicted as single-chain TNFSF fusion polypeptides, but may be any domain. [Figure 30D] Figure 30D shows an octahedral antibody comprising first, second, and third trimerization polypeptides that form a non-covalent homotrimeric structure, where D1, D2, and D3 are each heterodimeric Fc domains, D4, D5, and D6 are each Fab domains that specifically bind to a first target, D7, D8, and D9 are each variable region-exchanged Fab domains that specifically bind to a second target, and D10, D11, and D12 are each specifically bind to a third target. D10, D11, and D12 are each depicted as single-chain TNFSF fusion polypeptides, but may be any domain. [Figure 31]Figure 31 shows a tetrahedral antibody comprising first and second dimer-forming polypeptides that form a non-covalent homodimer, where D1 and D2 are each heterodimeric Fc domains, (A) D3, D4, D5, and D6 specifically bind to a first target (tetravalent, monospecific), (B) D3 and D4 specifically bind to the first target and D5 and D6 are Fab domains that specifically bind to a second target (tetravalent, 2+2 bispecific), (C) D3 and D4 are Fab domains that specifically bind to the first target and D5 and D6 are specifically bind to a second target (tetravalent, 2+2 bispecific), and (D) D3, D4, D5, and D6 are Fab domains that specifically bind to the first target (tetravalent, monospecific). The tetrahedral antibodies A to D are (A) four chains: a first H1 chain [D1 / D3], a second H1 chain [D2 / D4], a first H2 chain [D1 / D5], and a second H2 chain [D2 / D6], (B) six chains: a first H1 chain [D1 / D3], a second H1 chain [D2 / D4], a first H2 chain [D1 / D5], a second H2 chain [D2 / D6], a first L2 chain [D5], and a second L2 chain [D6], and (C) six chains: a first H1 chain [D1 / D3], second H1 chain [D2 / D4], first H2 chain [D1 / D5], second H2 chain [D2 / D6], first L1 chain [D3] and second L1 chain [D4] and (D) eight chains: first H1 chain [D1 / D3], second H1 chain [D2 / D4], first H2 chain [D1 / D5], second H2 chain [D2 / D6], first L1 chain [D3], second L1 chain [D4], first L2 chain [D5] and second L2 chain [D6]. [Figure 32]Figure 32 shows a tetrahedral antibody comprising first and second dimer-forming polypeptides that form a non-covalent homodimer, where D1 and D2 are each heterodimeric Fc domains, (A) D3 and D4 specifically bind to a first target and D5 and D6 specifically bind to a second target (tetravalent, 2+2 bispecific), (B) D5 and D6 specifically bind to a first target and D3 and D4 specifically bind to a second target (tetravalent, 2+2 bispecific), (C) D3 and D4 are Fab domains that specifically bind to a first target and D5 and D6 are variable region-exchanged Fab domains that specifically bind to a second target (tetravalent, 2+2 bispecific), and (D) D5 and D6 are Fab domains that specifically bind to a first target and D3 and D4 are variable region-exchanged Fab domains that specifically bind to a second target (tetravalent, 2+2 bispecific). The tetrahedral antibodies A to D consist of: (A) four chains: a first H1 chain [D1 / D3], a second H1 chain [D2 / D4], a first H2 chain [D1 / D5], and a second H2 chain [D2 / D6]; (B) four chains: a first H1 chain [D1 / D3], a second H1 chain [D2 / D4], a first H2 chain [D1 / D5], and a second H2 chain [D2 / D6]; and (C) eight chains: a first H1 chain [D1 / D3], a second H1 chain [D2 / D4], a first H2 chain [D1 / D5], and a second H2 chain [D2 / D6]. The eight H1 chains include a first H1 chain [D1 / D5], a second H1 chain [D2 / D6], a first L1 chain [D3], a second L1 chain [D4], a first L2 chain [D5] and a second L2 chain [D6], and (D) eight chains: a first H1 chain [D1 / D3], a second H1 chain [D2 / D4], a first H2 chain [D1 / D5], a second H2 chain [D2 / D6], a first L1 chain [D3], a second L1 chain [D4], a first L2 chain [D5] and a second L2 chain [D6]. [Figure 33]Figure 33 shows a tetrahedral antibody comprising first and second dimer-forming polypeptides that form a non-covalent homodimer, where each of D1 and D2 is a heterodimeric Fc domain, (A) D3, D4, and D5 specifically bind to a first target and D6 specifically binds to a second target (tetravalent, 3+1 bispecific), (B) D3, D4, and D5 specifically bind to the first target and D6 is a Fab domain that specifically binds to a second target (tetravalent, 3+1 bispecific), (C) D3, D4, and D5 are Fab domains that specifically bind to the first target and D6 is a variable region-exchanged Fab domain that specifically binds to a second target (tetravalent, 3+1 bispecific), and (D) D3, D4, and D5 are Fab domains that specifically bind to the first target and D6 is a variable region-exchanged Fab domain that specifically binds to a second target (tetravalent, 3+1 bispecific). The tetrahedral antibodies A to D consist of: (A) four chains: a first H1 chain [D1 / D3], a second H1 chain [D2 / D4], a first H2 chain [D1 / D5], and a first H3 chain [D2 / D6]; (B) five chains: a first H1 chain [D1 / D3], a second H1 chain [D2 / D4], a first H2 chain [D1 / D5], a first H3 chain [D2 / D6], and a first H3 chain [D6]; and (C) seven chains: a first H1 chain [D1 / D3], a second H1 chain [D2 / D4], a first The IgG1A-specific ... [Figure 34]Figure 34 shows a tetrahedral antibody comprising first and second dimer-forming polypeptides that form a non-covalent homodimer, where D1 and D2 are each heterodimeric Fc domains, (A) D3 and D4 specifically bind to a first target and D6 specifically binds to a second target (trivalent, 2+1 bispecific), (B) D3 and D4 specifically bind to a first target and D6 is a Fab domain that specifically binds to a second target (trivalent, 2+1 bispecific), (C) D3 and D4 are Fab domains that specifically bind to a first target and D6 is a variable region-exchanged Fab domain that specifically binds to a second target (trivalent, 2+1 bispecific), and (D) D3 and D4 are Fab domains that specifically bind to a first target and D6 is a variable region-exchanged Fab domain that specifically binds to a second target (trivalent, 2+1 bispecific). Tetrahedral antibodies A to D consist of: (A) four chains: a first H1 chain [D1 / D3], a second H1 chain [D2 / D4], a first H2 chain [D2 / D6], and a first Fc chain [D1]; (B) five chains: a first H1 chain [D1 / D3], a second H1 chain [D2 / D4], a first H2 chain [D2 / D6], a first Fc chain [D1], and a first L2 chain [D6]; and (C) six chains: a first H1 chain [D1 / D 3], second H1 chain [D2 / D4], first H2 chain [D2 / D6], first Fc chain [D1], first L1 chain [D3] and second L1 chain [D4], and (D) seven chains: first H1 chain [D1 / D3], second H1 chain [D2 / D4], first H2 chain [D2 / D6], first Fc chain [D1], first L1 chain [D3], second L1 chain [D4] and first L2 chain [D6]. [Figure 35]Figure 35 shows a tetrahedral antibody comprising first and second dimer-forming polypeptides that form a homodimer non-covalently, where D1 and D2 are each heterodimeric Fc domains, (A) D3 and D4 specifically bind to a first target, D5 specifically binds to a second target, and D6 specifically binds to a third target (tetravalent, 2+1+1 trispecific), and (B) D3 and D4 specifically bind to the first target, D5 specifically binds to the second target, and D6 specifically binds to the third target. (C) D3 and D4 are Fab domains that specifically bind to a first target, D5 specifically binds to a second target, and D6 specifically binds to a third target (tetravalent, 2+1+1 trispecific), and (D) D3 and D4 are Fab domains that specifically bind to a first target, D5 specifically binds to a second target, and D6 is a variable region-exchanged Fab domain that specifically binds to a third target (tetravalent, 2+1+1 trispecific). The tetrahedral antibodies A to D consist of: (A) four chains: a first H1 chain [D1 / D3], a second H1 chain [D2 / D4], a first H2 chain [D1 / D5], and a first H3 chain [D2 / D6]; (B) five chains: a first H1 chain [D1 / D3], a second H1 chain [D2 / D4], a first H2 chain [D1 / D5], a first H3 chain [D2 / D6], and a first H3 chain [D6]; and (C) six chains: a first H1 chain [D1 / D 3], the second H1 chain [D2 / D4], the first H2 chain [D1 / D5], the first H3 chain [D2 / D6], the first L1 chain [D3] and the second L1 chain [D4], and (D) seven chains: the first H1 chain [D1 / D3], the second H1 chain [D2 / D4], the first H2 chain [D1 / D5], the first H3 chain [D2 / D6], the first L1 chain [D3], the second L1 chain [D4] and the first L3 chain [D6]. [Figure 36]FIG. 36 illustrates a tetrahedral antibody comprising first and second dimerizing polypeptides that form a homodimer non-covalently, where D1 is a heterodimeric Fc domain and D2 is a Fab domain, where (A) D2 is a Fab that binds to a first target, and D3, D4, and D5 specifically bind to a second target (tetravalent, 3+1 bispecific), and (B) D2 is a Fab that binds to the first target, and D3 and D4 specifically bind to the second target, and D5 specifically binds to a third target. (C) D2 is a Fab that binds to a first target, D3 and D4 are variable region-exchanged Fab domains that specifically bind to a second target, and D5 is variable region-exchanged Fab domains that specifically bind to a third target (tetravalent, 2+1+1 trispecific), and (D) D2 is a Fab that binds to the first target, and D3, D4, and D5 are variable region-exchanged Fab domains that specifically bind to a second target (tetravalent, 4+1 bispecific). The tetrahedral antibodies A to D are (A) four chains: a first H1 chain [D1 / D3], a first H1 Fab chain [D2 / D4], a first H2 chain [D1 / D5], and a first Fab chain [D2]; (B) five chains: a first H1 chain [D1 / D3], a first H1 Fab chain [D2 / D4], a first H2 chain [D1 / D5], a first Fab chain [D2], and a first L2 chain [D5]; (C) six chains: a first H1 chain [D1 / D3]; (D) Seven chains: the first H1 chain [D1 / D3], the first H1 Fab chain [D2 / D4], the first H2 chain [D1 / D5], the first Fab chain [D2], the first L1 chain [D3], and the second L1 chain [D4]; (D) Seven chains: the first H1 chain [D1 / D3], the first H1 Fab chain [D2 / D4], the first H2 chain [D1 / D5], the first Fab chain [D2], the first L1 / L2 chain [D3], the second L1 / L2 chain [D4], and the third L1 / L2 chain [D5]. [Figure 37]Figure 37 shows a tetrahedral antibody comprising a first and second dimer-forming polypeptide that form a homodimer non-covalently, where D1 is a heterodimeric Fc domain and D2 is a Fab domain, (A) D2 is a variable region-exchanged Fab that binds to a first target, and D3, D4, and D5 specifically bind to a second target (tetravalent, 3+1 bispecific), (B) D2 is a variable region-exchanged Fab that binds to the first target, and D3 and D4 specifically bind to a second target, and D5 specifically binds to a third target. (C) D2 is a variable region-exchanged Fab that binds to the first target, D3 and D4 are Fab domains that specifically bind to the second target, and D5 is a Fab that specifically binds to a third target (tetravalent, 2+1+1 trispecific), and (D) D2 is a variable region-exchanged Fab that binds to the first target, and D3, D4, and D5 are Fab domains that specifically bind to the second target (tetravalent, 3+1 bispecific). The tetrahedral antibodies A to D are (A) four chains: a first H1 chain [D1 / D3], a first H1Fab chain [D2 / D4], a first H2 chain [D1 / D5], and a first Fab chain [D2]; (B) five chains: a first H1 chain [D1 / D3], a first H1Fab chain [D2 / D4], a first H2 chain [D1 / D5], a first Fab chain [D2], and a first L2 chain [D5]; (C) six chains: a first H1 chain [D1 / D3], a first H1Fab chain [D2 / D4], a first H2 chain [D1 / D5], a first Fab chain [D2], and a first L2 chain [D5]. It includes one H1 Fab chain [D2 / D4], a first H2 chain [D1 / D5], a first Fab chain [D2], a first L1 chain [D3] and a second L1 chain [D4], and (D) seven chains: a first H1 chain [D1 / D3], a first H1 Fab chain [D2 / D4], a first H2 chain [D1 / D5], a first Fab chain [D2], a first L1 / L2 chain [D3], a second L1 / L2 chain [D4] and a third L1 / L2 chain [D5]. [Figure 38]Figure 38 shows a tetrahedral antibody comprising a first and second dimer-forming polypeptide that form a non-covalent homodimer, where D1 is a heterodimeric Fc domain and D2 is a Fab domain, where (A) D2 is a Fab that binds to a first target, and D3 and D4 specifically bind to a second target (trivalent, 2+1 bispecific), (B) D2 is a variable region-exchanged Fab that binds to the first target, and D3 and D4 specifically bind to a second target, (C) D2 is a Fab that binds to the first target, and D3 and D4 are variable region-exchanged Fab domains that specifically bind to a second target (trivalent, 2+1 bispecific), and (D) D2 is a variable region-exchanged Fab that binds to the first target, and D3 and D4 are Fab domains that specifically bind to a second target (trivalent, 2+1 bispecific). The tetrahedral antibodies A to D are (A) four chains: a first H1 chain [D1 / D3], a first H1 Fab chain [D2 / D4], a first Fc chain [D1], and a first Fab chain [D2]; (B) four chains: a first H1 chain [D1 / D3], a first H1 Fab chain [D2 / D4], a first Fc chain [D1], and a first Fab chain [D2]; (C) six chains: a first H1 chain [D1 / D 3], the first H1 Fab chain [D2 / D4], the first Fc chain [D1], the first Fab chain [D2], the first L1 chain [D3] and the second L1 chain [D4], and (D) six chains: the first H1 chain [D1 / D3], the first H1 Fab chain [D2 / D4], the first Fc chain [D1], the first Fab chain [D2], the first L1 chain [D3] and the second L1 chain [D4]. [Figure 39]FIG. 39 shows a tetrahedral antibody comprising first and second dimerizing polypeptides that form a homodimer non-covalently, where D1 and D2 are each heterodimeric Fc domains, (A) D3, D4, D5, and D6 specifically bind to a first target, and D7 and D8 specifically bind to a second target (hexavalent, 4+2 bispecific), (B) D3 and D4 specifically bind to the first target, D5 and D6 specifically bind to a second target, and D7 and D8 are Fab domains. specifically binds to a third target (hexavalent, 2+2+2 trispecific), (C) D3 and D4 are Fab domains that specifically bind to a first target, D5 and D6 specifically bind to a second target, and D7 and D8 specifically bind to a third target (hexavalent, 2+2+2 trispecific), and (D) D3, D4, D5, and D6 are Fab domains that specifically bind to a first target, and D7 and D8 specifically bind to a second target (hexavalent, 4+2 bispecific). The tetrahedral antibodies A to D are (A) four chains: a first H1 chain [D1 / D3 / D7], a second H1 chain [D2 / D4 / D8], a first H2 chain [D1 / D5] and a second H2 chain [D2 / D6], (B) six chains: a first H1 chain [D1 / D3 / D7], a second H1 chain [D2 / D4 / D8], a first H2 chain [D1 / D5], a second H2 chain [D2 / D6], a first L2 chain [D5] and a second L2 chain [D6], and (C) six chains: a first H1 chain [D1 / D and (D)8 chains: first H1 chain [D1 / D3 / D7], second H1 chain [D2 / D4 / D8], first H2 chain [D1 / D5], second H2 chain [D2 / D6], first L1 chain [D3], and second L1 chain [D4]. D7 and D8 may be attached at the C-terminus of the first and second H1 chains (as shown) or at the C-terminus of the first and second H2 chains. D7 and D8 are represented as single chain TNFSF ligand fusion polypeptides, but may be any domain. [Figure 40]FIG. 40 shows a tetrahedral antibody comprising first and second dimer-forming polypeptides that form a homodimer non-covalently, where D1 and D2 are each heterodimeric Fc domains, (A) D3 and D4 specifically bind to a first target, D5 and D6 specifically bind to a second target, and D7 and D8 specifically bind to a third target (hexavalent, 2+2+2 trispecific), (B) D5 and D6 specifically bind to the first target, D3 and D4 specifically bind to the second target, and D7 and D8 specifically bind to a third target (hexavalent, 2+2+2 trispecific). (2+2 trispecific), (C) D3 and D4 are Fab domains that specifically bind to a first target, D5 and D6 are variable region-exchanged Fab domains that specifically bind to a second target, and D7 and D8 specifically bind to a third target (hexavalent, 2+2+2 trispecific), and (D) D5 and D6 are Fab domains that specifically bind to a first target, D3 and D4 are variable region-exchanged Fab domains that specifically bind to a second target, and D7 and D8 specifically bind to a third target (hexavalent, 2+2+2 trispecific). Tetrahedral antibodies A to D consist of: (A) four chains: the first H1 chain [D1 / D3 / D7], the second H1 chain [D2 / D4 / D8], the first H2 chain [D1 / D5], and the second H2 chain [D2 / D6]; (B) four chains: the first H1 chain [D1 / D3 / D7], the second H1 chain [D2 / D4 / D8], the first H2 chain [D1 / D5], and the second H2 chain [D2 / D6]; and (C) eight chains: the first H1 chain [D1 / D3 / D7], and the second H1 chain [D2 / D4 / D8]. , a first H2 chain [D1 / D5], a second H2 chain [D2 / D6], a first L1 chain [D3], a second L1 chain [D4], a first L2 chain [D5], and a second L2 chain [D6], and (D) eight chains: a first H1 chain [D1 / D3 / D7], a second H1 chain [D2 / D4 / D8], a first H2 chain [D1 / D5], a second H2 chain [D2 / D6], a first L1 chain [D3], a second L1 chain [D4], a first L2 chain [D5], and a second L2 chain [D6]. D7 and D8 may be attached at the C-terminus of the first and second H1 chains (as shown) or at the C-terminus of the first and second H2 chains. D7 and D8 are represented as single chain TNFSF ligand fusion polypeptides, but may be any domain. [Figure 41]FIG. 41 shows a tetrahedral antibody comprising first and second dimerizing polypeptides that form a homodimer non-covalently, where D1 and D2 are each heterodimeric Fc domains, (A) D3 and D4 specifically bind to a first target, D6 specifically binds to a second target, and D7 and D8 specifically bind to a third target (pentavalent, 2+2+1 trispecific), and (B) D3 and D4 specifically bind to the first target, D6 is a Fab domain that specifically binds to a second target, and D7 and D8 specifically bind to a third target. (C) D3 and D4 are Fab domains that specifically bind to a first target, D6 is a variable region-exchanged Fab domain that specifically binds to a second target, and D7 and D8 are Fab domains that specifically bind to a third target (pentavalent, 2+2+1 trispecific), and (D) D3 and D4 are Fab domains that specifically bind to a first target, D6 is a variable region-exchanged Fab domain that specifically binds to a second target, and D7 and D8 are Fab domains that specifically bind to a third target (pentavalent, 2+2+1 trispecific). Tetrahedral antibodies A to D consist of: (A) four chains: a first H1 chain [D1 / D3 / D7], a second H1 chain [D2 / D4 / D8], a first H2 chain [D2 / D6], and a first Fc chain [D1]; (B) five chains: a first H1 chain [D1 / D3 / D7], a second H1 chain [D2 / D4 / D8], a first H2 chain [D2 / D6], an Fc chain [D1], and an L2 chain [D6]; and (C) six chains: a first H1 chain [D1 / D3 / D7], second H1 chain [D2 / D4 / D8], first H2 chain [D2 / D6], first Fc chain [D1], first L1 chain [D3], and second L1 chain [D4], and (D)7 chains: first H1 chain [D1 / D3 / D7], second H1 chain [D2 / D4 / D8], first H2 chain [D2 / D6], first Fc chain [D1], first L1 chain [D3], second L1 chain [D4], and first L2 chain [D6]. D7 and D8 may be attached at the C-terminus of the first and second H1 chains (as shown) or at the C-terminus of the first and second H2 chains. D7 and D8 are depicted as single-chain TNFSF ligand fusion polypeptides, but may be any domain. [Figure 42]Figure 42 shows a tetrahedral antibody comprising first and second dimerizing polypeptides that form a homodimer non-covalently, where D1 is a heterodimeric Fc domain and D2 is a Fab domain, (A) D2 is a Fab domain that specifically binds to a first target, D3 and D4 specifically bind to a second target, and D7 and D8 specifically bind to a third target (pentavalent, 2+2+1 trispecific), (B) D2 is a variable region-exchanged Fab domain that specifically binds to the first target, D3 and D4 specifically bind to a second target, and D7 and D8 specifically bind to a third target. (C) D2 is a Fab domain that specifically binds to a first target, D3 and D4 are variable region-exchanged Fab domains that specifically bind to a second target, and D7 and D8 specifically bind to a third target (pentavalent, 2+2+1 trispecific), and (D) D2 is a variable region-exchanged Fab domain that specifically binds to a first target, D3 and D4 are Fab domains that specifically bind to a second target, and D7 and D8 specifically bind to a third target (pentavalent, 2+2+1 trispecific). The tetrahedral antibodies A to D are (A) four chains: a first H1 chain [D1 / D3 / D7], a second H1 chain [D2 / D4 / D8], a first Fc chain [D1], and a first Fab chain [D2]; (B) four chains: a first H1 chain [D1 / D3 / D7], a second H1 chain [D2 / D4 / D8], a first Fc chain [D1], and a first Fab chain [D2]; (C) six chains: a first H1 chain [D1 / D3 / D7], a second H1 chain [D2 / D4 / D8], a first Fc chain [D1], and a first Fab chain [D2]. The fusion polypeptide comprises two H1 chains [D2 / D4 / D8], a first Fc chain [D1], a first Fab chain [D2], a first L1 chain [D3], and a second L1 chain [D4], and six (D) chains: a first H1 chain [D1 / D3 / D7], a second H1 chain [D2 / D4 / D8], a first H2 chain [D2 / D6], a first Fc chain [D1], a first Fab chain [D2], a first L1 chain [D3], and a second L1 chain [D4]. D7 and D8 may be attached at the C-terminus of the first and second H1 chains (as shown) or at the C-terminus of the first and second H2 chains. D7 and D8 are shown as single-chain TNFSF ligand fusion polypeptides, but may be any domain. [Figure 43]Figure 43 shows ACE2 tetrahedron antibodies. Four forms of ACE2 tetrahedron antibodies are shown in c, d, e, and f. Each contains domains 1-4 and a dimer-forming polypeptide. The structures in a and b are standard Fc dimers. [Figure 44] Figure 44 shows the relative neutralization activity of ACE2 tetrahedron antibodies against live virus. Top panel: Demonstrates neutralization of live SARS-CoV-2 virus. Bottom panel: Demonstrates neutralization of NL63 (alpha coronavirus). ACE2 superdimer (6-05 SD) neutralizes the virus approximately three orders of magnitude better than the standard Fc fusion protein (ACE2Fc615). Also shown is purified dimer (6-05 D) and an unpurified mixture of dimer and superdimer (6-05 unpurified). [Figure 45] Figure 45 shows the pharmacokinetic curves of constructs 13-21 and 13-22. 13-21 corresponds to the wild-type ACE2-B13 superheterodimer tetrahedron antibody. 13-22 corresponds to the mutant ACE2-B13 superheterodimer tetrahedron antibody with the H378A mutation. [Figure 46] Figure 46 shows the pharmacokinetic curves of constructs 10-05 and 13-21. 10-05 corresponds to an ACE2-ACE2 superheterodimer tetrahedron antibody. 13-21 corresponds to a wt ACE2-B13 superheterodimer tetrahedron antibody. [Figure 47] Figure 47 shows the relative neutralizing activity of ACE2 core dimer (10-59), B-13 (12-09) and ACE2-B-13 superdimer (15-16). [Figures 48A-48P] In Figures 48A-48P, the relative neutralizing activity of various antibodies against 12 different variant viruses is compared against ACE2-B13 silent and ACE2-B13 active versions (represented by diamonds and circles). [Figure 49]Figure 49 shows the weight change in hamsters infected with South African SARS-CoV-2 virus treated with PBS control (PBS), 25 mg / kg REGN10933 and REG-CoV-2 cocktail (25 mg / kg each of Regeneron antibodies REGN10933 and REG108987), and 25 mg / kg of Fc-silenced ACE2-B13 (HB1516). [Figures 50A-50C] Figures 50A-C show the relative quantification of correct and mismatched pairs in a bispecific antibody. The main peak represents a correctly matched molecule. The arrows indicate the predicted positions of mismatched products. The main peak consists of two peaks due to residual O-glycans remaining after the deglycosylation procedure. [Figures 51A-51C] Figures 51A-C show the relative neutralizing activity of various antibodies against N439K and the South African variant. ACE2 superheterodimers (boxes) are listed in Tables 36, 37, and 38. DETAILED DESCRIPTION OF THE INVENTION

[0010] tetrahedral antibody The invention provides a tetrahedral antibody comprising a first, second, third and fourth domain, a) each of the first and second domains is selected from the group consisting of a Fab domain and an Fc domain; b) each of the first and second domains: i) a first polypeptide chain comprising a first N-terminus and a first C-terminus of the domain; and ii) a second polypeptide chain comprising a second N-terminus and a second C-terminus of said domain; Including, c) the first domain and the second domain are linked to each other by a non-peptidyl bond, wherein said non-peptidyl bond is i) (1) a covalent bond linking a first N-terminus of the first domain to a first N-terminus of the second domain; (2) a covalent bond linking the first C-terminus of the first domain and the first C-terminus of the second domain; (3) a covalent bond linking the first N-terminus of the first domain and the first C-terminus of the second domain; or (4) a covalent bond linking the first C-terminus of the first domain and the first N-terminus of the second domain; or ii) (1) a non-covalent bond between a first dimer-forming polypeptide attached to a first N-terminus of a first domain by a peptide bond or via a peptide linker and a second dimer-forming polypeptide attached to a first N-terminus of a second domain by a peptide bond or via a peptide linker; (2) a non-covalent bond between a first dimer-forming polypeptide attached to the first C-terminus of the first domain by a peptide bond or via a peptide linker and a second dimer-forming polypeptide attached to the first C-terminus of the second domain by a peptide bond or via a peptide linker; (3) a non-covalent bond between a first dimer-forming polypeptide attached to a first N-terminus of a first domain by a peptide bond or via a peptide linker and a second dimer-forming polypeptide attached to a first C-terminus of a second domain by a peptide bond or via a peptide linker; or (4) a non-covalent bond between a first dimer-forming polypeptide attached to a first C-terminus of the first domain by a peptide bond or via a peptide linker and a second dimer-forming polypeptide attached to a first N-terminus of the second domain by a peptide bond or via a peptide linker; and wherein the first and second dimer-forming polypeptides are not immunoglobulins, d) when the first domain is covalently linked at its first N-terminus to the second domain, the third domain is linked at its C-terminus to the second N-terminus of the first domain by a peptide bond or via a peptide linker; e) when a first domain is covalently linked at its first C-terminus to a second domain, said third domain is linked at its N-terminus to a second C-terminus of said first domain by a peptide bond or via a peptide linker; f) when the first domain is linked to the second domain via a first dimerization polypeptide linked to its first N-terminus, the third domain is linked at its C-terminus by a peptide bond or via a peptide linker, i) the N-terminus of the first dimer-forming polypeptide; ii) the second N-terminus of the first domain, or iii) the N-terminus of a third dimer-forming polypeptide, wherein the third dimer-forming polypeptide is linked at its C-terminus to the second N-terminus of the first domain by a peptide bond or via a peptide linker; binds to g) when the first domain is linked to the second domain via a first dimerization polypeptide linked to its first C-terminus, the third domain is linked at its N-terminus by a peptide bond or via a peptide linker, i) the C-terminus of the first dimer-forming polypeptide; ii) the second C-terminus of the first domain, or iii) the C-terminus of a third dimer-forming polypeptide, wherein the third dimer-forming polypeptide is linked at its N-terminus to the second C-terminus of the first domain by a peptide bond or via a peptide linker; binds to h) when the second domain is covalently linked at its first N-terminus to the first domain, the fourth domain is linked at its C-terminus to the second N-terminus of the second domain by a peptide bond or via a peptide linker; i) when the second domain is covalently linked at its first C-terminus to the first domain, the fourth domain is linked at its N-terminus to the second C-terminus of the second domain by a peptide bond or via a peptide linker; j) when the second domain is linked to the first domain via a second dimer-forming polypeptide linked to its first N-terminus, the fourth domain is linked at its C-terminus by a peptide bond or via a peptide linker, i) the N-terminus of the second dimer-forming polypeptide; ii) the second N-terminus of the second domain, or iii) the N-terminus of a fourth dimer-forming polypeptide, wherein the third dimer-forming polypeptide is linked at its C-terminus to the second N-terminus of the second domain by a peptide bond or via a peptide linker; binds to k) when the second domain is linked to the first domain via a second dimer-forming polypeptide linked to its first C-terminus, the fourth domain is linked at its N-terminus by a peptide bond or via a peptide linker, i) the C-terminus of the second dimer-forming polypeptide; ii) the second C-terminus of the second domain, or iii) the C-terminus of a fourth dimer-forming polypeptide, wherein the fourth dimer-forming polypeptide is linked at its N-terminus to the second C-terminus of the second domain by a peptide bond or via a peptide linker; binds to Tetrahedral antibodies are provided.

[0011] In a preferred embodiment, the non-peptidyl bond is a covalent bond connecting the first N-terminus of the first domain to the first N-terminus of the second domain. In this preferred embodiment, the third domain is linked at its C-terminus to the second N-terminus of the first domain by a peptide bond or via a peptide linker. Furthermore, in this preferred embodiment, the fourth domain is linked at its C-terminus to the second N-terminus of the second domain by a peptide bond or via a peptide linker.

[0012] In a preferred embodiment, the non-peptidyl bond is a non-covalent bond between a first dimer-forming polypeptide attached to the first N-terminus of the first domain by a peptide bond or via a peptide linker and a second dimer-forming polypeptide attached to the first N-terminus of the second domain by a peptide bond or via a peptide linker. In this preferred embodiment, the third domain is attached at its N-terminus to (a) the C-terminus of the first dimer-forming polypeptide or (b) the second C-terminus of the first domain by a peptide bond or via a peptide linker. Furthermore, in this preferred embodiment, the fourth domain is attached at its C-terminus to (a) the N-terminus of the second dimer-forming polypeptide or (b) the second N-terminus of the second domain by a peptide bond or via a peptide linker.

[0013] In an alternative embodiment, the non-peptidyl bond is a) a covalent bond linking a first C-terminus of the first domain to a first C-terminus of the second domain; b) a covalent bond linking the first C-terminus of the first domain to the first C-terminus of the second domain; or c) a covalent bond linking a first N-terminus of the first domain and a first C-terminus of the second domain; is.

[0014] In an alternative embodiment, the non-peptidyl bond is a) a non-covalent bond between a first dimer-forming polypeptide attached by a peptide bond or via a peptide linker to the first C-terminus of the first domain and a second dimer-forming polypeptide attached by a peptide bond or via a peptide linker to the first C-terminus of the second domain; b) a non-covalent bond between a first dimer-forming polypeptide attached to a first N-terminus of a first domain by a peptide bond or via a peptide linker and a second dimer-forming polypeptide attached to a first C-terminus of a second domain by a peptide bond or via a peptide linker; or c) a non-covalent bond between a first dimer-forming polypeptide attached by a peptide bond or via a peptide linker to a first C-terminus of the first domain and a second dimer-forming polypeptide attached by a peptide bond or via a peptide linker to a first N-terminus of the second domain; is.

[0015] In some aspects of the invention: a) the first domain is an Fc domain and the second domain is a Fab domain; b) the first and second domains are Fc domains; c) the first and second domains are Fab domains; d) the third and fourth domains are Fab domains; e) the third and / or fourth domain is selected from the group consisting of: (i) a secreted protein, and (ii) an extracellular domain of a transmembrane protein; f) the third domain is selected from the group consisting of (i) a secreted protein, and (ii) an extracellular domain of a transmembrane protein, and the fourth domain is a Fab domain; g) the third domain is IL-15; h) the third domain is IL-15 and the fourth domain is the IL-15Rα sushi domain; i) the third domain is IL-15 and the fourth domain is a Fab domain; j) the third and fourth domains are the two peptidase domains (PD) of ACE; k) the first and second domains are Fc domains and the third and fourth domains are selected from the group consisting of: i) a secreted protein, and (ii) an extracellular domain of a transmembrane protein; l) the first and second domains are Fc domains, the third domain is selected from the group consisting of (i) a secreted protein and (ii) an extracellular domain of a transmembrane protein, and the fourth domain is a Fab domain; m) the first and second domains are Fc domains and the third and fourth domains are Fab domains; n) the first and second domains are Fc domains and the third and fourth domains are peptidase domains (PDs) of ACE2; o) the first domain is an Fc domain and said second, third and fourth domains are Fab domains; p) the first domain is an Fc domain, the second domain is a Fab domain, the third domain is IL-15, and the fourth domain is an IL-15Rα sushi domain, or q) The first domain is an Fc domain, the second domain is an Fab domain, the third domain is IL-15, and the fourth domain is an Fab domain.

[0016] covalent bond In embodiments of the invention, the non-peptidyl bond between the first domain and the second domain is a covalent bond.

[0017] In embodiments of the invention, the covalent bond has the structure:

[0018] [ka]

[0019] wherein R2 is an organic structure connected to one of the first domain or the second domain, R4 is an organic structure connected to the remainder of the first domain or the second domain, and R1 is H or a portion of an additional cyclic structure, which may include R1 or a portion of R1, R2 or a portion of R2, and the carbon between R2 and the alkene double bond. Includes:

[0020] In embodiments of the invention, R1 and R2 are joined by at least one direct bond; a) a portion of R1, b) a portion of R2, c) the carbon between R2 and the alkene double bond, and d) Alkene double bond The ring structure includes:

[0021] In embodiments of the present invention, R1 is optionally substituted at any position.

[0022] [ka]

[0023] is selected from the group consisting of:

[0024] In embodiments of this invention, the carbon between R2 and the alkene double bond is directly bonded to R2 through a double bond and a single bond.

[0025] In embodiments of the present invention, R2 is optionally substituted at any position.

[0026] [ka]

[0027] [In the formula, R2 is bonded to R1 through its nitrogen atom, J is a bond or an organic structure comprising or consisting of a chain of 2, 3, 4, 5, 6, 7, 8, 9, 10 or more moieties selected from the group consisting of [PEG(y)]z, polyalkylene glycol, polyoxyalkylated polyol, polyvinyl alcohol, polyvinyl alkyl ether, poly(lactic acid), poly(lactic-glycolic acid), polysaccharide, branching residue, C1-C4 alkyl, amine, sulfur, oxygen, succinimide, maleimide, glycerin, triazole, isoxazolidine, C1-C4 acyl, succinyl, malonyl, glutaryl, phthalyl, adipoyl, and amino acid, wherein [PEG(y)]z is

[0028] [ka]

[0029] (y is 1-100, z is 1-10) is.

[0030] In some embodiments of the present invention, R1 and R2 taken together may be substituted at any position.

[0031] [ka]

[0032] [In the formula, J is a bond or an organic structure comprising or consisting of a chain of 2, 3, 4, 5, 6, 7, 8, 9, 10 or more moieties selected from the group consisting of [PEG(y)]z, polyalkylene glycol, polyoxyalkylated polyol, polyvinyl alcohol, polyvinyl alkyl ether, poly(lactic acid), poly(lactic-glycolic acid), polysaccharide, branching residue, C1-C4 alkyl, amine, sulfur, oxygen, succinimide, maleimide, glycerin, triazole, isoxazolidine, C1-C4 acyl, succinyl, malonyl, glutaryl, phthalyl, adipoyl, and amino acid, wherein [PEG(y)]z is

[0033] [ka]

[0034] (y is 1-100, z is 1-10) is.

[0035] In embodiments of this invention, the covalent bond may be substituted at any position, with the structure:

[0036] [ka]

[0037] [In the formula, J is a bond or an organic structure comprising or consisting of a chain of 2, 3, 4, 5, 6, 7, 8, 9, 10 or more moieties selected from the group consisting of [PEG(y)]z, polyalkylene glycol, polyoxyalkylated polyol, polyvinyl alcohol, polyvinyl alkyl ether, poly(lactic acid), poly(lactic-glycolic acid), polysaccharide, branching residue, C1-C4 alkyl, amine, sulfur, oxygen, succinimide, maleimide, glycerin, triazole, isoxazolidine, C1-C4 acyl, succinyl, malonyl, glutaryl, phthalyl, adipoyl, and amino acid, wherein [PEG(y)]z is

[0038] [ka]

[0039] (y is 1-100, z is 1-10) Includes.

[0040] In embodiments of this invention, the covalent bond has the structure:

[0041] [ka]

[0042] [In the formula, a) X a teeth, i) a chemical structure containing cyclooctane fused with dihydropyridazine; ii) a chemical structure comprising cyclooctene fused with pyridazine; a chemical structure selected from the group consisting of b) R a is a bond or X a to the first N-terminus of the first domain, c) R b is a bond or X ato the first N-terminus of the second domain] Includes.

[0043] In some embodiments of the invention, X a The structure:

[0044] [ka]

[0045] [In the formula, R c is H, alkyl, aryl or a tautomer thereof] Includes.

[0046] In embodiments of this invention, the covalent bond has the structure:

[0047] [ka]

[0048] [In the formula, R c is H, alkyl, aryl or a tautomer thereof] Includes.

[0049] In embodiments of the present invention, R a and R b is independently a bond or a chemical structure comprising or consisting of a chain of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more moieties, each moiety being independently selected from the group consisting of [PEG(y)]z, polyalkylene glycol, polyoxyalkylated polyol, polyvinyl alcohol, polyvinyl alkyl ether, poly(lactic acid), poly(lactic-co-glycolic acid), polysaccharide, branched residue, C1-C 10 Alkyl, C3-C 10 Cycloalkanes, C2-C 10 Alkenes, C5-C 10Cycloalkene, amine, sulfur, oxygen, succinimide, maleimide, glycerin, triazole, isoxazolidine, C2-C5 acyl, C2-C5 acylamino, C2-C5 acyloxy, succinyl, malonyl, glutaryl, phthalyl, adipoyl, amino acid, aryl group, heteroaryl group, carbamate, chemical structure having cyclooctane fused with dihydropyridazine, chemical structure having cyclooctene fused with triazole, chemical structure having cyclooctene fused with isoxazolidine, dibenzocyclooctene, dibenzoazacyclooctene,

[0050] [ka]

[0051] wherein X1 is CH or N, X2 is CH2 or a carbonyl group, R5 is an aryl or alkyl group, and [PEG(y)]z is

[0052] [ka]

[0053] (y is 1-100, z is 1-10) is selected from the group consisting of:

[0054] In embodiments of the present invention, R a and / or R b teeth, a) containing a [PEG(y)]z group; b) containing a polyalkylene glycol, polyoxyalkylated polyol, polyvinyl alcohol, polyvinyl alkyl ether, polylactic acid, polylactic-glycolic acid or polysaccharide group; c) containing a C1-C4 alkyl group; d) containing succinimide; e) containing amines; f) containing succinyl, malonyl, glutaryl, phthalyl or adipoyl; g) Contains malonyl; h) contains amino acids; i) Contains cysteine; j) contains lysine; k) [PEG(y)]z, polyalkylene glycol, polyoxyalkylated polyol, polyvinyl alcohol, polyvinyl alkyl ether, poly(lactic acid), poly(lactic-glycolic acid), polysaccharide, branched residue, C1-C 10 Alkyl, C3-C 10 Cycloalkanes, C2-C 10 Alkenes, C5-C 10 Cycloalkene, amine, sulfur, oxygen, succinimide, maleimide, glycerin, triazole, isoxazolidine C2-C5 acyl, C2-C5 acylamino, C2-C5 acyloxy, succinyl, malonyl, glutaryl, phthalyl, adipoyl, amino acid, aryl group, heteroaryl group, carbamate, chemical structure having cyclooctane fused with dihydropyridazine, chemical structure having cyclooctene fused with triazole, chemical structure having cyclooctene fused with isoxazolidine, dibenzocyclooctene, dibenzoazacyclooctene,

[0055] [ka]

[0056] consisting of a chain of three moieties selected from the group consisting of: l) [PEG(y)]z, polyalkylene glycol, polyoxyalkylated polyol, polyvinyl alcohol, polyvinyl alkyl ether, poly(lactic acid), poly(lactic-glycolic acid), polysaccharide, branched residue, C1-C 10 Alkyl, C3-C 10 Cycloalkanes, C2-C 10 Alkenes, C5-C 10Cycloalkene, amine, sulfur, oxygen, succinimide, maleimide, glycerin, triazole, isoxazolidine, C2-C5 acyl, C2-C5 acylamino, C2-C5 acyloxy, succinyl, malonyl, glutaryl, phthalyl, adipoyl, amino acid, aryl group, heteroaryl group, carbamate, chemical structure having cyclooctane fused with dihydropyridazine, chemical structure having cyclooctene fused with triazole, chemical structure having cyclooctene fused with isoxazolidine, dibenzocyclooctene, dibenzoazacyclooctene,

[0057] [ka]

[0058] consisting of a chain of four moieties selected from the group consisting of: m) [PEG(y)]z, polyalkylene glycol, polyoxyalkylated polyol, polyvinyl alcohol, polyvinyl alkyl ether, poly(lactic acid), poly(lactic-glycolic acid), polysaccharide, branched residue, C1-C 10 Alkyl, C3-C 10 Cycloalkanes, C2-C 10 Alkenes, C5-C 10 Cycloalkene, amine, sulfur, oxygen, succinimide, maleimide, glycerin, triazole, isoxazolidine, C2-C5 acyl, C2-C5 acylamino, C2-C5 acyloxy, succinyl, malonyl, glutaryl, phthalyl, adipoyl, amino acid, aryl group, heteroaryl group, carbamate, chemical structure having cyclooctane fused with dihydropyridazine, chemical structure having cyclooctene fused with triazole, chemical structure having cyclooctene fused with isoxazolidine, dibenzocyclooctene, dibenzoazacyclooctene,

[0059] [ka]

[0060] consisting of a chain of five moieties selected from the group consisting of: n) containing a [PEG(y)]z group attached to lysine; o) containing a C1-C4 acyl group linked to a succinimide group; p) containing lysine bound to C1-C4 acyl; q) containing a glutaryl-linked [PEG(y)]z group; r) [PEG(y)]z, C2-C5 acyl, succinyl, malonyl, glutaryl, amino acid, chemical structure having cyclooctane fused with dihydropyridazine, chemical structure having cyclooctene fused with triazole, chemical structure having cyclooctene fused with isoxazolidine, dibenzocyclooctene, dibenzoazacyclooctene,

[0061] [ka]

[0062] wherein X1 is CH or N, X2 is CH2 or a carbonyl group, R5 is an aryl or alkyl group, and [PEG(y)]z is

[0063] [ka]

[0064] (wherein y is 1 to 100, and z is 1 to 10). consisting of a chain of three, four or five moieties selected from the group consisting of: s) is a bond; t) is cysteine; u) It has a linear structure; v) It has a branched chain structure; w) Structure:

[0065] [ka]

[0066] having; x)

[0067] [ka]

[0068] [In the formula, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 1 to 30, 1 to 40, or 1 to 50] is; y)

[0069] [ka]

[0070] [In the formula, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 1 to 30, 1 to 40, or 1 to 50; x is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 1 to 30, 1 to 40, or 1 to 50; and z is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 1 to 30, 1 to 40, or 1 to 50] is; z)

[0071] [ka]

[0072] [In the formula, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 1 to 30, 1 to 40, or 1 to 50, and z is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 1 to 30, 1 to 40, or 1 to 50] or aa)

[0073] [ka]

[0074] [In the formula, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 1 to 30, 1 to 40, or 1 to 50] is.

[0075] In embodiments of the present invention, R a and / or R b Here is the part:

[0076] [ka]

[0077] [Wherein, X1 is CH or N, and X2 is CH2 or a carbonyl group] Includes.

[0078] non-covalent bond In embodiments of the invention, the non-peptidyl bond is a non-covalent bond between a first dimer-forming polypeptide linked to the first domain and a second dimer-forming polypeptide linked to the second domain.

[0079] In embodiments of the invention, the first and second dimer-forming polypeptides are a) a dimerization domain of an extracellular protein dimer, and b) dimerization domains of intracellular protein dimers; is selected from the group consisting of:

[0080] In embodiments of the invention, the first and second dimer-forming polypeptides are a) leucine zipper domain, b) collectrin-like domain (CLD), c) collectrin domain (CD), d) the CD8α extracellular domain, and e) CD8β extracellular domain, is selected from the group consisting of:

[0081] In a preferred embodiment of the tetrahedral antibody of the invention, the first and second dimerizing polypeptides are selected from a collectrin-like domain (CLD) and a collectrin domain (CD), preferably a collectrin-like domain (CLD).

[0082] In some aspects of the invention: a) the first dimer-forming polypeptide is the same as the second dimer-forming polypeptide; b) The dimer-forming polypeptide forms a homodimer.

[0083] In some aspects of the invention: a) the first dimer-forming polypeptide is different from the second dimer-forming polypeptide; b) the first and second dimer-forming polypeptides form a heterodimer.

[0084] In several aspects of the present invention, the first and second dimer-forming polypeptides form heterodimers, the dimer-forming polypeptides are collectrin-like domains (CLDs), and the CLDs contain substitutions that prevent the CLD dimer-forming polypeptides from forming homodimers, preferably the substitutions are made at Arg652, Arg710, Tyr641, Tyr633, Asn638, Glu639, Gln653, Asn636, Ser709, Asp713 and / or Arg716, more preferably Tyr641 and Tyr633 are substituted with positively charged amino acids lysine, arginine or histidine, and Arg652 and Arg710 are substituted with negatively charged amino acids glutamic acid or aspartic acid, or with the positively charged amino acid lysine.

[0085] In several aspects of the present invention, the first and second dimer-forming polypeptides form a heterodimer, the dimer-forming polypeptide is collectrin, and the collectrin dimer-forming polypeptide comprises a substitution that prevents the collectrin dimer-forming polypeptide from forming a homodimer, preferably the substitution is made at Arg59, Arg111, Tyr48 and / or Tyr40, more preferably Tyr48 and / or Tyr40 are substituted with a positively charged amino acid lysine, arginine or histidine, and Arg59 and / or Arg111 are substituted with a negatively charged amino acid glutamic acid or aspartic acid, or a positively charged amino acid lysine.

[0086] In embodiments, the dimerizing polypeptide is a collectrin-like domain (CLD), and the CLD comprises a substitution that promotes heterodimerization of the CLD dimerizing polypeptide, preferably: a) Tyr633 of either the first or second CLD dimer-forming polypeptide is preferably substituted with either a positively charged amino acid or a negatively charged amino acid; b) Tyr641 of either the first or second CLD dimer-forming polypeptide is preferably substituted with either a positively charged amino acid or a negatively charged amino acid; c) Arg652 of either the first or second CLD dimer-forming polypeptide is preferably substituted with either a positively charged amino acid or a negatively charged amino acid; d) Arg710 of either the first or second CLD dimer-forming polypeptide is preferably substituted with either a positively charged amino acid or a negatively charged amino acid; e) Ser709 of either the first or second CLD dimer-forming polypeptide is preferably substituted with either a positively charged amino acid or a negatively charged amino acid; and / or f) Asp713 of either the first or second CLD dimer-forming polypeptide is preferably substituted with either a positively charged amino acid or a negatively charged amino acid.

[0087] In some embodiments, the dimer-forming polypeptide is collectrin, and the collectrin dimer-forming polypeptide comprises a substitution that promotes heterodimerization of the collectrin dimer-forming polypeptide, preferably a) Tyr40 of either the first or second collectrin dimer-forming polypeptide is preferably substituted with either a positively charged amino acid or a negatively charged amino acid; b) Tyr48 of either the first or second collectrin dimer-forming polypeptide is preferably substituted with either a positively charged amino acid or a negatively charged amino acid; c) Arg59 of either the first or second collectrin dimer-forming polypeptide is preferably substituted with either a positively charged amino acid or a negatively charged amino acid; and / or d) Arg111 of either the first or second collectrin dimer-forming polypeptide is preferably substituted with either a positively charged amino acid or a negatively charged amino acid.

[0088] In embodiments, the dimerizing polypeptide is a collectrin-like domain (CLD), and the CLD comprises a substitution that promotes heterodimerization of the CLD dimerizing polypeptide, preferably: a) Tyr633 of the first CLD dimer-forming polypeptide is substituted with either a positively charged amino acid or a negatively charged amino acid, and Arg710 of the second CLD dimer-forming polypeptide is substituted with either the remaining positively charged amino acid or the remaining negatively charged amino acid; b) Tyr633 of the second CLD dimer-forming polypeptide is substituted with one of a positively charged amino acid or a negatively charged amino acid, and Arg710 of the first CLD dimer-forming polypeptide is substituted with one of the remaining positively charged amino acid or the remaining negatively charged amino acid; c) Tyr641 of the first CLD dimer-forming polypeptide is substituted with one of a positively charged amino acid or a negatively charged amino acid, and Arg652 of the second CLD dimer-forming polypeptide is substituted with one of the remaining positively charged amino acid or the remaining negatively charged amino acid; d) Tyr641 of the second CLD dimer-forming polypeptide is substituted with one of a positively charged amino acid or a negatively charged amino acid, and Arg652 of the first CLD dimer-forming polypeptide is substituted with one of the remaining positively charged amino acid or the remaining negatively charged amino acid; e) Arg652 of the first CLD dimer-forming polypeptide is substituted with either a positively charged amino acid or a negatively charged amino acid, and Arg638 of the second CLD dimer-forming polypeptide is substituted with either the remaining positively charged amino acid or the remaining negatively charged amino acid; f) Arg652 of the second CLD dimer-forming polypeptide is substituted with either a positively charged amino acid or a negatively charged amino acid, and Arg638 of the first CLD dimer-forming polypeptide is substituted with either the remaining positively charged amino acid or the remaining negatively charged amino acid; g) Arg710 of the first CLD dimer-forming polypeptide is substituted with either a positively charged amino acid or a negatively charged amino acid, and Glu639 of the second CLD dimer-forming polypeptide is substituted with either the remaining positively charged amino acid or the remaining negatively charged amino acid; h) Arg710 of the second CLD dimer-forming polypeptide is substituted with either a positively charged amino acid or a negatively charged amino acid, and Glu639 of the first CLD dimer-forming polypeptide is substituted with either the remaining positively charged amino acid or the remaining negatively charged amino acid; i) Ser709 of the first CLD dimer-forming polypeptide is substituted with either a positively charged amino acid or a negatively charged amino acid, and Arg716 of the second CLD dimer-forming polypeptide is substituted with either the remaining positively charged amino acid or the remaining negatively charged amino acid; j) Ser709 of the second CLD dimer-forming polypeptide is substituted with either a positively charged amino acid or a negatively charged amino acid, and Arg716 of the first CLD dimer-forming polypeptide is substituted with either the remaining positively charged amino acid or the remaining negatively charged amino acid; k) Asp713 of the first CLD dimer-forming polypeptide is substituted with either a positively charged amino acid or a negatively charged amino acid, and Arg716 of the second CLD dimer-forming polypeptide is substituted with either the remaining positively charged amino acid or the remaining negatively charged amino acid; and / or l) Agr713 of the second CLD dimer-forming polypeptide is substituted with either a positively charged amino acid or a negatively charged amino acid, and Arg716 of the first CLD dimer-forming polypeptide is substituted with either a positively charged amino acid or the remaining negatively charged amino acid.

[0089] In some embodiments, the dimer-forming polypeptide is collectrin, and the collectrin dimer-forming polypeptide comprises a substitution that promotes heterodimerization of the collectrin dimer-forming polypeptide, preferably a) Tyr40 of the first collectrin dimer-forming polypeptide is substituted with either a positively charged amino acid or a negatively charged amino acid, and Arg111 of the second collectrin dimer-forming polypeptide is substituted with either the remaining positively charged amino acid or the remaining negatively charged amino acid; b) Tyr40 of the second collectrin dimer-forming polypeptide is substituted with either a positively charged amino acid or a negatively charged amino acid, and Arg111 of the first collectrin dimer-forming polypeptide is substituted with either the remaining positively charged amino acid or the remaining negatively charged amino acid; c) Tyr48 of the first collectrin dimer-forming polypeptide is substituted with either a positively charged amino acid or a negatively charged amino acid, and Arg59 of the second collectrin dimer-forming polypeptide is substituted with either the remaining positively charged amino acid or the remaining negatively charged amino acid; and / or d) Tyr48 of the second collectrin dimer-forming polypeptide is substituted with either a positively charged amino acid or a negatively charged amino acid, and Arg59 of the first collectrin dimer-forming polypeptide is substituted with either a positively charged amino acid or the remaining negatively charged amino acid.

[0090] In some embodiments of the invention, the first and second dimer-forming polypeptides form a heterodimer; a) the first and second dimer-forming polypeptides are i) T cell receptor alpha and T cell receptor beta extracellular domains; ii) T cell receptor gamma and T cell receptor extracellular domain; iii) MHC class I alpha extracellular domain and beta2 microglobulin; iv) MHC class II α and MHC class II β extracellular domains, and v) CD8α and CD8β extracellular domains, selected from the group consisting of b) the first dimer-forming polypeptide is different from the second dimer-forming polypeptide; c) The first and second dimer-forming polypeptides form a heterodimer.

[0091] In some embodiments of the invention, the first and second dimer-forming polypeptides, when both are present, form homodimers in less than 30%, 20%, 10%, 5%, 4%, 3%, 2%, or 1% of the polypeptides.

[0092] In embodiments of the invention, the first dimerizing polypeptide comprises a disulfide bond with one or more second dimerizing polypeptides, preferably: a) the one or more disulfide bonds are at the interface between the first dimer-forming polypeptide and the second dimer-forming polypeptide, more preferably: i) when the first and second dimer-forming polypeptides are collectrin-like domains or collectrins, the one or more disulfide bonds are in the second and fourth helices of the collectrin-like domain or the corresponding regions of collectrin, or b) one or more disulfide bonds are between an immunoglobulin hinge region or a portion thereof comprising at least one cysteine ​​added to the N-terminus and / or C-terminus of a first dimer-forming polypeptide and an immunoglobulin hinge region or a portion thereof comprising at least one cysteine ​​added to the N-terminus and / or C-terminus of a second dimer-forming polypeptide, the hinge region being added to the first and second dimer-forming polypeptides directly or via a peptide linker, and preferably the first and second dimer-forming polypeptides are collectrin-like domains or collectrins.

[0093] domain In some aspects of the invention: a) the third and fourth domains are peptidase domains (PDs) of ACE2; b) The first and second dimerizing polypeptides are each a collectrin-like domain (CLD) of said ACE2.

[0094] In an embodiment in which the first and second domains are Fc domains, each polypeptide chain of the tetrahedral antibody comprises any one of the amino acid sequences shown in SEQ ID NOs: 74 to 119, more preferably the amino acid sequence shown in SEQ ID NO: 78.

[0095] In embodiments of the invention, the first and second domains are Fc domains.

[0096] In some aspects of the invention: a) the first and second domains are Fc domains and the third domain is a first type of Fab domain; b) the first and second domains are Fc domains and the third and fourth domains are independently selected from the group consisting of a first type of Fab domain and a second type of Fab domain; c) the first domain is an Fc domain and the second and third domains are independently selected from the group consisting of a first type of Fab domain and a second type of Fab domain; or d) the first domain is an Fc domain and the second, third, and fourth domains are independently selected from the group consisting of a first type of Fab domain, a second type of Fab domain, and a third type of Fab domain.

[0097] In embodiments of the invention, the tetrahedral antibody further comprises a fifth domain, the fifth domain being connected at its C-terminus by a peptide bond or via a peptide linker: a) the N-terminus of the first dimer-forming polypeptide; b) the second N-terminus of the first domain, or c) the N-terminus of a third dimer-forming polypeptide, wherein the third dimer-forming polypeptide is linked at its C-terminus to the second N-terminus of the first domain by a peptide bond or via a peptide linker; Combine with.

[0098] In some aspects of the invention: a) the first and second domains are Fc domains and the fifth domain is a first type of Fab domain; b) the first and second domains are Fc domains and the third and fourth domains are independently selected from the group consisting of a first type of Fab domain and a second type of Fab domain; c) the first and second domains are Fc domains and the fourth and fifth domains are independently selected from the group consisting of a first type of Fab domain and a second type of Fab domain; d) the first and second domains are Fc domains, and the third, fourth, and fifth domains are independently selected from the group consisting of a first type of Fab domain, a second type of Fab domain, and a third type of Fab domain; e) the first domain is an Fc domain and the second and fifth domains are independently selected from the group consisting of a first type of Fab domain and a second type of Fab domain; f) the first domain is an Fc domain and the second, third, and fifth domains are independently selected from the group consisting of a first type of Fab domain, a second type of Fab domain, and a third type of Fab domain; g) the first domain is an Fc domain and the second, fourth, and fifth domains are independently selected from the group consisting of a first type of Fab domain, a second type of Fab domain, and a third type of Fab domain; or h) the first domain is an Fc domain and the second, third, fourth and fifth domains are independently selected from the group consisting of a first type of Fab domain, a second type of Fab domain, a third type of Fab domain and a fourth type of Fab domain.

[0099] Tetrahedral antibodies further comprising a fifth and / or sixth domain In embodiments of the invention, the tetrahedral antibody further comprises a fifth and / or sixth domain, a) the first domain is linked to the second domain via a first dimerization polypeptide linked to its first N-terminus; i) the fifth domain is connected at its C-terminus by a peptide bond or via a peptide linker to: (1) the N-terminus of the first dimer-forming polypeptide; (2) the second N-terminus of the first domain, or (3) the N-terminus of a third dimer-forming polypeptide, wherein the third dimer-forming polypeptide is linked at its C-terminus to the second N-terminus of the first domain by a peptide bond or via a peptide linker; binds to b) the first domain is linked to the second domain via a first dimerization polypeptide linked to its first C-terminus; i) the fifth domain is connected at its N-terminus by a peptide bond or via a peptide linker to: (1) the C-terminus of the first dimer-forming polypeptide; (2) the second C-terminus of the first domain, or (3) the C-terminus of a third dimer-forming polypeptide, wherein the third dimer-forming polypeptide is linked at its N-terminus to the second C-terminus of the first domain by a peptide bond or via a peptide linker; binds to c) the second domain binds to the first domain via a second dimerization polypeptide linked to its first N-terminus; i) the sixth domain is connected at its C-terminus by a peptide bond or via a peptide linker, (1) the N-terminus of the second dimer-forming polypeptide; (2) the second N-terminus of the second domain, or (3) the N-terminus of a fourth dimer-forming polypeptide, wherein the fourth dimer-forming polypeptide is linked at its C-terminus to the second N-terminus of the second domain by a peptide bond or via a peptide linker; or d) the second domain is linked to the first domain via a second dimerization polypeptide linked to its first C-terminus; i) the sixth domain is connected at its N-terminus by a peptide bond or via a peptide linker, (1) the C-terminus of the second dimer-forming polypeptide; (2) the second C-terminus of the second domain, or ii) the C-terminus of a fourth dimer-forming polypeptide, wherein the fourth dimer-forming polypeptide is linked at its N-terminus to the second C-terminus of the second domain by a peptide bond or via a peptide linker; Combine with.

[0100] In some aspects of the invention: a) the first and second domains are Fc domains and the fifth domain is a first type of Fab domain; b) the first and second domains are Fc domains and the third and fourth domains are independently selected from the group consisting of a first type of Fab domain and a second type of Fab domain; c) the first and second domains are Fc domains and the fourth and fifth domains are independently selected from the group consisting of a first type of Fab domain and a second type of Fab domain; d) the first and second domains are Fc domains, and the third, fourth, and fifth domains are independently selected from the group consisting of a first type of Fab domain, a second type of Fab domain, and a third type of Fab domain; e) the first domain is an Fc domain and the second and fifth domains are independently selected from the group consisting of a first type of Fab domain and a second type of Fab domain; f) the first domain is an Fc domain and the second, third, and fifth domains are independently selected from the group consisting of a first type of Fab domain, a second type of Fab domain, and a third type of Fab domain; g) the first domain is an Fc domain and the second, fourth, and fifth domains are independently selected from the group consisting of a first type of Fab domain, a second type of Fab domain, and a third type of Fab domain; or h) the first domain is an Fc domain and the second, third, fourth and fifth domains are independently selected from the group consisting of a first type of Fab domain, a second type of Fab domain, a third type of Fab domain and a fourth type of Fab domain.

[0101] Tetrahedron antibody containing ACE2 PD In some aspects of the invention: a) the third, fourth, fifth and sixth domains are the PDs of the ACE2, respectively, and the dimerization polypeptides are the CLDs of the ACE2, respectively; b) the first and second domains are Fc domains, the third, fourth, fifth and sixth domains are PDs of the ACE2, and the dimerization polypeptides are CLDs of the ACE2, respectively, and preferably the first and second domains are linked to their respective dimerization polypeptides via peptide linkers; c) the third and fourth domains are each a PD of the ACE2, the fifth and sixth domains are each a Fab domain, and the dimerization polypeptides are each a CLD of the ACE2; d) the first and second domains are Fc domains, the third and fourth domains are PDs of the ACE2, the fifth and sixth domains are Fab domains, and the dimerizing polypeptides are CLDs of the ACE2, respectively; and preferably, the first and second domains are linked to their respective dimerizing polypeptides via peptide linkers; e) the third and fourth domains are each a Fab domain, the fifth and sixth domains are each a PD of the ACE2, and the dimerization polypeptides are each a CLD of the ACE2; f) the first and second domains are Fc domains, the third and fourth domains are Fab domains, the fifth and sixth domains are PDs of the ACE2, and the dimerizing polypeptides are CLDs of the ACE2, and preferably the first and second domains are linked to their respective dimerizing polypeptides via peptide linkers, or g) the first and second domains are Fc domains, the third and fourth domains are PDs of the ACE2, the fifth and sixth domains are Fab domains, the dimerization polypeptides are CLDs of the ACE2, respectively, and the first and second domains are linked to their respective dimerization polypeptides via peptide linkers; Preferably, the domains and linkers are characterized by one or more or all of the following properties: i) said Fc domain is characterized by one or more or all of the following properties: (1) It is a heterodimer. (2) the Fc domain of IgG1; (3) The Fc domain comprises silencing mutations that render it devoid of Fcγ receptor binding activity, and preferably, the mutations are one of the following combinations of mutations: a. P329G / L234A / L235A(PGLALA), b. L234A / L235A(LALA), c. P331S / L234A / L235A, d. L234F / L235E / P331S, and e. L234F / L235E / P329G, (4) comprising a mutation that enhances the activity of FcRn, preferably the mutation extends the half-life of the tetrahedral antibody, preferably the mutation is: a. The following mutation combination: L309D / Q311H / N434S(DHS), b. The following mutation combination: S239D / I298E, c. S239D, preferably the other Fc domain of said tetrahedral antibody, if present, contains the I298E mutation; or d. I298E, preferably the other Fc domain of said tetrahedral antibody, if present, comprises a S239D mutation; and (5) a mutation that eliminates its protein A binding site, preferably the mutation is H435R / Y436F (HY / RF); ii) the ACE2 peptidase domain contains a mutation that inhibits its angiotensin-converting enzyme activity, preferably the mutation is the H378A mutation; iii) the Fab domain is a chimeric Fab domain comprising a mouse variable region; iv) each of said peptide linkers is 23 amino acids in length and is derived from the stalk region of a TNF receptor, preferably said TNF receptor is TNF receptor 1B, and even more preferably said peptide linker consists of the amino acid sequence set forth in SEQ ID NO: 4468; v) The domains and peptide linkers are formed from two or three different polypeptide chains.

[0102] In some aspects of the invention: a) The third and fourth domains are the PDs of ACE2, respectively; b) the fifth domain, if present, is linked at its C-terminus by a peptide bond or via a peptide linker to the N-terminus of a third dimer-forming polypeptide, which is linked at its C-terminus by a peptide bond or via a peptide linker to the second N-terminus of the first domain; c) the sixth domain, if present, is linked at its C-terminus by a peptide bond or via a peptide linker to the N-terminus of the fourth dimer-forming polypeptide, which is linked at its C-terminus by a peptide bond or via a peptide linker to the second N-terminus of the second domain; and d) The first, second, third and fourth dimer-forming polypeptides are each a CLD of ACE2.

[0103] In some embodiments of the invention, the ACE2 PD comprises or consists of amino acids 18 to 615 of the ACE2 protein or a portion thereof.

[0104] In embodiments of the invention, the CLD of ACE2 comprises or consists of amino acids 616 to 740 of the ACE2 protein or a portion thereof.

[0105] In embodiments of the invention, the PD of ACE2 is catalytically active.

[0106] In embodiments of the invention, the PD of ACE2 is catalytically inactive.

[0107] In embodiments of the invention, the ACE2 PD comprises an R273Q or H378A mutation.

[0108] In embodiments of the invention, the Fc domain lacks Fcγ receptor binding activity.

[0109] In embodiments of the invention, the Fc domain comprises: a) P329G, L234A and L235A mutations (PGLALA), b) L234A and L235A mutations (LALA), c) P331S mutation, L234A mutation, and L235A mutation; d) L234F mutation, L235E mutation and P331S mutation, or e) L234F mutation, L235E mutation, and P329G mutation, Includes:

[0110] In some embodiments of the invention, the Fc domain comprises mutations that enhance the activity and / or half-life of FcRn. In some embodiments of the invention, the mutations include a combination of the following mutations: a) M252Y / S254T / T256E(YTE), b) L309D / Q311H / N434S(DHS), c) M428L / N434S(LS) is selected from.

[0111] In aspects of the invention, the mutation is: a) S239D / I298E, b) S239D, preferably I298E mutations in the remaining Fc domain of the tetrahedral antibody, if present, or c) I298E, preferably containing the S239D mutation, if present, in the remaining Fc domain of the tetrahedral antibody; is selected from.

[0112] In embodiments of the invention, the Fc domain comprises a mutation that eliminates its Protein A binding site, preferably the mutation is H435R / Y436F (HY / RF).

[0113] In embodiments of the invention, the Fab domain is a chimeric Fab domain comprising a murine variable region.

[0114] In embodiments of the invention, the tetrahedral antibody comprises one or more Fab domains, wherein the one or more Fab domains comprise the complementarity determining regions (CDRs) of the Fab domain of the B13A antibody.

[0115] In several aspects of the invention, one or more Fab domains comprise the VH and VL regions of the B13A antibody, and preferably the VH and VL regions comprise the amino acid sequences set forth in SEQ ID NOs: 463 and 464, or variants thereof having at least 90%, preferably at least 95%, more preferably at least 98% identity thereto.

[0116] In embodiments of the invention, one or more of the Fab domains are humanized.

[0117] In some embodiments of the present invention, the first and second domains are Fc domains, the third and fourth domains are ACE2 PDs, the fifth and sixth domains are Fab domains, the dimerizing polypeptides are ACE2 CLDs, the first and second domains are linked to their respective dimerizing polypeptides via peptide linkers, and the domains and peptide linkers of the tetrahedral antibody are formed by three different polypeptide chains. In a preferred embodiment, the three different polypeptide chains are designated H1, L2, and H2, a) the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 524, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 465, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 535, or the H1, L2 and H2 chains are variants having at least 90%, preferably 95%, and most preferably 98% identity to said sequences; b) the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 473, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 465, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 485, or the H1, L2 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences; c) the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 526, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 465, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 527, or the H1, L2 and H2 chains are variants having at least 90%, preferably 95%, and most preferably 98% identity to said sequences; d) the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 514, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 465, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 528, or the H1, L2 and H2 chains are variants having at least 90%, preferably 95%, and most preferably 98% identity to said sequences; e) the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 529, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 465, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 530, or the H1, L2 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences; f) the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 518, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 465, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 531, or the H1, L2 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences; g) the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 532, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 465, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 533, or the H1, L2 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences; or h) the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 522, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 465, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 534, or the H1, L2 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences.

[0118] In the above embodiment, the C-terminal portions of the H1 and H2 chains pair with each other to form domains 1 and 2, the N-terminal portion of the H1 chain is the ACE2 PD (domains 3 and 4), and the N-terminal portion of the H2 chain pairs with the L2 chain to form domains 5 and 6. Furthermore, the H1 chain contains a CLD dimerization domain between the portion paired with the H2 chain and the ACE2 PD. Figure 31B shows a schematic diagram of the structure of such a tetrahedral antibody, with the chains in the figure, from left to right, being L2, H2, H1, H1, H2, and L2. The invention also provides a method for producing a tetrahedral antibody, comprising recombinantly expressing four different polypeptide chains of this embodiment in a host cell.

[0119] In some embodiments of the present invention, the first and second domains are Fc domains, the third, fourth, fifth and sixth domains are ACE2 PDs, the dimerizing polypeptides are ACE2 CLDs, the first and second domains are linked to their respective dimerizing polypeptides via peptide linkers, and the domains and peptide linkers of the tetrahedral antibody are formed by two different polypeptide chains. In a preferred embodiment, the two different polypeptide chains are designated H1 and H2, a) the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 509 and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 510, or the H1 and H2 chains are variants having at least 90%, preferably 95%, and most preferably 98% identity to said sequences; b) the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 512 and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 513, or the H1 and H2 chains are variants having at least 90%, preferably 95%, and most preferably 98% identity to said sequences; c) the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 516 and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 517, or the H1 and H2 chains are variants having at least 90%, preferably 95%, and most preferably 98% identity to said sequences; d) the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 520 and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 521, or the H1 and H2 chains are variants having at least 90%, preferably 95%, and most preferably 98% identity to said sequences; e) the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 542 and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 543, or the H1 and H2 chains are variants having at least 90%, preferably 95%, and most preferably 98% identity to said sequences; f) the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 545 and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 546, or the H1 and H2 chains are variants having at least 90%, preferably 95%, and most preferably 98% identity to said sequences; g) the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 548 and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 549, or the H1 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences; or h) the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 551 and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 552, or the H1 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences.

[0120] In the above embodiment, the C-terminal portions of the H1 and H2 chains pair with each other to form domains 1 and 2, and the N-terminal portions of the H1 and H2 chains are ACE2 PDs (domains 3-6). Furthermore, the H1 chain contains a CLD dimerization domain between the portion paired with the H2 chain and the ACE2 PD. Figure 31A shows a schematic diagram of the structure of such a tetrahedral antibody, with the chains in the diagram, from left to right, being H2, H1, H1, and H2. The invention also provides a method for producing a tetrahedral antibody, comprising recombinantly expressing two different polypeptide chains of this embodiment in a host cell.

[0121] In some aspects of the invention: a) the third domain, the first dimer-forming polypeptide and the first polypeptide chain of the first domain are part of a first region of contiguous amino acids; b) the fourth domain, the second dimer-forming polypeptide and the first polypeptide chain of the second domain are part of a second region of contiguous amino acids; c) the fifth domain, the third dimer-forming polypeptide and the second polypeptide chain of the first domain are part of a third region of contiguous amino acids; d) the sixth domain, the fourth dimer-forming polypeptide and the second polypeptide chain of the second domain are part of a fourth region of consecutive amino acids; Here, each region of consecutive amino acids consists of an amino acid sequence selected from the group consisting of amino acids set forth in SEQ ID NOs: 74 to 119, or each region of consecutive amino acids is a variant having at least 90%, preferably at least 95%, more preferably at least 98% identity to the sequence.

[0122] Polynucleotides The present invention also provides polynucleotides encoding any one of the polypeptide chains of the present invention. In a preferred embodiment, the encoded polypeptide comprises any one of the amino acid sequences set forth in SEQ ID NOS: 74-119. In a preferred embodiment, the polynucleotide encodes any of the H1, L2, or H2 polypeptide chains of the above embodiments. In a preferred embodiment, the polynucleotide encodes a sequence of consecutive amino acids selected from the group consisting of amino acids set forth in SEQ ID NOS: 74-119, or a variant having at least 90%, preferably at least 95%, and more preferably at least 98% identity to said sequence. As will be understood by those skilled in the art, polynucleotides of the present invention may further comprise various sequences depending on the expression system used. For example, mRNA polynucleotides of the present invention may comprise a 5' untranslated region (UTR) and a 3' untranslated region (UTR). Additionally, the polynucleotide may encode a signal peptide sequence for proper translocation of the expressed polypeptide. Thus, polynucleotides of the invention may include, but are not limited to, cis-regulatory elements such as promoters, enhancers, and / or introns, untranslated sequences such as 5'UTR and 3'UTR sequences, and translated sequences such as a 5' cap or polyA tail, and / or a signal peptide sequence. Polynucleotides of the invention may include, but are not limited to, DNA or RNA, including mRNA, or modified versions thereof. Modified versions include versions containing non-standard nucleotides such as pseudouridine.

[0123] vector The present invention also provides vectors containing polynucleotides encoding polypeptides comprising polypeptide chains of the present invention. In a preferred embodiment, the vector encodes a polypeptide comprising any one of the amino acid sequences set forth in SEQ ID NOS: 74 to 119. In a preferred embodiment, the vector encodes a polypeptide comprising the H1, L2, and H2 polypeptide chains of an embodiment of the present invention comprising the three different polypeptide chains. In a preferred embodiment, the vector encodes a polypeptide comprising the H1 and H2 polypeptide chains of an embodiment of the present invention comprising the two different polypeptide chains. In these vectors, each polynucleotide is operably linked to a promoter that induces its expression in a host cell. The present invention also provides a method for producing a tetrahedral antibody, the method comprising the step of recombinantly expressing a vector in a host cell.

[0124] host cell The invention also provides a host cell comprising the vector of the invention. In a preferred embodiment, the host cell is used in a method for producing a tetrahedral antibody. The invention also provides a method for producing a tetrahedral antibody comprising two, three, or four different polypeptide chains, the method comprising the step of expressing the two, three, or four different polypeptide chains in a host cell of the invention.

[0125] Pharmaceutical Composition The invention also provides pharmaceutical compositions comprising a tetrahedral antibody of the invention comprising one or more PDs of ACE2 and one or more pharmaceutically acceptable excipients.

[0126] In a preferred embodiment, the pharmaceutical composition comprises a tetrahedral antibody, wherein the first and second domains are Fc domains, the third and fourth domains are ACE2 PDs, the fifth and sixth domains are Fab domains, the dimerizing polypeptides are ACE2 CLDs, and the first and second domains are linked to their respective dimerizing polypeptides via peptide linkers, and the domains and peptide linkers of the tetrahedral antibody are formed by three different polypeptide chains. In a preferred embodiment, the three different polypeptide chains are designated H1, L2, and H2, a) the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 524, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 465, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 535, or the H1, L2 and H2 chains are variants having at least 90%, preferably 95%, and most preferably 98% identity to said sequences; b) the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 473, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 465, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 485, or the H1, L2 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences; c) the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 526, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 465, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 527, or the H1, L2 and H2 chains are variants having at least 90%, preferably 95%, and most preferably 98% identity to said sequences; d) the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 514, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 465, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 528, or the H1, L2 and H2 chains are variants having at least 90%, preferably 95%, and most preferably 98% identity to said sequences; e) the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 529, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 465, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 530, or the H1, L2 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences; f) the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 518, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 465, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 531, or the H1, L2 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences; g) the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 532, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 465, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 533, or the H1, L2 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences; or h) the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 522, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 465, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 534, or the H1, L2 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences.

[0127] In a preferred embodiment, the pharmaceutical composition comprises a tetrahedral antibody, wherein the first and second domains are Fc domains, the third, fourth, fifth and sixth domains are ACE2 PDs, the dimerizing polypeptides are ACE2 CLDs, the first and second domains are linked to their respective dimerizing polypeptides via peptide linkers, and the domains and peptide linkers of the tetrahedral antibody are formed by two different polypeptide chains. In a preferred embodiment, the two different polypeptide chains are designated H1 and H2, a) the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 509 and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 510, or the H1 and H2 chains are variants having at least 90%, preferably 95%, and most preferably 98% identity to said sequences; b) the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 512 and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 513, or the H1 and H2 chains are variants having at least 90%, preferably 95%, and most preferably 98% identity to said sequences; c) the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 516 and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 517, or the H1 and H2 chains are variants having at least 90%, preferably 95%, and most preferably 98% identity to said sequences; d) the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 520 and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 521, or the H1 and H2 chains are variants having at least 90%, preferably 95%, and most preferably 98% identity to said sequences; e) the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 542 and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 543, or the H1 and H2 chains are variants having at least 90%, preferably 95%, and most preferably 98% identity to said sequences; f) the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 545 and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 546, or the H1 and H2 chains are variants having at least 90%, preferably 95%, and most preferably 98% identity to said sequences; g) the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 548 and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 549, or the H1 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences; or h) the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 551 and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 552, or the H1 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences.

[0128] Treatment method The invention also provides a method for treating COVID-19 in a subject, comprising administering to the subject a therapeutically effective amount of the above-described pharmaceutical composition comprising a tetrahedral antibody containing one or more ACE2 PDs.

[0129] Tetrahedral antibodies containing the seventh and / or eighth domains In embodiments of the invention, the tetrahedral antibody further comprises a seventh and / or eighth domain, a) the first domain is linked to the second domain by a covalent bond linked to its first N-terminus or via a first dimerization peptide linked to its first N-terminus; i) the seventh domain is connected at its N-terminus by a peptide bond or via a peptide linker, (1) the first C-terminus of the first domain, or (2) the second C-terminus of the first domain; binds to b) the first domain is linked to the second domain by a covalent bond linked to its first C-terminus or via a first dimerization peptide linked to its first C-terminus; i) the seventh domain is connected at its C-terminus by a peptide bond or via a peptide linker, (1) the first N-terminus of the first domain, or (2) a second N-terminus of the first domain; binds to c) the second domain is linked to the first domain by a covalent bond linked to its first N-terminus or via a second dimerization peptide linked to its first N-terminus; i) the eighth domain is connected at its N-terminus by a peptide bond or via a peptide linker, (1) the first C-terminus of the second domain, or (2) a second C-terminus of the second domain; or d) the second domain is linked to the first domain by a covalent bond linked to its first C-terminus or via a second dimerization peptide linked to its first C-terminus; i) the eighth domain is connected at its C-terminus by a peptide bond or via a peptide linker, (1) the first N-terminus of the second domain, or (2) a second N-terminus of the second domain; Combine with.

[0130] Tetrahedral antibodies for treating cancer In embodiments of the invention, the tetrahedral antibody comprises six domains: a) the first and second domains are Fc domains, the third and fourth domains are anti-CD20 Fab domains, and the fifth and sixth domains are anti-CD19 Fab domains; b) the first and second domains are Fc domains, the third and fourth domains are anti-CD19 Fab domains, and the fifth and sixth domains are anti-CD20 Fab domains; c) the first and second domains are Fc domains, the third and fourth domains are Fab domains of anti-CD20, the fifth and sixth domains are Fab domains of anti-CD19, and each dimerizing polypeptide is a CLD of ACE2; d) the first and second domains are Fc domains, the third and fourth domains are Fab domains of anti-CD19, the fifth and sixth domains are Fab domains of anti-CD20, and each dimerizing polypeptide is a CLD of ACE2; e) the first and second domains are Fc domains, the third and fourth domains are anti-CD20 Fab domains, the fifth and sixth domains are anti-CD19 Fab domains, each dimerizing polypeptide is a CLD of ACE2, and the first and second domains are each linked to each dimerizing polypeptide via a peptide linker; f) The first and second domains are Fc domains, the third and fourth domains are anti-CD19 Fab domains, the fifth and sixth domains are anti-CD20 Fab domains, each dimerizing polypeptide is an ACE2 CLD, and the first and second domains are each linked to their respective dimerizing polypeptides via a peptide linker.

[0131] In embodiments of the invention, the tetrahedral antibody comprises eight domains: a) the first and second domains are Fc domains, the third and fourth domains are anti-CD20 Fab domains, the fifth and sixth domains are anti-CD19 Fab domains, and the seventh and eighth domains are single-chain 4-1BB ligands; b) the first and second domains are Fc domains, the third and fourth domains are anti-CD19 Fab domains, the fifth and sixth domains are anti-CD20 Fab domains, and the seventh and eighth domains are single-chain 4-1BB ligands; c) the first and second domains are Fc domains, the third and fourth domains are Fab domains of anti-CD20, the fifth and sixth domains are Fab domains of anti-CD19, the seventh and eighth domains are single-chain 4-1BB ligands, and each dimerizing polypeptide is a CLD of ACE2; d) the first and second domains are Fc domains, the third and fourth domains are Fab domains of anti-CD19, the fifth and sixth domains are Fab domains of anti-CD20, the seventh and eighth domains are single-chain 4-1BB ligands, and each dimerizing polypeptide is a CLD of ACE2; e) the first and second domains are Fc domains, the third and fourth domains are anti-CD20 Fab domains, the fifth and sixth domains are anti-CD19 Fab domains, the seventh and eighth domains are single-chain 4-1BB ligands, and each dimerizing polypeptide is an ACE2 CLD, and the first and second domains are each linked to each dimerizing polypeptide via a peptide linker; or f) The first and second domains are Fc domains, the third and fourth domains are anti-CD19 Fab domains, the fifth and sixth domains are anti-CD20 Fab domains, the seventh and eighth domains are single-chain 4-1BB ligands, and each dimerizing polypeptide is an ACE2 CLD, and the first and second domains are each linked to their respective dimerizing polypeptides via a peptide linker.

[0132] In some aspects of the invention: a) The Fab domain of anti-CD19 is i) comprises the CDRs of the heavy and light chains of FMC63, and preferably the anti-CD19 Fab is the Fab domain of FMC63; ii) comprises the CDRs of the heavy and light chains of FMC60, and preferably the anti-CD19 Fab is the Fab domain of FMC60; or iii) comprises the CDRs of the heavy and light chains of FMC59, preferably the anti-CD19 Fab is the Fab domain of FMC59; and / or b) The Fab domain of anti-CD20 comprises the CDRs of rituximab, preferably the Fab domain of anti-CD20 is the Fab domain of rituximab.

[0133] In embodiments of the invention, the Fc domain is characterized by one or more or all of the following features: a) is a heterodimer; b) the Fc domain of IgG1; c) said Fc domain comprises silencing mutations such that it lacks Fcγ receptor binding activity, preferably said mutations being one of the following combinations of mutations: i) P329G / L234A / L235A(PGLALA), ii) L234A / L235A(LALA), iii) P331S / L234A / L235A, iv) L234F / L235E / P331S, and v) L234F / L235E / P329G, d) comprising a mutation that enhances the activity of FcRn, preferably said mutation increases the half-life of said tetrahedral antibody, preferably said mutation is: i) the following mutation combination: L309D / Q311H / N434S(DHS), ii) the combination of the following mutations: S239D / I298E; iii) S239D, preferably the other Fc domain of said tetrahedral antibody, if present, comprises the I298E mutation, or iv) I298E, preferably the other Fc domain of said tetrahedral antibody, if present, contains the S239D mutation; e) comprises a mutation that eliminates its Protein A binding site, preferably said mutation is H435R / Y436F (HY / RF).

[0134] In embodiments of the invention, each peptide linker is 23 amino acids in length and is derived from the stalk region of a TNF receptor, preferably the TNF receptor is TNF receptor 1B, and even more preferably the peptide linker consists of the amino acid sequence set forth in SEQ ID NO: 4468.

[0135] In some embodiments of the invention, the dimer-forming polypeptides are each the CLD of ACE2, and each ACE2 CLD comprises or consists of amino acids 616 to 740 of the ACE2 protein.

[0136] In an embodiment of the invention having six domains, said domains and peptide linkers are formed by four different polypeptide chains, preferably said four different polypeptide chains are designated L1, H1, L2 and H2, a) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 733, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 707, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 734, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 708, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences; b) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 735, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 709, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 736, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 710, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences; c) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 735, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 709, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 737, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 711, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences; d) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 738, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 712, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 739, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 713, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, and most preferably 98% identity to said sequences; e) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 740, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 714, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 741, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 715, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences; f) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 740, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 714, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 742, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 716, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, and most preferably 98% identity to said sequences; g) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4801, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4721, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4802, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4722, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences; h) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4803, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4723, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4804, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4724, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences; i) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4803, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4723, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4805, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4725, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, and most preferably 98% identity to said sequences; j) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4806, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4726, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4807, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4727, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences; k) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4808, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4728, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4809, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4729, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences; l) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4808, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4728, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4810, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4730, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, and most preferably 98% identity to said sequences; m) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4803, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4723, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4813, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4772, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences; n) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4803, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4723, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4814, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4773, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences; o) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4815, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4774, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4813, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4772, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences; p) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4815, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4774, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4814 and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4773, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences; q) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4816, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4775, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4809, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4729, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences; r) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4816, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4775, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4810, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4730, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences; s) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4817, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4776, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4809, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4729, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences; t) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4817, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4776, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4810, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4730, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences; u) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4803, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4723, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4814, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4794, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences; v) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4815, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4774, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4813, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4793, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, and most preferably 98% identity to said sequences; w) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4815, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4774, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4814 and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4794, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences; x) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4819, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4775, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4809, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4729, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences; y) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4819, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4775, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4810, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4730, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences; z) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4820, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4776, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4809, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4729, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences; or aa) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4820, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4776, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4810 and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4730, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences.

[0137] In another embodiment of the invention having six domains, the domains and peptide linkers are formed by four different polypeptide chains, the polypeptides being any of those shown in Table 54, preferably protein IDs 21-31 to 21-38 and 21-69 to 21-76.

[0138] In the above embodiment, the C-terminal portions of the H1 and H2 chains pair with each other to form domains 1 and 2, the N-terminal portion of the H1 chain pairs with the L1 chain to form domains 3 and 4, and the N-terminal portion of the H2 chain pairs with the L2 chain to form domains 5 and 6. Furthermore, the H1 chain contains a CLD dimerization domain between the portion paired with the H2 chain and the portion paired with the L1 chain. Figures 31C and 31D show schematic diagrams of the structure of such a tetrahedral antibody, with the chains in the figure, from left to right, being L2, H2, L1, H1, H1, L1, H2, and L2. The invention also provides a method for producing a tetrahedral antibody, the method comprising recombinantly expressing the four different polypeptide chains of this embodiment in a host cell.

[0139] In an embodiment of the invention having eight domains, said domains and peptide linkers are formed by four different polypeptide chains, preferably said four different polypeptide chains are designated L1, H1, L2 and H2, a) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 733, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 707, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 734, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 717, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, and most preferably 98% identity to said sequences; b) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 735, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 709, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 736, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 718, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences; c) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 735, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 709, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 737, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 719, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences; d) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 738, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 712, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 739, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 720, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, and most preferably 98% identity to said sequences; e) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 740, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 714, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 741, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 721, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences; f) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 740, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 714, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 742, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 722, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences; g) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 733, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 723, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 734, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 724, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences; h) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 735, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 725, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 736, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 726, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences; i) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 735, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 725, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 737, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 727, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, and most preferably 98% identity to said sequences; j) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 738, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 728, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 739, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 729, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences; k) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 740, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 730, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 741, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 731, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences; or l) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 740, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 730, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 742 and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 732, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences.

[0140] In the above embodiment, the C-terminal portion of H1 forms domains 7 and 8, and the C-terminal portion of H2 pairs with a portion of the H1 chain to form domains 1 and 2. The N-terminal portion of the H1 chain pairs with the L1 chain to form domains 3 and 4, and the N-terminal portion of the H2 chain pairs with the L2 chain to form domains 5 and 6. Furthermore, the H1 chain contains a CLD dimerization domain between the portion paired with the H2 chain and the portion paired with the L1 chain. Figure 37D shows a schematic diagram of the structure of such a tetrahedral antibody, with the chains in the diagram, from left to right, being L2, H2, L1, H1, H1, L1, H2, and L2. The invention also provides a method for producing a tetrahedral antibody, the method comprising recombinantly expressing four different polypeptide chains of this embodiment in a host cell.

[0141] Polynucleotides The invention also provides a polynucleotide encoding a polypeptide comprising any one of the polypeptide chains of the above aspects. In a preferred aspect, the polynucleotide encodes one of the L1, H1, L2 and H2 polypeptide chains of the above aspects.

[0142] vector The invention also provides vectors comprising polynucleotides encoding polypeptides comprising the polypeptide chains of the invention. In a preferred embodiment, the vector encodes a polypeptide comprising the L1, H1, L2, and H2 polypeptide chains of the invention comprising the four distinct polypeptide chains described above. In these vectors, each polynucleotide is operably linked to a promoter that directs expression of the polynucleotide in a host cell. The invention also provides methods for producing tetrahedral antibodies, the methods comprising recombinantly expressing the vector in a host cell.

[0143] host cell The present invention also provides a host cell comprising the vector of the present invention. In a preferred embodiment, the host cell is used in a method for producing a tetrahedral antibody. The present invention also provides a method for producing a tetrahedral antibody comprising four different polypeptide chains, the method comprising the step of expressing the four different polypeptide chains in a host cell of the invention described in the above embodiment.

[0144] Pharmaceutical Composition The invention also provides pharmaceutical compositions comprising a tetrahedral antibody of the invention comprising an anti-CD20 and / or anti-CD19 Fab domain, and one or more pharmaceutically acceptable excipients.

[0145] In a preferred embodiment, the pharmaceutical composition comprises a tetrahedral antibody comprising six domains, said domains and peptide linkers being formed by four different polypeptide chains, preferably said four different polypeptide chains being designated L1, H1, L2 and H2, a) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 733, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 707, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 734, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 708, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences; b) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 735, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 709, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 736, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 710, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences; c) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 735, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 709, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 737, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 711, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences; d) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 738, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 712, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 739, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 713, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, and most preferably 98% identity to said sequences; e) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 740, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 714, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 741, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 715, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences; or f) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 740, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 714, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 742 and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 716, or the L1, H1, L2 and H2 are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences.

[0146] In a preferred embodiment, the pharmaceutical composition comprises a tetrahedral antibody comprising eight domains, said domains and peptide linkers being formed by four different polypeptide chains, preferably said four different polypeptide chains being designated L1, H1, L2 and H2: a) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 733, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 707, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 734, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 717, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, and most preferably 98% identity to said sequences; b) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 735, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 709, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 736, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 718, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences; c) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 735, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 709, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 737, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 719, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences; d) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 738, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 712, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 739, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 720, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, and most preferably 98% identity to said sequences; e) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 740, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 714, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 741, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 721, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences; f) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 740, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 714, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 742, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 722, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences; g) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 733, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 723, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 734, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 724, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences; h) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 735, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 725, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 736, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 726, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences; i) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 735, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 725, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 737, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 727, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, and most preferably 98% identity to said sequences; j) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 738, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 728, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 739, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 729, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences; k) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 740, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 730, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 741, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 731, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences; or l) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 740, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 730, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 742 and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 732, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences.

[0147] Treatment method The invention also provides a method for treating cancer or an inflammatory disease in a subject, the method comprising administering to the subject a therapeutically effective amount of the above-described pharmaceutical composition comprising a tetrahedral antibody comprising an anti-CD20 and / or anti-CD19 Fab domain, preferably wherein the cancer is a B-cell cancer.

[0148] tetrahedral molecule The invention provides a tetrahedral molecule comprising first, second, third and fourth domains, a) the first and second domains each independently: i) a first polypeptide chain comprising a first N-terminus and a first C-terminus of the domain; and ii) optionally a second polypeptide chain comprising a second N-terminus and a second C-terminus of said domain; Including, b) the first domain and the second domain are: (1) a non-covalent bond between a first dimer-forming polypeptide attached to a first N-terminus of a first domain by a peptide bond or via a peptide linker and a second dimer-forming polypeptide attached to a first N-terminus of a second domain by a peptide bond or via a peptide linker; (2) a non-covalent bond between a first dimer-forming polypeptide attached to the first C-terminus of the first domain by a peptide bond or via a peptide linker and a second dimer-forming polypeptide attached to the first C-terminus of the second domain by a peptide bond or via a peptide linker; (3) a non-covalent bond between a first dimer-forming polypeptide attached to a first N-terminus of a first domain by a peptide bond or via a peptide linker and a second dimer-forming polypeptide attached to a first C-terminus of a second domain by a peptide bond or via a peptide linker; or (4) a non-covalent bond between a first dimer-forming polypeptide attached to a first C-terminus of the first domain by a peptide bond or via a peptide linker and a second dimer-forming polypeptide attached to a first N-terminus of the second domain by a peptide bond or via a peptide linker; are connected to each other by wherein the first and second dimer-forming polypeptides are not immunoglobulins, c) when the first domain is linked to the second domain via a first dimerization polypeptide linked to its first N-terminus, the third domain is linked at its C-terminus by a peptide bond or via a peptide linker, i) the N-terminus of the first dimer-forming polypeptide; ii) if present, the second N-terminus of the first domain; or iii) the N-terminus of a third dimer-forming polypeptide, wherein, if a second N-terminus of the first domain is present, the third dimer-forming polypeptide is linked at its C-terminus to the second N-terminus of the first domain by a peptide bond or via a peptide linker; binds to d) when the first domain is linked to the second domain via a first dimerization polypeptide linked to its first C-terminus, the third domain is linked at its N-terminus by a peptide bond or via a peptide linker, i) the C-terminus of the first dimer-forming polypeptide; ii) if present, the second C-terminus of the first domain; or iii) the C-terminus of a third dimer-forming polypeptide, wherein, if a second C-terminus of the first domain is present, the third dimer-forming polypeptide is linked at its N-terminus to the second C-terminus of the first domain by a peptide bond or via a peptide linker; binds to e) when the second domain is linked to the first domain via a second dimer-forming polypeptide linked to its first N-terminus, the fourth domain is linked at its C-terminus by a peptide bond or via a peptide linker, i) the N-terminus of the second dimer-forming polypeptide; ii) if present, the second N-terminus of the second domain; or iii) the N-terminus of a fourth dimer-forming polypeptide, wherein, if a second N-terminus of the second domain is present, the third dimer-forming polypeptide is linked at its C-terminus to the second N-terminus of the second domain by a peptide bond or via a peptide linker; and f) when the second domain is linked to the first domain via a second dimer-forming polypeptide linked to its first C-terminus, the fourth domain is linked at its N-terminus by a peptide bond or via a peptide linker, i) the C-terminus of the second dimer-forming polypeptide; ii) if present, the second C-terminus of the second domain; or iii) the C-terminus of a fourth dimer-forming polypeptide, wherein, if a second C-terminus of the second domain is present, the fourth dimer-forming polypeptide is linked at its N-terminus to the second C-terminus of the second domain by a peptide bond or via a peptide linker; is bonded to Tetrahedral molecules are also provided.

[0149] In some embodiments of the present invention, particularly in one embodiment of paragraph

[0157] , the tetrahedral antibody further comprises a fifth and / or sixth domain, a) the first domain is linked to the second domain via a first dimerization polypeptide linked to its first N-terminus; i) the fifth domain is connected at its C-terminus by a peptide bond or via a peptide linker, (1) the N-terminus of the first dimer-forming polypeptide; (2) the second N-terminus of the first domain, or (3) the N-terminus of a third dimer-forming polypeptide, wherein the third dimer-forming polypeptide is linked at its C-terminus to the second N-terminus of the first domain by a peptide bond or via a peptide linker; binds to b) the first domain is linked to the second domain via a first dimerization polypeptide linked to its first C-terminus; i) the fifth domain is connected at its N-terminus by a peptide bond or via a peptide linker, (1) the C-terminus of the first dimer-forming polypeptide; (2) the second C-terminus of the first domain, or (3) the C-terminus of a third dimer-forming polypeptide, wherein the third dimer-forming polypeptide is linked at its N-terminus to the second C-terminus of the first domain by a peptide bond or via a peptide linker; binds to c) the second domain binds to the first domain via a second dimerization polypeptide linked to its first N-terminus; i) the sixth domain is connected at its C-terminus by a peptide bond or via a peptide linker, (1) the N-terminus of the second dimer-forming polypeptide; (2) the N-terminus of the second dimer-forming polypeptide, or (3) the N-terminus of a fourth dimer-forming polypeptide, wherein the fourth dimer-forming polypeptide is linked at its C-terminus to the second N-terminus of the second domain by a peptide bond or via a peptide linker; or d) the second domain is linked to the first domain via a second dimerization polypeptide linked to its first C-terminus; i) the sixth domain is connected at its N-terminus by a peptide bond or via a peptide linker, (1) the C-terminus of the second dimer-forming polypeptide; (2) the second C-terminus of the second domain, or (3) the C-terminus of a fourth dimer-forming polypeptide, wherein the fourth dimer-forming polypeptide is linked at its N-terminus to the second C-terminus of the second domain by a peptide bond or via a peptide linker; Combine with.

[0150] In one embodiment of the tetrahedral molecule of the present invention, particularly the embodiment of paragraph

[0157] , the tetrahedral molecule further comprises a seventh and / or eighth domain, a) the first domain is linked to the second domain via a first dimerization polypeptide linked to its first N-terminus; i) the seventh domain is connected at its N-terminus by a peptide bond or via a peptide linker, (1) the first C-terminus of the first domain, or (2) the second C-terminus of the first domain; binds to b) the first domain is linked to the second domain via a first dimerization polypeptide linked to its first C-terminus; i) the seventh domain is connected at its C-terminus by a peptide bond or via a peptide linker, (1) the first N-terminus of the first domain, or (2) the second N-terminus of the first domain; binds to c) the second domain binds to the first domain via a second dimerization polypeptide linked to its first N-terminus; i) the eighth domain is connected at its N-terminus by a peptide bond or via a peptide linker, (1) the first C-terminus of the second domain, or (2) a second C-terminus of the second domain; or d) the second domain is linked to the first domain via a second dimerization polypeptide linked to its first C-terminus; i) the eighth domain is connected at its C-terminus by a peptide bond or via a peptide linker, (1) the first N-terminus of the second domain, or (2) the second N-terminus of the second domain; Combine with.

[0151] In one embodiment of the tetrahedral molecule of the present invention, particularly the embodiment of paragraph

[0157] , the tetrahedral molecule further comprises a ninth and / or tenth domain, a) The third domain is i) the ninth domain is linked at its C-terminus to the N-terminus of the first dimer-forming polypeptide by a peptide bond or via a peptide linker, and the ninth domain is linked at its C-terminus to the N-terminus of the third domain by a peptide bond or via a peptide linker; or ii) linked at its N-terminus by a peptide bond or via a peptide linker to the C-terminus of the first dimer-forming polypeptide, and the ninth domain linked at its N-terminus by a peptide bond or via a peptide linker to the C-terminus of the third domain; and / or b) The fourth domain is: i) the tenth domain is linked at its C-terminus to the N-terminus of the second dimer-forming polypeptide by a peptide bond or via a peptide linker, and the tenth domain is linked at its C-terminus to the N-terminus of the fourth domain by a peptide bond or via a peptide linker; or ii) linked at its N-terminus by a peptide bond or via a peptide linker to the C-terminus of a second dimer-forming polypeptide, and the tenth domain linked at its N-terminus by a peptide bond or via a peptide linker to the C-terminus of the fourth domain.

[0152] In one embodiment of the tetrahedral molecule of this invention, particularly in one embodiment of paragraph

[0157] , a) the first domain is an Fc domain or a Fab domain; b) the first domain is an Fc domain or a Fab domain, but the second domain is not an Fc domain or a Fab domain; c) the first domain is an Fc domain and the second domain is a Fab domain; d) the first and second domains are Fc domains; e) the first and second domains are Fab domains; f) the second, third and / or fourth domain is selected from the group consisting of: (i) a secreted protein, and (ii) an extracellular domain of a transmembrane protein; g) the third domain is selected from the group consisting of (i) a secreted protein and (ii) an extracellular domain of a transmembrane protein, and the fourth domain is a Fab domain; h) the third domain is IL-15; i) the third domain is IL-15 and the fourth domain is the IL-15Rα sushi domain; j) the third domain is IL-15 and the fourth domain is a Fab domain; k) the third and fourth domains are peptidase domains (PDs) of ACE2; l) the first and second domains are Fc domains and the third and fourth domains are selected from the group consisting of: i) a secreted protein, and (ii) an extracellular domain of a transmembrane protein; m) the first and second domains are Fc domains, the third domain is selected from the group consisting of (i) a secreted protein and (ii) an extracellular domain of a transmembrane protein, and the fourth domain is a Fab domain; n) the first and second domains are Fc domains and the third and fourth domains are Fab domains; o) the first and second domains are Fc domains and the third and fourth domains are peptidase domains (PDs) of ACE2; p) the first domain is an Fc domain and the second, third and fourth domains are Fab domains; q) the first domain is an Fc domain, the second domain is a Fab domain, the third domain is IL-15, and the fourth domain is an IL-15Rα sushi domain; r) the first domain is an Fc domain, the second domain is a Fab domain, the third domain is IL-15, and the fourth domain is a Fab domain; s) the first and / or second domain is a transmembrane domain of a protein other than ACE2 and / or collectrin, the first and second dimer-forming polypeptides are selected from collectrin-like domains (CLD) and collectrin domains (CD), and the first and second domains are (1) a non-covalent bond between a first dimer-forming polypeptide attached to a first N-terminus of a first domain by a peptide bond or via a peptide linker and a second dimer-forming polypeptide attached to a first N-terminus of a second domain by a peptide bond or via a peptide linker; or (2) a non-covalent bond between a first dimer-forming polypeptide attached to the first C-terminus of the first domain by a peptide bond or via a peptide linker and a second dimer-forming polypeptide attached to the first C-terminus of the second domain by a peptide bond or via a peptide linker; are bonded to each other by t) the first and / or second domain is a transmembrane domain of ACE2 and / or collectrin, the third and / or fourth domain is other than the ACE2 peptidase domain, and the first and second domains are (1) a non-covalent bond between a first dimer-forming polypeptide attached to a first N-terminus of a first domain by a peptide bond or via a peptide linker and a second dimer-forming polypeptide attached to a first N-terminus of a second domain by a peptide bond or via a peptide linker; or (2) a non-covalent bond between a first dimer-forming polypeptide attached to the first C-terminus of the first domain by a peptide bond or via a peptide linker and a second dimer-forming polypeptide attached to the first C-terminus of the second domain by a peptide bond or via a peptide linker; are bonded to each other by u) the first and / or second domain is an ACE2 transmembrane domain and / or collectrin, the first and second dimer-forming polypeptides are selected from a collectrin-like domain (CLD) and a collectrin domain (CD), the third and / or fourth domain is other than the ACE2 peptidase domain, and the first and second domains are (1) a non-covalent bond between a first dimer-forming polypeptide attached to a first N-terminus of a first domain by a peptide bond or via a peptide linker and a second dimer-forming polypeptide attached to a first N-terminus of a second domain by a peptide bond or via a peptide linker; or (2) a non-covalent bond between a first dimer-forming polypeptide attached to the first C-terminus of the first domain by a peptide bond or via a peptide linker and a second dimer-forming polypeptide attached to the first C-terminus of the second domain by a peptide bond or via a peptide linker; are bonded to each other by v) the first and second dimer-forming polypeptides are selected from a collectrin-like domain (CLD) and a collectrin domain (CD), preferably a CLD, and the first domain is a binding domain of a protein or a part or modified version thereof, a secreted protein or a part or modified version thereof, a transmembrane protein or a part or modified version thereof, an intracellular binding domain or a part or modified version thereof, and an antibody or a part or modified version thereof; selected from the group consisting of w) the first and second dimerizing polypeptides are selected from a collectrin-like domain (CLD) and a collectrin domain (CD), preferably a CLD, and the second domain is selected from the group consisting of a binding domain of a protein or a part or modified version thereof, a secreted protein or a part or modified version thereof, a transmembrane protein or a part or modified version thereof, an intracellular binding domain or a part or modified version thereof, and an antibody or a part or modified version thereof, x) the first and second dimerizing polypeptides are selected from a collectrin-like domain (CLD) and a collectrin domain (CD), preferably a CLD, and the third domain is selected from the group consisting of a binding domain of a protein or a part or modified version thereof, a secreted protein or a part or modified version thereof, a transmembrane protein or a part or modified version thereof, an intracellular binding domain or a part or modified version thereof, and an antibody or a part or modified version thereof. y) the first and second dimerizing polypeptides are selected from a collectrin-like domain (CLD) and a collectrin domain (CD), preferably a CLD, and the fourth domain is selected from the group consisting of a binding domain of a protein or a part or modified version thereof, a secreted protein or a part or modified version thereof, a transmembrane protein or a part or modified version thereof, an intracellular binding domain or a part or modified version thereof, and an antibody or a part or modified version thereof, z) the first and second dimerizing polypeptides are selected from collectrin-like domains (CLD) and collectrin domains (CD), preferably CLD, and the fifth domain, if present, is selected from the group consisting of a binding domain of a protein or a part or modified version thereof, a secreted protein or a part or modified version thereof, a transmembrane protein or a part or modified version thereof, an intracellular binding domain or a part or modified version thereof, and an antibody or a part or modified version thereof, aa) the first and second dimerizing polypeptides are selected from a collectrin-like domain (CLD) and a collectrin domain (CD), preferably a CLD, and the sixth domain, if present, is selected from the group consisting of a binding domain of a protein or a part or modified version thereof, a secreted protein or a part or modified version thereof, a transmembrane protein or a part or modified version thereof, an intracellular binding domain or a part or modified version thereof, and an antibody or a part or modified version thereof, bb) the first and second dimerizing polypeptides are selected from collectrin-like domains (CLD) and collectrin domains (CD), preferably CLD, and the seventh domain, if present, is selected from the group consisting of a binding domain of a protein or a part or modified version thereof, a secreted protein or a part or modified version thereof, a transmembrane protein or a part or modified version thereof, an intracellular binding domain or a part or modified version thereof, and an antibody or a part or modified version thereof, cc) the first and second dimerizing polypeptides are selected from collectrin-like domains (CLD) and collectrin domains (CD), preferably CLD, and the eighth domain, if present, is selected from the group consisting of binding domains of proteins or parts or modified versions thereof, secreted proteins or parts or modified versions thereof, transmembrane proteins or parts or modified versions thereof, intracellular binding domains or parts or modified versions thereof, and antibodies or parts or modified versions thereof, dd) the first and second dimerizing polypeptides are selected from a collectrin-like domain (CLD) and a collectrin domain (CD), preferably a CLD, and the first domain is other than a binding domain of a protein or a part or modified version thereof, a secreted protein or a part or modified version thereof, a transmembrane protein or a part or modified version thereof, an intracellular binding domain or a part or modified version thereof, and an antibody or a part or modified version thereof, ee) the first and second dimerizing polypeptides are selected from a collectrin-like domain (CLD) and a collectrin domain (CD), preferably a CLD, and the second domain is other than a binding domain of a protein or a part or modified version thereof, a secreted protein or a part or modified version thereof, a transmembrane protein or a part or modified version thereof, an intracellular binding domain or a part or modified version thereof, and an antibody or a part or modified version thereof, ff) the first and second dimerizing polypeptides are selected from a collectrin-like domain (CLD) and a collectrin domain (CD), preferably a CLD, and the third domain is other than a binding domain of a protein or a part or modified version thereof, a secreted protein or a part or modified version thereof, a transmembrane protein or a part or modified version thereof, an intracellular binding domain or a part or modified version thereof, and an antibody or a part or modified version thereof, gg) the first and second dimerizing polypeptides are selected from a collectrin-like domain (CLD) and a collectrin domain (CD), preferably a CLD, and the fourth domain is other than a binding domain of a protein or a part or modified version thereof, a secreted protein or a part or modified version thereof, a transmembrane protein or a part or modified version thereof, an intracellular binding domain or a part or modified version thereof, and an antibody or a part or modified version thereof, hh) the first and second dimerizing polypeptides are selected from a collectrin-like domain (CLD) and a collectrin domain (CD), preferably a CLD, and the fifth domain, if present, is other than a binding domain of a protein or a part or modified version thereof, a secreted protein or a part or modified version thereof, a transmembrane protein or a part or modified version thereof, an intracellular binding domain or a part or modified version thereof, and an antibody or a part or modified version thereof, ii) the first and second dimerizing polypeptides are selected from a collectrin-like domain (CLD) and a collectrin domain (CD), preferably a CLD, and the sixth domain, if present, is other than a binding domain of a protein or a part or modified version thereof, a secreted protein or a part or modified version thereof, a transmembrane protein or a part or modified version thereof, an intracellular binding domain or a part or modified version thereof, and an antibody or a part or modified version thereof, jj) the first and second dimerizing polypeptides are selected from a collectrin-like domain (CLD) and a collectrin domain (CD), preferably a CLD, and the seventh domain, if present, is other than a binding domain of a protein or a part or modified version thereof, a secreted protein or a part or modified version thereof, a transmembrane protein or a part or modified version thereof, an intracellular binding domain or a part or modified version thereof, and an antibody or a part or modified version thereof, kk) the first and second dimer-forming polypeptides are selected from a collectrin-like domain (CLD) and a collectrin domain (CD), preferably a CLD, and the eighth domain, if present, is other than a binding domain of a protein or a part or modified version thereof, a secreted protein or a part or modified version thereof, a transmembrane protein or a part or modified version thereof, an intracellular binding domain or a part or modified version thereof, and an antibody or a part or modified version thereof, ll) the first, second, third and / or fourth domain is a CD3 zeta chain intracellular binding domain, a CD28 intracellular binding domain or a 4-1BB intracellular binding domain, a CD3 epsilon chain intracellular binding domain, an ICOS intracellular binding domain, an OX40 intracellular binding domain or a 4-1BB intracellular binding domain; mm) if present, the 7th and / or 8th domain is a CD3 zeta chain intracellular binding domain, a CD28 intracellular binding domain or a 4-1BB intracellular binding domain, a CD3 epsilon chain intracellular binding domain, an ICOS intracellular binding domain, an OX40 intracellular binding domain or a 4-1BB intracellular binding domain; nn) the first, second, third and fourth domains are other than the ACE2 peptidase domain; oo) the first, second, third and fourth domains are other than an ACE2 peptidase domain, and the first and second dimer-forming polypeptides are each a collectrin-like domain (CLD); pp) the first, second, third and fourth domains are other than the ACE2 peptidase domain or the ACE2 transmembrane domain; qq) the first, second, third and fourth domains are other than an ACE2 peptidase domain or an ACE2 transmembrane domain, and the first and second dimer-forming polypeptides are each a collectrin-like domain (CLD); rr) the tetrahedral molecule comprises first, second, third, fourth, seventh and eighth domains, the first and second domains being linked to one another by a non-covalent bond between a first dimer-forming polypeptide attached to a first N-terminus of the first domain by a peptide bond or via a peptide linker, and a second dimer-forming polypeptide attached to a first N-terminus of the second domain by a peptide bond or via a peptide linker; i) the third and fourth domains are respectively a binding domain of a protein or a part or modified version thereof, preferably a binding domain of a secreted protein, an extracellular domain of a transmembrane protein or an antibody or part thereof, more preferably a single chain part of an antibody, more preferably a single chain or single domain antibody molecule, more preferably an scFV domain; ii) the first and second domains are each a transmembrane domain, preferably a transmembrane domain of TNFRSF1, TNFRSF1B, LTBR, ​​CD40, FasR, DCR3, CD27, CD30, DR4, DR5, DCR2, RANK, TWEAK-R, TACI, BAF-R, HVEM, BCMA, GITR, TROY, DR3 or XEDAR, more preferably a transmembrane domain of ACE2, collectrin, CD8a, CD8b, CD3zeta, CD3epsilon, CD28, ICOS, OX40 or 4-1BB, iii) the seventh and / or eighth domains are intracellular binding domains, preferably the intracellular binding domains of CD3 zeta chain, CD3 epsilon chain, CD28, ICOS, OX40 or 4-1BB, respectively; ss) the tetrahedral molecule comprises a first, second, third, fourth, seventh and eighth domain, the first and second domains being linked to each other by a non-covalent bond between a first dimerizing polypeptide attached to a first N-terminus of the first domain by a peptide bond or via a peptide linker and a second dimerizing polypeptide attached to a first N-terminus of the second domain by a peptide bond or via a peptide linker, the third and fourth domains being each an scFv domain, the first and second domains being each a transmembrane domain of ACE2, collectrin, CD8a, CD8b, CD3ζ, CD3ε, CD28, ICOS, OX40 or 4-1BB, and the seventh and / or eighth domains being each an intracellular binding domain of CD3ζ chain, CD3ε chain, CD28, ICOS, OX40 or 4-1BB, tt) the tetrahedral molecule comprises first, second, third, fourth, ninth and tenth domains, the first and second domains being linked to one another by a non-covalent bond between a first dimer-forming polypeptide attached to a first N-terminus of the first domain by a peptide bond or via a peptide linker, and a second dimer-forming polypeptide attached to a first N-terminus of the second domain by a peptide bond or via a peptide linker; i) the ninth and tenth domains are respectively a binding domain of a protein or a part or modified version thereof, preferably a binding domain of a secreted protein, an extracellular domain of a transmembrane protein or an antibody or part thereof, more preferably a single chain part of an antibody, more preferably a single chain or single domain antibody molecule, more preferably an scFV domain; ii) the third and fourth domains are each a transmembrane domain, preferably a transmembrane domain of TNFRSF1, TNFRSF1B, LTBR, ​​CD40, FasR, DCR3, CD27, CD30, DR4, DR5, DCR2, RANK, TWEAK-R, TACI, BAF-R, HVEM, BCMA, GITR, TROY, DR3 or XEDAR, more preferably a transmembrane domain of ACE2, collectrin, CD8a, CD8b, CD3ζ, CD3ε, CD28, ICOS, OX40 or 4-1BB; iii) the first and second domains are each an intracellular binding domain, preferably an intracellular binding domain of CD3 zeta chain, CD3 epsilon chain, CD28, ICOS, OX40 or 4-1BB; uu) the tetrahedral molecule comprises first, second, third, fourth, ninth and tenth domains, the first and second domains being linked to each other by a non-covalent bond between a first dimerizing polypeptide attached to a first N-terminus of the first domain by a peptide bond or via a peptide linker and a second dimerizing polypeptide attached to a first N-terminus of the second domain by a peptide bond or via a peptide linker, the ninth and tenth domains being each an scFv domain, the third and fourth domains being each a transmembrane domain of ACE2, collectrin, CD8a, CD8b, CD3zeta, CD3epsilon, CD28, ICOS, OX40 or 4-1BB, and the first and second domains being each a CD3zeta chain, CD3epsilon chain, CD28, ICOS, OX40 or 4-1BB intracellular binding domain, vv) the tetrahedral molecule comprises first, second, third, fourth, seventh and eighth domains, the first and second domains being linked to each other by a non-covalent bond between a first dimer-forming polypeptide attached to a first N-terminus of the first domain by a peptide bond or via a peptide linker, and a second dimer-forming polypeptide attached to a first N-terminus of the second domain by a peptide bond or via a peptide linker; i) the third and fourth domains are respectively a binding domain of a protein or a part or modified version thereof, preferably a binding domain of a secreted protein, an extracellular domain of a transmembrane protein or an antibody or part thereof, more preferably a single chain part of an antibody, more preferably a single chain or single domain antibody molecule, more preferably an scFV domain, ii) the first and second domains are each a transmembrane domain, preferably a transmembrane domain of TNFRSF1, TNFRSF1B, LTBR, ​​CD40, FasR, DCR3, CD27, CD30, DR4, DR5, DCR2, RANK, TWEAK-R, TACI, BAF-R, HVEM, BCMA, GITR, TROY, DR3 or XEDAR, more preferably a transmembrane domain of ACE2, collectrin, CD8a, CD8b, CD3ζ, CD3ε, CD28, ICOS, OX40 or 4-1BB; iii) the seventh and / or eighth domains are antigens or neoantigens, respectively; ww) the tetrahedral molecule comprises first, second, third, fourth, seventh and eighth domains, the first and second domains being linked to each other by a non-covalent bond between a first dimerizing polypeptide attached to a first N-terminus of the first domain by a peptide bond or via a peptide linker and a second dimerizing polypeptide attached to a first N-terminus of the second domain by a peptide bond or via a peptide linker, the third and fourth domains being each an scFv domain, the first and second domains being each a transmembrane domain of ACE2, collectrin, CD8a, CD8b, CD3ζ, CD3ε, CD28, ICOS, OX40 or 4-1BB, and the seventh and / or eighth domains being each an antigen or neoantigen, xx) the tetrahedral molecule comprises first, second, third, fourth, ninth and tenth domains, the first and second domains being linked to one another by a non-covalent bond between a first dimer-forming polypeptide attached to a first N-terminus of the first domain by a peptide bond or via a peptide linker, and a second dimer-forming polypeptide attached to a first N-terminus of the second domain by a peptide bond or via a peptide linker; i) the ninth and tenth domains are respectively a binding domain of a protein or a part or modified version thereof, preferably a binding domain of a secreted protein, an extracellular domain of a transmembrane protein or an antibody or part thereof, more preferably a single chain part of an antibody, more preferably a single chain or single domain antibody molecule, more preferably an scFV domain; ii) the third and fourth domains are each a transmembrane domain, preferably a transmembrane domain of TNFRSF1, TNFRSF1B, LTBR, ​​CD40, FasR, DCR3, CD27, CD30, DR4, DR5, DCR2, RANK, TWEAK-R, TACI, BAF-R, HVEM, BCMA, GITR, TROY, DR3 or XEDAR, more preferably a transmembrane domain of ACE2, collectrin, CD8a, CD8b, CD3ζ, CD3ε, CD28, ICOS, OX40 or 4-1BB; iii) the first and second domains are antigens or neoantigens, respectively; yy) The tetrahedral molecule comprises first, second, third, fourth, ninth and tenth domains, the first and second domains being linked to each other by a non-covalent bond between a first dimerizing polypeptide attached to a first N-terminus of the first domain by a peptide bond or via a peptide linker and a second dimerizing polypeptide attached to a first N-terminus of the second domain by a peptide bond or via a peptide linker, the ninth and tenth domains each being an scFv, the third and fourth domains being the transmembrane domains of ACE2, collectrin, CD8a, CD8b, CD3ζ, CD3ε, CD28, ICOS, OX40 or 4-1BB, respectively, and the first and second domains being an antigen or neoantigen, respectively.

[0153] In embodiments of the invention comprising transmembrane domains as the first and second domains, preferably the tetrahedral molecule comprises first and second dimerizing polypeptides naturally associated with said transmembrane domains. For example, if the first and second domains are the transmembrane domains of ACE2, the first and second dimerizing polypeptides are collectrin-like domains (CLDs). Thus, in a preferred embodiment of any of the above embodiments, the first and second domains are the transmembrane domains of ACE2 and the first and second dimerizing polypeptides are collectrin-like domains (CLDs).

[0154] In several aspects of the present invention, particularly one aspect of paragraph

[0157] , the peptidyl bond is a non-covalent bond between a first dimer-forming polypeptide linked to the first domain and a second dimer-forming polypeptide linked to the second domain.

[0155] In some embodiments of the present invention, particularly in one embodiment of paragraph

[0157] , the first and second dimer-forming polypeptides are a) a dimerization domain of an extracellular protein dimer, and b) dimerization domains of intracellular protein dimers; is selected from the group consisting of:

[0156] Aspects of the invention, particularly paragraph

[0157] In one embodiment, the first and second dimer-forming polypeptides are a) leucine zipper domain, b) collectrin-like domain (CLD), c) collectrin domain (CD), d) the CD8α extracellular domain, and e) CD8β extracellular domain, is selected from the group consisting of:

[0157] In a preferred embodiment of the tetrahedral molecule of this invention, particularly in one of the embodiments described in paragraph

[0157] , the first and second dimer-forming polypeptides are selected from a collectrin-like domain (CLD) and a collectrin domain (CD), preferably a collectrin-like domain (CLD).

[0158] In some aspects of the invention: a) the first dimer-forming polypeptide is the same as the second dimer-forming polypeptide; b) The dimer-forming polypeptide forms a homodimer.

[0159] In some aspects of the invention: a) the first dimer-forming polypeptide is different from the second dimer-forming polypeptide; b) the first and second dimer-forming polypeptides form a heterodimer.

[0160] In embodiments of the invention, the first and second dimer-forming polypeptides form a heterodimer comprising: a) the first and second dimer-forming polypeptides are i) T cell receptor alpha and T cell receptor beta extracellular domains; ii) T cell receptor gamma and T cell receptor extracellular domain; iii) MHC class I alpha extracellular domain and beta2 microglobulin; iv) MHC class II α and MHC class II β extracellular domains, and v) CD8α and CD8β extracellular domains, selected from the group consisting of b) the first dimer-forming polypeptide is different from the second dimer-forming polypeptide; c) The first and second dimer-forming polypeptides form a heterodimer.

[0161] In some embodiments of the invention, the first and second dimer-forming polypeptides, when both are present, form homodimers in less than 30%, 20%, 10%, 5%, 4%, 3%, 2%, or 1% of the polypeptides.

[0162] Fusion protein dimer The present invention provides a non-natural fusion protein dimer comprising a dimer of a first dimerizing polypeptide and a second dimerizing polypeptide, a) the first dimer-forming polypeptide is linked at its N-terminus or C-terminus to the first domain by a peptide bond or via a peptide linker; b) the second dimer-forming polypeptide is optionally linked at its N-terminus or C-terminus to the second domain by a peptide bond or via a peptide linker; c) the first and second dimer-forming polypeptides are i) a collectrin-like domain (CLD), and ii) Collectrin domain (CD) selected from the group consisting of d) the first dimer-forming polypeptide is optionally linked at its remaining free N-terminus or C-terminus to a third domain by a peptide bond or via a peptide linker; e) the second dimer-forming polypeptide is optionally linked at its remaining free N-terminus or C-terminus to the fourth domain by a peptide bond or via a peptide linker; Non-natural fusion protein dimers are also provided.

[0163] In one of the above embodiments, the first and second dimerizing polypeptides are collectrin-like domains (CLDs).

[0164] In embodiments of the invention, the tetrahedral molecule or non-natural fusion protein dimer comprises: a) i) ACE2 PD at the N-terminal side of the dimer-forming polypeptide; and / or ii) the transmembrane domain of ACE2 and / or the transmembrane domain of collectrin at the C-terminal end of the dimer-forming polypeptide; does not contain, or b) i) ACE2 PD at the N-terminal side of the dimer-forming polypeptide; and / or ii) the transmembrane domain of ACE2 and / or the transmembrane domain of collectrin at the C-terminal end of the amer-forming polypeptide; Includes:

[0165] In several aspects of the present invention, the first and second dimer-forming polypeptides form heterodimers, the dimer-forming polypeptides are collectrin-like domains (CLDs), and the CLDs contain substitutions that prevent the CLD dimer-forming polypeptides from forming homodimers, preferably the substitutions are made at Arg652, Arg710, Tyr641, Tyr633, Asn638, Glu639, Gln653, Asn636, Ser709, Asp713 and / or Arg716, more preferably Tyr641 and Tyr633 are substituted with positively charged amino acids lysine, arginine or histidine, and Arg652 and Arg710 are substituted with negatively charged amino acids glutamic acid or aspartic acid, or with the positively charged amino acid lysine.

[0166] In several aspects of the present invention, the first and second dimer-forming polypeptides form a heterodimer, the dimer-forming polypeptide is collectrin, and the collectrin dimer-forming polypeptide comprises a substitution that prevents the collectrin dimer-forming polypeptide from forming a homodimer, preferably the substitution is made at Arg59, Arg111, Tyr48 and / or Tyr40, more preferably Tyr48 and / or Tyr40 are substituted with a positively charged amino acid lysine, arginine or histidine, and Arg59 and / or Arg111 are substituted with a negatively charged amino acid glutamic acid or aspartic acid, or a positively charged amino acid lysine.

[0167] In embodiments, the dimerizing polypeptide is a collectrin-like domain (CLD), and the CLD comprises a substitution that promotes heterodimerization of the CLD dimerizing polypeptide, preferably: a) Tyr633 of either the first or second CLD dimer-forming polypeptide is preferably substituted with either a positively charged amino acid or a negatively charged amino acid; b) Tyr641 of either the first or second CLD dimer-forming polypeptide is preferably substituted with either a positively charged amino acid or a negatively charged amino acid; c) Arg652 of either the first or second CLD dimer-forming polypeptide is preferably substituted with either a positively charged amino acid or a negatively charged amino acid; d) Arg710 of either the first or second CLD dimer-forming polypeptide is preferably substituted with either a positively charged amino acid or a negatively charged amino acid; e) Ser709 of either the first or second CLD dimer-forming polypeptide is preferably substituted with either a positively charged amino acid or a negatively charged amino acid; and / or f) Arg713 of either the first or second CLD dimer-forming polypeptide is preferably substituted with either a positively charged amino acid or a negatively charged amino acid.

[0168] In some embodiments, the dimer-forming polypeptide is collectrin, and the collectrin dimer-forming polypeptide comprises a substitution that promotes heterodimerization of the collectrin dimer-forming polypeptide, preferably a) Tyr40 of either the first or second collectrin dimer-forming polypeptide is preferably substituted with either a positively charged amino acid or a negatively charged amino acid; b) Tyr48 of either the first or second collectrin dimer-forming polypeptide is preferably substituted with either a positively charged amino acid or a negatively charged amino acid; c) Arg59 of either the first or second collectrin dimer-forming polypeptide is preferably substituted with either a positively charged amino acid or a negatively charged amino acid; and / or d) Arg111 of either the first or second collectrin dimer-forming polypeptide is preferably substituted with either a positively charged amino acid or a negatively charged amino acid.

[0169] In embodiments, the dimerizing polypeptide is a collectrin-like domain (CLD), and the CLD comprises a substitution that promotes heterodimerization of the CLD dimerizing polypeptide, preferably: a) Tyr633 of the first CLD dimer-forming polypeptide is substituted with either a positively charged amino acid or a negatively charged amino acid, and Arg710 of the second CLD dimer-forming polypeptide is substituted with either the remaining positively charged amino acid or the remaining negatively charged amino acid; b) Tyr633 of the second CLD dimer-forming polypeptide is substituted with one of a positively charged amino acid or a negatively charged amino acid, and Arg710 of the first CLD dimer-forming polypeptide is substituted with one of the remaining positively charged amino acid or the remaining negatively charged amino acid; c) Tyr641 of the first CLD dimer-forming polypeptide is substituted with one of a positively charged amino acid or a negatively charged amino acid, and Arg652 of the second CLD dimer-forming polypeptide is substituted with one of the remaining positively charged amino acid or the remaining negatively charged amino acid; d) Tyr641 of the second CLD dimer-forming polypeptide is substituted with one of a positively charged amino acid or a negatively charged amino acid, and Arg652 of the first CLD dimer-forming polypeptide is substituted with one of the remaining positively charged amino acid or the remaining negatively charged amino acid; e) Arg652 of the first CLD dimer-forming polypeptide is substituted with either a positively charged amino acid or a negatively charged amino acid, and Arg638 of the second CLD dimer-forming polypeptide is substituted with either the remaining positively charged amino acid or the remaining negatively charged amino acid; f) Arg652 of the second CLD dimer-forming polypeptide is substituted with either a positively charged amino acid or a negatively charged amino acid, and Arg638 of the first CLD dimer-forming polypeptide is substituted with either the remaining positively charged amino acid or the remaining negatively charged amino acid; g) Arg710 of the first CLD dimer-forming polypeptide is substituted with either a positively charged amino acid or a negatively charged amino acid, and Glu639 of the second CLD dimer-forming polypeptide is substituted with either the remaining positively charged amino acid or the remaining negatively charged amino acid; h) Arg710 of the second CLD dimer-forming polypeptide is substituted with either a positively charged amino acid or a negatively charged amino acid, and Glu639 of the first CLD dimer-forming polypeptide is substituted with either the remaining positively charged amino acid or the remaining negatively charged amino acid; i) Ser709 of the first CLD dimer-forming polypeptide is substituted with either a positively charged amino acid or a negatively charged amino acid, and Arg716 of the second CLD dimer-forming polypeptide is substituted with either the remaining positively charged amino acid or the remaining negatively charged amino acid; j) Ser709 of the second CLD dimer-forming polypeptide is substituted with either a positively charged amino acid or a negatively charged amino acid, and Arg716 of the first CLD dimer-forming polypeptide is substituted with either the remaining positively charged amino acid or the remaining negatively charged amino acid; k) Asp713 of the first CLD dimer-forming polypeptide is substituted with either a positively charged amino acid or a negatively charged amino acid, and Arg716 of the second CLD dimer-forming polypeptide is substituted with either the remaining positively charged amino acid or the remaining negatively charged amino acid; and / or l) Agr713 of the second CLD dimer-forming polypeptide is substituted with either a positively charged amino acid or a negatively charged amino acid, and Arg716 of the first CLD dimer-forming polypeptide is substituted with either a positively charged amino acid or the remaining negatively charged amino acid.

[0170] In some embodiments, the dimer-forming polypeptide is collectrin, and the collectrin dimer-forming polypeptide comprises a substitution that promotes heterodimerization of the collectrin dimer-forming polypeptide, preferably a) Tyr40 of the first collectrin dimer-forming polypeptide is substituted with either a positively charged amino acid or a negatively charged amino acid, and Arg111 of the second collectrin dimer-forming polypeptide is substituted with either the remaining positively charged amino acid or the remaining negatively charged amino acid; b) Tyr40 of the second collectrin dimer-forming polypeptide is substituted with either a positively charged amino acid or a negatively charged amino acid, and Arg111 of the first collectrin dimer-forming polypeptide is substituted with either the remaining positively charged amino acid or the remaining negatively charged amino acid; c) Tyr48 of the first collectrin dimer-forming polypeptide is substituted with either a positively charged amino acid or a negatively charged amino acid, and Arg59 of the second collectrin dimer-forming polypeptide is substituted with either the remaining positively charged amino acid or the remaining negatively charged amino acid; and / or d) Tyr48 of the second collectrin dimer-forming polypeptide is substituted with either a positively charged amino acid or a negatively charged amino acid, and Arg59 of the first collectrin dimer-forming polypeptide is substituted with either a positively charged amino acid or the remaining negatively charged amino acid.

[0171] octahedral antibody The invention provides an octahedral antibody comprising a first, second, third, fourth, fifth and sixth domain, a) each of the first, second and third domains is selected from the group consisting of a Fab domain and an Fc domain; b) each of the first, second and third domains: i) a first polypeptide chain comprising a first N-terminus of the domain; and ii) a second polypeptide chain comprising a second N-terminus of said domain; Including, c) the first N-terminus of the first domain, the first N-terminus of the second domain, and the first N-terminus of the third domain are linked to each other by a non-peptidyl bond, wherein said non-peptidyl bond is i) a branched covalent bond, or ii) (1) a first trimerizing polypeptide attached to a first N-terminus of the first domain by a peptide bond or via a peptide linker; (2) a second trimerizing polypeptide linked to the first N-terminus of the second domain by a peptide bond or via a peptide linker; and (3) a third trimerizing polypeptide linked to the first N-terminus of the third domain by a peptide bond or via a peptide linker; is a non-covalent bond between wherein the first, second and third trimer-forming polypeptides are not immunoglobulins, d) the fourth domain is connected at its C-terminus by a peptide bond or via a peptide linker, i) the second N-terminus of the first domain, or ii) the N-terminus of the first trimer-forming polypeptide; binds to e) the fifth domain is connected at its C-terminus by a peptide bond or via a peptide linker, i) the second N-terminus of the second domain, or ii) the N-terminus of a second trimerizing polypeptide; binds to f) the sixth domain is connected at its C-terminus by a peptide bond or via a peptide linker, i) the second N-terminus of the third domain, or ii) the N-terminus of the third trimer-forming polypeptide binds to Octahedral antibodies are also provided.

[0172] In an embodiment of the octahedral antibody of the invention, the non-peptidyl bond is a non-covalent bond between a first trimerizing polypeptide linked to a first N-terminus of the first domain, a first trimerizing polypeptide linked to a first N-terminus of the second domain, and a first trimerizing polypeptide linked to a first N-terminus of the third domain, wherein the first, second, and third trimerizing polypeptides are selected from the group consisting of OX40L / TNFLSF4, CD40L / TNFLSF5, FASL / TNFLSF6, CD70L / TNFLSF7, and CD30L / TNFLSF8. , 4-1BBL / TNFLSF9, TRAIL / TNFLSF10, RANKL / TNFLSF11, TWEAK / TNFLSF12, APRIL / TNFLSF13, BAFF / TNFLSF13B, LIGHT / TNFLSF14, VEGI / TNFLSF15, GITRL / TNFLSF18, ectodysplasin ATNFLSF19, TNF / TNFLSF2, lymphotoxin α / TNFLSF1, and lymphotoxin β / TNFLSF3. In a preferred embodiment, the trimerizing polypeptides are selected from the group consisting of SEQ ID NOs: 787 to 790 (TNFSF1), SEQ ID NOs: 791 to 792 (TNFSF2), SEQ ID NOs: 793 to 795 (TNFSF3), SEQ ID NOs: 796 to 798 (TNFSF4), SEQ ID NOs: 799 to 802 (TNFSF5), SEQ ID NOs: 803 to 806, SEQ ID NOs: 807 to 809 (TNFSF7), SEQ ID NOs: 810 to 813 (TNFSF8), SEQ ID NOs: 814 to 816 (TNFSF9), and SEQ ID NOs: 820 to 822 (TNFSF10). TNFSF9), SEQ ID NOs: 817 to 820 (TNFSF10), SEQ ID NOs: 821 to 822 (TNFSF11), SEQ ID NOs: 823 to 827 (TNFSF12), SEQ ID NOs: 828 to 831 (TNFSF13), SEQ ID NOs: 832 to 833 (TNFSF13B), SEQ ID NOs: 834 to 837 (TNFSF14), SEQ ID NOs: 838 to 841 (TNFSF15), and SEQ ID NOs: 842 to 843 (TNFSF18).

[0173] In embodiments of the invention, the octahedral antibody further comprises a 7th, 8th and / or 9th domain, a) the seventh domain is linked at its C-terminus to the second N-terminus of the first domain by a peptide bond or via a peptide linker; b) the eighth domain is linked at its C-terminus to the second N-terminus of the second domain by a peptide bond or via a peptide linker; and / or c) The ninth domain is linked at its C-terminus to the second N-terminus of the third domain by a peptide bond or via a peptide linker.

[0174] In embodiments of the invention, the octahedral molecule further comprises a 10th, 11th and / or 12th domain; a) the tenth domain is connected at its N-terminus by a peptide bond or via a peptide linker, i) the first C-terminus of the first domain, or ii) a second C-terminus of the first domain; binds to b) the 11th domain is connected at its N-terminus by a peptide bond or via a peptide linker, i) the first C-terminus of the second domain, or ii) a second C-terminus of the second domain; binds to c) the 12th domain is connected at its N-terminus by a peptide bond or via a peptide linker, i) the first C-terminus of the third domain, or ii) the second C-terminus of the third domain; Combine with.

[0175] In some embodiments, the first, second, and third domains of the octahedral antibodies of the invention may be any of the domains described herein as the first and second domains of the tetrahedral antibodies of the invention. In some embodiments, the fourth, fifth, and sixth domains of the octahedral antibodies of the invention may be any of the domains described herein as the third and fourth domains of the tetrahedral antibodies of the invention. In some embodiments, the seventh, eighth, and ninth domains of the octahedral antibodies of the invention may be any of the domains described herein as the fifth and sixth domains of the tetrahedral antibodies of the invention. In some embodiments, the tenth, eleventh, and twelfth domains of the octahedral antibodies of the invention may be any of the domains described herein as the seventh and eighth domains of the tetrahedral antibodies of the invention. Furthermore, all such domains may contain any of the features (e.g., mutations) described for the domains of the tetrahedral antibodies of the invention.

[0176] octahedral molecule The invention provides an octahedral molecule comprising first, second, third, fourth, fifth and sixth domains, a) at least one of the first, second and third domains is not a Fab or Fc domain; and Each of the first, second, third, fourth, fifth and sixth domains independently comprises: i) a first polypeptide chain comprising a first N-terminus and a first C-terminus of the domain; and ii) optionally a second polypeptide chain comprising a second N-terminus and a second C-terminus of said domain; Including, b) the first N-terminus of the first domain, the first N-terminus of the second domain, and the first N-terminus of the third domain are (1) a first trimerizing polypeptide linked by a peptide bond or via a peptide linker to a first N-terminus of a first domain; (2) a second trimerizing polypeptide linked to the first N-terminus of the second domain by a peptide bond or via a peptide linker; and (3) a third trimerizing polypeptide linked to the first N-terminus of the third domain by a peptide bond or via a peptide linker; are bound to each other by non-covalent bonds between wherein the first, second and third trimer-forming polypeptides are not immunoglobulins, c) the fourth domain is connected at its first C-terminus by a peptide bond or via a peptide linker i) the N-terminus of the first trimer-forming polypeptide, or ii) if present, the second N-terminus of the first domain; binds to d) the fifth domain is connected at its first C-terminus by a peptide bond or via a peptide linker, i) the N-terminus of the second trimer-forming polypeptide, or ii) if present, the second N-terminus of the second domain; and e) the sixth domain is connected at its first C-terminus by a peptide bond or via a peptide linker to i) the N-terminus of a third trimer-forming polypeptide, or ii) the second N-terminus of the third domain, if present; binds to Octahedral molecules are also provided.

[0177] In one embodiment of the octahedral molecule of the invention, particularly the embodiment of paragraph

[0185] , the first, second, and third trimerizing polypeptides are selected from members of the TNF ligand superfamily consisting of OX40L / TNFLSF4, CD40L / TNFLSF5, FASL / TNFLSF6, CD70L / TNFLSF7, CD30L / TNFLSF8, 4-1BBL / TNFLSF9, TRAIL / TNFLSF10, RANKL / TNFLSF11, TWEAK / TNFLSF12, APRIL / TNFLSF13, BAFF / TNFLSF13B, LIGHT / TNFLSF14, VEGI / TNFLSF15, GITRL / TNFLSF18, ectodysplasin ATNFLSF19, TNF / TNFLSF2, lymphotoxin α / TNFLSF1, and lymphotoxin β / TNFLSF3. In a preferred embodiment, the trimerizing polypeptides are selected from the group consisting of SEQ ID NOs: 787 to 790 (TNFSF1), SEQ ID NOs: 791 to 792 (TNFSF2), SEQ ID NOs: 793 to 795 (TNFSF3), SEQ ID NOs: 796 to 798 (TNFSF4), SEQ ID NOs: 799 to 802 (TNFSF5), SEQ ID NOs: 803 to 806, SEQ ID NOs: 807 to 809 (TNFSF7), SEQ ID NOs: 810 to 813 (TNFSF8), SEQ ID NOs: 814 to 816 (TNFSF9), and SEQ ID NOs: 820 to 822 (TNFSF10). TNFSF9), SEQ ID NOs: 817 to 820 (TNFSF10), SEQ ID NOs: 821 to 822 (TNFSF11), SEQ ID NOs: 823 to 827 (TNFSF12), SEQ ID NOs: 828 to 831 (TNFSF13), SEQ ID NOs: 832 to 833 (TNFSF13B), SEQ ID NOs: 834 to 837 (TNFSF14), SEQ ID NOs: 838 to 841 (TNFSF15), and SEQ ID NOs: 842 to 843 (TNFSF18).

[0178] In some embodiments of the present invention, particularly in one embodiment of paragraph

[0185] , the octahedral molecule further contains a seventh, eighth and / or ninth domain, a) if present, the seventh domain is linked at its C-terminus to the second N-terminus of the first domain by a peptide bond or via a peptide linker; b) if present, the eighth domain is linked at its C-terminus to the second N-terminus of the second domain by a peptide bond or via a peptide linker; and / or c) If present, the ninth domain is linked at its C-terminus to the second N-terminus of the third domain by a peptide bond or via a peptide linker.

[0179] In some embodiments of the present invention, particularly in one embodiment of paragraph

[0185] , the compound further comprises a tenth, eleventh and / or twelfth domain, a) The tenth domain is: i) at its N-terminus, by a peptide bond or via a peptide linker, to the C-terminus of the first domain; or ii) at its C-terminus, by a peptide bond or via a peptide linker, to the N-terminus of the fourth domain; to combine, b) The 11th domain is: i) at its N-terminus to the first C-terminus of the second domain by a peptide bond or via a peptide linker; or ii) at its C-terminus, by a peptide bond or via a peptide linker, to the N-terminus of the fifth domain; to combine, c) The 12th domain is: i) at its N-terminus to the first C-terminus of the third domain by a peptide bond or via a peptide linker; or ii) at its C-terminus, by a peptide bond or via a peptide linker, to the N-terminus of the sixth domain; Combine.

[0180] In some embodiments, particularly one embodiment described in paragraph

[0185] , the first, second, and third domains of the octahedral molecules of the present invention may be any of the domains described herein as the first and second domains of the tetrahedral antibodies or molecules of the present invention, preferably other than the Fc or Fab domains. In some embodiments, the fourth, fifth, and sixth domains of the octahedral molecules of the present invention may be any of the domains described herein as the third and fourth domains of the tetrahedral antibodies or molecules of the present invention, preferably other than the Fc or Fab domains. In some embodiments, the seventh, eighth, and ninth domains of the octahedral molecules of the present invention may be any of the domains described herein as the fifth and sixth domains of the tetrahedral antibodies or molecules of the present invention. In some embodiments, the tenth, eleventh, and twelfth domains of the octahedral molecules of the present invention may be any of the domains described herein as the seventh and eighth domains of the tetrahedral antibodies or molecules of the present invention, or as the ninth and tenth domains of the tetrahedral molecules of the present invention. Furthermore, all such domains may contain any of the features (mutations, etc.) described for the domains of the tetrahedral antibodies of the invention.

[0181] In one embodiment of the octahedral molecule of the invention, particularly the embodiment in paragraph

[0185] , the first, second, and third domains are each other than an Fc or Fab domain. In one embodiment of the octahedral molecule of the invention, particularly the embodiment in paragraph

[0185] , the first, second, third, fourth, fifth, and sixth domains are each other than an Fc or Fab domain.

[0182] In one embodiment of the octahedral molecule of this invention, particularly in one embodiment of paragraph

[0185] : a) the first, second and / or third domain is selected from the group consisting of: (i) a secreted protein, and (ii) an extracellular domain of a transmembrane protein; b) the fourth, fifth and / or sixth domain is selected from the group consisting of: (i) a secreted protein, and (ii) an extracellular domain of a transmembrane protein; c) the first, second and third trimerizing polypeptides are selected from members of the TNF ligand superfamily consisting of OX40L / TNFLSF4, CD40L / TNFLSF5, FASL / TNFLSF6, CD70L / TNFLSF7, CD30L / TNFLSF8, 4-1BBL / TNFLSF9, TRAIL / TNFLSF10, RANKL / TNFLSF11, TWEAK / TNFLSF12, APRIL / TNFLSF13, BAFF / TNFLSF13B, LIGHT / TNFLSF14, VEGI / TNFLSF15, GITRL / TNFLSF18, ectodysplasin ATNFLSF19, TNF / TNFLSF2, lymphotoxin alpha / TNFLSF1 and lymphotoxin beta / TNFLSF3; d) The first, second, and third trimer-forming polypeptides are SEQ ID NOs: 787 to 790 (TNFSF1), SEQ ID NOs: 791 to 792 (TNFSF2), SEQ ID NOs: 793 to 795 (TNFSF3), SEQ ID NOs: 796 to 798 (TNFSF4), SEQ ID NOs: 799 to 802 (TNFSF5), SEQ ID NOs: 803 to 806, SEQ ID NOs: 807 to 809 (TNFSF7), SEQ ID NOs: 810 to 813 (TNFSF8), SEQ ID NOs: 814 to 816 (TNFSF9), NFSF9), SEQ ID NOs: 817 to 820 (TNFSF10), SEQ ID NOs: 821 to 822 (TNFSF11), SEQ ID NOs: 823 to 827 (TNFSF12), SEQ ID NOs: 828 to 831 (TNFSF13), SEQ ID NOs: 832 to 833 (TNFSF13B), SEQ ID NOs: 834 to 837 (TNFSF14), SEQ ID NOs: 838 to 841 (TNFSF15), and SEQ ID NOs: 842 to 843 (TNFSF18), e) the first, second and third trimerizing polypeptides are selected from members of the TNF ligand superfamily consisting of OX40L / TNFLSF4, CD40L / TNFLSF5, FASL / TNFLSF6, CD70L / TNFLSF7, CD30L / TNFLSF8, 4-1BBL / TNFLSF9, TRAIL / TNFLSF10, RANKL / TNFLSF11, TWEAK / TNFLSF12, APRIL / TNFLSF13, BAFF / TNFLSF13B, LIGHT / TNFLSF14, VEGI / TNFLSF15, GITRL / TNFLSF18, ectodysplasin ATNFLSF19, TNF / TNFLSF2, lymphotoxin alpha / TNFLSF1 and lymphotoxin beta / TNFLSF3, and the first, second and / or third domains are transmembrane domains that are not naturally associated with the selected first, second and third trimerizing polypeptides; f) The first, second, and third trimer-forming polypeptides are SEQ ID NOs: 787 to 790 (TNFSF1), SEQ ID NOs: 791 to 792 (TNFSF2), SEQ ID NOs: 793 to 795 (TNFSF3), SEQ ID NOs: 796 to 798 (TNFSF4), SEQ ID NOs: 799 to 802 (TNFSF5), SEQ ID NOs: 803 to 806, SEQ ID NOs: 807 to 809 (TNFSF7), SEQ ID NOs: 810 to 813 (TNFSF8), SEQ ID NOs: 814 to 816 (TNFSF9), SEQ ID NOs: 817 to 820 (TNFSF10), SEQ ID NOs: 821 to 822 (TNFSF11), SEQ ID NOs: 823 to 824 (TNFSF12), SEQ ID NOs: 825 to 826 (TNFSF13), SEQ ID NOs: 827 to 828 (TNFSF14), SEQ ID NOs: 829 to 830 (TNFSF15), SEQ ID NOs: 831 to 832 (TNFSF16), SEQ ID NOs: 833 to 834 (TNFSF17), SEQ ID NOs: 835 to 836 (TNFSF18), SEQ ID NOs: 837 to 838 (TNFSF19), SEQ ID NOs: 839 to 840 (TNFSF20), SEQ ID NOs: 841 to 842 (TNFSF21), SEQ ID NOs: 843 to 844 (TNFSF22), SEQ ID NOs: 845 to 846 (TNFSF23), SEQ ID 22 (TNFSF11), SEQ ID NOs: 823-827 (TNFSF12), SEQ ID NOs: 828-831 (TNFSF13), SEQ ID NOs: 832-833 (TNFSF13B), SEQ ID NOs: 834-837 (TNFSF14), SEQ ID NOs: 838-841 (TNFSF15) and SEQ ID NOs: 842-843 (TNFSF18), wherein the first, second and / or third domain is a transmembrane domain that is not naturally associated with the selected first, second and third trimerizing polypeptides. g) the first domain is selected from the group consisting of a binding domain of a protein or a portion or modified version thereof, a secreted protein or a portion or modified version thereof, a transmembrane protein or a portion or modified version thereof, an intracellular binding domain or a portion or modified version thereof, and an antibody or a portion or modified version thereof; h) the second domain is selected from the group consisting of a binding domain of a protein or a portion or modified version thereof, a secreted protein or a portion or modified version thereof, a transmembrane protein or a portion or modified version thereof, an intracellular binding domain or a portion or modified version thereof, and an antibody or a portion or modified version thereof, i) the third domain is selected from the group consisting of a binding domain of a protein or a portion or modified version thereof, a secreted protein or a portion or modified version thereof, a transmembrane protein or a portion or modified version thereof, an intracellular binding domain or a portion or modified version thereof, and an antibody or a portion or modified version thereof; j) the fourth domain is selected from the group consisting of a binding domain of a protein or a portion or modified version thereof, a secreted protein or a portion or modified version thereof, a transmembrane protein or a portion or modified version thereof, an intracellular binding domain or a portion or modified version thereof, and an antibody or a portion or modified version thereof; k) the fifth domain is selected from the group consisting of a binding domain of a protein or a portion or modified version thereof, a secreted protein or a portion or modified version thereof, a transmembrane protein or a portion or modified version thereof, an intracellular binding domain or a portion or modified version thereof, and an antibody or a portion or modified version thereof, l) the sixth domain is selected from the group consisting of a binding domain of a protein or a portion or modified version thereof, a secreted protein or a portion or modified version thereof, a transmembrane protein or a portion or modified version thereof, an intracellular binding domain or a portion or modified version thereof, and an antibody or a portion or modified version thereof; m) if present, the seventh domain is selected from the group consisting of a binding domain of a protein or a portion or modified version thereof, a secreted protein or a portion or modified version thereof, a transmembrane protein or a portion or modified version thereof, an intracellular binding domain or a portion or modified version thereof, and an antibody or a portion or modified version thereof; n) if present, the eighth domain is selected from the group consisting of a binding domain of a protein or a portion or modified version thereof, a secreted protein or a portion or modified version thereof, a transmembrane protein or a portion or modified version thereof, an intracellular binding domain or a portion or modified version thereof, and an antibody or a portion or modified version thereof; o) if present, the ninth domain is selected from the group consisting of a binding domain of a protein or a portion or modified version thereof, a secreted protein or a portion or modified version thereof, a transmembrane protein or a portion or modified version thereof, an intracellular binding domain or a portion or modified version thereof, and an antibody or a portion or modified version thereof; p) if present, the tenth domain is selected from the group consisting of a binding domain of a protein or a portion or modified version thereof, a secreted protein or a portion or modified version thereof, a transmembrane protein or a portion or modified version thereof, an intracellular binding domain or a portion or modified version thereof, and an antibody or a portion or modified version thereof; q) if present, the 11th domain is selected from the group consisting of a binding domain of a protein or a portion or modified version thereof, a secreted protein or a portion or modified version thereof, a transmembrane protein or a portion or modified version thereof, an intracellular binding domain or a portion or modified version thereof, and an antibody or a portion or modified version thereof; r) if present, the twelfth domain is selected from the group consisting of a binding domain of a protein or a portion or modified version thereof, a secreted protein or a portion or modified version thereof, a transmembrane protein or a portion or modified version thereof, an intracellular binding domain or a portion or modified version thereof, and an antibody or a portion or modified version thereof; s) the first domain is other than a binding domain of a protein or a portion or modified version thereof, a secreted protein or a portion or modified version thereof, a transmembrane protein or a portion or modified version thereof, an intracellular binding domain or a portion or modified version thereof, and an antibody or a portion or modified version thereof, t) the second domain is other than a binding domain of a protein or a portion or modified version thereof, a secreted protein or a portion or modified version thereof, a transmembrane protein or a portion or modified version thereof, an intracellular binding domain or a portion or modified version thereof, and an antibody or a portion or modified version thereof; u) the third domain is other than a binding domain of a protein or a portion or modified version thereof, a secreted protein or a portion or modified version thereof, a transmembrane protein or a portion or modified version thereof, an intracellular binding domain or a portion or modified version thereof, and an antibody or a portion or modified version thereof; v) the fourth domain is other than a binding domain of a protein or a portion or modified version thereof, a secreted protein or a portion or modified version thereof, a transmembrane protein or a portion or modified version thereof, an intracellular binding domain or a portion or modified version thereof, and an antibody or a portion or modified version thereof; w) the fifth domain is other than a binding domain of a protein or a portion or modified version thereof, a secreted protein or a portion or modified version thereof, a transmembrane protein or a portion or modified version thereof, an intracellular binding domain or a portion or modified version thereof, and an antibody or a portion or modified version thereof; x) the sixth domain is other than a binding domain of a protein or a portion or modified version thereof, a secreted protein or a portion or modified version thereof, a transmembrane protein or a portion or modified version thereof, an intracellular binding domain or a portion or modified version thereof, and an antibody or a portion or modified version thereof; y) if present, the seventh domain is other than a binding domain of a protein or a portion or modified version thereof, a secreted protein or a portion or modified version thereof, a transmembrane protein or a portion or modified version thereof, an intracellular binding domain or a portion or modified version thereof, and an antibody or a portion or modified version thereof; z) if present, the eighth domain is other than a binding domain of a protein or a portion or modified version thereof, a secreted protein or a portion or modified version thereof, a transmembrane protein or a portion or modified version thereof, an intracellular binding domain or a portion or modified version thereof, and an antibody or a portion or modified version thereof; aa) if present, the ninth domain is other than a binding domain of a protein or a part or modified version thereof, a secreted protein or a part or modified version thereof, a transmembrane protein or a part or modified version thereof, an intracellular binding domain or a part or modified version thereof, and an antibody or a part or modified version thereof; bb) if present, the tenth domain is other than a binding domain of a protein or a portion or modified version thereof, a secreted protein or a portion or modified version thereof, a transmembrane protein or a portion or modified version thereof, an intracellular binding domain or a portion or modified version thereof, and an antibody or a portion or modified version thereof; cc) if present, the 11th domain is other than a binding domain of a protein or a portion or modified version thereof, a secreted protein or a portion or modified version thereof, a transmembrane protein or a portion or modified version thereof, an intracellular binding domain or a portion or modified version thereof, and an antibody or a portion or modified version thereof; dd) if present, the twelfth domain is other than a binding domain of a protein or a portion or modified version thereof, a secreted protein or a portion or modified version thereof, a transmembrane protein or a portion or modified version thereof, an intracellular binding domain or a portion or modified version thereof, and an antibody or a portion or modified version thereof; ee) the first, second, third, fourth, fifth and / or sixth domain is a CD3 zeta chain intracellular binding domain, a CD28 intracellular binding domain or a 4-1BB intracellular binding domain, a CD3 epsilon chain intracellular binding domain, an ICOS intracellular binding domain, an OX40 intracellular binding domain or a 4-1BB intracellular binding domain; ff) if present, the 10th, 11th and / or 12th domains are the CD3 zeta chain intracellular binding domain, the CD28 intracellular binding domain or the 4-1BB intracellular binding domain, the CD3 epsilon chain intracellular binding domain, the ICOS intracellular binding domain, the OX40 intracellular binding domain or the 4-1BB intracellular binding domain; gg) the octahedral molecule comprises 1st, 2nd, 3rd, 4th, 5th, 6th, 10th, 11th and 12th domains; i) the fourth, fifth and sixth domains are respectively a binding domain or a part or modified version of a protein, preferably a binding domain of a secreted protein, an extracellular domain of a transmembrane protein or an antibody or part thereof, more preferably a single chain part of an antibody, more preferably a single chain or single domain antibody molecule, more preferably an scFV domain; ii) the first, second and third domains are each a transmembrane domain, more preferably a transmembrane domain of TNFRSFl, TNFRSFlB, LTBR, ​​CD40, FasR, DCR3, CD27, CD30, DR4, DR5, DCR2, RANK, TWEAK-R, TACI, BAF-R, HVEM, BCMA, GITR, TROY, DR3 or XEDAR, more preferably a transmembrane domain of ACE2, collectrin, CD8a, CD8b, CD3ζ, CD3ε, CD28, ICOS, OX40, 4-1BB, TNFSF1, TNFSF2, TNFSF3, TNFSF4, TNFSF5, TNFSF6, TNFSF7, TNFSF8, TNFSF9, TNFSF10, TNFSF11, TNFSF12, TNFSF13, TNFSF13B, TNFSF14, TNFSF15 or TNFSF18; iii) the tenth, eleventh and twelfth domains are N-terminally linked to the C-termini of the first, second and third domains, respectively, and each is an intracellular binding domain, preferably an intracellular binding domain of the CD3 zeta chain, the CD3 epsilon chain, CD28, ICOS, OX40 or 4-1BB; hh) the octahedral molecule comprises domains 1, 2, 3, 4, 5, 6, 10, 11 and 12, wherein domains 4, 5 and 6 are each scFv domains, domains 1, 2 and 3 are transmembrane domains of ACE2, collectrin, CD8a, CD8b, CD3ζ, CD3ε, CD28, ICOS, OX40 or 4-1BB, and domains 10, 11 and 12 are N-terminally linked to the C-terminus of domains 1, 2 and 3, respectively, and are each the intracellular binding domain of CD3ζ chain, CD3ε chain, CD28, ICOS, OX40 or 4-1BB; ii) the octahedral molecule comprises a 1st, 2nd, 3rd, 4th, 5th, 6th, 10th, 11th and 12th domain; i) the tenth, eleventh and twelfth domains are C-terminally linked to the N-terminus of the fourth, fifth and sixth domains, respectively, and each is a binding domain of a protein or a part or modified version thereof, preferably a binding domain of a secreted protein, an extracellular domain of a transmembrane protein or an antibody or part thereof, more preferably a single chain part of an antibody, more preferably a single chain or single domain antibody molecule, more preferably an scFV domain; ii) the fourth, fifth and sixth domains are each a transmembrane domain, more preferably the transmembrane domain of TNFSF1, TNFSF2, TNFSF3, TNFSF4, TNFSF5, TNFSF6, TNFSF7, TNFSF8, TNFSF9, TNFSF10, TNFSF11, TNFSF12, TNFSF13, TNFSF13B, TNFSF14, TNFSF15 or TNFSF18, more preferably the transmembrane domain of ACE2, collectrin, CD8a, CD8b, CD3zeta, CD3epsilon, CD28, ICOS, OX40, 4-1BB, TNFRSF1, TNFRSF1B, LTBR, ​​CD40, FasR, DCR3, CD27, CD30, DR4, DR5, DCR2, RANK, TWEAK-R, TACI, BAF-R, HVEM, BCMA, GITR, TROY, DR3 or XEDAR; iii) the first, second and third domains are each an intracellular binding domain, preferably an intracellular binding domain of CD3 zeta chain, CD3 epsilon chain, CD28, ICOS, OX40 or 4-1BB; jj) the octahedral molecule comprises domains 1, 2, 3, 4, 5, 6, 10, 11 and 12, the 10th, 11th and 12th domains being C-terminally linked to the N-terminus of domains 4, 5 and 6, respectively, each being an scFv domain, the 4th, 5th and 6th domains being transmembrane domains of ACE2, collectrin, CD8a, CD8b, CD3zeta, CD3epsilon, CD28, ICOS, OX40 or 4-1BB, and the 1st, 2nd and 3rd domains being intracellular binding domains of CD3zeta chain, CD3epsilon chain, CD28, ICOS, OX40 or 4-1BB, respectively; kk) the octahedral molecule comprises a 1st, 2nd, 3rd, 4th, 5th, 6th, 10th, 11th and 12th domain; i) the fourth, fifth and sixth domains are respectively a binding domain or a part or modified version of a protein, preferably a binding domain of a secreted protein, an extracellular domain of a transmembrane protein or an antibody or part thereof, more preferably a single chain part of an antibody, more preferably a single chain or single domain antibody molecule, more preferably an scFV domain; ii) the first, second and third domains are each a transmembrane domain, more preferably a transmembrane domain of TNFRSFl, TNFRSFlB, LTBR, ​​CD40, FasR, DCR3, CD27, CD30, DR4, DR5, DCR2, RANK, TWEAK-R, TACI, BAF-R, HVEM, BCMA, GITR, TROY, DR3 or XEDAR, more preferably a transmembrane domain of ACE2, collectrin, CD8a, CD8b, CD3ζ, CD3ε, CD28, ICOS, OX40, 4-1BB, TNFSF1, TNFSF2, TNFSF3, TNFSF4, TNFSF5, TNFSF6, TNFSF7, TNFSF8, TNFSF9, TNFSF10, TNFSF11, TNFSF12, TNFSF13, TNFSF13B, TNFSF14, TNFSF15 or TNFSF18; iii) the tenth, eleventh and twelfth domains are N-terminally linked to the C-termini of the first, second and third domains, respectively, and each is an antigen or neoantigen; ll) the octahedral molecule comprises domains 1, 2, 3, 4, 5, 6, 10, 11 and 12, wherein domains 4, 5 and 6 are each scFv domains, domains 1, 2 and 3 are transmembrane domains of ACE2, collectrin, CD8a, CD8b, CD3ζ, CD3ε, CD28, ICOS, OX40 or 4-1BB, and domains 10, 11 and 12 are N-terminally linked to the C-termini of domains 1, 2 and 3, respectively, and each is an antigen or neoantigen; mm) the octahedral molecule comprises a 1st, 2nd, 3rd, 4th, 5th, 6th, 10th, 11th and 12th domain; i) the tenth, eleventh and twelfth domains are C-terminally linked to the N-terminus of the fourth, fifth and sixth domains, respectively, and each is a binding domain of a protein or a part or modified version thereof, preferably a binding domain of a secreted protein, an extracellular domain of a transmembrane protein or an antibody or part thereof, more preferably a single chain part of an antibody, more preferably a single chain or single domain antibody molecule, more preferably an scFV domain; ii) the fourth, fifth and sixth domains are each a transmembrane domain, more preferably the transmembrane domain of TNFSF1, TNFSF2, TNFSF3, TNFSF4, TNFSF5, TNFSF6, TNFSF7, TNFSF8, TNFSF9, TNFSF10, TNFSF11, TNFSF12, TNFSF13, TNFSF13B, TNFSF14, TNFSF15 or TNFSF18, more preferably the transmembrane domain of ACE2, collectrin, CD8a, CD8b, CD3zeta, CD3epsilon, CD28, ICOS, OX40, 4-1BB, TNFRSF1, TNFRSF1B, LTBR, ​​CD40, FasR, DCR3, CD27, CD30, DR4, DR5, DCR2, RANK, TWEAK-R, TACI, BAF-R, HVEM, BCMA, GITR, TROY, DR3 or XEDAR; iii) the first, second and third domains are antigens or neo-antigens, respectively; or nn) The octahedral molecule comprises domains 1, 2, 3, 4, 5, 6, 10, 11 and 12, wherein domains 10, 11 and 12 are C-terminally linked to the N-terminus of domains 4, 5 and 6, respectively, each being an scFv domain, wherein domains 4, 5 and 6 are transmembrane domains of ACE2, collectrin, CD8a, CD8b, CD3ζ, CD3ε, CD28, ICOS, OX40 or 4-1BB, respectively, and domains 1, 2 and 3 are antigens or neoantigens, respectively.

[0183] In embodiments of the invention that include transmembrane domains as the first, second, and third domains, the octahedral molecule preferably includes first, second, and third trimerizing polypeptides that are naturally associated with said transmembrane domains, e.g., if the first, second, and third domains are the transmembrane domains of TNFSF1, the first, second, and third trimerizing polypeptides are the extracellular domains of TNFSF1.

[0184] Any preferred embodiment of the octahedral molecule of this invention, particularly paragraph

[0185] In one embodiment, the first, second and third domains are each a transmembrane domain. Alternatively, any preferred embodiment of the octahedral molecule of the invention, particularly paragraph

[0186] In one embodiment, the fourth, fifth and sixth domains are each transmembrane domains.

[0185] Tetrahedral and octahedral antibodies or molecules In some aspects of the invention, a) one or more of the first, second, third, fourth, fifth, sixth, seventh and eighth domains of a tetrahedral antibody or molecule, or one or more of the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh and twelfth domains of an octahedral antibody or molecule, are Fc domains, and said one or more Fc domains are independently selected from any of the Fc domains disclosed herein; b) one or more of the first, second, third, fourth, fifth, sixth, seventh and eighth domains of a tetrahedral antibody or molecule, or one or more of the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh and twelfth domains of an octahedral antibody or molecule, are Fab domains, and one or more of said Fc domains are independently selected from any of the Fc domains disclosed herein; c) one or more of the third, fourth, fifth, sixth, seventh and eighth domains of the tetrahedral antibody or molecule, or one or more of the fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh and twelfth domains of the octahedral antibody or molecule, are secreted proteins, and said one or more secreted proteins are independently selected from any of the secreted proteins disclosed herein; d) one or more of the third, fourth, fifth, sixth, seventh and eighth domains of the tetrahedral antibody or molecule, or one or more of the fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh and twelfth domains of the octahedral antibody or molecule, are extracellular domains of transmembrane proteins, and said one or more extracellular domains of transmembrane proteins are independently selected from any of the extracellular domains of transmembrane proteins disclosed herein; e) one or more of the third, fourth, fifth, sixth, seventh and eighth domains of a tetrahedron or one or more of the fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh and twelfth domains of an octahedral antibody or molecule are i) contains the structure of a compound that is an approved drug for treating a subject suffering from a disease; ii) biologically active, including organic compounds with a molecular weight of less than 1000 daltons, DNA aptamers, RNA aptamers, oligonucleotides or protein structures; iii) iii) containing a primary or secondary amine, iv) aripiprazole or oseltamivir; v) is a respiratory drug, antiasthmatic, analgesic, antidepressant, antianginal, antiarrhythmic, antihypertensive, antidiabetic, antihistamine, anti-infective, antibiotic, anti-inflammatory, antiparkinsonian, antipsychotic, antipyretic, antiulcer, attention deficit hyperactivity disorder (ADHD), central nervous system stimulant, decongestant or psychostimulant; vi) Alprenolol, acebutolol, amidefrin, amineptine, amosulalol, amoxapine, amfetaminil, atenolol, atomoxetine, balofloxacin, bamethan, befunolol, benazepril, benfluorex, benzoctamine, betahistine, betaxolol, bevantolol, bifemelane, bisoprolol, brinzolamide, bufenide, butethamine, camilofine, carazolol, carticaine, carvedilol, cephaeline, ciprofloxacin, clozapine, clobenzorex, clorprenaline, cyclosporine Lopentamine, delapril, demexiptyline, denopamine, desipramine, desloratadine, diclofenac, dimetofrine, dioxadrol, dobutamine, dopexamine, doripenem, dorzolamide, droprenilamine, duloxetine, eltoprazine, enalapril, enoxacin, epinephrine, ertapenem, esaprazole, esmolol, etoxadrol, fasudil, fendiline, fenetylline, fenfluramine, fenoldopam, fenoterol, fenproporex, flecainide, fluoxetine, formoterol , frovatriptan, gaboxadol, garenoxacin, gatifloxacin, grepafloxacin, hexoprenaline, imidapril, indalpine, indecainide, indeloxazine hydrochloride, isoxsuprine, ispronicline, labetalol, landiolol, lapatinib, levofacetoperane, lisinopril, lomefloxacin, lotrafiban, maprotiline, mecamylamine, mefloquine, mepindolol, meropenem, metapramine, metaproterenol, methoxyphenamine, dextrorotatory methylphenidate, methylphenidate, methipranol rol, metoprolol, mitoxantrone, mivazerol, moexipril, moprolol, moxifloxacin, nebivolol, nifenalol, nipradilol, norfloxacin, nortriptyline, nylidrin, olanzapine, oxamniquine, oxprenolol, oxyfedrine, paroxetine, perhexiline, phenmetrazine, phenylephrine, phenylpropylmethylamine, phoredrin, picirolex, pimetyline, pindolol, pipemidic acid, pyridocaine, practolol, pradofloxacin, pramipexole,pramiverine, prenalterol, prenylamine, prilocaine, procaterol, pronethalol, propafenone, propranolol, propylhexedrine, protokylol, protriptyline, pseudoephedrine, reboxetine, rasagiline, (r)-rasagiline, repinotan, reproterol, rimiterol, ritodrine, safinamide, salbutamol / albuterol, salmeterol, sarizotan, sertraline, silodosin, sotalol, soterenol, sparfloxacin, spirapril, sulfinalol, synephrine, tamsulosin, tevanicline, tianeptine, tirofiban, tretoquinol, trimetazidine, troxipide, varenicline, vildagliptin, viloxazine, viquidil, or xamoterol. vii) contains a biologically active protein; viii) is biologically active so as to have target binding activity; ix) is an independently folding protein or portion thereof; x) is a glycosylated protein; xi) containing intrachain disulfide bonds; xii) bind to cytokines; xiii) binds to a cytokine, wherein the cytokine is TNFα; xiv) atrial natriuretic peptide (ANP), calcitonin, corticotropin-releasing hormone (CRH), endothelin, exenatide, gastric inhibitory polypeptide (GIP), glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 (GLP-2), analogs of GLP-1 or GLP-2, glucagon vasoactive intestinal peptide (GVIP), ghrelin, peptide YY, or secretin, or portions thereof; xv) comprising a consecutive amino acid sequence within the sequence HGEGTFTSDVSSYLEEQAAKEFIAWLVKGRG (SEQ ID NO: 4657); xvi) contains at least one consecutive amino acid sequence identical to consecutive amino acids present in the heavy chain of the Fab or Fab' of the antibody; xvii) contains at least one consecutive amino acid sequence identical to consecutive amino acids present in the light chain of the Fab or Fab' of the antibody; xviii) comprising the Fab or Fab' or a portion of at least one Fab or Fab' of at least one antibody, xix) containing Fab-1 or Fab'1 of an antibody or a portion thereof; xx) containing Fab-2 or Fab'2 of an antibody or a portion thereof; xxi) containing two Fab or Fab' arms of an antibody, xxii) contains at least one consecutive amino acid sequence identical to a consecutive amino acid sequence present in a single-chain antibody; or xxiii) contains at least one consecutive amino acid sequence identical to that present in the TNFα receptor; f) the tetrahedral or octahedral antibody comprises a covalent bond, the covalent bond being selected from the covalent bonds disclosed herein or comprising a heterobifunctional crosslinker disclosed herein; and / or g) the tetrahedral or octahedral antibody or molecule comprises one or more peptide linkers, said one or more peptide linkers independently comprising: i) consecutive amino acids of the sequence TSTSPTRSMAPGAVHLPQPVSTRSQHTQPTPEPSTAPSTSFLLPMGPSPPAEGSTGD (SEQ ID NO: 3227), or consecutive amino acids present in said sequence; ii) consecutive amino acids of the sequence GGGGAGGGGAGGGGAGGGGAGGGGAGGG (SEQ ID NO: 226), or consecutive amino acids present in said sequence; or iii) a peptide linker as disclosed herein; is selected from.

[0186] Figures 1-14 and 29A-42 schematically illustrate various non-limiting examples of tetrahedral and octahedral antibodies of the present invention. Descriptions of the various domains of these tetrahedral and octahedral antibodies are provided in the brief description of the figures (represented by ellipses of various colors and / or patterns). Each figure represents an embodiment of the present invention. Additionally, the Examples of this application provide specific tetrahedral antibodies, each of which is an embodiment of the present invention. The present invention contemplates generating variants of each of these specific tetrahedral antibodies. Specifically, where the tetrahedral antibodies disclosed in the Examples contain modified sequences, the present invention specifically contemplates variants in which the modified sequences are replaced with wild-type sequences. Conversely, the present invention specifically contemplates modifying any of the tetrahedral antibodies by replacing the wild-type sequences, if present, with mutant counterparts containing any of the relevant mutations described herein.

[0187] The invention provides a method for the preparation of a tetrahedral or octahedral antibody of the invention, as a proportion (w / w) of peptide-containing molecules in a composition, comprising administering to the subject a tetrahedral or octahedral antibody of the invention at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, at least 19%, at least 20%, at least 21%, at least 22%, at least 23%, at least 24%, at least 25%, at least 26%, at least 27%, at least 28%, at least 29%, at least 30%, at least 31%, at least 32%, at least 33%, at least 34%, at least 35%, at least 36%, at least 37%, at least 38%, at least 39%, at least 40%, at least 41%, at least 42%, at least 43%, at least 44%, at least 45%, at least 46%, at least 47%, at least 48%, at least 49%, at least 50%, at least 51%, at least 52%, Also provided are compositions comprising at least 53%, at least 54%, at least 55%, at least 56%, at least 57%, at least 58%, at least 59%, at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99%.

[0188] Manufacturing method The present invention also provides a method for producing a tetrahedral antibody of the present invention comprising four domains, wherein the non-peptidyl bond of the tetrahedral antibody is a non-covalent bond between a first dimer-forming polypeptide attached to a first N-terminus of a first domain and a second dimer-forming polypeptide attached to a first N-terminus of a second domain, the method comprising: a) recombinantly expressing in a host cell each of the following polypeptides: i) in the N-terminal to C-terminal direction, (1) a third domain (optional); (2) a first dimer-forming polypeptide; (3) the first polypeptide chain of the first domain wherein (if a third domain is present) the C-terminus of the third domain is joined by a peptide bond or via a peptide linker to the N-terminus of the first dimer-forming polypeptide, and the C-terminus of the first dimer-forming polypeptide is joined by a peptide bond or via a peptide linker to the N-terminus of the first polypeptide chain of the first domain; ii) from its N-terminus to its C-terminus, (1) A fourth domain (optional), (2) a second dimer-forming polypeptide; (3) a first polypeptide chain of the second domain; wherein (if a fourth domain is present) the C-terminus of the fourth domain is joined by a peptide bond or via a peptide linker to the N-terminus of the second dimer-forming polypeptide, and the C-terminus of the second dimer-forming polypeptide is joined by a peptide bond or via a peptide linker to the N-terminus of the first polypeptide chain of the second domain; iii) in the N-terminal to C-terminal direction, (1) a third domain, if not present in the first polypeptide; a. a third dimer-forming polypeptide, the C-terminus of which is linked to the N-terminus of the second polypeptide chain of the first domain by a peptide bond or via a peptide linker; or b. a second polypeptide chain of the first domain; wherein the C-terminus of the third domain is linked by a peptide bond or via a peptide linker to the N-terminus of the third dimer-forming polypeptide or the second polypeptide chain of the first domain; iv) in the N-terminal to C-terminal direction, (1) a fourth domain, if not present in the second polypeptide; a. a fourth dimer-forming polypeptide, the C-terminus of which is linked by a peptide bond or via a peptide linker to the N-terminus of the second polypeptide chain of the first domain; or b. a second polypeptide chain of the first domain; a fourth polypeptide comprising: a C-terminus of the fourth domain linked by a peptide bond or via a peptide linker to the N-terminus of the fourth dimer-forming polypeptide or a second polypeptide chain of the first domain; and v) one or more additional polypeptides (optional) comprising the second polypeptide chain of the third and / or fourth domain (if present); Includes:

[0189] The present invention also provides a method for producing a tetrahedral antibody of the present invention comprising four domains, wherein the non-peptidyl bond of the tetrahedral antibody is a non-covalent bond between a first dimer-forming polypeptide attached to a first C-terminus of a first domain and a second dimer-forming polypeptide attached to a first N-terminus of a second domain, the method comprising: a) recombinantly expressing in a host cell each of the following polypeptides: i) in the N-terminal to C-terminal direction, (1) a first polypeptide chain of a first domain; (2) a first dimer-forming polypeptide; (3) the third domain; wherein the C-terminus of the first polypeptide chain of the first domain is linked by a peptide bond or via a peptide linker to the N-terminus of the first dimer-forming polypeptide, and the C-terminus of the first dimer-forming polypeptide is linked by a peptide bond or via a peptide linker to the N-terminus of the third domain, optionally ii) from its N-terminus to its C-terminus, (1) A fourth domain (optional), (2) a second dimer-forming polypeptide; (3) a first polypeptide chain of the second domain; wherein (if the fourth domain is present) the C-terminus of the fourth domain is joined by a peptide bond or via a peptide linker to the N-terminus of the second dimer-forming polypeptide, and the C-terminus of the second dimer-forming polypeptide is joined by a peptide bond or via a peptide linker to the N-terminus of the first polypeptide chain of the second domain; iii) in the N-terminal to C-terminal direction, (1) a second polypeptide chain of the first domain; a. a third dimer-forming polypeptide, the C-terminus of which is linked to the N-terminus of the third domain by a peptide bond or via a peptide linker; or b. a third domain, if not present in said first polypeptide; wherein the C-terminus of the second polypeptide chain of the first domain is linked by a peptide bond or via a peptide linker to the N-terminus of the third dimer-forming polypeptide or the third domain; iv) in the N-terminal to C-terminal direction, (1) a fourth domain, if not present in the second polypeptide; a. a fourth dimer-forming polypeptide, the C-terminus of which is linked by a peptide bond or via a peptide linker to the N-terminus of the second polypeptide chain of the first domain; or b. a second polypeptide chain of the first domain; a fourth polypeptide comprising: a C-terminus of the fourth domain linked by a peptide bond or via a peptide linker to the N-terminus of the fourth dimer-forming polypeptide or a second polypeptide chain of the first domain; and v) one or more additional polypeptides (optional) comprising the second polypeptide chain of the third and / or fourth domain (if present); Includes.

[0190] The present invention also provides a method for producing a tetrahedral antibody of the present invention comprising four domains, wherein the non-peptidyl bond of the tetrahedral antibody is a non-covalent bond between a first dimer-forming polypeptide attached to a first N-terminus of the first domain and a second dimer-forming polypeptide attached to a first C-terminus of the second domain, the method comprising: a) recombinantly expressing in a host cell each of the following polypeptides: i) in the N-terminal to C-terminal direction, (1) a third domain (optional); (2) a first dimer-forming polypeptide; (3) a first polypeptide chain of the first domain; wherein (if a third domain is present) the C-terminus of the third domain is joined by a peptide bond or via a peptide linker to the N-terminus of the first dimer-forming polypeptide, and the C-terminus of the first dimer-forming polypeptide is joined by a peptide bond or via a peptide linker to the N-terminus of the first polypeptide chain of the first domain; ii) from its N-terminus to its C-terminus, (1) a first polypeptide chain of the second domain; (2) a second dimer-forming polypeptide; (3) the third domain; wherein the C-terminus of the first polypeptide chain of the second domain is linked by a peptide bond or via a peptide linker to the N-terminus of the second dimer-forming polypeptide, and the C-terminus of the second dimer-forming polypeptide is linked by a peptide bond or via a peptide linker to the N-terminus of the third domain, optionally iii) in the N-terminal to C-terminal direction, (1) a third domain, if not present in the first polypeptide; a. a third dimer-forming polypeptide, the C-terminus of which is linked to the N-terminus of the second polypeptide chain of the first domain by a peptide bond or via a peptide linker; or b. a second polypeptide chain of the first domain; wherein the C-terminus of the third domain is linked by a peptide bond or via a peptide linker to the N-terminus of the third dimer-forming polypeptide or the second polypeptide chain of the first domain; iv) in the N-terminal to C-terminal direction, (1) a second polypeptide chain of the first domain; a. a fourth dimer-forming polypeptide, the C-terminus of which is linked to the N-terminus of the fourth domain by a peptide bond or via a peptide linker; or b. a fourth domain, if not present in said second polypeptide; a fourth polypeptide comprising: a C-terminus of the second polypeptide chain of the first domain linked by a peptide bond or via a peptide linker to the N-terminus of the fourth dimer-forming polypeptide or the fourth domain; and v) one or more additional polypeptides (optional) comprising the second polypeptide chain of said third and / or fourth (if present) domain, Includes.

[0191] The present invention also provides a method for producing a tetrahedral antibody of the present invention comprising four domains, wherein the non-peptidyl bond of the tetrahedral antibody is a non-covalent bond between a first dimer-forming polypeptide attached to a first C-terminus of a first domain and a second dimer-forming polypeptide attached to a first C-terminus of a second domain, the method comprising: a) recombinantly expressing in a host cell each of the following polypeptides: i) in the N-terminal to C-terminal direction, (1) a first polypeptide chain of a first domain; (2) a first dimer-forming polypeptide; (3) the third domain; wherein the C-terminus of the first polypeptide chain of the first domain is linked by a peptide bond or via a peptide linker to the N-terminus of the first dimer-forming polypeptide, and the C-terminus of the first dimer-forming polypeptide is linked by a peptide bond or via a peptide linker to the N-terminus of the third domain, optionally ii) from its N-terminus to its C-terminus, (1) a first polypeptide chain of the second domain; (2) a second dimer-forming polypeptide; (3) the third domain; wherein the C-terminus of the first polypeptide chain of the second domain is linked by a peptide bond or via a peptide linker to the N-terminus of the second dimer-forming polypeptide, and the C-terminus of the second dimer-forming polypeptide is linked by a peptide bond or via a peptide linker to the N-terminus of the third domain, optionally iii) in the N-terminal to C-terminal direction, (1) a second polypeptide chain of the first domain; a. a third dimer-forming polypeptide, the C-terminus of which is linked to the N-terminus of the third domain by a peptide bond or via a peptide linker; or b. a third domain, if not present in said first polypeptide; wherein the C-terminus of the second polypeptide chain of the first domain is linked by a peptide bond or via a peptide linker to the N-terminus of the third dimer-forming polypeptide or the third domain; iv) in the N-terminal to C-terminal direction, (1) a second polypeptide chain of the first domain; a. a fourth dimer-forming polypeptide, the C-terminus of which is linked to the N-terminus of the fourth domain by a peptide bond or via a peptide linker; or b. a fourth domain, if not present in said second polypeptide; a fourth polypeptide comprising: a C-terminus of the second polypeptide chain of the first domain linked by a peptide bond or via a peptide linker to the N-terminus of the fourth dimer-forming polypeptide or the fourth domain; and v) one or more additional polypeptides (optional) comprising the second polypeptide chain of the third and / or fourth (if present) domain; Includes:

[0192] The present invention also provides a method for producing a tetrahedral antibody of the present invention comprising a fifth and / or sixth domain, wherein the non-peptidyl bond of the tetrahedral antibody is a non-covalent bond between a first dimer-forming polypeptide attached to a first N-terminus of the first domain and a second dimer-forming polypeptide attached to a first N-terminus of the second domain, the method comprising: a) recombinantly expressing in a host cell each of the following polypeptides: i) in the N-terminal to C-terminal direction, (1) the third or fifth domain (if any); (2) a first dimer-forming polypeptide; (3) a first polypeptide chain of the first domain; wherein the C-terminus of the third domain or fifth domain (if present) is linked by a peptide bond or via a peptide linker to the N-terminus of the first dimer-forming polypeptide, and the C-terminus of the first dimer-forming polypeptide is linked by a peptide bond or via a peptide linker to the N-terminus of the first polypeptide chain of the first domain. ii) from its N-terminus to its C-terminus, (1) the fourth or sixth domain (if any); (2) a second dimer-forming polypeptide; (3) a first polypeptide chain of the second domain; wherein the C-terminus of the fourth domain or sixth domain (if present) is linked by a peptide bond or via a peptide linker to the N-terminus of the second dimer-forming polypeptide, and the C-terminus of the second dimer-forming polypeptide is linked by a peptide bond or via a peptide linker to the N-terminus of the first polypeptide chain of the second domain; iii) in the N-terminal to C-terminal direction, (1) the third domain, if not present in the first polypeptide, or the fifth domain, if present; a. a third dimer-forming polypeptide, the C-terminus of which is linked to the N-terminus of the second polypeptide chain of the first domain by a peptide bond or via a peptide linker; or b. a second polypeptide chain of the first domain; wherein the C-terminus of the third domain or the fifth domain (if present) is linked by a peptide bond or via a peptide linker to the N-terminus of the second polypeptide chain of the third dimer-forming polypeptide or the first domain; iv) in the N-terminal to C-terminal direction, (1) the fourth domain, if not present in the second polypeptide, or the sixth domain, if present; a. a fourth dimer-forming polypeptide, the C-terminus of which is linked by a peptide bond or via a peptide linker to the N-terminus of the second polypeptide chain of the first domain; or b. a second polypeptide chain of the first domain; a fourth polypeptide comprising: a C-terminus of the fourth domain or the sixth domain (if present) linked by a peptide bond or via a peptide linker to the N-terminus of the second polypeptide chain of the fourth dimer-forming polypeptide or the first domain; and v) one or more additional polypeptides (optional) comprising the second polypeptide chain of said third, fourth, fifth and / or sixth (if present) domains; Includes.

[0193] The present invention also provides a method for producing the tetrahedral antibody of the present invention comprising a fifth and / or sixth domain, wherein the non-peptidyl bond of the tetrahedral antibody is a non-covalent bond between a first dimer-forming polypeptide attached to a first C-terminus of the first domain and a second dimer-forming polypeptide attached to a first N-terminus of the second domain, the method comprising: a) recombinantly expressing in a host cell each of the following polypeptides: i) in the N-terminal to C-terminal direction, (1) a first polypeptide chain of a first domain; (2) a first dimer-forming polypeptide; (3) the third or fifth domain (if any); wherein the C-terminus of the first polypeptide chain of the first domain is linked by a peptide bond or via a peptide linker to the N-terminus of the first dimer-forming polypeptide, and the C-terminus of the first dimer-forming polypeptide is linked by a peptide bond or via a peptide linker to the N-terminus of the third domain or fifth domain (if present), ii) from its N-terminus to its C-terminus, (1) the fourth or sixth domain (if any); (2) a second dimer-forming polypeptide; (3) a first polypeptide chain of the second domain; wherein the C-terminus of the fourth domain or sixth domain (if present) is linked by a peptide bond or via a peptide linker to the N-terminus of the second dimer-forming polypeptide, and the C-terminus of the second dimer-forming polypeptide is linked by a peptide bond or via a peptide linker to the N-terminus of the first polypeptide chain of the second domain; iii) in the N-terminal to C-terminal direction, (1) a second polypeptide chain of the first domain; a. a third dimer-forming polypeptide, the C-terminus of which is linked by a peptide bond or via a peptide linker to the N-terminus of the third domain or the fifth domain (if present); or b. the third domain, if not present in said first polypeptide, or the fifth domain, if present; wherein the C-terminus of the second polypeptide chain of the first domain is linked by a peptide bond or via a peptide linker to the N-terminus of the third dimer-forming polypeptide or the third domain or the fifth domain (if present); iv) in the N-terminal to C-terminal direction, (1) the fourth domain, if not present in the second polypeptide, or the sixth domain, if present; a. a fourth dimer-forming polypeptide, the C-terminus of which is linked by a peptide bond or via a peptide linker to the N-terminus of the second polypeptide chain of the first domain; or b. a second polypeptide chain of the first domain; a fourth polypeptide comprising: a C-terminus of the fourth domain or the sixth domain (if present) linked by a peptide bond or via a peptide linker to the N-terminus of the second polypeptide chain of the fourth dimer-forming polypeptide or the first domain; and v) one or more additional polypeptides (optional) comprising the second polypeptide chain of the third, fourth, fifth and / or sixth (if present) domain; Includes.

[0194] The present invention also provides a method for producing a tetrahedral antibody of the present invention comprising a fifth and / or sixth domain, wherein the non-peptidyl bond of the tetrahedral antibody is a non-covalent bond between a first dimer-forming polypeptide attached to a first N-terminus of the first domain and a second dimer-forming polypeptide attached to a first C-terminus of the second domain, the method comprising: a) recombinantly expressing in a host cell each of the following polypeptides: i) in the N-terminal to C-terminal direction, (1) the third or fifth domain (if any); (2) a first dimer-forming polypeptide; (3) a first polypeptide chain of the first domain; wherein the C-terminus of the third domain or fifth domain (if present) is linked by a peptide bond or via a peptide linker to the N-terminus of the first dimer-forming polypeptide, and the C-terminus of the first dimer-forming polypeptide is linked by a peptide bond or via a peptide linker to the N-terminus of the first polypeptide chain of the first domain. ii) from its N-terminus to its C-terminus, (1) a first polypeptide chain of the second domain; (2) a second dimer-forming polypeptide; (3) the fourth or sixth domain (if any); wherein the C-terminus of the first polypeptide chain of the first domain is linked by a peptide bond or via a peptide linker to the N-terminus of the second dimer-forming polypeptide, and the C-terminus of the second dimer-forming polypeptide is linked by a peptide bond or via a peptide linker to the N-terminus of the fourth domain or sixth domain (if present), iii) in the N-terminal to C-terminal direction, (1) the third domain, if not present in the first polypeptide, or the fifth domain, if present; a. a third dimer-forming polypeptide, the C-terminus of which is linked to the N-terminus of the second polypeptide chain of the first domain by a peptide bond or via a peptide linker; or b. a second polypeptide chain of the first domain; a third polypeptide comprising: a C-terminus of the third domain or the fifth domain (if present) linked by a peptide bond or via a peptide linker to the N-terminus of the second polypeptide chain of the third dimer-forming polypeptide or the first domain; and iv) in the N-terminal to C-terminal direction, (1) a second polypeptide chain of the first domain; a. a fourth dimer-forming polypeptide, the C-terminus of which is linked by a peptide bond or via a peptide linker to the N-terminus of the fourth domain or the sixth domain (if present); or b. the fourth domain, if absent in the second polypeptide, or the sixth domain (if present); a fourth polypeptide comprising: a C-terminus of the second polypeptide chain of the first domain linked by a peptide bond or via a peptide linker to the N-terminus of the fourth dimer-forming polypeptide or the fourth domain or the sixth domain (if present); and v) one or more additional polypeptides (optional) comprising the second polypeptide chain of the third, fourth, fifth and / or sixth (if present) domain; Includes.

[0195] The present invention also provides a method for producing a tetrahedral antibody of the present invention comprising a fifth and / or sixth domain, wherein the non-peptidyl bond of the tetrahedral antibody is a non-covalent bond between a first dimer-forming polypeptide attached to a first C-terminus of the first domain and a second dimer-forming polypeptide attached to a first C-terminus of the second domain, and the method comprises: a) recombinantly expressing in a host cell each of the following polypeptides: i) in the N-terminal to C-terminal direction, (1) a first polypeptide chain of a first domain; (2) a first dimer-forming polypeptide; (3) the third or fifth domain (if any); wherein the C-terminus of the first polypeptide chain of the first domain is linked by a peptide bond or via a peptide linker to the N-terminus of the first dimer-forming polypeptide, and the C-terminus of the first dimer-forming polypeptide is linked by a peptide bond or via a peptide linker to the N-terminus of the third domain or fifth domain (if present), ii) from its N-terminus to its C-terminus, (1) a first polypeptide chain of the second domain; (2) a second dimer-forming polypeptide; (3) the fourth or sixth domain (if any); wherein the C-terminus of the first polypeptide chain of the first domain is linked by a peptide bond or via a peptide linker to the N-terminus of the second dimer-forming polypeptide, and the C-terminus of the second dimer-forming polypeptide is linked by a peptide bond or via a peptide linker to the N-terminus of the fourth domain or sixth domain (if present), iii) in the N-terminal to C-terminal direction, (1) a second polypeptide chain of the first domain; (a) a third dimer-forming polypeptide, the C-terminus of which is linked by a peptide bond or via a peptide linker to the N-terminus of the third domain or the fifth domain (if present); or (b) the third domain, if not present in the first polypeptide, or the fifth domain, if present; wherein the C-terminus of the second polypeptide chain of the first domain is linked by a peptide bond or via a peptide linker to the N-terminus of the third dimer-forming polypeptide or the third domain or the fifth domain (if present); iv) in the N-terminal to C-terminal direction, (1) a second polypeptide chain of the first domain; (a) a fourth dimer-forming polypeptide, the C-terminus of which is linked by a peptide bond or via a peptide linker to the N-terminus of the fourth domain or the sixth domain (if present); or (b) the fourth domain, if not present in the second polypeptide, or the sixth domain, if present; a fourth polypeptide comprising: a C-terminus of the second polypeptide chain of the first domain linked by a peptide bond or via a peptide linker to the N-terminus of the fourth dimer-forming polypeptide or the fourth domain or the sixth domain (if present); and c. one or more additional polypeptides (optional) comprising the second polypeptide chain of the third, fourth, fifth and / or sixth (if present) domain; Includes:

[0196] domain In this specification, numbering is used to facilitate description and identification of each domain of tetrahedral and octahedral antibodies. The first domain may be referred to as "D1" or "Domain 1." The same principle applies to the remaining domains of the invention (i.e., for example, the second domain may be referred to as "D2" or "Domain 2"). Furthermore, unless otherwise specified, tetrahedral antibodies of the invention may lack one or more domains, without affecting the numbering of the other domains. For example, a tetrahedral antibody of the invention may include domains 1, 2, 3, 4, and 6, but not domain 5. As another example, a tetrahedral antibody of the invention may include domains 1, 2, 3, 4, 7, and 8, but not domains 5 and 6 (see, e.g., Figure 42).

[0197] In principle, the first and second domains of the tetrahedral antibodies of the invention can be interchanged, i.e., in some embodiments, features described as applying to the first domain can equally be applied to the second domain. Similarly, the third and fourth domains of the tetrahedral antibodies of the invention can be interchanged, the fifth and sixth domains of the invention can be interchanged, and the seventh and eighth domains can be interchanged.

[0198] Similarly, with respect to the octahedral antibodies of the invention, domains 1, 2 and 3 of the invention may be interchanged, domains 4, 5 and 6 may be interchanged, domains 7, 8 and 9 may be interchanged, and domains 10, 11 and 12 may be interchanged. As explained above, interchangeable in this context means that features described in the specification as applying to any domain may also be applied to the other domains.

[0199] Similarly, those skilled in the art will understand that domains 1 and 2 of tetrahedral antibodies of the invention and domains 1, 2, and 3 of octahedral antibodies of the invention serve similar structural purposes, and therefore descriptions applying to domains 1 and 2 of tetrahedral antibodies of the invention are equivalent insofar as they apply to domains 1, 2, and 3 of octahedral antibodies of the invention. Similar equivalences apply between domains 3 and 4 of tetrahedral antibodies of the invention and domains 4, 5, and 6 of octahedral antibodies of the invention. Furthermore, similar equivalences apply between domains 5 and 6 of tetrahedral antibodies of the invention and domains 7, 8, and 9 of octahedral antibodies of the invention. Furthermore, similar equivalences apply between domains 7 and 8 of tetrahedral antibodies of the invention and domains 10, 11, and 12 of octahedral antibodies of the invention.

[0200] chain Various aspects of this invention include domains comprised of "heavy chains" and "light chains." Heavy chains of the invention may be referred to as "H chains" or "H1," "H2," "H3," etc. Similarly, light chains of the invention may be referred to as "L chains" or "L1," "L2," "L3," etc. These chains are aspects of the invention. Additionally, these chains in combination with the corresponding heavy or light chains are also aspects of the invention.

[0201] An embodiment of a tetrahedral antibody of the invention comprises a first heavy chain ("H1") and a second heavy chain ("H2"). The H1 and H2 chains may pair with each other to form domains 1 and 2. H1 may also pair with a light chain to form domains 3 and 4, and H2 may also pair with a light chain to form domains 5 and 6. The H1 and H2 chains may also form homodimers. In such cases, a dimerizing polypeptide on the H1 chain forms a heterodimer with a dimerizing polypeptide on the H2 chain. The H1 or H2 chain may also comprise domains 7 and 8 described herein. The H1 and / or H2 chain may comprise a dimerizing polypeptide between domains 1 and 3 and / or between domains 2 and 4. In each of the tetrahedral antibodies of the invention, the H1 and H2 chains may comprise one or more peptide linkers. When the H1 and / or H2 chains comprise a dimerizing polypeptide, a peptide linker may be present between either domain 1 or 2 and the dimerizing polypeptide, between the dimerizing polypeptide and domain 3 or 4, or both. A peptide linker may also be present between domain 1 or 2 and the dimerizing polypeptide, between the dimerizing polypeptide and domain 5 or 6, or both.

[0202] Similar principles apply to the octahedral antibodies of the present invention. The H1 and H2 chains pair with each other to form domains 1, 2, and 3. H1 may also pair with a light chain to form domains 4, 5, and 6, while H2 may pair with a light chain to form domains 7, 8, and 9. The H1 or H2 chain may also contain domains 10, 11, and 12, as described herein.

[0203] Various embodiments of the invention include Fc fusion proteins. In such embodiments, a portion of an "Fc fusion chain" may pair with an "Fc chain" to form an Fc domain. The Fc domain of the invention is typically domain 1 and / or 2 of a tetrahedral antibody of the invention and domains 1, 2 and / or 3 of an octahedral antibody of the invention. The "Fc fusion chain" also typically includes portions that form domains 3, 4, 5 and / or 6 of a tetrahedral antibody of the invention and domains 4, 5, 6, 7, 8, 9, 10, 11 and / or 12 of an octahedral antibody of the invention.

[0204] In tetrahedral antibodies of the invention, the "Fc fusion chain" may comprise a dimerizing polypeptide between the portion forming part of domains 1 and 2 and the portion forming domains 3 and 4. In an alternative embodiment, the "Fc fusion chain" may lack a dimerizing polypeptide, as the "Fc chains" of domains 1 and 2 each comprise a dimerizing polypeptide at their respective N-termini. In an alternative to this embodiment, the "Fc chains" of domains 1 and 2 are linked at their respective N-termini by a covalent bond.

[0205] The present invention specifically contemplates tetrahedral and octahedral antibodies in which (1) the "Fc fusion chain" comprises a dimerizing polypeptide between the portion forming part of domains 1 and 2 and the portion forming domains 3 and 4, and (2) domains 3 and 4 are not ACE2 peptidase domains.

[0206] In the octahedral antibodies of the invention, the "Fc fusion chain" may comprise a trimerizing polypeptide between the portion forming part of domains 1, 2 and 3 and the portion forming domains 4, 5 and 6.

[0207] In each of the tetrahedral antibodies of the invention, the "Fc fusion chain" may comprise one or more peptide linkers between the portion forming part of Domain 1 and the portion forming Domain 3 or 5. When the "Fc fusion chain" comprises dimerizing polypeptides, a peptide linker may be present between Domain 1 and the dimerizing polypeptide, between the dimerizing polypeptide and Domain 3 or 5, or both. Similarly, the "Fc fusion chain" may comprise a peptide linker between the portion forming part of Domain 2 and the portion forming Domain 4 or 6. When the "Fc fusion chain" comprises dimerizing polypeptides, a peptide linker may be present between Domain 2 and the dimerizing polypeptide, between the dimerizing polypeptide and Domain 4 or 6, or both.

[0208] In each of the octahedral antibodies of the invention, the "Fc fusion chain" may comprise a peptide linker between the portion forming part of domain 1 and the portion forming domain 4 or 7, between the portion forming part of domain 2 and the portion forming domain 5 or 8, and between the portion forming part of domain 3 and the portion forming domain 6 or 9. In each of these cases, when the "Fc fusion chain" comprises a trimerizing polypeptide, the "Fc fusion chain" may comprise a peptide linker either between the portion forming part of domains 1, 2, and 3 and the trimerizing polypeptide, between the trimerizing polypeptide and the portion forming domains 4, 5, and 6, or both.

[0209] term As used herein, unless stated otherwise, the following terms shall have the definition set forth below.

[0210] Peptidyl Bond: Structure

[0211] [ka]

[0212] The peptidyl bond may be a peptide bond.

[0213] Consecutive amino acids: Multiple amino acids arranged in a chain, each joined to the previous amino acid by a peptide bond, although the first amino acid in the chain may not be joined to the previous amino acid. The amino acids in the chain may be naturally occurring, non-naturally occurring, or may include mixtures thereof. The amino acids may be genetically encoded, naturally occurring but non-genetically encoded, or non-naturally occurring, or a selection thereof, unless otherwise specified.

[0214] N-terminal amino acid residue: The terminal residue of two or more consecutive amino acids having a free α-amino (NH2) functional group or a derivative of an α-amino (NH2) functional group.

[0215] N-terminus: The free α-amino (NH2) group (or a derivative thereof) of the N-terminal amino acid residue.

[0216] C-terminal amino acid residue: The terminal residue of two or more consecutive amino acids having a free α-carboxyl (COOH) functional group or a derivative of an α-carboxyl (COOH) functional group.

[0217] C-terminus: The free α-carboxyl (COOH) group (or a derivative thereof) of the C-terminal amino acid residue.

[0218] By "biologically active structure" herein is meant a structure of a molecule or fragment thereof that, in a biological context (e.g., in an organism, cell, or in vitro model thereof), performs a function or effect, or stimulates or responds to a function, effect, or response, capable of treating a disease or condition, or localizing or targeting a compound of the invention to a site of disease or condition in the body. Biologically active structures may include at least one of the following structures: a polypeptide, a nucleic acid, a small molecule, e.g., a small organic or inorganic molecule.

[0219] "Bond", unless otherwise specified or contrary to context, is understood to include covalent bonds, dipole-dipole interactions such as hydrogen bonding, and intermolecular interactions such as van der Waals forces.

[0220] A "signal sequence" is a short (3-60 amino acids long) peptide chain that directs post-translational transport of a polypeptide.

[0221] "Amino acid," as used herein, in one embodiment, refers to the L- or D-isomers of the genetically encoded amino acids, namely, isoleucine, alanine, leucine, asparagine, lysine, aspartic acid, methionine, cysteine, phenylalanine, glutamic acid, threonine, glutamine, tryptophan, glycine, valine, proline, arginine, serine, histidine, tyrosine, selenocysteine, and pyrrolidine, and also includes homocysteine ​​and homoselenocysteine.

[0222] Other examples of amino acids include the L or D isomers of taurine, GABA, dopamine, lanthionine, 2-aminoisobutyric acid, dehydroalanine, ornithine, and citrulline, as well as amino acids with alkylene chains shortened or extended by up to two carbon atoms, amino acids containing optionally substituted aryl groups, and amino acids containing halogenated groups, including halogenated alkyl and aryl groups, as well as non-naturally occurring homologues and synthetically modified forms thereof, including beta or gamma amino acids and cyclic analogs.

[0223] Due to the presence of ionizable amino and carboxyl groups, in these embodiments, the amino acids may be in the form of acidic or basic salts, or in neutral form. Individual amino acid residues may also be modified by oxidation or reduction. Other contemplated modifications include hydroxylation of proline and lysine, phosphorylation of the hydroxyl group of serine or threonine residues, and methylation of the α-amino group of lysine, arginine, and histidine side chains.

[0224] Covalent derivatives may be prepared by linking particular functional groups to amino acid side chains or to the N- or C-terminus.

[0225] Compounds containing amino acids with R group substitutions are within the scope of the present invention. It is understood that substituents and substitution patterns on the compounds of the present invention can be selected by one skilled in the art to provide chemically stable compounds from readily available starting materials.

[0226] By "naturally occurring amino acids" herein is meant the genetically encoded amino acids, namely, isoleucine, alanine, leucine, asparagine, lysine, aspartic acid, methionine, cysteine, phenylalanine, glutamic acid, threonine, glutamine, tryptophan, glycine, valine, proline, arginine, serine, histidine, tyrosine, selenocysteine, pyrrolysine, and the L- or D-isomers of homocysteine ​​and homoselenocysteine.

[0227] "Unnatural amino acid," as used herein, refers to chemically modified L- or D-isomers of isoleucine, alanine, leucine, asparagine, lysine, aspartic acid, methionine, cysteine, phenylalanine, glutamic acid, threonine, glutamine, tryptophan, glycine, valine, proline, arginine, serine, histidine, tyrosine, selenocysteine, pyrrolidine, homocysteine, homoselenocysteine, taurine, GABA, dopamine, lanthionine, 2-aminoisobutyric acid, dehydroalanine, ornithine, or citrulline, including cysteine ​​and selenocysteine ​​derivatives having a C3-C10 aliphatic side chain between the alpha carbon and the S or Se. In some embodiments, the aliphatic side chain is alkylene. In other embodiments, the aliphatic side chain is alkenylene or alkynylene.

[0228] In addition to the consecutive amino acid sequences described herein, it is contemplated that variants thereof can be produced by introducing appropriate nucleotide changes into the encoding DNA and / or by synthesis of the desired consecutive amino acid sequence. Those skilled in the art will appreciate that if expression is by a chosen synthetic method (e.g., rather than chemical synthesis), for example, by changing the number or position of glycosylation sites or altering membrane anchoring characteristics, the amino acid changes may alter post-translational processing of the consecutive amino acids described herein.

[0229] Modifications of the sequences described herein can be made using, for example, the techniques and guidelines for conservative and non-conservative mutations set forth in U.S. Patent No. 5,364,934. Modifications may involve the substitution, deletion, or insertion of one or more codons encoding consecutive amino acids of interest, resulting in a change in the amino acid sequence compared to the native sequence. Optionally, the modification involves the substitution of at least one amino acid with another amino acid in one or more of the domains. Guidance for determining which amino acid residues may be inserted, substituted, or deleted without adversely affecting the desired activity can be found by comparing the sequence with that of a homologous known protein and minimizing the number of amino acid sequence changes made in regions of high homology. Amino acid substitutions may result from replacing one amino acid with another amino acid having similar structural and / or chemical properties, e.g., replacing leucine with serine, i.e., conservative amino acid substitutions. Insertions or deletions may involve approximately 1 to 5 amino acids. Permissible variations may be determined by systematically inserting, deleting, or substituting amino acids in the sequence and testing the resulting variants for activity exhibited by the full-length or mature native sequence, It is understood that terminal modifications are within the scope of the invention disclosed herein.

[0230] Amino acid sequence variants of binding partners are produced with a variety of goals in mind, including increasing the affinity of the binding partner for its ligand, facilitating the stability, purification and manufacture of the binding partner, altering its plasma half-life, improving therapeutic efficacy, and reducing the severity or occurrence of side effects during therapeutic use of the binding partner.

[0231] Amino acid sequence variants, including insertion, substitution, or deletion variants, are also contemplated herein. Such variants can typically be produced by site-directed mutagenesis of nucleotides in DNA encoding the target-binding monomer, resulting in DNA encoding the variant, followed by expression of the DNA in recombinant cell culture. Fragments having up to about 100-150 amino acid residues can also be conveniently produced by in vitro synthesis. Such amino acid sequence variants are predetermined variants and are not found in nature. The variants will exhibit the qualitative biological activity (including target binding) of the non-variant form, although not necessarily with the same quantitative value. While the site for introducing an amino acid sequence mutation is predetermined, the mutation itself need not be. For example, to optimize the performance of a mutation at a given site, random or saturation mutagenesis (possibly inserting all 20 residues) can be performed at the target codon, and the expressed variants screened for the optimal combination of desired activity. Such screening is within the ordinary skill in the art.

[0232] Amino acid insertions usually range from about 1 to 10 amino acid residues; substitutions are usually introduced for single residues; deletions range from about 1 to 30 residues. Deletions or insertions are preferably made in adjacent pairs, i.e., a deletion of two residues or an insertion of two residues. It will be abundantly clear from the following discussion that substitutions, deletions, insertions, or combinations thereof may be introduced or combined to arrive at a final construct.

[0233] As used herein, "modification" refers to an amino acid substitution, insertion, and / or deletion in a polypeptide sequence or a change to a moiety chemically linked to a protein. For example, a modification may be an altered carbohydrate or PEG structure attached to a protein. As used herein, an "amino acid modification" refers to an amino acid substitution, insertion, and / or deletion in a polypeptide sequence. For clarity, unless otherwise stated, an amino acid modification is always with respect to an amino acid encoded by DNA, e.g., the 20 amino acids for which DNA and RNA have codons.

[0234] As used herein, "amino acid substitution" or "substitution" refers to the replacement of an amino acid at a particular position in a parent polypeptide sequence with a different amino acid. Notably, in some aspects, the substitution is for an amino acid that does not naturally occur in or among organisms at the particular position. For example, the substitution E272Y refers to a variant polypeptide, in this case an Fc variant, in which glutamic acid at position 272 has been replaced with tyrosine. For clarity, a protein that has been engineered to change the nucleic acid coding sequence but not the starting amino acid (e.g., replacing CGG (which encodes arginine) with CGA (which still encodes arginine) to increase host organism expression levels) is not an "amino acid substitution," i.e., if the protein has the same amino acid at a particular starting position despite the creation of a new gene encoding the same protein, it is not an amino acid substitution.

[0235] As used herein, "amino acid insertion" or "insertion" refers to the addition of an amino acid sequence at a particular position in a parent polypeptide sequence. For example, -233E or 233E indicates the insertion of glutamic acid after position 233 and before position 234. Furthermore, -233ADE or A233ADE indicates the insertion of AlaAspGlu after position 233 and before position 234.

[0236] As used herein, "amino acid deletion" or "deletion" refers to the removal of an amino acid sequence at a particular position in a parent polypeptide sequence. For example, E233- or E233# or E233( ) indicates the deletion of a glutamic acid at position 233. Additionally, EDA233- or EDA233# indicates the deletion of the sequence GluAspAla beginning at position 233.

[0237] The terms "variant protein" or "protein variant" or "variant" as used herein refer to a protein that differs from its parent protein by at least one amino acid modification. A protein variant may refer to the protein itself, a composition containing the protein, or the amino acid sequence encoding it. Preferably, a protein variant has at least one amino acid modification compared to the parent protein, e.g., about 1 to about 70 amino acid modifications, preferably about 1 to about 5 amino acid modifications, compared to the parent. As described below, in some embodiments, the parent polypeptide, e.g., the Fc parent polypeptide, is a human wild-type sequence such as an Fc region derived from IgG1, IgG2, IgG3, or IgG4; however, a human sequence containing a variant may also function as a "parent polypeptide," e.g., the IgG1 / 2 hybrid in Figure 13 is an example. As used herein, a protein variant sequence preferably has at least about 80%, most preferably at least about 90%, and more preferably at least about 95 to 98 to 99% identity to the parent protein sequence. A variant protein may refer to the variant protein itself, a composition containing the protein variant, or the DNA sequence encoding it. Thus, the term "antibody variant" or "variant antibody" as used herein refers to an antibody that differs from a parent antibody by at least one amino acid modification; "IgG variant" or "variant IgG" as used herein refers to an antibody that differs from a parent IgG (again, often from a human IgG sequence) by at least one amino acid modification; and "immunoglobulin variant" or "variant immunoglobulin" as used herein refers to an immunoglobulin sequence that differs from that of a parent immunoglobulin sequence by at least one amino acid modification. "Fc variant" or "variant Fc" as used herein refers to a protein comprising an amino acid modification in the Fc domain. Fc variants of the present invention are defined according to the amino acid modification that constitutes them. Thus, for example, N434S or 434S is an Fc variant with a substituted serine at position 434 compared to the parent Fc polypeptide, where the numbering is according to the EU index.Similarly, M428L / N434S defines an Fc variant having substitutions M428L and N434S compared to the parent Fc polypeptide. The identity of the WT amino acids may not be specified, in which case the variant is referred to as 428L / 434S. Note that the order in which the substitutions are provided is arbitrary; i.e., for example, 428L / 434S is the same Fc variant as M428L / N434S, etc. For all positions discussed in this invention related to antibodies, unless otherwise stated, amino acid position numbering follows the EU index. The EU index or EU numbering scheme as in Kabat refers to EU antibody numbering (Edelman et al., 1969, Proc Natl Acad Sci USA 63:78-85, incorporated herein by reference in its entirety). Modifications may be additions, deletions, or substitutions. Substitutions may include naturally occurring amino acids, and in some cases, synthetic amino acids. Examples include U.S. Pat. No. 6,586,207; WO 98 / 48032; WO 03 / 073238; U.S. Patent Application Publication No. 2004 / 0214988; WO 05 / 35727; WO 05 / 74524; J.W. Chin et al., (2002), Journal of the American Chemical Society 124:9026-9027; J.W. Chin, & P.G. Schultz, (2002), ChemBioChem 11:1135-1137; J.W. Chin, et al., (2002), PICAS United States of America 99:11020-11024, and L. Wang, & P.G. Schultz, (2002), Chem. 1-10 (all incorporated by reference in their entirety).

[0238] As used herein, "protein" refers to at least two covalently linked amino acids, including proteins, polypeptides, oligopeptides, and peptides. The terms "protein" and "consecutive amino acids" are used interchangeably herein. A peptidyl group may include naturally occurring amino acids and peptide bonds or synthetic peptidomimetic structures, i.e., "analogs," such as peptoids (see Simon et al., PNAS USA 89(20):9367 (1992) (incorporated by reference in its entirety)). Amino acids may be either naturally occurring or synthetic (e.g., not DNA-encoded), as understood by those skilled in the art. For example, homo-phenylalanine, citrulline, ornithine, and norleucine are contemplated synthetic amino acids for purposes of the present invention, and both D- and L- (R or S)-constitutive amino acids may be utilized. Variants of the present invention may include modifications including, for example, but not limited to, the use of synthetic amino acids incorporated using the technology developed by Cropp & Shultz, 2004, Trends Genet. 20(12):625-30; Anderson et al., 2004, Proc Natl Acad Sci USA 101 (2):7566-71; Zhang et al., 2003, 303(5656):371-3; and Chin et al., 2003, Science 301(5635):964-7 (all incorporated by reference in their entirety). Additionally, polypeptides may include synthetic derivatization of one or more side chains or termini, glycosylation, pegylation, circular permutation, cyclization, linkers to other molecules, fusion to proteins or protein domains, and addition of peptide tags or labels.

[0239] The term "residue" as used herein refers to a position in a protein and its associated amino acid identity. For example, asparagine 297 (also called Asn297 or N297) is the residue at position 297 in the human antibody IgG1.

[0240] As used herein, "Fab" or "Fab region" refers to a polypeptide comprising the VH, CH1, VL, and CL immunoglobulin domains. Fab may refer to this region in isolation or in the context of a full-length antibody, antibody fragment, or Fab fusion protein. By "Fv" or "Fv fragment" or "Fv region" herein is meant a polypeptide comprising the VL and VH domains of a single antibody.

[0241] "IgG subclass modification" or "isotype modification," as used herein, refers to an amino acid modification that converts an amino acid in an IgG isotype to the corresponding amino acid in a different aligned IgG isotype. For example, because IgG1 contains tyrosine and IgG2 contains phenylalanine at EU296, the F296Y substitution in IgG2 is considered an IgG subclass modification.

[0242] The term "non-naturally occurring modification" refers to a non-isotypic amino acid modification. For example, the substitution 434S in IgG1, IgG2, IgG3, or IgG4 (or hybrids thereof) is considered a non-naturally occurring modification, since no IgG contains serine at position 434.

[0243] The term "effector function," as used herein, refers to a biochemical event that results from the interaction of an antibody Fc region with an Fc receptor or ligand. Effector functions include, but are not limited to, ADCC, ADCP, and CDC.

[0244] The term "IgG Fc ligand," as used herein, refers to a biologically derived molecule, preferably a polypeptide, that binds to the Fc region of an IgG antibody to form an Fc / Fc ligand complex. Fc ligands include, but are not limited to, FcγRIs, FcγRIIs, FcγRIIIs, FcRn, C1q, C3, mannan-binding lectin, mannose receptor, staphylococcal protein A, streptococcal protein G, and viral FcγRs. Fc ligands also include Fc receptor homologs (FcRHs), a family of Fc receptors that are homologous to FcγRs (Davis et al., 2002, Immunological Reviews 190:123-136, incorporated by reference in its entirety). Fc ligands may also include undiscovered molecules that bind to Fc. Specific IgG Fc ligands are FcRn and Fcγ receptors. As used herein, the term "Fc ligand" refers to a molecule, preferably a polypeptide, derived from a living organism that binds to the Fc region of an antibody to form an Fc / Fc ligand complex.

[0245] The term "Fcγ receptor", "FcγR" or "FcgR" as used herein refers to a member of the protein family that binds to the Fc region of an IgG antibody and is encoded by the FcγR gene. In humans, this family includes, but is not limited to, FcγRI (CD64), which includes the isoforms FcγRIa, FcγRIb, and FcγRIc; FcγRII (CD32), which includes the isoforms FcγRIIa (including allotypes H131 and R131), FcγRIIb (including FcγRIIb-1 and FcγRIIb-2), and FcγRIIc; and FcγRIII (CD16), which includes the isoforms FcγRIIIa (including allotypes V158 and F158) and FcγRIIIb (including allotypes FcγRIIb-NA1 and FcγRIIb-NA2) (Jefferis et al., 2002, Immunol Lett 82:57-65 (incorporated by reference in its entirety)), as well as undiscovered human FcγR or FcγR isoforms or allotypes. FcγRs may be derived from organisms including, but not limited to, humans, mice, rats, rabbits, and monkeys. Mouse FcγRs include, but are not limited to, FcγRI (CD64), FcγRII (CD32), FcγRIII (CD16), and FcγRIII-2 (CD16-2), as well as undiscovered mouse FcγRs or FcγR isoforms or allotypes.

[0246] The term "FcRn" or "neonatal Fc receptor" as used herein refers to a protein that binds to the Fc region of an IgG antibody and is at least partially encoded by the FcRn gene. FcRn may be derived from organisms including, but not limited to, humans, mice, rats, rabbits, and monkeys. As known in the art, a functional FcRn protein comprises two polypeptides, often referred to as a heavy chain and a light chain. The light chain is β-2-microglobulin, and the heavy chain is encoded by the FcRn gene. Unless otherwise specified in the specification, FcRn or FcRn protein refers to the complex of the FcRn heavy chain with β-2-microglobulin. Various FcRn variants used to enhance binding to the FcRn receptor, and in some cases to enhance serum half-life, are shown in the brief description section of Figure 11.

[0247] The term "parent polypeptide" as used herein refers to a starting polypeptide that is subsequently modified to generate a variant. A parent polypeptide may be a naturally occurring polypeptide or a variant or engineered version of a naturally occurring polypeptide. A parent polypeptide may refer to the polypeptide itself, a composition comprising the parent polypeptide, or the amino acid sequence that encodes it. Thus, a "parent immunoglobulin" as used herein refers to an unmodified immunoglobulin polypeptide that is modified to generate a variant, and a "parent antibody" as used herein refers to an unmodified antibody that is modified to generate a variant antibody. It should be noted that "parent antibody" includes known commercial recombinantly produced antibodies as outlined below.

[0248] The term "Fc fusion protein" or "immunoadhesin," as used herein, refers to a protein comprising an Fc region typically linked (optionally by a linker moiety as described herein) to another protein, e.g., a binding moiety for a target protein as described herein. In some cases, one monomer of the heterodimeric protein comprises an antibody heavy chain (including an scFv or further comprising a light chain), and the other monomer is an Fc fusion comprising a variant Fc domain and a ligand.

[0249] The term "position" as used herein means a location in the sequence of a protein. Positions may be numbered sequentially or according to established formats, such as the EU index for antibody numbering.

[0250] The term "target antigen" as used herein refers to the molecule to which the va...

Claims

1. 1. A tetrahedral antibody comprising a first, second, third and fourth domain, a) each of said first and second domains is selected from the group consisting of a Fab domain and an Fc domain; b) each of said first and second domains: i) a first polypeptide chain comprising a first N-terminus and a first C-terminus of the domain; and ii) a second polypeptide chain comprising a second N-terminus and a second C-terminus of said domain; Including, c) the first domain and the second domain are linked to each other by a non-peptidyl bond, wherein the non-peptidyl bond is (1) a non-covalent bond between a first dimer-forming polypeptide attached to the first N-terminus of the first domain by a peptide bond or via a peptide linker and a second dimer-forming polypeptide attached to the first N-terminus of the second domain by a peptide bond or via a peptide linker; (2) a non-covalent bond between a first dimer-forming polypeptide attached to the first C-terminus of the first domain by a peptide bond or via a peptide linker and a second dimer-forming polypeptide attached to the first C-terminus of the second domain by a peptide bond or via a peptide linker; (3) a non-covalent bond between a first dimer-forming polypeptide attached to the first N-terminus of the first domain by a peptide bond or via a peptide linker and a second dimer-forming polypeptide attached to the first C-terminus of the second domain by a peptide bond or via a peptide linker; or (4) a non-covalent bond between a first dimer-forming polypeptide attached to the first C-terminus of the first domain by a peptide bond or via a peptide linker and a second dimer-forming polypeptide attached to the first N-terminus of the second domain by a peptide bond or via a peptide linker; and wherein the first and second dimer-forming polypeptides are ACE2 collectrin-like domain (CLD) dimer-forming polypeptides, respectively. d) when the first domain is linked to the second domain via a first dimerization polypeptide linked to its first N-terminus, the third domain is linked at its C-terminus by a peptide bond or via a peptide linker, i) the N-terminus of the first dimer-forming polypeptide; ii) a second N-terminus of the first domain; or iii) the N-terminus of the third dimer-forming polypeptide, wherein the third dimer-forming polypeptide is linked at its C-terminus to the second N-terminus of the first domain by a peptide bond or via a peptide linker; binds to e) when the first domain is linked to the second domain via a first dimerization polypeptide linked to its first C-terminus, the third domain is linked at its N-terminus by a peptide bond or via a peptide linker, i) the C-terminus of the first dimer-forming polypeptide; ii) a second C-terminus of the first domain; or iii) the C-terminus of the third dimer-forming polypeptide, wherein the third dimer-forming polypeptide is linked at its N-terminus to the second C-terminus of the first domain by a peptide bond or via a peptide linker; binds to f) when the second domain is linked to the first domain via a second dimer-forming polypeptide linked to its first N-terminus, the fourth domain is linked at its C-terminus by a peptide bond or via a peptide linker, i) the N-terminus of the second dimer-forming polypeptide; ii) a second N-terminus of the second domain; or iii) the N-terminus of the third dimer-forming polypeptide, wherein the third dimer-forming polypeptide is linked at its C-terminus to the second N-terminus of the second domain by a peptide bond or via a peptide linker; binds to g) when the second domain is linked to the first domain via a second dimer-forming polypeptide linked to its first C-terminus, the fourth domain is linked at its N-terminus by a peptide bond or via a peptide linker, i) the C-terminus of the second dimer-forming polypeptide; ii) a second C-terminus of the second domain; or iii) the C-terminus of the fourth dimer-forming polypeptide, wherein the fourth dimer-forming polypeptide is linked at its N-terminus to the second C-terminus of the second domain by a peptide bond or via a peptide linker; is bonded to Tetrahedral antibodies.

2. a) the first domain is an Fc domain and the second domain is a Fab domain; b) the first and second domains are Fc domains; c) said first and second domains are Fab domains; d) said third and fourth domains are Fab domains; e) the third and / or fourth domain is selected from the group consisting of: (i) a secreted protein, and (ii) an extracellular domain of a transmembrane protein; f) the third domain is selected from the group consisting of (i) a secreted protein and (ii) an extracellular domain of a transmembrane protein, and the fourth domain is a Fab domain; g) the third domain is IL-15; h) the third domain is IL-15 and the fourth domain is an IL-15Rα sushi domain; i) the third domain is IL-15 and the fourth domain is a Fab domain; j) the third and fourth domains are each the peptidase domain (PD) of ACE2; k) the first and second domains are Fc domains and the third and fourth domains are selected from the group consisting of: (i) a secreted protein, and (ii) an extracellular domain of a transmembrane protein; l) the first and second domains are Fc domains, the third domain is selected from the group consisting of (i) a secreted protein and (ii) an extracellular domain of a transmembrane protein, and the fourth domain is a Fab domain; m) said first and second domains are Fc domains and said third and fourth domains are Fab domains; n) the first and second domains are Fc domains, and the third and fourth domains are peptidase domains (PDs) of ACE2, respectively; o) the first domain is an Fc domain and the second, third and fourth domains are Fab domains; p) the first domain is an Fc domain, the second domain is a Fab domain, the third domain is IL-15, and the fourth domain is an IL-15Rα sushi domain, or q) the first domain is an Fc domain, the second domain is a Fab domain, the third domain is IL-15, and the fourth domain is a Fab domain; The tetrahedral antibody of claim 1.

3. a) the first dimer-forming polypeptide is the same as the second dimer-forming polypeptide; b) the dimer-forming polypeptide forms a homodimer; The tetrahedral antibody of claim 1.

4. The first dimer-forming polypeptide comprises one or more disulfide bonds with the second dimer-forming polypeptide, preferably: a) said one or more disulfide bonds are at the interface between said first dimer-forming polypeptide and said second dimer-forming polypeptide, more preferably: i) when the first and second dimer-forming polypeptides are collectrin-like domains or collectrins, the one or more disulfide bonds are in the second and fourth helices of the collectrin-like domains or the corresponding regions of collectrins, or b) the one or more disulfide bonds are between an immunoglobulin hinge region or a portion thereof comprising at least one cysteine ​​added to the N-terminus and / or C-terminus of the first dimer-forming polypeptide and an immunoglobulin hinge region or a portion thereof comprising at least one cysteine ​​added to the N-terminus and / or C-terminus of the second dimer-forming polypeptide, the hinge region being added to the first and second dimer-forming polypeptides directly or via a peptide linker, and preferably the first and second dimer-forming polypeptides are collectrin-like domains or collectrins. The tetrahedral antibody of claim 3.

5. further comprising a fifth and / or sixth domain; a) the first domain binds to the second domain via a first dimerization polypeptide linked to its first N-terminus; i) the fifth domain is connected at its C-terminus by a peptide bond or via a peptide linker, (1) the N-terminus of the first dimer-forming polypeptide; (2) the second N-terminus of the first domain, or (3) the N-terminus of the third dimer-forming polypeptide, wherein the third dimer-forming polypeptide is linked at its C-terminus to the second N-terminus of the first domain by a peptide bond or via a peptide linker; binds to b) the first domain is linked to the second domain via a first dimerization polypeptide linked to its first C-terminus; i) the fifth domain is connected at its N-terminus by a peptide bond or via a peptide linker, (1) the C-terminus of the first dimer-forming polypeptide; (2) the second C-terminus of the first domain, or (3) the C-terminus of the third dimer-forming polypeptide, wherein the third dimer-forming polypeptide is linked at its N-terminus to the second C-terminus of the first domain by a peptide bond or via a peptide linker; binds to c) the second domain is linked to the first domain via a second dimerization polypeptide linked to its first N-terminus; i) the sixth domain is connected at its C-terminus by a peptide bond or via a peptide linker, (1) the N-terminus of the second dimer-forming polypeptide; (2) the second N-terminus of the second domain, or (3) the N-terminus of the fourth dimer-forming polypeptide, wherein the fourth dimer-forming polypeptide is linked at its C-terminus to the second N-terminus of the second domain by a peptide bond or via a peptide linker; or d) the second domain is linked to the first domain via a second dimerization polypeptide linked to its first C-terminus; i) the sixth domain is connected at its N-terminus by a peptide bond or via a peptide linker, (1) the C-terminus of the second dimer-forming polypeptide; (2) the second C-terminus of the second domain, or (3) the C-terminus of the fourth dimer-forming polypeptide, wherein the fourth dimer-forming polypeptide is linked at its N-terminus to the second C-terminus of the second domain by a peptide bond or via a peptide linker; binds to The tetrahedral antibody of claim 1.

6. a) the first and second domains are Fc domains and the fifth domain is a first type of Fab domain; b) said first and second domains are Fc domains and said third and fourth domains are independently selected from the group consisting of a first type of Fab domain and a second type of Fab domain; c) said first and second domains are Fc domains and said fourth and fifth domains are independently selected from the group consisting of a first type of Fab domain and a second type of Fab domain; d) said first and second domains are Fc domains and said third, fourth and fifth domains are independently selected from the group consisting of a first type of Fab domain, a second type of Fab domain and a third type of Fab domain; e) the first domain is an Fc domain and the second and fifth domains are independently selected from the group consisting of a first type of Fab domain and a second type of Fab domain; f) the first domain is an Fc domain and the second, third, and fifth domains are independently selected from the group consisting of a first type of Fab domain, a second type of Fab domain, and a third type of Fab domain; g) the first domain is an Fc domain and the second, fourth, and fifth domains are independently selected from the group consisting of a first type of Fab domain, a second type of Fab domain, and a third type of Fab domain; h) the first domain is an Fc domain and the second, third, fourth and fifth domains are independently selected from the group consisting of a first type of Fab domain, a second type of Fab domain, a third type of Fab domain and a fourth type of Fab domain; or i) the first and second domains are Fc domains, the third and fourth domains are peptidase domains (PD) of the ACE2, and the fifth and sixth domains are Fab domains; The tetrahedral antibody of claim 5.

7. further comprising a seventh and / or eighth domain; a) the first domain is linked to the second domain by a covalent bond linked to its first N-terminus or via a first dimerization peptide linked to its first N-terminus; i) the seventh domain is connected at its N-terminus by a peptide bond or via a peptide linker, (1) the first C-terminus of the first domain, or (2) a second C-terminus of the first domain; binds to b) the first domain is linked to the second domain by a covalent bond linked to its first C-terminus or via a first dimerization peptide linked to its first C-terminus; i) the seventh domain is connected at its C-terminus by a peptide bond or via a peptide linker, (1) the first N-terminus of the first domain, or (2) a second N-terminus of the first domain; binds to c) the second domain is linked to the first domain by a covalent bond linked to its first N-terminus or via a second dimerization peptide linked to its first N-terminus; i) the eighth domain is connected at its N-terminus by a peptide bond or via a peptide linker, (1) the first C-terminus of the second domain, or (2) a second C-terminus of the second domain; or d) the second domain is linked to the first domain by a covalent bond linked to its first C-terminus or via a second dimerization peptide linked to its first C-terminus; i) the eighth domain is connected at its C-terminus by a peptide bond or via a peptide linker, (1) the first N-terminus of the second domain, or (2) a second N-terminus of the second domain; binds to The tetrahedral antibody of claim 5.

8. a) the first and second domains are Fc domains, the third and fourth domains are anti-CD20 Fab domains, and the fifth and sixth domains are anti-CD19 Fab domains; b) the first and second domains are Fc domains, the third and fourth domains are anti-CD19 Fab domains, and the fifth and sixth domains are anti-CD20 Fab domains; c) the first and second domains are Fc domains, the third and fourth domains are Fab domains of anti-CD20, the fifth and sixth domains are Fab domains of anti-CD19, and each dimer-forming polypeptide is a CLD of ACE2; d) the first and second domains are Fc domains, the third and fourth domains are anti-CD19 Fab domains, the fifth and sixth domains are anti-CD20 Fab domains, and each dimer-forming polypeptide is an ACE2 CLD; e) the first and second domains are Fc domains, the third and fourth domains are anti-CD20 Fab domains, the fifth and sixth domains are anti-CD19 Fab domains, each dimerizing polypeptide is a CLD of ACE2, and the first and second domains are each linked to each dimerizing polypeptide via a peptide linker; f) the first and second domains are Fc domains, the third and fourth domains are anti-CD19 Fab domains, the fifth and sixth domains are anti-CD20 Fab domains, each dimerizing polypeptide is an ACE2 CLD, and the first and second domains are each linked to each dimerizing polypeptide via a peptide linker; The tetrahedral antibody of claim 5.

9. a) the first and second domains are Fc domains, the third and fourth domains are anti-CD20 Fab domains, the fifth and sixth domains are anti-CD19 Fab domains, and the seventh and eighth domains are single-chain 4-1BB ligand; b) the first and second domains are Fc domains, the third and fourth domains are anti-CD19 Fab domains, the fifth and sixth domains are anti-CD20 Fab domains, and the seventh and eighth domains are a single chain 4-1BB ligand; c) the first and second domains are Fc domains, the third and fourth domains are Fab domains of anti-CD20, the fifth and sixth domains are Fab domains of anti-CD19, the seventh and eighth domains are single-chain 4-1BB ligands, and each dimer-forming polypeptide is a CLD of ACE2; d) the first and second domains are Fc domains, the third and fourth domains are Fab domains of anti-CD19, the fifth and sixth domains are Fab domains of anti-CD20, the seventh and eighth domains are single-chain 4-1BB ligand, and each dimer-forming polypeptide is a CLD of ACE2; e) the first and second domains are Fc domains, the third and fourth domains are anti-CD20 Fab domains, the fifth and sixth domains are anti-CD19 Fab domains, the seventh and eighth domains are single-chain 4-1BB ligands, and each dimerizing polypeptide is an ACE2 CLD, and the first and second domains are each linked to each dimerizing polypeptide via a peptide linker; or f) the first and second domains are Fc domains, the third and fourth domains are anti-CD19 Fab domains, the fifth and sixth domains are anti-CD20 Fab domains, the seventh and eighth domains are single-chain 4-1BB ligands, each dimerizing polypeptide is an ACE2 CLD, and the first and second domains are linked to each dimerizing polypeptide via a peptide linker; The tetrahedral antibody of claim 8.

10. a) the anti-CD19 Fab domain is i) comprising the CDRs of the heavy and light chains of FMC63, respectively, and preferably the anti-CD19 Fab is the Fab domain of FMC63; ii) comprising the CDRs of the heavy and light chains of FMC60, respectively, and preferably the anti-CD19 Fab is the Fab domain of FMC60; or iii) comprising the CDRs of the heavy and light chains of FMC59, respectively, and preferably said anti-CD19 Fab is the Fab domain of FMC59; and / or b) the anti-CD20 Fab domain comprises the CDRs of rituximab, preferably the anti-CD20 Fab domain is the Fab domain of rituximab; The tetrahedral antibody of claim 8.

11. The Fc domain is characterized by one or more or all of the following properties: a) is a heterodimer; b) the Fc domain of IgG1; c) said Fc domain comprises silencing mutations such that it lacks Fcγ receptor binding activity, preferably said mutations being one of the following combinations of mutations: i) P329G / L234A / L235A (PGLALA), ii) L234A / L235A (LALA), iii) P331S / L234A / L235A, iv) L234F / L235E / P331S, and v) L234F / L235E / P329G, d) comprising mutations that enhance the activity of FcRn, preferably said mutations increase the half-life of said tetrahedral antibody, preferably said mutations are the following combination of mutations: L309D / Q311H / N434S (DHS); e) comprising a mutation that eliminates its Protein A binding site, preferably said mutation is H435R / Y436F (HY / RF), The tetrahedral antibody of claim 8.

12. The tetrahedral antibody of claim 8, wherein each of the peptide linkers is 23 amino acids in length and is derived from the stalk region of a TNF receptor, preferably the TNF receptor is TNF receptor 1B, and even more preferably the peptide linker is composed of the amino acid sequence set forth in SEQ ID NO: 4468.

13. The tetrahedral antibody of claim 8, wherein each of the dimer-forming polypeptides is a CLD of ACE2, and each ACE2 CLD comprises or consists of amino acids 616 to 740 of the ACE2 protein.

14. the domains and peptide linkers are formed by four different polypeptide chains, preferably the four different polypeptide chains are designated L1, H1, L2 and H2, a) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 733, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 707, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 734, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 708, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, and most preferably 98% identity to said sequences; b) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 735, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 709, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 736, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 710, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, and most preferably 98% identity to said sequences; c) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 735, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 709, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 737, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 711, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences; d) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 738, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 712, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 739, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 713, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, and most preferably 98% identity to said sequences; e) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 740, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 714, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 741, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 715, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, and most preferably 98% identity to said sequences; f) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 740, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 714, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 742, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 716, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, and most preferably 98% identity to said sequences; g) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4801, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4721, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4802, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4722, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, and most preferably 98% identity to said sequences; h) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4803, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4723, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4804, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4724, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences; i) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4803, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4723, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4805, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4725, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, and most preferably 98% identity to said sequences; j) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4806, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4726, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4807, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4727, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, and most preferably 98% identity to said sequences; k) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4808, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4728, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4809, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4729, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences; l) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4808, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4728, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4810, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4730, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, and most preferably 98% identity to said sequences; m) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4803, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4723, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4813, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4772, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, and most preferably 98% identity to said sequences; n) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4803, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4723, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4814, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4773, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, and most preferably 98% identity to said sequences; o) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4815, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4774, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4813, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4772, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences; p) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4815, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4774, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4814, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4773, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences; q) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4816, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4775, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4809, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4729, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences; r) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4816, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4775, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4810, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4730, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, and most preferably 98% identity to said sequences; s) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4817, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4776, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4809, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4729, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, and most preferably 98% identity to said sequences; t) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4817, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4776, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4810, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4730, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, and most preferably 98% identity to said sequences; u) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4803, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4723, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4813, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4793, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences; v) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4803, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4723, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4814, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4794, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, and most preferably 98% identity to said sequences; w) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4815, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4774, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4813, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4793, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences; x) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4815, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4774, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4814, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4794, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences; y) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4819, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4775, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4809, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4729, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences; z) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4819, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4775, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4810, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4730, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences; aa) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4820, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4776, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4809 and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4729, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences; or bb) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4820, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4776, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4810, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4730, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences; The tetrahedral antibody of claim 8.

15. The tetrahedral antibody of claim 14, wherein the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4819, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 4775, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4810, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 4730, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, and most preferably 98% identity to said sequences.

16. the domains and peptide linkers are formed by four different polypeptide chains, preferably the four different polypeptide chains are designated L1, H1, L2 and H2, a) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 733, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 707, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 734, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 717, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, and most preferably 98% identity to said sequences; b) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 735, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 709, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 736, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 718, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, and most preferably 98% identity to said sequences; c) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 735, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 709, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 737, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 719, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences; d) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 738, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 712, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 739, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 720, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, and most preferably 98% identity to said sequences; e) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 740, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 714, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 741, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 721, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences; f) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 740, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 714, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 742, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 722, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, and most preferably 98% identity to said sequences; g) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 733, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 723, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 734, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 724, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, and most preferably 98% identity to said sequences; h) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 735, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 725, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 736, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 726, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences; i) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 735, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 725, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 737, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 727, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, and most preferably 98% identity to said sequences; j) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 738, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 728, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 739, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 729, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, and most preferably 98% identity to said sequences; k) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 740, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 730, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 741, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 731, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, most preferably 98% identity to said sequences; or l) the L1 chain comprises the amino acid sequence set forth in SEQ ID NO: 740, the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 730, the L2 chain comprises the amino acid sequence set forth in SEQ ID NO: 742, and the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 732, or the L1, H1, L2 and H2 chains are variants having at least 90%, preferably 95%, and most preferably 98% identity to said sequences; The tetrahedral antibody of claim 9.

17. A polynucleotide encoding a polypeptide comprising any one of the polypeptide chains of claim 14.

18. 15. A vector comprising polynucleotides encoding a polypeptide comprising four different polypeptide chains as described in claim 14, wherein each polynucleotide is operably linked to a promoter that directs expression of the polynucleotide in a host cell.

19. 17. A vector comprising one or more polynucleotides of claim 16, each polynucleotide operably linked to a promoter that directs expression of said polynucleotide in a host cell.

20. A host cell comprising the vector of claim 17 or 18.

21. 20. The host cell of claim 19 for use in a method for producing a tetrahedral antibody.

22. 15. A method for producing a tetrahedral antibody, comprising recombinantly expressing in a host cell four different polypeptide chains according to claim 14.

23. 20. A method for producing a tetrahedral antibody, comprising recombinantly expressing the vector of claim 17 or 18 in a host cell.

24. 20. A method for producing a tetrahedral antibody comprising four different polypeptide chains, the method comprising expressing the four different polypeptide chains in a host cell according to claim 19.

25. A pharmaceutical composition comprising the tetrahedral antibody of any one of claims 8 to 15 and one or more pharmaceutically acceptable excipients.

26. 25. A method of treating cancer or an inflammatory disease in a subject, comprising administering to said subject a therapeutically effective amount of the pharmaceutical composition of claim 24, wherein preferably said cancer is a B-cell cancer.

27. A tetrahedral molecule comprising first, second, third and fourth domains, a) the first and second domains each independently comprise: i) a first polypeptide chain comprising a first N-terminus and a first C-terminus of the domain; and ii) optionally a second polypeptide chain comprising a second N-terminus and a second C-terminus of said domain; Including, b) the first domain and the second domain are (1) a non-covalent bond between a first dimer-forming polypeptide attached to the first N-terminus of the first domain by a peptide bond or via a peptide linker and a second dimer-forming polypeptide attached to the first N-terminus of the second domain by a peptide bond or via a peptide linker; (2) a non-covalent bond between a first dimer-forming polypeptide attached to the first C-terminus of the first domain by a peptide bond or via a peptide linker and a second dimer-forming polypeptide attached to the first C-terminus of the second domain by a peptide bond or via a peptide linker; (3) a non-covalent bond between a first dimer-forming polypeptide attached to the first N-terminus of the first domain by a peptide bond or via a peptide linker and a second dimer-forming polypeptide attached to the first C-terminus of the second domain by a peptide bond or via a peptide linker; or (4) a non-covalent bond between a first dimer-forming polypeptide attached to the first C-terminus of the first domain by a peptide bond or via a peptide linker and a second dimer-forming polypeptide attached to the first N-terminus of the second domain by a peptide bond or via a peptide linker; are connected to each other by wherein the first and second dimer-forming polypeptides are each the collectrin-like domain (CLD) of ACE2; c) when the first domain is linked to the second domain via a first dimerization polypeptide linked to its first N-terminus, the third domain is linked at its C-terminus by a peptide bond or via a peptide linker, i) the N-terminus of the first dimer-forming polypeptide; ii) if present, the second N-terminus of said first domain; or iii) the N-terminus of the third dimer-forming polypeptide, wherein, if a second N-terminus of the first domain is present, the third dimer-forming polypeptide is linked at its C-terminus to the second N-terminus of the first domain by a peptide bond or via a peptide linker; binds to d) when the first domain is linked to the second domain via a first dimerization polypeptide linked to its first C-terminus, the third domain is linked at its N-terminus by a peptide bond or via a peptide linker, i) the C-terminus of the first dimer-forming polypeptide; ii) if present, the second C-terminus of said first domain; or iii) the C-terminus of the third dimer-forming polypeptide, wherein if a second C-terminus of the first domain is present, the third dimer-forming polypeptide is linked at its N-terminus to the second C-terminus of the first domain by a peptide bond or via a peptide linker; binds to e) when the second domain is linked to the first domain via a second dimer-forming polypeptide linked to its first N-terminus, the fourth domain is linked at its C-terminus by a peptide bond or via a peptide linker, i) the N-terminus of the second dimer-forming polypeptide; ii) if present, the second N-terminus of said second domain; or iii) the N-terminus of the fourth dimer-forming polypeptide, wherein, if a second N-terminus of the second domain is present, the third dimer-forming polypeptide is linked at its C-terminus to the second N-terminus of the second domain by a peptide bond or via a peptide linker; binds to f) when the second domain is linked to the first domain via a second dimer-forming polypeptide linked to its first C-terminus, the fourth domain is linked at its N-terminus by a peptide bond or via a peptide linker, i) the C-terminus of the second dimer-forming polypeptide; ii) if present, the second C-terminus of said second domain; or iii) the C-terminus of the fourth dimer-forming polypeptide, wherein, if a second C-terminus of the second domain is present, the fourth dimer-forming polypeptide is linked at its N-terminus to the second C-terminus of the second domain by a peptide bond or via a peptide linker; is bonded to Tetrahedral molecule.

28. a) the first domain is an Fc domain or a Fab domain; b) the first domain is an Fc domain or an Fab domain, and the second domain is not an Fc domain or an Fab domain; c) the first domain is an Fc domain and the second domain is a Fab domain; d) said first and second domains are Fc domains; e) said first and second domains are Fab domains; f) the second, third and / or fourth domain is selected from the group consisting of: (i) a secreted protein, and (ii) an extracellular domain of a transmembrane protein; g) the third domain is selected from the group consisting of (i) a secreted protein and (ii) an extracellular domain of a transmembrane protein, and the fourth domain is a Fab domain; h) said third domain is IL-15; i) the third domain is IL-15 and the fourth domain is an IL-15Rα sushi domain; j) the third domain is IL-15 and the fourth domain is a Fab domain; k) the third and fourth domains are each the peptidase domain (PD) of ACE2; l) the first and second domains are Fc domains and the third and fourth domains are selected from the group consisting of: (i) a secreted protein, and (ii) an extracellular domain of a transmembrane protein; m) the first and second domains are Fc domains, the third domain is selected from the group consisting of (i) a secreted protein and (ii) an extracellular domain of a transmembrane protein, and the fourth domain is a Fab domain. n) said first and second domains are Fc domains and said third and fourth domains are Fab domains; o) the first and second domains are Fc domains, and the third and fourth domains are peptidase domains (PDs) of ACE2, respectively; p) the first domain is an Fc domain and the second, third and fourth domains are Fab domains; q) the first domain is an Fc domain, the second domain is a Fab domain, the third domain is IL-15, and the fourth domain is an IL-15Rα sushi domain, or r) the first domain is an Fc domain, the second domain is a Fab domain, the third domain is IL-15, and the fourth domain is a Fab domain; 27. The tetrahedral antibody of claim 26.

29. A non-natural fusion protein dimer comprising a dimer of a first dimer-forming polypeptide and a second dimer-forming polypeptide, a) the first dimer-forming polypeptide is linked at its N-terminus or C-terminus to a first domain by a peptide bond or via a peptide linker, and the second dimer-forming polypeptide is linked at its N-terminus or C-terminus to a second domain by a peptide bond or via a peptide linker, as appropriate; b) the first and second dimer-forming polypeptides are i) a collectrin-like domain (CLD), and ii) collectrin domain (CD), selected from the group consisting of c) the first dimer-forming polypeptide is optionally linked at its remaining free N-terminus or C-terminus to a third domain by a peptide bond or via a peptide linker; d) the second dimer-forming polypeptide is optionally linked at its remaining free N-terminus or C-terminus to a fourth domain by a peptide bond or via a peptide linker; e) the non-natural fusion protein dimer is i) the dimer-forming polypeptide does not contain ACE2 PD at the N-terminus thereof; and / or ii) the dimer-forming polypeptide does not contain the transmembrane domain of ACE2 on the C-terminal side; Non-natural fusion protein dimers.

30. A composition comprising the tetrahedral antibody of any one of claims 1 to 15 in an amount of at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% by weight of peptide-containing molecules in the composition (w / w).

31. 30. A pharmaceutical composition comprising the composition of claim 29 and one or more pharmaceutically acceptable excipients.

32. the first domain is an Fc domain and the second, third and fourth domains are Fab domains; a) said third and fourth domains comprise a first type of Fab and said second domain comprises a second type of Fab; i) the first type of Fab is formed from the VH-CH of the H1 or H2 chain and the VL-CL of the L1 chain, and the second type of Fab is formed from the VL-CH of the H1 chain and the VH-CL of the L2 chain; ii) the first type of Fab is formed from the VL-CH of the H1 or H2 chain and the VH-CL of the L1 chain, and the second type of Fab is formed from the VH-CH of the H2 chain and the VL-CL of the L2 chain; or iii) the first type of Fab is formed by the VH-CH of the H1 or H2 chain and the VL-CL of the L1 chain, and the second type of Fab is formed by the VH-CH of the H2 chain and the VL-CL of the L2 chain; wherein VL is the V region of a kappa and / or lambda light chain, and / or b) said third and fourth domains comprise a first type of Fab and said second domain comprises a second type of Fab; i) one type of Fab contains the mutations Q39K and S183E in its heavy chain portion and the mutations Q38E and V133K in its light chain portion, and the other type of Fab contains the mutations S183K and Q38E in its heavy chain portion and the mutations V133E and Q39K in its light chain portion; ii) one type of Fab contains the mutations Q39K and S183E in its heavy chain portion and the mutations Q38E and V133K in its light chain portion, and the other type of Fab contains the mutations S183K and Q38K in its heavy chain portion and the mutations V133E and Q39E in its light chain portion; iii) one type of Fab contains the mutations Q39E and S183E in its heavy chain portion and the mutations Q38E and V133K in its light chain portion, and the other type of Fab contains the mutations S183K and Q38E in its heavy chain portion and the mutations V133E and Q39K in its light chain portion; iv) one type of Fab contains the mutations Q39E and S183E in its heavy chain portion and the mutations Q38K and V133K in its light chain portion, and the other type of Fab contains the mutations S183K and Q38K in its heavy chain portion and the mutations S176E and Q39E in its light chain portion; v) one type of Fab contains the mutations Q39K and S183E in its heavy chain portion and the mutations Q38E and S176K in its light chain portion, and the other type of Fab contains the mutations S183K and Q38E in its heavy chain portion and the mutations S176E and Q39K in its light chain portion; vi) one type of Fab contains the mutations Q39K and S183E in its heavy chain portion and the mutations Q38E and S176K in its light chain portion, and the other type of Fab contains the mutations S183K and Q38K in its heavy chain portion and the mutations S176E and Q39E in its light chain portion; vii) one type of Fab comprises the mutations Q39E and S183E in its heavy chain portion and the mutations Q38E and S176K in its light chain portion, and the other type of Fab comprises the mutations S183K and Q38E in its heavy chain portion and the mutations S176E and Q39K in its light chain portion; or viii) one type of Fab contains the mutations Q39E and S183E in its heavy chain portion and the mutations Q38K and S176K in its light chain portion, and the other type of Fab contains the mutations S183K and Q38K in its heavy chain portion and the mutations S176E and Q39E in its light chain portion; A tetrahedral antibody according to any one of claims 1 to 3.

33. the third, fourth, fifth and sixth domains are Fab domains; a) the third and fourth domains comprise a first type of Fab and the fifth and / or sixth domains comprise a second type of Fab; i) the first type of Fab is formed by the VH-CH of the H1 chain and the VL-CL of the L1 chain, and the second type of Fab is formed by the VL-CH of the H2 chain and the VH-CL of the L2 chain; ii) the first type of Fab is formed from the VL-CH of the H1 chain and the VH-CL of the L1 chain, and the second type of Fab is formed from the VH-CH of the H2 chain and the VL-CL of the L2 chain; or iii) the first type of Fab is formed by the VH-CH of the H1 chain and the VL-CL of the L1 chain, and the second type of Fab is formed by the VH-CH of the H2 chain and the VL-CL of the L2 chain; wherein VL is the V region of a kappa and / or lambda light chain, and / or b) said third and fourth domains comprise a first type of Fab and said fifth and / or sixth domains comprise a second type of Fab; i) one type of Fab contains the mutations Q39K and S183E in its heavy chain portion and the mutations Q38E and V133K in its light chain portion, and the other type of Fab contains the mutations S183K and Q38E in its heavy chain portion and the mutations V133E and Q39K in its light chain portion; ii) one type of Fab contains the mutations Q39K and S183E in its heavy chain portion and the mutations Q38E and V133K in its light chain portion, and the other type of Fab contains the mutations S183K and Q38K in its heavy chain portion and the mutations V133E and Q39E in its light chain portion; iii) one type of Fab contains the mutations Q39E and S183E in its heavy chain portion and the mutations Q38E and V133K in its light chain portion, and the other type of Fab contains the mutations S183K and Q38E in its heavy chain portion and the mutations V133E and Q39K in its light chain portion; iv) one type of Fab contains the mutations Q39E and S183E in its heavy chain portion and the mutations Q38K and V133K in its light chain portion, and the other type of Fab contains the mutations S183K and Q38K in its heavy chain portion and the mutations S176E and Q39E in its light chain portion; v) one type of Fab contains the mutations Q39K and S183E in its heavy chain portion and the mutations Q38E and S176K in its light chain portion, and the other type of Fab contains the mutations S183K and Q38E in its heavy chain portion and the mutations S176E and Q39K in its light chain portion; vi) one type of Fab contains the mutations Q39K and S183E in its heavy chain portion and the mutations Q38E and S176K in its light chain portion, and the other type of Fab contains the mutations S183K and Q38K in its heavy chain portion and the mutations S176E and Q39E in its light chain portion; vii) one type of Fab comprises the mutations Q39E and S183E in its heavy chain portion and the mutations Q38E and S176K in its light chain portion, and the other type of Fab comprises the mutations S183K and Q38E in its heavy chain portion and the mutations S176E and Q39K in its light chain portion; or viii) one type of Fab contains the mutations Q39E and S183E in its heavy chain portion and the mutations Q38K and S176K in its light chain portion, and the other type of Fab contains the mutations S183K and Q38K in its heavy chain portion and the mutations S176E and Q39E in its light chain portion; The tetrahedral antibody of claim 5.

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