Tetrahedral antibodies

Abstract

The present invention provides a tetrahedral antibody comprising a first domain, a second domain, a third domain, and a fourth domain wherein each of the first domain and the second domain is selected from the group consisting of a Fab domain and an Fc domain, wherein each of the first domain and the second domain comprises 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 structural domain and the second structural domain are connected between a first N end of the first structural domain and a first N end of the second structural domain and between a first C end of the first structural domain and a first C end of the second structural domain; non-peptidyl linkages 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 are joined to each other.

Description

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

[0002] Throughout the application, various publications are cited, including publications cited in parentheses. The entire disclosures of all publications mentioned in this application are incorporated by reference into this application to provide additional description of the art to which the invention pertains and features of the art that may be used in the present invention.

[0003] Sequence Listing Reference

[0004] This application incorporates by reference the nucleotide sequence present in the file named "230112_91300-D-PCT_SequenceListing_DH.xml", which is 11.3 megabytes in size, created on January 9, 2022 in IBM-PC machine format with operating system compatibility with MS-Windows, and which is included as part of this application in the xml file filed on January 12, 2023. Background Art

[0005] Antibodies are a diverse family of vertebrate proteins that include 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 the central hinge region has striking similarities to the triangular molecular geometry of three peripheral atoms in which a central atom is bonded to the corners of a triangle. The planar configuration of this binding domain is sufficient to allow antibodies to perform their normal functions. Therefore, efforts to engineer antibodies and antibody-like molecules have generally adopted the natural planar configuration of antibody binding domains so far. However, when the binding domains of engineered antibodies and antibody-like molecules are intended to be combined with multiple targets (engage), the planar configuration of the binding domain is not ideally suited to allow the binding domain to be combined with multiple targets simultaneously (engaging). Summary of the invention

[0006] The present invention provides a tetrahedral antibody comprising a first domain, a second domain, a third domain and a fourth domain, wherein:

[0007] a) each of the first domain and the second domain is selected from the group consisting of a Fab domain and an Fc domain,

[0008] b) each of the first domain and the second domain comprises:

[0009] i) a first polypeptide chain comprising a first N-terminus and a first C-terminus of the domain, and

[0010] ii) a second polypeptide chain comprising a second N-terminus and a second C-terminus of the domain,

[0011] c) the first domain and the second domain are joined to each other via a non-peptidyl linkage, wherein the non-peptidyl linkage is:

[0012] i) Covalent Linking

[0013] (1) connected to the first N-terminus of the first domain and the first N-terminus of the second domain,

[0014] (2) connected to the first C-terminus of the first domain and the first C-terminus of the second domain,

[0015] (3) connected to the first N-terminus of the first domain and the first C-terminus of the second domain, or

[0016] (4) connected to the first C-terminus of the first domain and the first N-terminus of the second domain, or

[0017] ii) Non-covalent attachment

[0018] (1) between a first dimerization polypeptide connected to the first N-terminus of the first domain by a peptide bond or by a peptide linker and a second dimerization polypeptide connected to the first N-terminus of the second domain by a peptide bond or by a peptide linker,

[0019] (2) between a first dimerization polypeptide connected to the first C-terminus of the first domain by a peptide bond or by a peptide linker and a second dimerization polypeptide connected to the first C-terminus of the second domain by a peptide bond or by a peptide linker,

[0020] (3) between a first dimerization polypeptide connected to the first N-terminus of the first domain by a peptide bond or by a peptide linker and a second dimerization polypeptide connected to the first C-terminus of the second domain by a peptide bond or by a peptide linker, or

[0021] (4) between a first dimerization polypeptide connected to the first C-terminus of the first domain by a peptide bond or by a peptide linker and a second dimerization polypeptide connected to the first N-terminus of the second domain by a peptide bond or by a peptide linker,

[0022] wherein the first dimerization polypeptide and the second dimerization polypeptide are not immunoglobulin polypeptides,

[0023] d) if the first domain is joined to the second domain by a covalent link to a first N-terminus of the first domain, the third domain is linked at its C-terminus to the second N-terminus of the first domain by a peptide bond or by a peptide linker,

[0024] e) if the first domain is joined to the second domain by a covalent link to a first C-terminus of the first domain, the third domain is linked at its N-terminus to the second C-terminus of the first domain by a peptide bond or by a peptide linker,

[0025] f) if the first domain is joined to the second domain via a first dimerization polypeptide linked to a first N-terminus of the first domain, the third domain is linked at its C-terminus via a peptide bond or via a peptide linker

[0026] i) the N-terminus of the first dimerization polypeptide,

[0027] ii) the second N-terminus of the first domain, or

[0028] iii) the N-terminus of a third dimerization polypeptide, wherein the third dimerization polypeptide is linked at its C-terminus to the second N-terminus of the first domain via a peptide bond or via a peptide linker,

[0029] g) if the first domain is joined to the second domain via a first dimerization polypeptide linked to a first C-terminus of the first domain, the third domain is linked at its N-terminus via a peptide bond or via a peptide linker

[0030] i) the C-terminus of the first dimerization polypeptide,

[0031] ii) the second C-terminus of the first domain, or

[0032] iii) the C-terminus of the third dimerization polypeptide, wherein the third dimerization polypeptide is linked at its N-terminus to the second C-terminus of the first domain via a peptide bond or via a peptide linker,

[0033] h) if the second domain is joined to the first domain by a covalent link to a first N-terminus of the second domain, the fourth domain is linked at its C-terminus to the second N-terminus of the second domain by a peptide bond or by a peptide linker,

[0034] i) if the second domain is joined to the first domain by a covalent link to the first C-terminus of the second domain, the fourth domain is linked at its N-terminus to the second C-terminus of the second domain by a peptide bond or by a peptide linker,

[0035] j) if the second domain is joined to the first domain via a second dimerization polypeptide linked to a first N-terminus of the second domain, the fourth domain is linked at its C-terminus via a peptide bond or via a peptide linker

[0036] i) the N-terminus of the second dimerization polypeptide,

[0037] ii) the second N-terminus of the second domain, or

[0038] iii) the N-terminus of the fourth dimerization polypeptide, wherein the third dimerization polypeptide is linked at its C-terminus to the second N-terminus of the second domain via a peptide bond or via a peptide linker,

[0039] k) if the second domain is joined to the first domain via a second dimerization polypeptide linked to a first C-terminus of the second domain, the fourth domain is linked at its N-terminus via a peptide bond or via a peptide linker

[0040] i) the C-terminus of the second dimerization polypeptide,

[0041] ii) the second C-terminus of the second domain, or

[0042] iii) the C-terminus of the fourth dimerization polypeptide, wherein the fourth dimerization polypeptide is linked at its N-terminus to the second C-terminus of the second domain via a peptide bond or via a peptide linker.

[0043] The present invention also provides a tetrahedral molecule, which comprises a first domain, a second domain, a third domain and a fourth domain, wherein:

[0044] a) the first domain and the second domain each independently comprise:

[0045] i) a first polypeptide chain comprising a first N-terminus and a first C-terminus of the domain, and

[0046] ii) optionally a second polypeptide chain comprising a second N-terminus and a second C-terminus of the domain,

[0047] b) The first domain and the second domain are joined to each other by a non-covalent bond between

[0048] (1) between a first dimerization polypeptide connected to the first N-terminus of the first domain by a peptide bond or by a peptide linker and a second dimerization polypeptide connected to the first N-terminus of the second domain by a peptide bond or by a peptide linker,

[0049] (2) between a first dimerization polypeptide connected to the first C-terminus of the first domain by a peptide bond or by a peptide linker and a second dimerization polypeptide connected to the first C-terminus of the second domain by a peptide bond or by a peptide linker,

[0050] (3) between a first dimerization polypeptide connected to the first N-terminus of the first domain by a peptide bond or by a peptide linker and a second dimerization polypeptide connected to the first C-terminus of the second domain by a peptide bond or by a peptide linker, or

[0051] (4) between a first dimerization polypeptide connected to the first C-terminus of the first domain by a peptide bond or by a peptide linker and a second dimerization polypeptide connected to the first N-terminus of the second domain by a peptide bond or by a peptide linker,

[0052] wherein the first dimerization polypeptide and the second dimerization polypeptide are not immunoglobulin polypeptides,

[0053] c) if the first domain is joined to the second domain via a first dimerization polypeptide linked to a first N-terminus of the first domain, the third domain is linked at its C-terminus via a peptide bond or via a peptide linker

[0054] i) the N-terminus of the first dimerization polypeptide,

[0055] ii) the second N-terminus of the first domain, if present, or

[0056] iii) the N-terminus of the third dimerization polypeptide, wherein the third dimerization polypeptide is linked at its C-terminus to the second N-terminus of the first domain, if the second N-terminus of the first domain exists, via a peptide bond or via a peptide linker,

[0057] d) if the first domain is joined to the second domain via a first dimerization polypeptide linked to a first C-terminus of the first domain, the third domain is linked at its N-terminus via a peptide bond or via a peptide linker to

[0058] i) the C-terminus of the first dimerization polypeptide,

[0059] ii) the second C-terminus of the first domain, if present, or

[0060] iii) the C-terminus of the third dimerization polypeptide, wherein the third dimerization polypeptide is linked at its N-terminus to the second C-terminus of the first domain, if the second C-terminus of the first domain exists, via a peptide bond or via a peptide linker,

[0061] e) if the second domain is linked to the first domain via a second dimerization polypeptide linked to a first N-terminus of the second domain, the fourth domain is linked at its C-terminus via a peptide bond or via a peptide linker

[0062] i) the N-terminus of the second dimerization polypeptide,

[0063] ii) the second N-terminus of the second domain, if present, or

[0064] iii) the N-terminus of the fourth dimerization polypeptide, wherein the third dimerization polypeptide is linked at its C-terminus to the second N-terminus of the second domain, if the second N-terminus of the second domain is present, via a peptide bond or via a peptide linker, and

[0065] f) if the second domain is joined to the first domain via a second dimerization polypeptide linked to a first C-terminus of the second domain, the fourth domain is linked at its N-terminus via a peptide bond or via a peptide linker

[0066] i) the C-terminus of the second dimerization polypeptide,

[0067] ii) the second C-terminus of the second domain, if present, or

[0068] iii) the C-terminus of the fourth dimeric polypeptide, wherein the fourth dimeric polypeptide is linked at its N-terminus to the second C-terminus of the second domain, if the second C-terminus of the second domain exists, via a peptide bond or via a peptide linker.

[0069] The present invention also provides a non-naturally occurring fusion protein dimer, comprising a dimer of a first dimerizing polypeptide and a second dimerizing polypeptide, wherein:

[0070] a) the first dimerization polypeptide is linked at its N-terminus or C-terminus to the first domain via a peptide bond or via a peptide linker,

[0071] b) a second dimerization polypeptide is optionally linked to the second domain at its N-terminus or C-terminus via a peptide bond or via a peptide linker,

[0072] c) the first dimerization polypeptide and the second dimerization polypeptide are selected from the group consisting of:

[0073] i) collectrin-like domain (CLD), and

[0074] ii) collectrin domain (CD),

[0075] d) the first dimerization polypeptide is optionally linked at its remaining free N-terminus or C-terminus to the third domain via a peptide bond or via a peptide linker, and

[0076] e) The second dimerization polypeptide is optionally linked to the fourth domain at its remaining free N-terminus or C-terminus via a peptide bond or via a peptide linker.

[0077] The present invention also provides an octahedral antibody, which comprises a first domain, a second domain, a third domain, a fourth domain, a fifth domain and a sixth domain, wherein:

[0078] a) each of the first domain, the second domain and the third domain is selected from the group consisting of a Fab domain and an Fc domain,

[0079] b) each of the first domain, the second domain and the third domain comprises:

[0080] i) a first polypeptide chain comprising a first N-terminus and a first C-terminus of the domain, and

[0081] ii) a second polypeptide chain comprising a second N-terminus and a second C-terminus of the domain,

[0082] 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 joined to each other via a non-peptidyl linkage, wherein the non-peptidyl linkage is:

[0083] i) the side chains are covalently linked, or

[0084] ii) non-covalent bonding between

[0085] (1) a first trimerizing polypeptide connected to the first N-terminus of the first domain via a peptide bond or via a peptide linker,

[0086] (2) a second trimerizing polypeptide connected to the first N-terminus of the second domain via a peptide bond or via a peptide linker,

[0087] (3) a third trimerizing polypeptide connected to the first N-terminus of the third domain via a peptide bond or via a peptide linker,

[0088] wherein the first trimerizing polypeptide, the second trimerizing polypeptide and the third trimerizing polypeptide are not immunoglobulin polypeptides,

[0089] d) the fourth domain is linked at its C-terminus via a peptide bond or via a peptide linker to:

[0090] i) the second N-terminus of the first domain, or

[0091] ii) the N-terminus of the first trimerizing polypeptide,

[0092] e) the fifth domain is linked at its C-terminus via a peptide bond or via a peptide linker to:

[0093] i) the second N-terminus of the second domain, or

[0094] ii) the N-terminus of the second trimerizing polypeptide, and

[0095] f) the sixth domain is linked at its C-terminus via a peptide bond or via a peptide linker to:

[0096] i) the second N-terminus of the third domain, or

[0097] ii) the N-terminus of the third trimerizing polypeptide. BRIEF DESCRIPTION OF THE DRAWINGS

[0098] Figure 1 : General schematic structure of a tetrahedral antibody, showing the positions of the D1 domain, D2 domain, D3 domain, D4 domain (A to D), D5 domain and D6 domain (D) as well as the positions of covalent linkages (A) and non-covalent linkages (B to D).

[0099] Figure 2 :With Figure 1Schematic structure of a covalently linked tetrahedral antibody shown in A, wherein (A) D1, D2, D3 and D4 are all different; (B) D1 and D2 are different; D3 and D4 are the same; (C) D1 and D2 are the same; D3 and D4 are different; (D) D1 and D2 are the same; D3 and D4 are the same.

[0100] Figure 3 :With Figure 1 Schematic structure of a non-covalently linked tetrahedral antibody shown in B, wherein (A) D1, D2, D3 and D4 are all different; (B) D1 and D2 are different; D3 and D4 are the same; (C) D1 and D2 are the same; D3 and D4 are different; (D) D1 and D2 are the same; D3 and D4 are the same. A pair of dimerized polypeptides forms a heterodimer pair in (A to C) and a homodimer pair in (D).

[0101] Figure 4 :With Figure 1 Schematic structure of a non-covalently linked tetrahedral antibody shown in C, wherein (A) D1, D2, D3 and D4 are all different; (B) D1 and D2 are different; D3 and D4 are the same; (C) D1 and D2 are the same; D3 and D4 are different; (D) D1 and D2 are the same; D3 and D4 are the same. A pair of dimerized polypeptides forms a heterodimer pair in (AC) and a homodimer pair in (D).

[0102] Figure 5 :With Figure 1 Schematic structure of a non-covalently linked tetrahedral antibody shown in D, wherein D1 and D2 are different, wherein in the D3 to D6 domains, (A) D3 to D6 are all different; (B) D4 and D5 are the same, D3 and D6 are different; (C) D4 and D6 are the same, D3 and D5 are different; (D) D3 and D4 are the same, D5 and D6 are different. A pair of dimerized polypeptides forms a heterodimer pair in (A to D).

[0103] Figure 6 :With Figure 1 Schematic structure of a non-covalently linked tetrahedral antibody shown in D, wherein D1 and D2 are different, wherein in the D3 to D6 domains, (A) D3 and D6 are the same, D4 ​​and D6 are the same; (B) D3 and D5 are the same, D4 ​​and D5 are the same; (C) D3 and D4 are the same, D5 and D6 are the same; (D) D3 to D6 are the same. A pair of dimerized polypeptides forms a heterodimer pair in (A to D).

[0104] Figure 7 :With Figure 1Schematic structure of a non-covalently linked tetrahedral antibody shown in D, wherein D1 and D2 are different, there is no D6 domain, wherein in the D3 to D5 domains, (A) D3 to D5 are all different; (B) D4 and D5 are the same and different from D3; (C) D3 and D5 are the same and different from D4; (D) D3 to D5 are all the same. A pair of dimerized polypeptides forms a heterodimer pair in (A to D).

[0105] Fig. 8A :With Figure 1 Schematic structure of a non-covalently linked tetrahedral antibody shown in D, wherein D1 and D2 are the same, wherein in the D3 to D6 domains, (A) D3 to D6 are all of the first type; (B) D3 to D6 are all of the second type; (C) D3 and D4 are of the first type, and D5 and D6 are of the second type; (D) D3 and D5 are of the first type, and D4 and D6 are of the second type. A pair of dimerized polypeptides forms a homodimer pair in (A to D).

[0106] Figure 8B :With Figure 1 Schematic structure of a non-covalently linked tetrahedral antibody shown in D, wherein D1 and D2 are the same, wherein in the D3 to D6 domains, (A) D3 to D6 are all of the first type; (B) D3 to D6 are all of the second type; (C) D3 and D4 are of the first type, and D5 and D6 are of the second type; (D) D3 and D4 are of the second type, and D5 and D6 are of the first type. A pair of dimerized polypeptides forms a homodimer pair in (A to D).

[0107] Fig. 9 :With Figure 1 Schematic structure of a non-covalently linked tetrahedral antibody shown in D, wherein D1 and D2 are the same, wherein in the D3 to D5 domains, (A) D3 to D6 are all of the first type, (B) D3 to D6 are all of the second type; (C) D4 and D5 are of the first type, D3 and D6 are of the second type; (D) D3 and D6 are of the first type, and D4 and D5 are of the second type. Each of the two pairs of dimerized polypeptides forms a heterodimer pair in (A to D).

[0108] Fig.10 :With Figure 1Schematic structure of a non-covalently linked tetrahedral antibody shown in D, (A to B) wherein D1 and D2 are the same, wherein in the D3 to D5 domains, (A) D3 to D6 are all of the first type, and (B) D3 to D6 are all of the second type; (C to D) wherein D1 and D2 are different, wherein in the D3 to D5 domains, (C) D3 and D4 are of the first type, and D5 and D6 are of the second type; (D) D3 and D5 are of the first type, and D4 and D6 are of the second type. Each of the two pairs of dimerized polypeptides forms a homodimer pair in (A to B). Each of the two different pairs of dimerized polypeptides forms a separate homodimer pair in (C to D).

[0109] Fig.11 : Schematic structures of tetrahedral antibodies (A) Rc6-P4-Rc6, (B) Rc66SIDE-P4-Rc66SIDE, Rc66SIDE-P16-Rc66SIDE, (D) Rc66SIDE-P28-Rc66SIDE, (E) B19c66-P4-Rc6m (F) Soc66-P28-6Ec66, (G) HA9c66AAC9-P4-HA9c66AAC9 and (H) HA9c66AAC9-P4-IL15c6AAC9.

[0110] Fig.12 : Preparation of tetrahedral antibody Rc6-P4-Rc6.

[0111] Fig.13 :With Figure 1 B shows the preparation of non-covalently linked tetrahedral antibodies.

[0112] Fig.14 : Preparation of tetrahedral antibody ACE2RQ740c60PG-ACE2RQ740c60PG.

[0113] Fig.15 : Analysis of tetrahedral antibody ACE2RQ740c60PG-ACE2RQ740c60PG by SE-HPLC.

[0114] Fig.16: Tetrahedral antibodies with different peptide linkers were analyzed by SE-HPLC: (L-1) ACE2RQ740c60PGRF-ACE2RQ740c60PGRF, (L-185) ACE2RQ740c60PGRF185-ACE2RQ740c60PGRF185, (L-198) ACE2RQ740c60PGRF198-ACE2RQ740c60PGRF198, (L-208) ACE2RQ740c60PGRF198 740c60PGRF208-ACE2RQ740c60PGRF208, (L-212)ACE2RQ740c60PGRF235-ACE2RQ740c60PGRF235, (L-235 )ACE2RQ740c60PGRF235-ACE2RQ740c60PGRF235, (L-240)ACE2RQ740c60PGRF240-ACE2RQ740c60PGRF240.

[0115] Fig.17 : Analysis of tetrahedral antibody ACE2RQ740c60PG-ACE2RQ740c60PG by SE-HPLC / MALS.

[0116] Fig.18 : Stoichiometric binding analysis of a mixture of the tetrahedral antibody ACE2RQ740c60PG-ACE2RQ740c60PG and the ACE monomer ACE2RQ615c60PG.

[0117] Fig.19 : Preparation of tetrahedral antibody ACE2740FcG9-ACE2740FcG9.

[0118] Fig. 20 : Analysis of tetrahedral antibody ACE2740FcG9-ACE2740FcG9 by SE-HPLC.

[0119] Fig.21 : Analysis of tetrahedral antibody ACE2740FcG9-ACE2740FcG9 by SE-HPLC / MALS.

[0120] Fig. 22 : Analysis of tetrahedral antibody ACE2RQ740FcPG-ACE2RQ740FcPG by SE-HPLC / MALS.

[0121] Fig.23 : Stoichiometric binding analysis of impure preparations of tetrahedral antibody ACE2740FcG9-ACE2740FcG9 and ACE2 dimer ACE2740FcG9.

[0122] Fig.24 : Stoichiometric binding analysis of a mixture of tetrahedral antibody ACE2740FcG9-ACE2740FcG9 and ACE2 dimer ACE2-740Fc-G9.

[0123] Fig.25 : Stoichiometric binding analysis of a mixture of tetrahedral antibody ACE2RQ740FcPG-ACE2RQ740FcPG and ACE2 dimer ACE2-740Fc-G9.

[0124] Fig.26 : Stoichiometric binding analysis of a mixture of tetrahedral antibody ACE2740FcG9-ACE2740FcG9 and ACE2 dimer ACE2-615Fc-G9.

[0125] Fig. 27 : The inhibitory effects of ACE2 tetrahedral antibodies ACE2740FcG9-ACE2740FcG9 and ACE2RQ740FcPG-ACE2RQ740FcPG, and ACE2 dimers ACE2-615Fc-G9 and ACE2RQ615FcPG on SARS-CoV-2-VSV pseudovirus infection.

[0126] Fig.28 : The inhibitory effects of ACE2 tetrahedral antibodies ACE2740FcG9-ACE2740FcG9 and ACE2RQ740FcPG-ACE2RQ740FcPG and ACE2 dimers ACE2-740Fc-G9 and ACE2RQ740FcPG on SARS-CoV-2-VSV pseudovirus infection.

[0127] Fig.29A : A tetrahedral antibody comprising a first dimerization polypeptide and a second dimerization polypeptide that are non-covalently linked to form a homodimer, wherein D1 and D2 are each a heterodimeric Fc domain, and D3 and D4 are each a Fab domain that specifically binds to a first target.

[0128] Fig.29B : A tetrahedral antibody comprising a first dimerization polypeptide and a second dimerization polypeptide that are non-covalently linked to form a homodimer, wherein D1 and D2 are each a heterodimeric Fc domain, D3 and D4 are each a Fab domain that specifically binds to a first target, and D5 and D6 are each a variable region-exchanged Fab domain that specifically binds to a second target.

[0129] Fig.29C: A tetrahedral antibody comprising a first dimerization polypeptide and a second dimerization polypeptide that form a homodimer non-covalent connection, wherein D1 and D2 are each a heterodimer Fc domain, D3 and D4 are each a Fab domain that specifically binds to a first target, and D7 and D8 are each a domain that specifically binds to a second target. D7 and D8 are each shown as a single-chain TNFSF fusion polypeptide, but can be any domain.

[0130] Fig.29D :: A tetrahedral antibody comprising a first dimerization polypeptide and a second dimerization polypeptide that form a homodimer non-covalently linked, wherein D1 and D2 are each a heterodimer Fc domain, D3 and D4 are each a Fab domain that specifically binds to a first target, D5 and D6 are each a variable region exchanged Fab domain that specifically binds to a second target, and D7 and D8 are each a domain that specifically binds to a third target. D7 and D8 are shown as single-chain TNFSF fusion polypeptides, but can be any domain.

[0131] Fig. 30A : An octahedral antibody comprising a first trimerizing polypeptide, a second trimerizing polypeptide and a third trimerizing polypeptide that are non-covalently linked to form a homologous trimer, wherein D1, D2 and D3 are each a heterodimeric Fc domain, and D4, D5 and D6 are each a Fab domain that specifically binds to a first target.

[0132] Fig. 30B : An octahedral antibody comprising a first trimerizing polypeptide, a second trimerizing polypeptide and a third trimerizing polypeptide that are non-covalently linked to form a homologous trimer, wherein D1, D2 and D3 are each a heterodimeric Fc domain, D4, D5 and D6 are each a Fab domain that specifically binds to a first target, and D7, D8 and D9 are each a variable region-exchanged Fab domain that specifically binds to a second target.

[0133] Fig. 30C : An octahedral antibody comprising a first trimerizing polypeptide, a second trimerizing polypeptide and a third trimerizing polypeptide that form a homotrimer non-covalently linked, 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 D10, D11 and D12 each specifically bind to a second target. D10, D11 and D12 are each shown as single-chain TNFSF fusion polypeptides, but can be any domain.

[0134] Fig.30D: An octahedral antibody comprising a first trimerizing polypeptide, a second trimerizing polypeptide and a third trimerizing polypeptide that form a homologous trimer non-covalently linked, 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, 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 bound to a third target. D10, D11 and D12 are each shown as single-chain TNFSF fusion polypeptides, but can be any domain.

[0135] Fig.31 : A tetrahedral antibody comprising a first dimerizing polypeptide and a second dimerizing polypeptide that form a non-covalent homodimer connection, wherein D1 and D2 are each heterodimeric Fc domains, wherein (A) D3, D4, D5 and D6 specifically bind to a first target (tetravalent, monospecific), (B) D3 and D4 specifically bind to the first target, D5 and D6 specifically bind to the second target (tetravalent, 2+2 bispecific), (C) D3 and D4 are Fab domains that specifically bind to the first target, D5 and D6 specifically bind to the second target (tetravalent, 2+2 bispecific), and (D) D3, D4, D5 and D6 are Fab domains that specifically bind to the first target (tetravalent, 2+2 bispecific). The tetrahedral antibodies of A to D include (A) four chains: the first H1 chain [D1 / D3], the second H1 chain [D2 / D4], the first H2 chain [D1 / D5], and the second H2 chain [D2 / D6], (B) six chains: the first H1 chain [D1 / D3], the second H1 chain [D2 / D4], the first H2 chain [D1 / D5], the second H2 chain [D2 / D6], the first L2 chain [D5], and the second L2 chain [D6], (C) six chains: the 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].

[0136] Fig.32: A tetrahedral antibody comprising a first dimerizing polypeptide and a second dimerizing polypeptide that form a non-covalent homodimer connection, wherein D1 and D2 are each heterodimeric Fc domains, wherein (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 the first target, and D5 and D6 are variable region-exchanged Fab domains that specifically bind to the second target (tetravalent, 2+2 bispecific), and (D) D5 and D6 are Fab domains that specifically bind to the first target, and D3 and D4 are variable region-exchanged Fab domains that specifically bind to the second target (tetravalent, 2+2 bispecific). The tetrahedral antibodies of A to D include (A) four chains: the first H1 chain [D1 / D3], the second H1 chain [D2 / D4], the first H2 chain [D1 / D5] and the second H2 chain [D2 / D6], (B) four chains: the first H1 chain [D1 / D3], the second H1 chain [D2 / D4], the first H2 chain [D1 / D5] and the second H2 chain [D2 / D6], (C) eight chains: the first H1 chain [D1 / D3], the second H1 chain [D2 / D4], the first H2 chain [D1 / D5] and the second H2 chain [D2 / D6]. 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], 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].

[0137] Fig.33: A tetrahedral antibody comprising a first dimerizing polypeptide and a second dimerizing polypeptide that form a non-covalent homodimer connection, wherein D1 and D2 are each heterodimeric Fc domains, wherein (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 the second target (tetravalent, 3+1 bispecific), (C) D3, D4 and D5 are Fab domains that specifically bind to the first target and D6 specifically binds to the 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 the second target (tetravalent, 3+1 bispecific). Tetrahedral antibodies from A to D include (A) four chains: the first H1 chain [D1 / D3], the second H1 chain [D2 / D4], the first H2 chain [D1 / D5], and the first H3 chain [D2 / D6], (B) five 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], and the first L3 chain [D6], (C) 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], and the first L3 chain [D6]. one H2 chain [D1 / D5], the first H3 chain [D2 / D6], the first L1 / L2 chain [D3], the second L1 / L2 chain [D4], and the third L1 / L2 chain [D5], and (D) eight 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 / L2 chain [D3], the second L1 / L2 chain [D4], the third L1 / L2 chain [D5], and the first L3 chain [D6].

[0138] Fig.34: A tetrahedral antibody comprising a first dimerizing polypeptide and a second dimerizing polypeptide that form a non-covalent homodimer connection, wherein D1 and D2 are each heterodimeric Fc domains, wherein (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 the first target, and D6 is a Fab domain that specifically binds to the second target (trivalent, 2+1 bispecific), (C) D3 and D4 are Fab domains that specifically bind to the first target, and D6 specifically binds to the second target (trivalent, 2+1 bispecific), and (D) D3 and D4 are Fab domains that specifically bind to the first target, and D6 is a variable region-exchanged Fab domain that specifically binds to the second target (trivalent, 2+1 bispecific). The tetrahedral antibodies of A to D include (A) four chains: the first H1 chain [D1 / D3], the second H1 chain [D2 / D4], the first H2 chain [D2 / D6], and the first Fc chain [D1], (B) five chains: the first H1 chain [D1 / D3], the second H1 chain [D2 / D4], the first H2 chain [D2 / D6], the first Fc chain [D1], and the first L2 chain [D6], (C) six chains: the first H1 chain [D1 / D3], 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].

[0139] Fig.35: A tetrahedral antibody comprising a first dimerizing polypeptide and a second dimerizing polypeptide that form a homodimer non-covalently linked, wherein D1 and D2 are each a heterodimeric Fc domain, wherein (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), (B) D3 and D4 specifically bind to a first target, D5 specifically binds to a second target, and D6 is a Fa specifically binding to a third target b domain (tetravalent, 2+1+1 trispecific), (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; D6 is a variable region exchange Fab domain that specifically binds to a third target (tetravalent, 2+1+1 trispecific). Tetrahedral antibodies from A to D include (A) four chains: the first H1 chain [D1 / D3], the second H1 chain [D2 / D4], the first H2 chain [D1 / D5], and the first H3 chain [D2 / D6], (B) five 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], and the first L3 chain [D6], (C) six chains: the first H1 chain [D1 / D3], second H1 chain [D2 / D4], first H2 chain [D1 / D5], first H3 chain [D2 / D6], 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 [D1 / D5], first H3 chain [D2 / D6], first L1 chain [D3], second L1 chain [D4] and first L3 chain [D6].

[0140] Fig.36: A tetrahedral antibody comprising a first dimerizing polypeptide and a second dimerizing polypeptide that form a homodimer non-covalently linked, wherein D1 is a heterodimeric Fc domain, D2 is a Fab domain, wherein (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), (B) D2 is a Fab that binds to a first target, D3 and D4 specifically bind to a second target, and D5 is a Fab that specifically binds to a third target Fab with exchanged variable regions (tetravalent, 2+1+1 trispecific), (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 specifically binds to a third target (tetravalent, 2+1+1 trispecific), and (D) D2 is a Fab that binds to a first target, D3, D4 and D5 are variable region exchanged Fab domains that specifically bind to a second target (tetravalent, 4+1 bispecific). The tetrahedral antibodies of A to D include (A) four chains: the first H1 chain [D1 / D3], the first H1 Fab chain [D2 / D4], the first H2 chain [D1 / D5] and the first Fab chain [D2], (B) five 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] and the first L2 chain [D5], (C) six chains: the first H1 chain [D1 / D3], first H1Fab chain [D2 / D4], first H2 chain [D1 / D5], first Fab chain [D2], first L1 chain [D3] and second L1 chain [D4], and (D) seven chains: first H1 chain [D1 / D3], first H1Fab chain [D2 / D4], first H2 chain [D1 / D5], first Fab chain [D2], first L1 / L2 chain [D3], second L1 / L2 chain [D4] and third L1 / L2 chain [D5].

[0141] Fig.37: A tetrahedral antibody comprising a first dimerizing polypeptide and a second dimerizing polypeptide that form a non-covalent homodimer connection, wherein D1 is a heterodimeric Fc domain, D2 is a Fab domain, wherein (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 a first target, D3 and D4 specifically bind to a second target, and D5 is specific (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 specifically binds to the third target (tetravalent, 2+1+1 trispecific), and (D) D2 is a variable region-exchanged Fab that binds to the first target, D3, D4 and D5 are Fab domains that specifically bind to the second target (tetravalent, 3+1 bispecific). The tetrahedral antibodies of A to D include (A) four chains: the first H1 chain [D1 / D3], the first H1 Fab chain [D2 / D4], the first H2 chain [D1 / D5] and the first Fab chain [D2], (B) five 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] and the first L2 chain [D5], (C) six chains: the first H1 chain [D1 / D3], first H1Fab chain [D2 / D4], first H2 chain [D1 / D5], first Fab chain [D2], first L1 chain [D3] and second L1 chain [D4], and (D) seven chains: first H1 chain [D1 / D3], first H1Fab chain [D2 / D4], first H2 chain [D1 / D5], first Fab chain [D2], first L1 / L2 chain [D3], second L1 / L2 chain [D4] and third L1 / L2 chain [D5].

[0142] Fig.38: A tetrahedral antibody comprising a first dimerizing polypeptide and a second dimerizing polypeptide that form a non-covalent homodimer connection, wherein D1 is a heterodimeric Fc domain, D2 is a Fab domain, wherein (A) D2 is a Fab that binds to a first target, 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, D3 and D4 specifically bind to the second target, (C) D2 is a Fab that binds to the first target, D3 and D4 are variable region-exchanged Fab domains that specifically bind to the second target (trivalent, 2+1 bispecific), and (D) 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 (trivalent, 2+1 bispecific). The tetrahedral antibody of AD includes (A) four chains: the first H1 chain [D1 / D3], the first H1 Fab chain [D2 / D4], the first Fc chain [D1] and the first Fab chain [D2], (B) four chains: the first H1 chain [D1 / D3], the first H1 Fab chain [D2 / D4], the first Fc chain [D1] and the first Fab chain [D2], (C) 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], 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].

[0143] Fig.39: A tetrahedral antibody comprising a first dimerizing polypeptide and a second dimerizing polypeptide that form a non-covalent homodimer connection, wherein D1 and D2 are each heterodimeric Fc domains, wherein (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 a first target, D5 and D6 are Fab domains that specifically bind to a second target, and D7 and D8 specifically binds to a third target (hexavalent, 2+2+2 trispecific), (C) D3 and D4 are Fab domains that specifically bind to the first target, D5 and D6 specifically bind to the second target, D7 and D8 specifically bind to the third target (hexavalent, 2+2+2 trispecific), and (D) D3, D4, D5 and D5 are Fab domains that specifically bind to the first target, D7 and D8 specifically bind to the second target (hexavalent, 4+2 bispecific). The tetrahedral antibodies A to D include (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) six chains: the first H1 chain [D1 / D3 / D7], the second H1 chain [D2 / D4 / D8], the first H2 chain [D1 / D5], the second H2 chain [D2 / D6], the first L2 chain [D5], and the second L2 chain [D6], (C) six chains: the first H1 chain [D [D] eight 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], second L1 chain [D4], first L2 chain [D5] and second L2 chain [D6]. D7 and D8 can be connected to the C-terminus of the first H1 chain and the second H1 chain (as shown in the figure) or to the C-terminus of the first H2 chain and the second H2 chain. D7 and D8 are shown as single-chain TNFSF ligand fusion polypeptides, but can be any domain.

[0144] Fig.40: A tetrahedral antibody comprising a first dimerizing polypeptide and a second dimerizing polypeptide that form a non-covalent homodimer connection, wherein D1 and D2 are each a heterodimeric Fc domain, wherein (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 a first target, D3 and D4 specifically bind to a second target, and D7 and D8 specifically bind 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 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 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). The tetrahedral antibodies of A to D include (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], (C) eight chains: the first H1 chain [D1 / D3 / D7], the second H1 chain [D2 / D4 / D8], 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], and (D) eight 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], second L1 chain [D4], first L2 chain [D5] and second L2 chain [D6]. D7 and D8 can be linked to the C-termini of the first H1 chain and the second H1 chain (as shown) or to the C-termini of the first H2 chain and the second H2 chain. D7 and D8 are shown as single-chain TNFSF ligand fusion polypeptides, but can be any domain.

[0145] Fig.41: A tetrahedral antibody comprising a first dimerizing polypeptide and a second dimerizing polypeptide that form a non-covalent homodimer connection, wherein D1 and D2 are each heterodimeric Fc domains, wherein (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), (B) D3 and D4 specifically bind to a first target, D6 is a Fab domain that specifically binds to a second target, and D7 and D8 specifically bind to and a third target (pentavalent, 2+2+1 trispecific), (C) D3 and D4 are Fab domains that specifically bind to the first target, D6 specifically binds to the second target, and D7 and D8 specifically bind to the third target (pentavalent, 2+2+1 trispecific), and (D) D3 and D4 are Fab domains that specifically bind to the first target, D6 is a variable region-exchanged Fab domain that specifically binds to the second target, and D7 and D8 specifically bind to the third target (pentavalent, 2+2+1 trispecific). Tetrahedral antibodies from A to D include (A) four chains: the first H1 chain [D1 / D3 / D7], the second H1 chain [D2 / D4 / D8], the first H2 chain [D2 / D6], and the first Fc chain [D1]; (B) five chains: the first H1 chain [D1 / D3 / D7], the second H1 chain [D2 / D4 / D8], the first H2 chain [D2 / D6], the Fc chain [D1], and the L2 chain [D6]; (C) six chains: the first H1 chain [D1 / D 3 / 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 (D) seven 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 can be connected to the C-terminus of the first H1 chain and the second H1 chain (as shown) or to the C-terminus of the first H2 chain and the second H2 chain. D7 and D8 are shown as single-chain TNFSF ligand fusion polypeptides, but can be any domain.

[0146] Fig.42: A tetrahedral antibody comprising a first dimerizing polypeptide and a second dimerizing polypeptide that form a non-covalent homodimer connection, wherein D1 is a heterodimeric Fc domain, D2 is a Fab domain, wherein (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 the second target, D7 and D8 specifically bind to the third target (C) D2 is a Fab domain that specifically binds to the first target, D3 and D4 are variable region-swapped Fab domains that specifically bind to the second target, and D7 and D8 specifically bind to the third target (pentavalent, 2+2+1 trispecific), and (D) D2 is a variable region-swapped Fab domain that specifically binds to the first target, D3 and D4 are Fab domains that specifically bind to the second target, and D7 and D8 specifically bind to the third target (pentavalent, 2+2+1 trispecific). The tetrahedral antibody of A to D includes (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: first H1 chain [D1 / D3 / D7], second H1 chain [D2 / D4 / D8], first Fc chain [D1], and first Fab chain [D2]. (C) Six chains: first H1 chain [D1 / D3 / D7], second H1 chain [D2 / D4 / D8], first Fc chain [D1], first Fab chain [D2], first L1 chain [D3], and second L1 chain [D4], and (D) Six chains: first H1 chain [D1 / D3 / D7], second H1 chain [D2 / D4 / D8], first H2 chain [D2 / D6], first Fc chain [D1], first Fab chain [D2], first L1 chain [D3], and second L1 chain [D4]. D7 and D8 can be attached to the C-termini of the first H1 chain and the second H1 chain (as shown) or to the C-termini of the first H2 chain and the second H2 chain. D7 and D8 are shown as single chain TNFSF ligand fusion polypeptides, but can be any domain.

[0147] Fig.43 : ACE2 tetrahedral antibodies. Four forms of ACE2 tetrahedral antibodies are shown in Figures c, d, e and f. Each antibody contains domains 1-4 and a dimerized polypeptide. The structures in Figures a and b are standard Fc dimers.

[0148] Fig.44: Relative neutralizing activity of ACE2 tetrahedral antibodies against live viruses. Upper panel: shows the neutralization of live SARS-CoV-2 virus. Lower panel: shows the neutralization of NL63 (alpha coronavirus). ACE2 superdimer (6-05 SD) neutralizes the virus better at a level about 3 orders of magnitude higher than the standard Fc fusion protein (ACE2Fc615). Also shown are the purified dimer (6-05 D) and the impure mixture of dimer and superdimer (6-05 impure).

[0149] Fig.45 : Pharmacokinetic curves of constructs 13-21 and 13-22. 13-21 corresponds to wt ACE2-B13 superdimer tetrahedron antibody. 13-22 corresponds to mutant ACE2-B13 superdimer tetrahedron antibody with H378A mutation.

[0150] Fig.46 : Pharmacokinetic curves of constructs 10-05 and 13-21. 10-05 corresponds to ACE2-ACE2 superdimer tetrahedron antibody. 13-21 corresponds to wt ACE2-B13 superdimer tetrahedron antibody.

[0151] Fig.47 : Relative neutralizing activities of ACE2 core dimer (10-59), B-13 (12-09) and ACE2-B-13 superdimer (15-16).

[0152] Figure 48A-Figure 48P : The relative neutralizing activity of various antibodies against 12 different variant viruses was compared with ACE2-B13 silent version and ACE2-B13-active version (represented by diamonds and circles).

[0153] Fig.49 : Body weight changes of hamsters infected with the South African SARS-CoV-2 virus treated with PBS control (PBS), 25 mg / kg REGN10933, REG-CoV-2 cocktail (25 mg / kg each of Regeneron antibodies REGN 10933 and REG108987), and 25 mg / kg Fc-silent ACE2-B13 (HB1516).

[0154] Figure 50A-50C : Relative quantification of correct and incorrect pairing in bispecific antibodies. The main peak represents correctly paired molecules. Arrows point to the locations where mispaired products may appear. The main peak consists of two peaks, which are due to the residual O-glycans after the deglycosylation process.

[0155] Figure 51A-Figure 51C: Relative neutralizing activity of various antibodies against N439K and South African variants. ACE2 superdimers (squares) are described in Tables 36, 37 and 38. DETAILED DESCRIPTION

[0156] Tetrahedral Antibody

[0157] The present invention provides a tetrahedral antibody comprising a first domain, a second domain, a third domain and a fourth domain, wherein:

[0158] a) each of the first domain and the second domain is selected from the group consisting of a Fab domain and an Fc domain,

[0159] b) each of the first domain and the second domain comprises:

[0160] i) a first polypeptide chain comprising a first N-terminus and a first C-terminus of the domain, and

[0161] ii) a second polypeptide chain comprising a second N-terminus and a second C-terminus of the domain,

[0162] c) the first domain and the second domain are joined to each other via a non-peptidyl linkage, wherein the non-peptidyl linkage is:

[0163] i) Covalent Linking

[0164] (1) connected to the first N-terminus of the first domain and the first N-terminus of the second domain,

[0165] (2) connected to the first C-terminus of the first domain and the first C-terminus of the second domain,

[0166] (3) connected to the first N-terminus of the first domain and the first C-terminus of the second domain, or

[0167] (4) connected to the first C-terminus of the first domain and the first N-terminus of the second domain, or

[0168] ii) Non-covalent attachment

[0169] (1) between a first dimerization polypeptide connected to the first N-terminus of the first domain by a peptide bond or by a peptide linker and a second dimerization polypeptide connected to the first N-terminus of the second domain by a peptide bond or by a peptide linker,

[0170] (2) between a first dimerization polypeptide connected to the first C-terminus of the first domain by a peptide bond or by a peptide linker and a second dimerization polypeptide connected to the first C-terminus of the second domain by a peptide bond or by a peptide linker,

[0171] (3) between a first dimerization polypeptide connected to the first N-terminus of the first domain by a peptide bond or by a peptide linker and a second dimerization polypeptide connected to the first C-terminus of the second domain by a peptide bond or by a peptide linker, or

[0172] (4) between a first dimerization polypeptide connected to the first C-terminus of the first domain by a peptide bond or by a peptide linker and a second dimerization polypeptide connected to the first N-terminus of the second domain by a peptide bond or by a peptide linker,

[0173] wherein the first dimerization polypeptide and the second dimerization polypeptide are not immunoglobulin polypeptides,

[0174] d) if the first domain is joined to the second domain by a covalent link to a first N-terminus of the first domain, the third domain is linked at its C-terminus to the second N-terminus of the first domain by a peptide bond or by a peptide linker,

[0175] e) if the first domain is joined to the second domain by a covalent link to a first C-terminus of the first domain, the third domain is linked at its N-terminus to the second C-terminus of the first domain by a peptide bond or by a peptide linker,

[0176] f) if the first domain is joined to the second domain via a first dimerization polypeptide linked to a first N-terminus of the first domain, the third domain is linked at its C-terminus via a peptide bond or via a peptide linker

[0177] i) the N-terminus of the first dimerization polypeptide,

[0178] ii) the second N-terminus of the first domain, or

[0179] iii) the N-terminus of a third dimerization polypeptide, wherein the third dimerization polypeptide is linked at its C-terminus to the second N-terminus of the first domain via a peptide bond or via a peptide linker,

[0180] g) if the first domain is joined to the second domain via a first dimerization polypeptide linked to a first C-terminus of the first domain, the third domain is linked at its N-terminus via a peptide bond or via a peptide linker

[0181] i) the C-terminus of the first dimerization polypeptide,

[0182] ii) the second C-terminus of the first domain, or

[0183] iii) the C-terminus of the third dimerization polypeptide, wherein the third dimerization polypeptide is linked at its N-terminus to the second C-terminus of the first domain via a peptide bond or via a peptide linker,

[0184] h) if the second domain is joined to the first domain by a covalent link to a first N-terminus of the second domain, the fourth domain is linked at its C-terminus to the second N-terminus of the second domain by a peptide bond or by a peptide linker,

[0185] i) if the second domain is joined to the first domain by a covalent link to the first C-terminus of the second domain, the fourth domain is linked at its N-terminus to the second C-terminus of the second domain by a peptide bond or by a peptide linker,

[0186] j) if the second domain is joined to the first domain via a second dimerization polypeptide linked to a first N-terminus of the second domain, the fourth domain is linked at its C-terminus via a peptide bond or via a peptide linker

[0187] i) the N-terminus of the second dimerization polypeptide,

[0188] ii) the second N-terminus of the second domain, or

[0189] iii) the N-terminus of the fourth dimerization polypeptide, wherein the third dimerization polypeptide is linked at its C-terminus to the second N-terminus of the second domain via a peptide bond or via a peptide linker,

[0190] k) if the second domain is joined to the first domain via a second dimerization polypeptide linked to a first C-terminus of the second domain, the fourth domain is linked at its N-terminus via a peptide bond or via a peptide linker

[0191] i) the C-terminus of the second dimerization polypeptide,

[0192] ii) the second C-terminus of the second domain, or

[0193] iii) the C-terminus of the fourth dimerization polypeptide, wherein the fourth dimerization polypeptide is linked at its N-terminus to the second C-terminus of the second domain via a peptide bond or via a peptide linker.

[0194] In a preferred embodiment, the non-peptidyl link is a covalent link to the first N-terminus of the first domain and the second N-terminus of the second domain. In this preferred embodiment, the third domain is connected to the second N-terminus of the first domain at its C-terminus by a peptide bond or by a peptide linker. In addition, in this preferred embodiment, the fourth domain is connected to the second N-terminus of the second domain at its C-terminus by a peptide bond or by a peptide linker.

[0195] In a preferred embodiment, the non-peptidyl connection is a non-covalent connection between a first dimerization polypeptide connected to the first N-terminus of the first domain by a peptide bond or by a peptide connector and a second dimerization polypeptide connected to the first N-terminus of the second domain by a peptide bond or by a peptide connector. In this preferred embodiment, the third domain is connected to the C-terminus of (a) the first dimerization polypeptide or (b) the second C-terminus of the first domain at its N-terminus by a peptide bond or by a peptide connector. In addition, in this preferred embodiment, the fourth domain is connected to the N-terminus of (a) the second dimerization polypeptide or (b) the second N-terminus of the second domain at its C-terminus by a peptide bond or by a peptide connector.

[0196] In an alternative embodiment, the non-peptidyl linkage is a covalent linkage:

[0197] a) is linked to the first C-terminus of the first domain and the first C-terminus of the second domain,

[0198] b) is linked to the first C-terminus of the first domain and the first C-terminus of the second domain, or

[0199] c) is linked to the first N-terminus of the first domain and the first C-terminus of the second domain.

[0200] In an alternative embodiment, the non-peptidyl linkage is a non-covalent linkage:

[0201] a) between a first dimerization polypeptide linked to the first C-terminus of the first domain by a peptide bond or by a peptide linker and a second dimerization polypeptide linked to the first C-terminus of the second domain by a peptide bond or by a peptide linker,

[0202] b) between a first dimerization polypeptide linked to the first N-terminus of the first domain by a peptide bond or by a peptide linker and a second dimerization polypeptide linked to the first C-terminus of the second domain by a peptide bond or by a peptide linker, or

[0203] c) between a first dimerization polypeptide linked to the first C-terminus of the first domain by a peptide bond or by a peptide linker and a second dimerization polypeptide linked to the first N-terminus of the second domain by a peptide bond or by a peptide linker.

[0204] In an embodiment of the present invention:

[0205] a) the first domain is an Fc domain, and the second domain is a Fab domain,

[0206] b) the first domain and the second domain are Fc domains,

[0207] c) the first domain and the second domain are Fab domains,

[0208] d) the third domain and the fourth domain are Fab domains,

[0209] e) the third domain and / or the fourth domain is selected from the group consisting of (i) an extracellular domain of a secretory protein and (ii) a transmembrane protein,

[0210] f) the third domain is selected from the group consisting of (i) a secretory protein and (ii) an extracellular domain of a transmembrane protein, and the fourth domain is Fab,

[0211] g) the third domain is IL-15,

[0212] h) the third domain is IL-15, and the fourth domain is the IL-15Rα sushi domain,

[0213] i) the third domain is IL-15, and the fourth domain is Fab,

[0214] j) the third domain and the fourth domain are each an ACE2 peptidase domain (PD),

[0215] k) the first domain and the second domain are Fc domains, and the third domain and the fourth domain are selected from the group consisting of (i) a secretory protein and (ii) an extracellular domain of a transmembrane protein,

[0216] l) the first domain and the second domain are Fc domains, the third domain is selected from the group consisting of (i) a secretory protein and (ii) an extracellular domain of a transmembrane protein, and the fourth domain is Fab,

[0217] m) the first domain and the second domain are Fc domains, and the third domain and the fourth domain are Fab domains,

[0218] n) the first domain and the second domain are Fc domains, the third domain and the fourth domain are each an ACE2 peptidase domain (PD),

[0219] o) the first domain is an Fc domain, and the second domain, the third domain and the fourth domain are Fab domains,

[0220] 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

[0221] 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 Fab.

[0222] Covalent attachment

[0223] In an embodiment of the invention, the non-peptidyl linkage between the first domain and the second domain is a covalent linkage.

[0224] In an embodiment of the invention, the covalent linkage comprises the following structure:

[0225] a)

[0226] b) or

[0227] c)

[0228] Where R 2 represents an organic structure connected to the first domain or the second domain, R 4 represents an organic structure connected to the other of the first domain or the second domain, wherein R 1 is H or is part of an additional structure as a ring structure, wherein the additional ring structure includes R 1 or R 1 part and may also include R 2 or R 2 Part of R 2 and the carbon between the double bonds of the olefins.

[0229] In an embodiment of the present invention, R 1 and R 2 connected by at least one direct bond to form a ring structure comprising

[0230] a) R 1 part of

[0231] b) R 2 part of

[0232] c) R 2 and the carbon between the double bonds of the olefins, and

[0233] d) Olefin double bond.

[0234] In an embodiment of the present invention, R 1 Selected from the group consisting of:

[0235] a)

[0236] b) as well as

[0237] c)

[0238] It is optionally substituted at any position.

[0239] In an embodiment of the present invention, R 2The carbon between the double bond of the olefin directly binds to R through the double bond and single bond. 2 Bonding.

[0240] In an embodiment of the present invention, R 2 yes

[0241] a)

[0242] b) or

[0243] c)

[0244] which is optionally substituted at any position,

[0245] Where R 2 By R 2 The nitrogen atom is connected to R 1 ,and

[0246] wherein 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-co-glycolic acid), polysaccharides, branched residues, C 1 -C 4 Alkyl, amine, sulfur, oxygen, succinimide, maleimide, glycerol, triazole, isoxazolidine, C 1 -C 4 acyl, succinyl, malonyl, glutaryl, phthaloyl, adipoyl and amino acids,

[0247] where [PEG(y)]z is:

[0248]

[0249] Where y=1-100, z=1-10.

[0250] In an embodiment of the present invention, R 1 and R 2 Put together:

[0251]

[0252]

[0253] which is optionally substituted at any position,

[0254] wherein 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-co-glycolic acid), polysaccharides, branched residues, C 1 -C 4 Alkyl, amine, sulfur, oxygen, succinimide, maleimide, glycerol, triazole, isoxazolidine, C 1 -C 4 acyl, succinyl, malonyl, glutaryl, phthaloyl, adipoyl and amino acids,

[0255] where [PEG(y)]z is:

[0256]

[0257] Where y=1-100, z=1-10.

[0258] In an embodiment of the invention, the covalent linkage comprises the following structure:

[0259]

[0260] which is optionally substituted at any position,

[0261] wherein 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-co-glycolic acid), polysaccharides, branched residues, C 1 -C 4 Alkyl, amine, sulfur, oxygen, succinimide, maleimide, glycerol, triazole, isoxazolidine, C 1 -C 4 acyl, succinyl, malonyl, glutaryl, phthaloyl, adipoyl and amino acids,

[0262] where [PEG(y)]z is:

[0263]

[0264] Where y=1-100, z=1-10.

[0265] In an embodiment of the invention, the covalent linkage comprises the following structure:

[0266]

[0267] in:

[0268] a)X a is a chemical structure selected from the group consisting of:

[0269] i) a chemical structure comprising a cyclooctane fused to a dihydropyridazine,

[0270] ii) a chemical structure comprising a cyclooctene fused to a pyridazine,

[0271] b) R a Is X a a bond or chemical structure connected to the first N-terminus of the first domain, and

[0272] c) R b Is X a A bond or chemical structure connected to the first N-terminus of the second domain.

[0273] In an embodiment of the present invention, X a Includes structure: Where R c is H, alkyl or aryl, or a tautomer thereof.

[0274] In an embodiment of the invention, the covalent linkage comprises the structure: Where R c is H, alkyl or aryl, or a tautomer thereof.

[0275] In an embodiment 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, wherein each moiety is independently selected from the group consisting of: [PEG(y)]z, polyalkylene glycol, polyoxyalkyl polyol, polyvinyl alcohol, polyvinyl alkyl ether, poly(lactic acid), poly(lactic-co-glycolic acid), polysaccharide, branched residue, C 1 -C 10 Alkyl, C 3 -C 10 Cycloalkanes, C 2 -C 10 Olefins, C 5 -C 10 Cyclic olefins, amines, sulfur, oxygen, succinimide, maleimide, glycerol, triazole, isoxazolidine, C 2 -C 5 Acyl, C2 -C 5 Amide, C 2 -C 5 acyloxy, succinyl, malonyl, glutaryl, phthaloyl, adipoyl, amino acid, aryl, heteroaryl, carbamate, chemical structure containing cyclooctane fused to dihydropyridazine, chemical structure containing cyclooctene fused to triazole, chemical structure containing cyclooctene fused to isoxazolidine, dibenzocyclooctene, dibenzoazacyclooctene, Where X 1 is CH or N, X 2 Yes CH 2 or carbonyl, R 5 is aryl or alkyl, wherein [PEG(y)]z is: Where y=1-100, z=1-10.

[0276] In an embodiment of the present invention, R a and / or R b Each independently:

[0277] a) comprises a [PEG(y)]z group;

[0278] b) comprises a polyalkylene glycol, a polyoxyalkylated polyol, a polyvinyl alcohol, a polyvinyl alkyl ether, a poly(lactic acid), a poly(lactic-glycolic acid) or a polysaccharide group;

[0279] c) Contains C 1 -C 4 alkyl;

[0280] d) contains succinimide;

[0281] e) contains an amine;

[0282] f) contains succinyl, malonyl, glutaryl, phthaloyl or adipoyl groups;

[0283] g) contains a malonyl group;

[0284] h) contains amino acids;

[0285] i) contains cysteine;

[0286] j) contains lysine;

[0287] k) is composed of a chain of 3 moieties selected from the group consisting of: [PEG(y)]z, polyalkylene glycol, polyoxyalkyl polyol, polyvinyl alcohol, polyvinyl alkyl ether, poly(lactic acid), poly(lactic-co-glycolic acid), polysaccharide, branched residue, C 1 -C 10Alkyl, C 3 -C 10 Cycloalkanes, C 2 -C 10 Olefins, C 5 -C 10 Cyclic olefins, amines, sulfur, oxygen, succinimide, maleimide, glycerol, triazole, isoxazolidine, C 2 -C 5 Acyl, C 2 -C 5 Amide, C 2 -C 5 acyloxy, succinyl, malonyl, glutaryl, phthaloyl, adipoyl, amino acid, aryl, heteroaryl, carbamate, chemical structure containing cyclooctane fused to dihydropyridazine, chemical structure containing cyclooctene fused to triazole, chemical structure containing cyclooctene fused to isoxazolidine, dibenzocyclooctene, dibenzoazacyclooctene,

[0288] l) is composed of a chain of 4 moieties selected from the group consisting of: [PEG(y)]z, polyalkylene glycol, polyoxyalkylene polyol, polyvinyl alcohol, polyvinyl alkyl ether, poly(lactic acid), poly(lactic-co-glycolic acid), polysaccharide, branched residue, C 1 -C 10 Alkyl, C 3 -C 10 Cycloalkanes, C 2 -C 10 Olefins, C 5 -C 10 Cyclic olefins, amines, sulfur, oxygen, succinimide, maleimide, glycerol, triazole, isoxazolidine, C 2 -C 5 Acyl, C 2 -C 5 Amide, C 2 -C 5 acyloxy, succinyl, malonyl, glutaryl, phthaloyl, adipoyl, amino acid, aryl, heteroaryl, carbamate, chemical structure containing cyclooctane fused to dihydropyridazine, chemical structure containing cyclooctene fused to triazole, chemical structure containing cyclooctene fused to isoxazolidine, dibenzocyclooctene, dibenzoazacyclooctene,

[0289] m) is composed of a chain of 5 moieties selected from the group consisting of: [PEG(y)]z, polyalkylene glycol, polyoxyalkyl polyol, polyvinyl alcohol, polyvinyl alkyl ether, poly(lactic acid), poly(lactic-co-glycolic acid), polysaccharide, branched residue, C1 -C 10 Alkyl, C 3 -C 10 Cycloalkanes, C 2 -C 10 Olefins, C 5 -C 10 Cyclic olefins, amines, sulfur, oxygen, succinimide, maleimide, glycerol, triazole, isoxazolidine, C 2 -C 5 Acyl, C 2 -C 5 Amide, C 2 -C 5 acyloxy, succinyl, malonyl, glutaryl, phthaloyl, adipoyl, amino acid, aryl, heteroaryl, carbamate, chemical structure containing cyclooctane fused to dihydropyridazine, chemical structure containing cyclooctene fused to triazole, chemical structure containing cyclooctene fused to isoxazolidine, dibenzocyclooctene, dibenzoazacyclooctene,

[0290] n) comprising a [PEG(y)]z group bonded to a lysine;

[0291] o) comprising a C bonded to a succinimide group 1 -C 4 acyl group;

[0292] p) including with C 1 -C 4 acyl-bonded lysine;

[0293] q) comprising a [PEG(y)]z group bonded to a glutaryl group;

[0294] r) is composed of a chain of three, four or five moieties selected from the group consisting of: [PEG(y)]z, C 2 -C 5 acyl, succinyl, malonyl, glutaryl, amino acid, chemical structure containing cyclooctane fused to dihydropyridazine, chemical structure containing cyclooctene fused to triazole, chemical structure containing cyclooctene fused to isoxazolidine, dibenzocyclooctene, dibenzoazacyclooctene, Where X 1 is CH or N, X 2 Yes CH 2 or carbonyl, R 5 is aryl or alkyl, wherein [PEG(y)]z is: Where y = 1-100, z = 1-10;

[0295] s) is a key;

[0296] t) is cysteine;

[0297] u) has a linear structure; or

[0298] v) having a branched structure;

[0299] w) has the structure:

[0300] x) is: wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 1-30, 1-40 or 1-50;

[0301] y) is: wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 1-30, 1-40, or 1-50, x is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 1-30, 1-40, or 1-50, and z is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 1-30, 1-40, or 1-50;

[0302] z) is: wherein x is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 1-30, 1-40, or 1-50 and z is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 1-30, 1-40, or 1-50; or

[0303] aa) is: wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 1-30, 1-40, or 1-50.

[0304] In an embodiment of the present invention, R a and / or R b Include Part, where X 1 CH or N, X 2 CH 2 or carbonyl.

[0305] Non-covalent attachment

[0306] In an embodiment of the invention, the non-peptidyl linkage is a non-covalent linkage between a first dimerization polypeptide linked to the first domain and a second dimerization polypeptide linked to the second domain.

[0307] In an embodiment of the invention, the first dimerization polypeptide and the second dimerization polypeptide are selected from the group consisting of:

[0308] a) a dimerization domain of an extracellular protein dimer, and

[0309] b) Dimerization domain of intracellular protein dimer.

[0310] In an embodiment of the invention, the first dimerization polypeptide and the second dimerization polypeptide are selected from the group consisting of:

[0311] a) Leucine zipper domain,

[0312] b) collectrin-like domain (CLD),

[0313] c) collectrin domain (CD),

[0314] d) CD8α extracellular domain, and

[0315] e) CD8β extracellular domain.

[0316] In a preferred embodiment of the tetrahedral antibody of the present invention, the first dimerization polypeptide and the second dimerization polypeptide are selected from the group consisting of a collector protein-like domain (CLD) and a collector protein domain (CD), preferably a collector protein-like domain (CLD).

[0317] In an embodiment of the present invention,

[0318] a) the first dimerization polypeptide is identical to the second dimerization polypeptide, and

[0319] b) The polypeptides dimerize to form homodimers.

[0320] In an embodiment of the present invention,

[0321] a) the first dimerization polypeptide is different from the second dimerization polypeptide, and

[0322] b) The first dimerization polypeptide and the second dimerization polypeptide form a heterodimer.

[0323] In an embodiment of the present invention, wherein the first dimerization polypeptide and the second dimerization polypeptide form a heterodimer, the dimerization polypeptide is a collector protein-like domain (CLD), and the CLD includes substitutions that disrupt homodimer formation in the CLD dimerization polypeptide, preferably wherein the substitutions are at Arg652, Arg710, Tyr641, Tyr633, Asn638, Glu639, Gln653, Asn636, Ser709, Asp713 and / or Arg716, more preferably wherein Tyr641 and Tyr333 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 positively charged amino acids lysine.

[0324] In an embodiment of the present invention, wherein the first dimerization polypeptide and the second dimerization polypeptide form a heterodimer, the dimerization polypeptide is a collection protein, and the collection protein dimerization polypeptide includes a substitution that destroys the homodimer formation in the collection protein dimerization polypeptide, preferably wherein the substitution is at Arg59, Arg111, Tyr48 and / or Tyr40, more preferably wherein Tyr48 and / or Tyr40 are substituted with positively charged amino acids lysine, arginine or histidine, and Arg59 and / or Arg111 are substituted with negatively charged amino acids glutamic acid or aspartic acid or positively charged amino acids lysine.

[0325] In embodiments where the dimerizing polypeptide is a collector protein-like domain (CLD), the CLD comprises substitutions that promote heterodimer formation in the CLD dimerizing polypeptide, preferably:

[0326] a) preferably, replacing Tyr633 on the first CLD dimerization polypeptide or the second CLD dimerization polypeptide with a positively charged amino acid or a negatively charged amino acid;

[0327] b) preferably, replacing Tyr641 on the first CLD dimerization polypeptide or the second CLD dimerization polypeptide with a positively charged amino acid or a negatively charged amino acid;

[0328] c) preferably, replacing Arg652 on the first CLD dimerization polypeptide or the second CLD dimerization polypeptide with a positively charged amino acid or a negatively charged amino acid;

[0329] d) preferably, replacing Arg710 on the first CLD dimerization polypeptide or the second CLD dimerization polypeptide with a positively charged amino acid or a negatively charged amino acid;

[0330] e) preferably replacing Ser709 on the first CLD dimerization polypeptide or the second CLD dimerization polypeptide with a positively charged amino acid or a negatively charged amino acid; and / or

[0331] f) Preferably, Asp713 on the first CLD dimerization polypeptide or the second CLD dimerization polypeptide is substituted with a positively charged amino acid or a negatively charged amino acid.

[0332] In embodiments where the dimerizing polypeptide is a gleanin, the gleanin dimerizing polypeptide comprises substitutions that promote heterodimer formation in the gleanin dimerizing polypeptide, preferably:

[0333] a) preferably, replacing Tyr40 on the first collection protein dimerization polypeptide or the second collection protein dimerization polypeptide with a positively charged amino acid or a negatively charged amino acid;

[0334] b) preferably, replacing Tyr48 on the first collection protein dimerization polypeptide or the second collection protein dimerization polypeptide with a positively charged amino acid or a negatively charged amino acid;

[0335] c) preferably, replacing Arg59 on the first collectin dimerization polypeptide or the second collectin dimerization polypeptide with a positively charged amino acid or a negatively charged amino acid; and / or

[0336] d) Preferably, Arg111 on the first harvest protein dimerization polypeptide or the second harvest protein dimerization polypeptide is substituted with a positively charged amino acid or a negatively charged amino acid.

[0337] In embodiments where the dimerizing polypeptide is a collector protein-like domain (CLD), the CLD comprises substitutions that promote heterodimer formation in the CLD dimerizing polypeptide, preferably:

[0338] a) replacing Tyr633 on the first CLD dimerization polypeptide with a positively charged amino acid or a negatively charged amino acid, and replacing Arg710 on the second CLD dimerization polypeptide with the other of a positively charged amino acid or a negatively charged amino acid;

[0339] b) replacing Tyr633 on the second CLD dimerization polypeptide with a positively charged amino acid or a negatively charged amino acid, and replacing Arg710 on the first CLD dimerization polypeptide with the other of a positively charged amino acid or a negatively charged amino acid;

[0340] c) replacing Tyr641 on the first CLD dimerization polypeptide with a positively charged amino acid or a negatively charged amino acid, and replacing Arg652 on the second CLD dimerization polypeptide with the other of the positively charged amino acid or the negatively charged amino acid;

[0341] d) replacing Tyr641 on the second CLD dimerization polypeptide with a positively charged amino acid or a negatively charged amino acid, and replacing Arg652 on the first CLD dimerization polypeptide with the other of a positively charged amino acid or a negatively charged amino acid;

[0342] e) replacing Arg652 on the first CLD dimerization polypeptide with a positively charged amino acid or a negatively charged amino acid, and replacing Asn638 on the second CLD dimerization polypeptide with the other of a positively charged amino acid or a negatively charged amino acid;

[0343] f) replacing Arg652 on the second CLD dimerization polypeptide with a positively charged amino acid or a negatively charged amino acid, and replacing Arg638 on the first CLD dimerization polypeptide with the other of a positively charged amino acid or a negatively charged amino acid;

[0344] g) replacing Arg710 on the first CLD dimerization polypeptide with a positively charged amino acid or a negatively charged amino acid, and replacing Glu639 on the second CLD dimerization polypeptide with the other of a positively charged amino acid or a negatively charged amino acid;

[0345] h) replacing Arg710 on the second CLD dimerization polypeptide with a positively charged amino acid or a negatively charged amino acid, and replacing Glu639 on the first CLD dimerization polypeptide with the other of a positively charged amino acid or a negatively charged amino acid;

[0346] i) replacing Ser709 on the first CLD dimerization polypeptide with a positively charged amino acid or a negatively charged amino acid, and replacing Arg716 on the second CLD dimerization polypeptide with the other of a positively charged amino acid or a negatively charged amino acid;

[0347] j) replacing Ser709 on the second CLD dimerization polypeptide with a positively charged amino acid or a negatively charged amino acid, and replacing Arg716 on the first CLD dimerization polypeptide with the other of a positively charged amino acid or a negatively charged amino acid;

[0348] k) replacing Asp713 on the first CLD dimerization polypeptide with a positively charged amino acid or a negatively charged amino acid, and replacing Arg716 on the second CLD dimerization polypeptide with the other of a positively charged amino acid or a negatively charged amino acid; and / or

[0349] 1) Substituting Asp713 on the second CLD dimerization polypeptide with a positively charged amino acid or a negatively charged amino acid, and substituting Arg716 on the first CLD dimerization polypeptide with the other of a positively charged amino acid or a negatively charged amino acid.

[0350] In embodiments where the dimerizing polypeptide is a gleanin, the gleanin dimerizing polypeptide comprises substitutions that promote heterodimer formation in the gleanin dimerizing polypeptide, preferably:

[0351] a) replacing Tyr40 on the first collection protein dimerization polypeptide with a positively charged amino acid or a negatively charged amino acid, and replacing Arg111 on the second collection protein dimerization polypeptide with the other of a positively charged amino acid or a negatively charged amino acid;

[0352] b) replacing Tyr40 on the second collection protein dimerization polypeptide with a positively charged amino acid or a negatively charged amino acid, and replacing Arg111 on the first collection protein dimerization polypeptide with the other of a positively charged amino acid or a negatively charged amino acid;

[0353] c) replacing Tyr48 on the first collection protein dimerization polypeptide with a positively charged amino acid or a negatively charged amino acid, and replacing Arg59 on the second collection protein dimerization polypeptide with the other of a positively charged amino acid or a negatively charged amino acid; and / or

[0354] d) replacing Tyr48 on the second collection protein dimerization polypeptide with a positively charged amino acid or a negatively charged amino acid, and replacing Arg59 on the first collection protein dimerization polypeptide with the other of a positively charged amino acid or a negatively charged amino acid.

[0355] In embodiments wherein the first dimerizing polypeptide and the second dimerizing polypeptide form a heterodimer:

[0356] a) the first dimerization polypeptide and the second dimerization polypeptide are selected from the group consisting of:

[0357] i) T cell receptor alpha extracellular domain and T cell receptor beta extracellular domain,

[0358] ii) a T cell receptor gamma extracellular domain and a T cell receptor extracellular domain,

[0359] iii) MHC class I alpha extracellular domain and beta-2 microglobulin,

[0360] iv) an MHC class II alpha extracellular domain and an MHC class II beta extracellular domain, and

[0361] v) CD8α extracellular domain and CD8β extracellular domain,

[0362] b) the first dimerization polypeptide is different from the second dimerization polypeptide, and

[0363] c) the first dimerization polypeptide and the second dimerization polypeptide form a heterodimer.

[0364] In some embodiments of the invention, the first dimerizing polypeptide and the second dimerizing polypeptide form less than 30%, 20%, 10%, 5%, 4%, 3%, 2% or 1% homodimers when present with each other.

[0365] In an embodiment of the present invention, the first dimerization polypeptide and the second dimerization polypeptide comprise more than one disulfide bond, preferably:

[0366] a) the one or more disulfide bonds are at the interface between the first dimerization polypeptide and the second dimerization polypeptide, more preferably wherein:

[0367] i) if the first dimerization polypeptide and the second dimerization polypeptide are a accretin-like domain or a accretin, the one or more disulfide bonds are in the second helix and the fourth helix of the accretin-like domain or in the corresponding regions of the accretin, or

[0368] b) the one or more disulfide bonds are located between an immunoglobulin hinge region or a portion of the hinge region comprising at least one cysteine ​​attached to the N-terminus and / or C-terminus of the first dimerization polypeptide and the second dimerization polypeptide, wherein the hinge region is attached to the first dimerization polypeptide and the second dimerization polypeptide directly or through a peptide linker, preferably wherein the first dimerization polypeptide and the second dimerization polypeptide are collection protein-like domains or collection proteins.

[0369] Domain

[0370] In an embodiment of the present invention,

[0371] a) the third domain and the fourth domain are each an ACE2 peptidase domain (PD), and

[0372] b) the first dimerization polypeptide and the second dimerization polypeptide are each an ACE2 recruitment protein-like domain (CLD),

[0373] In embodiments where the first domain and the second domain are Fc domains, each polypeptide chain of the tetrahedral antibody comprises an amino acid sequence set forth in any one of SEQ ID NOs:74 to 119, more preferably an amino acid sequence set forth in SEQ ID NO:78.

[0374] In an embodiment of the invention, the first domain and the second domain are Fc domains.

[0375] In an embodiment of the present invention:

[0376] a) the first domain and the second domain are Fc domains, and the third domain is a Fab domain of the first type,

[0377] b) the first domain and the second domain are Fc domains, and the third domain and the fourth domain are independently selected from the group consisting of a first type of Fab domain and a second type of Fab domain,

[0378] c) the first domain is an Fc domain, and the second domain and the third domain are independently selected from the group consisting of a first type of Fab domain and a second type of Fab domain, or

[0379] d) the first domain is an Fc domain, and the second domain, the third domain and the fourth domain 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.

[0380] In an embodiment of the invention, the tetrahedral antibody additionally comprises a fifth domain, wherein the fifth domain is linked at its C-terminus via a peptide bond or via a peptide linker to:

[0381] a) the N-terminus of the first dimerization polypeptide,

[0382] b) the second N-terminus of the first domain, or

[0383] c) the N-terminus of the third dimerization polypeptide, wherein the third dimerization polypeptide is linked at its C-terminus to the second N-terminus of the first domain via a peptide bond or via a peptide linker.

[0384] In an embodiment of the present invention,

[0385] a) the first domain and the second domain are Fc domains, and the fifth domain is a Fab domain of the first type,

[0386] b) the first domain and the second domain are Fc domains, and the third domain and the fifth domain are independently selected from the group consisting of a first type of Fab domain and a second type of Fab domain,

[0387] c) the first domain and the second domain are Fc domains, and the fourth domain and the fifth domain are independently selected from the group consisting of a first type of Fab domain and a second type of Fab domain,

[0388] d) the first domain and the second domain are Fc domains, and the third domain, the fourth domain and the fifth domain 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,

[0389] e) the first domain is an Fc domain, and the second domain and the fifth domain are independently selected from the group consisting of a first type of Fab domain and a second type of Fab domain,

[0390] f) the first domain is an Fc domain, and the second domain, the third domain and the fifth domain 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,

[0391] g) the first domain is an Fc domain, and the second domain, the fourth domain and the fifth domain 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

[0392] 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.

[0393] Tetrahedral antibodies comprising a fifth domain and / or a sixth domain

[0394] In an embodiment of the invention, the tetrahedral antibody additionally comprises a fifth domain and / or a sixth domain, wherein:

[0395] a) the first domain is joined to the second domain via a first dimerization polypeptide linked to a first N-terminus of the first domain, wherein

[0396] i) the fifth domain is linked at its C-terminus via a peptide bond or via a peptide linker to:

[0397] (1) the N-terminus of the first dimerization polypeptide,

[0398] (2) the second N-terminus of the first domain, or

[0399] (3) an N-terminus of a third dimerization polypeptide, wherein the third dimerization polypeptide is connected at its C-terminus to the second N-terminus of the first domain via a peptide bond or via a peptide linker,

[0400] b) the first domain is joined to the second domain via a first dimerization polypeptide linked to a first C-terminus of the first domain, wherein

[0401] i) the fifth domain is linked at its N-terminus via a peptide bond or via a peptide linker to:

[0402] (1) the C-terminus of the first dimerization polypeptide,

[0403] (2) the second C-terminus of the first domain, or

[0404] (3) the C-terminus of the third dimerization polypeptide, wherein the third dimerization polypeptide is connected at its N-terminus to the second C-terminus of the first domain via a peptide bond or via a peptide linker,

[0405] c) the second domain is joined to the first domain via a second dimerization polypeptide linked to a first N-terminus of the second domain, wherein

[0406] i) the sixth domain is linked at its C-terminus via a peptide bond or via a peptide linker to:

[0407] (1) the N-terminus of the second dimerization polypeptide,

[0408] (2) the second N-terminus of the second domain, or

[0409] (3) the N-terminus of a fourth dimerization polypeptide, wherein the fourth dimerization polypeptide is linked at its C-terminus to the second N-terminus of the second domain via a peptide bond or via a peptide linker, or

[0410] d) the second domain is joined to the first domain via a second dimerization polypeptide linked to a first C-terminus of the second domain, wherein

[0411] i) the sixth domain is linked at its N-terminus via a peptide bond or via a peptide linker to:

[0412] (1) the C-terminus of the second dimerization polypeptide,

[0413] (2) the second C-terminus of the second domain, or

[0414] ii) the C-terminus of the fourth dimeric polypeptide, wherein the fourth dimeric polypeptide is linked at its N-terminus to the second C-terminus of the second domain via a peptide bond or via a peptide linker.

[0415] In an embodiment of the present invention:

[0416] a) the first domain and the second domain are Fc domains, and the fifth domain is a Fab domain of the first type,

[0417] b) the first domain and the second domain are Fc domains, and the third domain and the fifth domain are independently selected from the group consisting of a first type of Fab domain and a second type of Fab domain,

[0418] c) the first domain and the second domain are Fc domains, and the fourth domain and the fifth domain are independently selected from the group consisting of a first type of Fab domain and a second type of Fab domain,

[0419] d) the first domain and the second domain are Fc domains, and the third domain, the fourth domain and the fifth domain 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,

[0420] e) the first domain is an Fc domain, and the second domain and the fifth domain are independently selected from the group consisting of a first type of Fab domain and a second type of Fab domain,

[0421] f) the first domain is an Fc domain, and the second domain, the third domain and the fifth domain 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,

[0422] g) the first domain is an Fc domain, and the second domain, the fourth domain and the fifth domain 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,

[0423] 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.

[0424] Tetrahedral antibodies containing ACE2 PD

[0425] In an embodiment of the present invention:

[0426] a) the third domain, the fourth domain, the fifth domain and the sixth domain are each ACE2PD, and the dimerization polypeptide is each ACE2 CLD,

[0427] b) the first domain and the second domain are Fc domains, the third domain, the fourth domain, the fifth domain and the sixth domain are each an ACE2 PD, and the dimerization polypeptide is each an ACE2 CLD, preferably wherein the first domain and the second domain are each connected to their respective dimerization polypeptides via a peptide linker,

[0428] c) the third domain and the fourth domain are each ACE2 PD, the fifth domain and the sixth domain are each a Fab domain, and the dimerization polypeptide is each ACE2 CLD,

[0429] d) the first domain and the second domain are Fc domains, the third domain and the fourth domain are each ACE2 PD, the fifth domain and the sixth domain are each a Fab domain, and the dimerization polypeptide is each ACE2 CLD, preferably wherein the first domain and the second domain are each connected to their respective dimerization polypeptides via a peptide linker,

[0430] e) the third domain and the fourth domain are each a Fab domain, the fifth domain and the sixth domain are each an ACE2 PD, and the dimerization polypeptide is each an ACE2 CLD, or

[0431] f) the first domain and the second domain are Fc domains, the third domain and the fourth domain are each a Fab domain, the fifth domain and the sixth domain are each an ACE2 PD, and the dimerization polypeptide is each an ACE2 CLD, preferably wherein the first domain and the second domain are each connected to their respective dimerization polypeptides via a peptide linker, or

[0432] g) the first domain and the second domain are Fc domains, the third domain and the fourth domain are ACE2 PD, the fifth domain and the sixth domain are Fab domains, the dimerization polypeptides are each ACE2 CLD, and the first domain and the second domain are each connected to their respective dimerization polypeptides via a peptide linker,

[0433] Preferably such domains and linkers are characterized by one or more or all of the following features:

[0434] i) The Fc domain is characterized by one or more or all of the following features:

[0435] (1) is a heterodimer,

[0436] (2) is the IgG1 Fc domain,

[0437] (3) comprising a silent mutation, so that the Fc domain lacks Fcγ receptor binding activity, preferably wherein such mutation is one of the following mutation combinations:

[0438] a.P329G / L234A / L235A(PGLALA),

[0439] b.L234A / L235A(LALA),

[0440] c.P331S / L234A / L235A,

[0441] d.L234F / L235E / P331S, and

[0442] e.L234F / L235E / P329G,

[0443] (4) comprising mutations that enhance FcRn activity, preferably wherein such mutations extend the half-life of the tetrahedral antibody, preferably wherein the mutations are:

[0444] a. Combination of the following mutations: L309D / Q311H / N434S (DHS),

[0445] b. Combination of the following mutations: S239D / I298E,

[0446] c.S239D, preferably wherein the other Fc domain of the tetrahedral antibody, if present, comprises an I298E mutation, or

[0447] d. I298E, preferably wherein the other Fc domain of the tetrahedral antibody, if present, comprises an S239D mutation, and

[0448] (5) comprising mutations that eliminate their protein A binding sites, preferably wherein such mutations are H435R / Y436F (HY / RF),

[0449] ii) the ACE2 peptidase domain comprises a mutation that blocks its angiotensin converting enzyme activity, preferably wherein such mutation is a H378A mutation,

[0450] iii) the Fab domain is a chimeric Fab domain comprising a murine variable region,

[0451] iv) the peptide linkers each have a length of 23 amino acids and are derived from the stalk region of a TNF receptor, preferably wherein the TNF receptor is TNF receptor 1B, more preferably wherein the peptide linker consists of the amino acid sequence set forth in SEQ ID NO: 4468,

[0452] v) Such domains and peptide linkers are formed from two or three different types of polypeptide chains.

[0453] In an embodiment of the present invention:

[0454] a) the third domain and the fourth domain are each ACE2 PD,

[0455] b) the fifth domain, if present, is linked at its C-terminus to the N-terminus of the third dimeric polypeptide via a peptide bond or via a peptide linker, wherein the third dimeric polypeptide is linked at its C-terminus to the second N-terminus of the first domain via a peptide bond or via a peptide linker,

[0456] c) the sixth domain, if present, is linked at its C-terminus to the N-terminus of the fourth dimeric polypeptide via a peptide bond or via a peptide linker, wherein the fourth dimeric polypeptide is linked at its C-terminus to the second N-terminus of the second domain via a peptide bond or via a peptide linker, and

[0457] d) the first dimerization polypeptide, the second dimerization polypeptide, the third dimerization polypeptide and the fourth dimerization polypeptide are each an ACE2 CLD.

[0458] In an embodiment of the present invention, ACE2 PD comprises or consists of amino acids 18-615 of the ACE2 protein or a portion thereof.

[0459] In an embodiment of the present invention, the ACE2 CLD comprises or consists of amino acids 616-740 of the ACE2 protein or a portion thereof.

[0460] In an embodiment of the invention, ACE2 PD is catalytically active.

[0461] In an embodiment of the invention, ACE2 PD is catalytically inactive.

[0462] In an embodiment of the invention, the ACE2 PD comprises a R273Q or H378A mutation.

[0463] In an embodiment of the invention, the Fc domain lacks Fcγ receptor binding activity.

[0464] In an embodiment of the invention, the Fc domain comprises:

[0465] a) P329G mutation, L234A mutation and L235A mutation (PGLALA);

[0466] b) L234A mutation and L235A mutation (LALA),

[0467] c) P331S mutation, L234A mutation and L235A mutation,

[0468] d) L234F mutation, L235E mutation and P331S mutation, or

[0469] e) L234F mutation, L235E mutation and P329G mutation.

[0470] In an embodiment of the present invention, the Fc domain comprises a mutation that enhances FcRn activity and / or half-life. In an embodiment of the present invention, such mutation is selected from any combination of the following mutations:

[0471] a)M252Y / S254T / T256E(YTE),

[0472] b) L309D / Q311H / N434S(DHS),

[0473] c)M428L / N434S(LS).

[0474] In an embodiment of the invention, such mutations are selected from:

[0475] a) S239D / I298E,

[0476] b) S239D, preferably wherein the other Fc domain of the tetrahedral antibody, if present, comprises an I298E mutation, or

[0477] c) I298E, preferably wherein the other Fc domain of the tetrahedral antibody, if present, comprises the S239D mutation.

[0478] In an embodiment of the invention, the Fc domain comprises a mutation that eliminates its protein A binding site, preferably wherein such mutation is H435R / Y436F (HY / RF).

[0479] In an embodiment of the invention, the Fab domain is a chimeric Fab domain comprising a murine variable region.

[0480] In an embodiment of the invention, the tetrahedral antibody comprises one or more Fab domains, and the one or more Fab domains comprise the complementarity determining regions (CDRs) of the Fab domain of the B13A antibody.

[0481] In an embodiment of the present invention, one or more Fab domains include VH and VL regions from the B13A antibody, preferably wherein the VH and VL regions comprise the amino acid sequences listed in SEQ ID NOs 463 and 464 or variants thereof, the amino acid sequences of the variants having at least 90%, preferably at least 95%, and more preferably at least 98% identity with said sequences.

[0482] In an embodiment of the invention, more than one Fab domain is humanized.

[0483] In an embodiment of the present invention, the first domain and the second domain are Fc domains, the third domain and the fourth domain are ACE2 PD, the fifth and sixth domains are Fab domains, the dimerized polypeptides are each ACE2 CLD, the first domain and the second domain are each connected to their respective dimerized polypeptides by a peptide linker, wherein the domains and peptide linkers of the tetrahedral antibody are formed by three different types of polypeptide chains. In a preferred embodiment, the three different types of polypeptide chains are represented as H1, L2 and H2, wherein:

[0484] 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 wherein the H1 chain, the L2 chain and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;

[0485] 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 wherein the H1 chain, the L2 chain and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;

[0486] 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 wherein the H1 chain, the L2 chain and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;

[0487] 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 wherein the H1 chain, the L2 chain and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;

[0488] 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 wherein the H1 chain, the L2 chain and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;

[0489] 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 wherein the H1 chain, the L2 chain and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences,

[0490] 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 wherein the H1 chain, the L2 chain and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences; or

[0491] 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 wherein the H1 chain, L2 chain and H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences.

[0492] In the above embodiment, the C-terminal portions of the H1 chain and the H2 chain are paired with each other to form each of domain 1 and domain 2, the N-terminal portion of the H1 chain is ACE2 PD (domain 3 and domain 4), and the N-terminal portion of the H2 chain is paired with the L2 chain to form domain 5 and domain 6. In addition, the H1 chain contains a CLD dimerization domain between the portion paired with the H2 chain and the ACE2 PD. Fig.31 B provides a schematic diagram of the structure of such a tetrahedral antibody, wherein the chains in the schematic diagram are L2, H2, H1, H1, H2, L2 from left to right. The present invention also provides a method for producing a tetrahedral antibody, the method comprising recombinantly expressing three different types of polypeptide chains of the present embodiment in a host cell.

[0493] In an embodiment of the present invention, the first domain and the second domain are Fc domains, the third domain, the fourth domain, the fifth domain and the sixth domain are each ACE2 PD, and the dimerization polypeptide is each ACE2 CLD, wherein the first domain and the second domain are each connected to their respective dimerization polypeptides by a peptide linker, wherein the domains and the peptide linker of the tetrahedral antibody are formed by two different types of polypeptide chains. In a preferred embodiment, the two different types of polypeptide chains are represented as H1 and H2, wherein:

[0494] 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 wherein the H1 chain and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;

[0495] 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 wherein the H1 chain and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;

[0496] 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 wherein the H1 chain and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;

[0497] 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 wherein the H1 chain and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;

[0498] 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 wherein the H1 chain and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;

[0499] 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 wherein the H1 chain and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;

[0500] 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 wherein the H1 chain and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences; or

[0501] 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 wherein the H1 chain and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences.

[0502] In the above embodiment, the C-terminal portions of the H1 chain and the H2 chain are paired with each other to form each of domain 1 and domain 2, and the N-terminal portions of the H1 chain and the H2 chain are ACE2 PD (domain 3 to domain 6). In addition, the H1 chain contains a CLD dimerization domain between the portion paired with the H2 chain and the ACE2 PD. Fig.31A provides a schematic diagram of such a tetrahedral antibody structure, wherein the chains in the schematic diagram are H2, H1, H1, H2 from left to right. The present invention also provides a method for producing a tetrahedral antibody, the method comprising recombinantly expressing two different types of polypeptide chains of the present embodiment in a host cell.

[0503] In an embodiment of the present invention:

[0504] a) the third domain, the first dimerization polypeptide and the first polypeptide chain of the first domain are part of a first stretch of consecutive amino acids,

[0505] b) the fourth domain, the second dimerization polypeptide and the first polypeptide chain of the second domain are part of a second stretch of consecutive amino acids,

[0506] c) the fifth domain, the third dimerization polypeptide and the second polypeptide chain of the first domain are part of a third stretch of consecutive amino acids, and

[0507] d) the sixth domain, the fourth dimerization polypeptide and the second polypeptide chain of the second domain are part of a fourth stretch of consecutive amino acids,

[0508] wherein each stretch of consecutive amino acids consists of an amino acid sequence selected from the group consisting of SEQ ID NOs: 74 to 119, or wherein such each stretch of consecutive amino acids is a variant having at least 90%, preferably at least 95%, more preferably at least 98% identity with said sequence.

[0509] Polynucleotide

[0510] The present invention also provides a polynucleotide encoding any one of the polypeptide chains of the present invention. In a preferred embodiment, the encoded polypeptide comprises an amino acid sequence listed in any one of SEQ ID NOs: 74 to 119. In a preferred embodiment, the polynucleotide encodes one of the H1, L2 or H2 polypeptide chains of the above embodiments. In a preferred embodiment, the polynucleotide encodes a stretch of consecutive amino acids of an amino acid sequence selected from the group consisting of SEQ ID NOs: 74 to 119 or a variant having at least 90%, preferably at least 95%, and more preferably at least 98% identity with the sequence. As will be appreciated by those skilled in the art, the polynucleotide of the present invention may include various additional sequences, depending on the type of expression system used. For example, the mRNA polynucleotide of the present invention may include a 5' untranslated region (UTR) and a 3' untranslated region (UTR). In addition, the polynucleotide may encode a signal peptide sequence for appropriate translocation of the expressed polypeptide. Therefore, the polynucleotides of the present invention are not limited and may include cis-regulatory elements such as promoters, enhancers and / or introns, non-translated sequences such as 5'UTR sequences and 3'UTR sequences, and translated sequences such as 5'cap or poly-A tail and / or signal peptide sequences. The polynucleotides of the present invention are not limited and may include DNA or RNA, including mRNA or modified forms thereof. Modified forms include forms containing non-standard nucleotides such as pseudouridine.

[0511] Carrier

[0512] The present invention also provides a vector comprising a polynucleotide encoding a polypeptide comprising any polypeptide chain of the present invention. In a preferred embodiment, the vector encodes a polypeptide comprising an amino acid sequence listed in any one of 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, the embodiment comprising three different polypeptide chains as described above. In a preferred embodiment, the vector encodes a polypeptide comprising the H1 polypeptide chain and the H2 polypeptide chain of an embodiment of the present invention, the embodiment comprising two different polypeptide chains as described above. In these vectors, each polynucleotide is operably linked to a promoter that directs the expression of the polynucleotide in a host cell. The present invention also provides a method for producing a tetrahedral antibody, the method comprising recombinantly expressing any of these vectors in a host cell.

[0513] Host cells

[0514] The present invention also provides a host cell comprising any of the vectors of the present invention. In a preferred embodiment, the host cell is used for a method for producing a tetrahedral antibody. The present invention also provides a method for producing a tetrahedral antibody comprising two, three or four different types of polypeptide chains, the method comprising expressing two, three or four different types of polypeptide chains in a host cell of the present invention.

[0515] Pharmaceutical composition

[0516] The present invention also provides a pharmaceutical composition comprising any one of the tetrahedral antibodies of the present invention comprising one or more ACE2 PDs and one or more pharmaceutically acceptable excipients.

[0517] In a preferred embodiment, the pharmaceutical composition comprises a tetrahedral antibody, wherein the first domain and the second domain are Fc domains, the third domain and the fourth domain are ACE2 PD, the fifth domain and the sixth domain are Fab domains, the dimerization polypeptides are each ACE2 CLD, and the first domain and the second domain are each connected to their respective dimerization polypeptides by a peptide linker, wherein the domains and peptide linkers of the tetrahedral antibody are formed by three different types of polypeptide chains. In a preferred embodiment, the three different types of polypeptide chains are represented as H1, L2 and H2, wherein:

[0518] 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 wherein the H1 chain, the L2 chain and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;

[0519] 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 wherein the H1 chain, the L2 chain and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;

[0520] 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 wherein the H1 chain, the L2 chain and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;

[0521] 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 wherein the H1 chain, the L2 chain and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;

[0522] 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 wherein the H1 chain, the L2 chain and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;

[0523] 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 wherein the H1 chain, the L2 chain and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences,

[0524] 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 wherein the H1 chain, the L2 chain and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences; or

[0525] 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 wherein the H1 chain, L2 chain and H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences.

[0526] In a preferred embodiment, the pharmaceutical composition comprises a tetrahedral antibody, wherein the first domain and the second domain are Fc domains, the third domain, the fourth domain, the fifth domain, and the sixth domain are each ACE2 PD, and the dimerization polypeptide is each ACE2 CLD, wherein the first domain and the second domain are each connected to their respective dimerization polypeptides by a peptide linker, wherein the domains and the peptide linker of the tetrahedral antibody are formed by two different types of polypeptide chains. In a preferred embodiment, the two different types of polypeptide chains are represented as H1 and H2, wherein:

[0527] 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 wherein the H1 chain and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;

[0528] 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 wherein the H1 chain and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;

[0529] 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 wherein the H1 chain and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;

[0530] 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 wherein the H1 chain and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;

[0531] 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 wherein the H1 chain and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;

[0532] 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 wherein the H1 chain and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;

[0533] 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 wherein the H1 chain and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences; or

[0534] 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 wherein the H1 chain and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences.

[0535] Treatment

[0536] The present invention also provides a method for treating Covid-19 in an individual, the method comprising administering to the individual a therapeutically effective amount of any one of the above-mentioned pharmaceutical compositions comprising a tetrahedral antibody comprising more than one ACE2 PD.

[0537] Tetrahedral antibody comprising the seventh domain and / or the eighth domain

[0538] In an embodiment of the present invention, the tetrahedral antibody further comprises a seventh domain and / or an eighth domain, wherein:

[0539] a) the first domain is joined to the second domain via a covalent link to a first N-terminus of the first domain or via a first dimerization polypeptide linked to a first N-terminus of the first domain, wherein

[0540] i) the seventh domain is linked at its N-terminus via a peptide bond or via a peptide linker to:

[0541] (1) the first C-terminus of the first domain, or

[0542] (2) the second C-terminus of the first domain,

[0543] b) the first domain is joined to the second domain via a covalent link to a first C-terminus of the first domain or via a first dimerization polypeptide linked to a first C-terminus of the first domain, wherein

[0544] i) the seventh domain is linked at its C-terminus via a peptide bond or via a peptide linker to:

[0545] (1) the first N-terminus of the first domain, or

[0546] (2) the second N-terminus of the first domain,

[0547] c) the second domain is joined to the first domain via a covalent link to a first N-terminus of the second domain or via a second dimerization polypeptide linked to a first N-terminus of the second domain, wherein

[0548] i) the eighth domain is linked at its N-terminus via a peptide bond or via a peptide linker to:

[0549] (1) the first C-terminus of the second domain, or

[0550] (2) the second C-terminus of the second domain, or

[0551] d) the second domain is joined to the first domain via a covalent link to the first C-terminus of the second domain or via a second dimerization polypeptide linked to the first C-terminus of the second domain, wherein

[0552] i) the eighth domain is linked at its C-terminus via a peptide bond or via a peptide linker to:

[0553] (1) the first N-terminus of the second domain, or

[0554] (2) The second N-terminus of the second domain.

[0555] Tetrahedral antibodies for cancer therapy

[0556] In an embodiment of the invention, the tetrahedral antibody comprises six domains, wherein:

[0557] a) the first domain and the second domain are Fc domains, the third domain and the fourth domain are anti-CD20 Fab domains, and the fifth domain and the sixth domain are anti-CD19 Fab domains;

[0558] b) the first domain and the second domain are Fc domains, the third domain and the fourth domain are anti-CD19 Fab domains, and the fifth domain and the sixth domain are anti-CD20 Fab domains;

[0559] c) the first domain and the second domain are Fc domains, the third domain and the fourth domain are anti-CD20 Fab domains, the fifth domain and the sixth domain are anti-CD19 Fab domains, and each dimerization polypeptide is an ACE2 CLD;

[0560] d) the first domain and the second domain are Fc domains, the third domain and the fourth domain are anti-CD19 Fab domains, the fifth domain and the sixth domain are anti-CD20 Fab domains, and each dimerization polypeptide is an ACE2 CLD;

[0561] e) the first domain and the second domain are Fc domains, the third domain and the fourth domain are anti-CD20 Fab domains, the fifth domain and the sixth domain are anti-CD19 Fab domains, and each dimerization polypeptide is ACE2 CLD, and the first domain and the second domain are each connected to their respective dimerization polypeptides by a peptide linker;

[0562] f) the first domain and the second domain are Fc domains, the third domain and the fourth domain are anti-CD19 Fab domains, the fifth domain and the sixth domain are anti-CD20 Fab domains, and each dimerization polypeptide is ACE2 CLD, and the first domain and the second domain are each connected to their respective dimerization polypeptides by a peptide linker.

[0563] In an embodiment of the invention, the tetrahedral antibody comprises eight domains, wherein:

[0564] a) the first domain and the second domain are Fc domains, the third domain and the fourth domain are anti-CD20 Fab domains, the fifth domain and the sixth domain are anti-CD19 Fab domains, and the seventh domain and the eighth domain are single-chain 4-1BB ligands;

[0565] b) the first domain and the second domain are Fc domains, the third domain and the fourth domain are anti-CD19 Fab domains, the fifth domain and the sixth domain are anti-CD20 Fab domains, and the seventh domain and the eighth domain are single-chain 4-1BB ligands;

[0566] c) the first domain and the second domain are Fc domains, the third domain and the fourth domain are anti-CD20 Fab domains, the fifth domain and the sixth domain are anti-CD19 Fab domains, the seventh domain and the eighth domain are single-chain 4-1BB ligands, and each dimerization polypeptide is ACE2CLD;

[0567] d) the first domain and the second domain are Fc domains, the third domain and the fourth domain are anti-CD19 Fab domains, the fifth domain and the sixth domain are anti-CD20 Fab domains, the seventh domain and the eighth domain are single-chain 4-1BB ligands, and each dimerization polypeptide is ACE2 CLD;

[0568] e) the first domain and the second domain are Fc domains, the third domain and the fourth domain are anti-CD20 Fab domains, the fifth domain and the sixth domain are anti-CD19 Fab domains, the seventh domain and the eighth domain are single-chain 4-1BB ligands, and each dimerization polypeptide is ACE2 CLD, and the first domain and the second domain are each connected to their respective dimerization polypeptides by a peptide linker; or

[0569] f) the first domain and the second domain are Fc domains, the third domain and the fourth domain are anti-CD19 Fab domains, the fifth domain and the sixth domain are anti-CD20 Fab domains, the seventh domain and the eighth domain are single-chain 4-1BB ligands, and each dimerization polypeptide is ACE2 CLD, and the first domain and the second domain are each connected to their respective dimerization polypeptides by a peptide linker.

[0570] In an embodiment of the present invention:

[0571] a) Anti-CD19 Fab domain comprising:

[0572] i) CDRs of both the heavy and light chains of FMC63, preferably wherein the anti-CD19 Fab is the Fab domain of FMC63;

[0573] ii) CDRs of both the heavy and light chains of FMC60, preferably wherein the anti-CD19 Fab is the Fab domain of FMC60; or

[0574] iii) CDRs of both the heavy and light chains of FMC59, preferably wherein the anti-CD19 Fab is the Fab domain of FMC59; and / or

[0575] b) the anti-CD20 Fab domain comprises the CDRs of rituximab, preferably wherein the anti-CD20 Fab is the Fab domain of rituximab.

[0576] In an embodiment of the invention, the Fc domain is characterized by one or more or all of the following features:

[0577] a) is a heterodimer,

[0578] b) is an IgG1 Fc domain,

[0579] c) comprises a silent mutation such that the Fc domain lacks Fcγ receptor binding activity, preferably wherein such mutation is one of the following combinations of mutations:

[0580] i)P329G / L234A / L235A(PGLALA),

[0581] ii) L234A / L235A(LALA),

[0582] iii) P331S / L234A / L235A,

[0583] iv) L234F / L235E / P331S, and

[0584] v)L234F / L235E / P329G,

[0585] d) comprises a mutation that enhances FcRn activity, preferably wherein such mutation increases the half-life of the tetrahedral antibody, preferably wherein the mutation is:

[0586] i) the combination of the following mutations: L309D / Q311H / N434S (DHS),

[0587] ii) a combination of the following mutations: S239D / I298E,

[0588] iii) S239D, preferably wherein the other Fc domain of the tetrahedral antibody, if present, comprises an I298E mutation, or

[0589] iv) I298E, preferably wherein the other Fc domain of the tetrahedral antibody, if present, comprises an S239D mutation, and

[0590] e) comprising mutations that eliminate their protein A binding sites, preferably wherein such mutations are H435R / Y436F (HY / RF).

[0591] In an embodiment of the invention, the peptide linkers each have a length of 23 amino acids and are derived from the stalk region of a TNF receptor, preferably wherein the TNF receptor is TNF receptor 1B, and more preferably wherein the peptide linker consists of the amino acid sequence set forth in SEQ ID NO:4468.

[0592] In an embodiment of the present invention, the dimerizing polypeptides are each ACE2 CLD, wherein each ACE2 CLD comprises or consists of amino acids 616-740 of the ACE2 protein.

[0593] In an embodiment of the invention comprising six domains, wherein such domains and peptide linkers are formed by four different types of polypeptide chains, preferably wherein the four different types of polypeptide chains are denoted L1, H1, L2 and H2, wherein:

[0594] 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 wherein the L1 chain, the H1 chain, the L2 chain and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;

[0595] 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 wherein the L1 chain, the H1 chain, the L2 chain, and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;

[0596] 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 wherein the L1 chain, the H1 chain, the L2 chain, and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;

[0597] 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 wherein the L1 chain, the H1 chain, the L2 chain, and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;

[0598] 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 wherein the L1 chain, the H1 chain, the L2 chain and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences; or

[0599] 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 wherein the L1 chain, the H1 chain, the L2 chain, and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;

[0600] 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 wherein the L1 chain, the H1 chain, the L2 chain, and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;

[0601] 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 wherein the L1 chain, the H1 chain, the L2 chain, and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;

[0602] 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 wherein the L1 chain, the H1 chain, the L2 chain, and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;

[0603] 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 wherein the L1 chain, the H1 chain, the L2 chain, and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;

[0604] 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 wherein the L1 chain, the H1 chain, the L2 chain, and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;

[0605] 1) 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 wherein the L1 chain, the H1 chain, the L2 chain, and the H2 chain are variants having at least 90%, preferably at least 95%, and more preferably at least 98% identity to said sequences;

[0606] 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 wherein the L1 chain, the H1 chain, the L2 chain, and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;

[0607] 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 wherein the L1 chain, the H1 chain, the L2 chain, and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;

[0608] 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 wherein the L1 chain, the H1 chain, the L2 chain, and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;

[0609] 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 wherein the L1 chain, the H1 chain, the L2 chain, and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;

[0610] 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 wherein the L1 chain, the H1 chain, the L2 chain, and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;

[0611] 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 wherein the L1 chain, the H1 chain, the L2 chain, and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;

[0612] 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 wherein the L1 chain, the H1 chain, the L2 chain, and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;

[0613] 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 wherein the L1 chain, the H1 chain, the L2 chain, and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;

[0614] 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 wherein the L1 chain, the H1 chain, the L2 chain, and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;

[0615] 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 wherein the L1 chain, the H1 chain, the L2 chain, and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;

[0616] 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 wherein the L1 chain, the H1 chain, the L2 chain, and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;

[0617] 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 wherein the L1 chain, the H1 chain, the L2 chain, and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;

[0618] 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 wherein the L1 chain, the H1 chain, the L2 chain, and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;

[0619] 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 wherein the L1 chain, the H1 chain, the L2 chain and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences; or

[0620] 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 wherein the L1 chain, H1 chain, L2 chain and H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences.

[0621] In another embodiment of the invention comprising six domains, wherein such domains and peptide linkers are formed by four different types of polypeptide chains, the polypeptides are any of the polypeptides listed in Table 54, preferably protein IDs 21-31 to 21-38 and 21-69 to 21-76.

[0622] In the above embodiment, the C-terminal portions of the H1 chain and the H2 chain are paired with each other to form each of the domain 1 and the domain 2, the N-terminal portion of the H1 chain is paired with the L1 chain to form the third domain and the fourth domain, and the N-terminal portion of the H2 chain is paired with L2 to form the fifth domain and the sixth domain. In addition, the H1 chain contains a CLD dimerization domain between the portion paired with the H2 chain and the portion paired with the L1 chain. Fig.31 C and Fig.31 D provides a schematic diagram of such a tetrahedral antibody structure, wherein the chains in the schematic diagram are L2, H2, L1, H1, H1, L1, H2 and L2 from left to right. The present invention provides a method for producing a tetrahedral antibody, the method comprising recombinantly expressing four different types of polypeptide chains of the present embodiment in a host cell.

[0623] In an embodiment of the invention comprising eight domains, wherein such domains and peptide linkers are formed by four different types of polypeptide chains, preferably the four different types of polypeptide chains are denoted L1, H1, L2, H2, wherein:

[0624] 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 wherein the L1 chain, the H1 chain, the L2 chain and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;

[0625] 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 wherein the L1 chain, the H1 chain, the L2 chain, and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;

[0626] 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 wherein the L1 chain, the H1 chain, the L2 chain, and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;

[0627] 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 wherein the L1 chain, the H1 chain, the L2 chain, and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;

[0628] 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 wherein the L1 chain, the H1 chain, the L2 chain, and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;

[0629] 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 wherein the L1 chain, the H1 chain, the L2 chain, and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;

[0630] 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 wherein the L1 chain, the H1 chain, the L2 chain, and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;

[0631] 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 wherein the L1 chain, the H1 chain, the L2 chain, and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;

[0632] 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 wherein the L1 chain, the H1 chain, the L2 chain, and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;

[0633] 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 wherein the L1 chain, the H1 chain, the L2 chain, and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;

[0634] 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 wherein the L1 chain, the H1 chain, the L2 chain and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences; or

[0635] 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 wherein the L1 chain, H1 chain, L2 chain and H2 chain are variants having at least 90%, preferably at least 95%, and more preferably at least 98% identity with said sequences.

[0636] In the above embodiment, the C-terminal portion of the H1 chain forms domain 7 and domain 8, and the C-terminal portion of the H2 chain pairs with a portion of the H1 chain to form each of domain 1 and domain 2, the N-terminal portion of the H1 chain pairs with the L1 chain to form the third domain and the fourth domain, and the N-terminal portion of the H2 chain pairs with L2 to form the fifth domain and the sixth domain. In addition, the H1 chain contains a CLD dimerization domain between the portion paired with the H2 chain and the portion paired with the L1 chain. Fig.37 D provides a schematic diagram of such a tetrahedral antibody structure, wherein the chains in the schematic diagram are L2, H2, L1, H1, H1, L1, H2, L2 from left to right. The present invention provides a method for producing a tetrahedral antibody, the method comprising recombinantly expressing four different types of polypeptide chains of the present embodiment in a host cell.

[0637] Polynucleotide

[0638] The present invention also provides a polynucleotide encoding a polypeptide of any of the polypeptide chains in the above embodiments. In a preferred embodiment, the polynucleotide encodes one of the L1, H1, L2 and H2 polypeptide chains in the above embodiments.

[0639] Carrier

[0640] The present invention also provides a vector comprising a polynucleotide encoding a polypeptide comprising any polypeptide chain of the present invention. In a preferred embodiment, the vector encodes a polypeptide comprising L1, H1, L2 and H2 polypeptide chains of an embodiment of the present invention, wherein the embodiment comprises four different polypeptide chains as described above. In these vectors, each polynucleotide is operably linked to a promoter that directs the expression of the polynucleotide in a host cell. The present invention also provides a method for producing a tetrahedral antibody, comprising recombinantly expressing any of these vectors in a host cell.

[0641] Host cells

[0642] The present invention also provides a host cell comprising any of the vectors of the present invention. In a preferred embodiment, the host cell is used for a method for producing a tetrahedral antibody. The present invention also provides a method for producing a tetrahedral antibody comprising four different types of polypeptide chains, the method comprising expressing four different polypeptide chains in a host cell of the present invention as described in the above embodiments.

[0643] Pharmaceutical composition

[0644] The present invention also provides a pharmaceutical composition comprising any tetrahedral antibody of the present invention and one or more pharmaceutically acceptable excipients, wherein the tetrahedral antibody comprises an anti-CD20 Fab domain and / or an anti-CD19 Fab domain.

[0645] In a preferred embodiment, the pharmaceutical composition comprises a tetrahedral antibody comprising six domains, wherein such domains and peptide linkers are formed by four different types of polypeptide chains, preferably the four different types of polypeptide chains are denoted L1, H1, L2 and H2, wherein:

[0646] 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 wherein the L1 chain, the H1 chain, the L2 chain and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;

[0647] 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 wherein the L1 chain, the H1 chain, the L2 chain, and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;

[0648] 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 wherein the L1 chain, the H1 chain, the L2 chain, and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;

[0649] 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 wherein the L1 chain, the H1 chain, the L2 chain, and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;

[0650] 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 wherein the L1 chain, the H1 chain, the L2 chain and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences; or

[0651] 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 wherein the L1 chain, H1 chain, L2 chain and H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences.

[0652] In a preferred embodiment, the pharmaceutical composition comprises a tetrahedral antibody comprising eight domains, wherein such domains and peptide linkers are formed by four different types of polypeptide chains, preferably four different types of polypeptide chains are denoted L1, H1, L2 and H2, and:

[0653] 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 wherein the L1 chain, the H1 chain, the L2 chain and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;

[0654] 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 wherein the L1 chain, the H1 chain, the L2 chain, and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;

[0655] 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 wherein the L1 chain, the H1 chain, the L2 chain, and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;

[0656] 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 wherein the L1 chain, the H1 chain, the L2 chain, and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;

[0657] 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 wherein the L1 chain, the H1 chain, the L2 chain, and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;

[0658] 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 wherein the L1 chain, the H1 chain, the L2 chain, and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;

[0659] 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 wherein the L1 chain, the H1 chain, the L2 chain, and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;

[0660] 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 wherein the L1 chain, the H1 chain, the L2 chain, and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;

[0661] 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 wherein the L1 chain, the H1 chain, the L2 chain, and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;

[0662] 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 wherein the L1 chain, the H1 chain, the L2 chain, and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences;

[0663] 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 wherein the L1 chain, the H1 chain, the L2 chain and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences; or

[0664] 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 wherein the L1 chain, H1 chain, L2 chain and H2 chain are variants having at least 90%, preferably at least 95%, and more preferably at least 98% identity with said sequences.

[0665] Treatment

[0666] The present invention also provides a method for treating cancer or inflammatory diseases in an individual, the method comprising administering to the individual a therapeutically effective amount of any one of the above-mentioned pharmaceutical compositions, wherein the pharmaceutical composition comprises a tetrahedral antibody comprising an anti-CD20 Fab domain and / or an anti-CD19 Fab domain, preferably wherein the cancer is a B-cell cancer.

[0667] Tetrahedral molecule

[0668] The present invention also provides a tetrahedral molecule, which comprises a first domain, a second domain, a third domain and a fourth domain, wherein:

[0669] a) the first domain and the second domain each independently comprise:

[0670] i) a first polypeptide chain comprising a first N-terminus and a first C-terminus of the domain, and

[0671] ii) optionally a second polypeptide chain comprising a second N-terminus and a second C-terminus of the domain,

[0672] b) The first domain and the second domain are joined to each other via a non-covalent bond between

[0673] (1) between a first dimerization polypeptide connected to the first N-terminus of the first domain by a peptide bond or by a peptide linker and a second dimerization polypeptide connected to the first N-terminus of the second domain by a peptide bond or by a peptide linker,

[0674] (2) between a first dimerization polypeptide connected to the first C-terminus of the first domain by a peptide bond or by a peptide linker and a second dimerization polypeptide connected to the first C-terminus of the second domain by a peptide bond or by a peptide linker,

[0675] (3) between a first dimerization polypeptide connected to the first N-terminus of the first domain by a peptide bond or by a peptide linker and a second dimerization polypeptide connected to the first C-terminus of the second domain by a peptide bond or by a peptide linker, or

[0676] (4) between a first dimerization polypeptide connected to the first C-terminus of the first domain by a peptide bond or by a peptide linker and a second dimerization polypeptide connected to the first N-terminus of the second domain by a peptide bond or by a peptide linker,

[0677] wherein the first dimerization polypeptide and the second dimerization polypeptide are not immunoglobulin polypeptides,

[0678] c) if the first domain is joined to the second domain via a first dimerization polypeptide linked to a first N-terminus of the first domain, the third domain is linked at its C-terminus via a peptide bond or via a peptide linker

[0679] i) the N-terminus of the first dimerization polypeptide,

[0680] ii) the second N-terminus of the first domain, if present, or

[0681] iii) the N-terminus of the third dimerization polypeptide, wherein the third dimerization polypeptide is linked at its C-terminus to the second N-terminus of the first domain, if the second N-terminus of the first domain exists, via a peptide bond or via a peptide linker,

[0682] d) if the first domain is joined to the second domain via a first dimerization polypeptide linked to a first C-terminus of the first domain, the third domain is linked at its N-terminus via a peptide bond or via a peptide linker to

[0683] i) the C-terminus of the first dimerization polypeptide,

[0684] ii) the second C-terminus of the first domain, if present, or

[0685] iii) the C-terminus of the third dimerization polypeptide, wherein the third dimerization polypeptide is linked at its N-terminus to the second C-terminus of the first domain, if the second C-terminus of the first domain exists, via a peptide bond or via a peptide linker,

[0686] e) if the second domain is linked to the first domain via a second dimerization polypeptide linked to a first N-terminus of the second domain, the fourth domain is linked at its C-terminus via a peptide bond or via a peptide linker

[0687] i) the N-terminus of the second dimerization polypeptide,

[0688] ii) the second N-terminus of the second domain, if present, or

[0689] iii) the N-terminus of the fourth dimerization polypeptide, wherein the third dimerization polypeptide is linked at its C-terminus to the second N-terminus of the second domain, if the second N-terminus of the second domain exists, via a peptide bond or via a peptide linker, and

[0690] f) if the second domain is joined to the first domain via a second dimerization polypeptide linked to a first C-terminus of the second domain, the fourth domain is linked at its N-terminus via a peptide bond or via a peptide linker

[0691] i) the C-terminus of the second dimerization polypeptide,

[0692] ii) the second C-terminus of the second domain, if present, or

[0693] iii) the C-terminus of the fourth dimeric polypeptide, wherein the fourth dimeric polypeptide is linked at its N-terminus to the second C-terminus of the second domain, if the second C-terminus of the second domain exists, via a peptide bond or via a peptide linker.

[0694] In an embodiment of the invention, in particular in any of the embodiments of the preceding paragraphs, the tetrahedral antibody additionally comprises a fifth domain and / or a sixth domain, wherein:

[0695] a) the first domain is joined to the second domain via a first dimerization polypeptide linked to a first N-terminus of the first domain, wherein

[0696] i) the fifth domain is linked at its C-terminus via a peptide bond or via a peptide linker to:

[0697] (1) the N-terminus of the first dimerization polypeptide,

[0698] (2) the second N-terminus of the first domain, or

[0699] (3) an N-terminus of a third dimerization polypeptide, wherein the third dimerization polypeptide is connected at its C-terminus to the second N-terminus of the first domain via a peptide bond or via a peptide linker,

[0700] b) the first domain is joined to the second domain via a first dimerization polypeptide linked to a first C-terminus of the first domain, wherein

[0701] i) the fifth domain is linked at its N-terminus via a peptide bond or via a peptide linker to:

[0702] (1) the C-terminus of the first dimerization polypeptide,

[0703] (2) the second C-terminus of the first domain, or

[0704] (3) the C-terminus of the third dimerization polypeptide, wherein the third dimerization polypeptide is connected at its N-terminus to the second C-terminus of the first domain via a peptide bond or via a peptide linker,

[0705] c) the second domain is joined to the first domain via a second dimerization polypeptide linked to a first N-terminus of the second domain, wherein

[0706] i) the sixth domain is linked at its C-terminus via a peptide bond or via a peptide linker to:

[0707] (1) the N-terminus of the second dimerization polypeptide,

[0708] (2) the second N-terminus of the second domain, or

[0709] (3) the N-terminus of a fourth dimerization polypeptide, wherein the fourth dimerization polypeptide is linked at its C-terminus to the second N-terminus of the second domain via a peptide bond or via a peptide linker, or

[0710] d) the second domain is joined to the first domain via a second dimerization polypeptide linked to a first C-terminus of the second domain, wherein

[0711] i) the sixth domain is linked at its N-terminus via a peptide bond or via a peptide linker to:

[0712] (1) the C-terminus of the second dimerization polypeptide,

[0713] (2) the second C-terminus of the second domain, or

[0714] (3) the C-terminus of the fourth dimerization polypeptide, wherein the fourth dimerization polypeptide is linked at its N-terminus to the second C-terminus of the second domain via a peptide bond or via a peptide linker.

[0715] In an embodiment of the tetrahedral molecule of the present invention, in particular in any of the embodiments of the two preceding paragraphs, the tetrahedral molecule further comprises a seventh domain and / or an eighth domain, wherein:

[0716] a) the first domain is joined to the second domain via a first dimerization polypeptide linked to a first N-terminus of the first domain, wherein

[0717] i) the seventh domain is linked at its N-terminus via a peptide bond or via a peptide linker to:

[0718] (1) the first C-terminus of the first domain, or

[0719] (2) the second C-terminus of the first domain,

[0720] b) the first domain is joined to the second domain via a first dimerization polypeptide linked to a first C-terminus of the first domain, wherein

[0721] i) the seventh domain is linked at its C-terminus via a peptide bond or via a peptide linker to:

[0722] (1) the first N-terminus of the first domain, or

[0723] (2) the second N-terminus of the first domain,

[0724] c) the second domain is joined to the first domain via a second dimerization polypeptide linked to a first N-terminus of the second domain, wherein

[0725] i) the eighth domain is linked at its N-terminus via a peptide bond or via a peptide linker to:

[0726] (1) the first C-terminus of the second domain, or

[0727] (2) the second C-terminus of the second domain, or

[0728] d) the second domain is joined to the first domain via a second dimerization polypeptide linked to a first C-terminus of the second domain, wherein

[0729] i) the eighth domain is linked at its C-terminus via a peptide bond or via a peptide linker to:

[0730] (1) the first N-terminus of the second domain, or

[0731] (2) The second N-terminus of the second domain.

[0732] In an embodiment of the tetrahedral molecule of the present invention, in particular in any of the embodiments of the preceding three paragraphs, the tetrahedral molecule further comprises a ninth domain and / or a tenth domain, wherein:

[0733] a) The third domain

[0734] i) is linked at its C-terminus to the N-terminus of the first dimerization polypeptide via a peptide bond or via a peptide linker, wherein the ninth domain is linked at its C-terminus to the N-terminus of the third domain via a peptide bond or via a peptide linker; or

[0735] ii) linked at its N-terminus to the C-terminus of the first dimerization polypeptide via a peptide bond or via a peptide linker, wherein the ninth domain is linked at its N-terminus to the C-terminus of the third domain via a peptide bond or via a peptide linker; and / or

[0736] b) The fourth domain

[0737] i) is linked at its C-terminus to the N-terminus of a second dimerization polypeptide via a peptide bond or via a peptide linker, wherein the tenth domain is linked at its C-terminus to the N-terminus of the fourth domain via a peptide bond or via a peptide linker; or

[0738] ii) is linked at its N-terminus to the C-terminus of a second dimerization polypeptide via a peptide bond or via a peptide linker, wherein the tenth domain is linked at its N-terminus to the C-terminus of the fourth domain via a peptide bond or via a peptide linker.

[0739] In any embodiment of the tetrahedral molecule of the present invention, in particular in any embodiment of the preceding four paragraphs:

[0740] a) the first domain is an Fc domain or a Fab domain,

[0741] b) the first domain is an Fc domain or a Fab domain, and the second domain is not an Fc domain or a Fab domain,

[0742] c) the first domain is an Fc domain, and the second domain is a Fab domain,

[0743] d) the first domain and the second domain are Fc domains,

[0744] e) the first domain and the second domain are Fab domains,

[0745] f) the second domain, the third domain and / or the fourth domain are selected from the group consisting of (i) a secretory protein and (ii) an extracellular domain of a transmembrane protein,

[0746] g) the third domain is selected from the group consisting of (i) a secretory protein and (ii) an extracellular domain of a transmembrane protein, and the fourth domain is Fab,

[0747] h) the third domain is IL-15,

[0748] i) the third domain is IL-15, and the fourth domain is the IL-15Rα sushi domain,

[0749] j) the third domain is IL-15, the fourth domain is Fab,

[0750] k) the third domain and the fourth domain are each an ACE2 peptidase domain (PD),

[0751] l) the first domain and the second domain are Fc domains, and the third domain and the fourth domain are selected from the group consisting of (i) a secretory protein and (ii) an extracellular domain of a transmembrane protein,

[0752] m) the first domain and the second domain are Fc domains, the third domain is selected from the group consisting of (i) a secretory protein and (ii) an extracellular domain of a transmembrane protein, and the fourth domain is Fab,

[0753] n) the first domain and the second domain are Fc domains, and the third domain and the fourth domain are Fab domains,

[0754] o) the first domain and the second domain are Fc domains, the third domain and the fourth domain are each an ACE2 peptidase domain (PD),

[0755] p) the first domain is an Fc domain, and the second domain, the third domain and the fourth domain are Fab domains,

[0756] 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,

[0757] 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 Fab,

[0758] s) the first domain and / or the second domain is a transmembrane domain of a protein other than ACE2 and / or lectin, the first dimerization polypeptide and the second dimerization polypeptide are selected from a lectin-like domain (CLD) and a lectin domain (CD), and the first domain and the second domain are joined to each other by a non-covalent connection between

[0759] (1) between a first dimerization polypeptide connected to the first N-terminus of the first domain via a peptide bond or via a peptide linker and a second dimerization polypeptide connected to the first N-terminus of the second domain via a peptide bond or via a peptide linker, or

[0760] (2) between a first dimerization polypeptide connected to the first C-terminus of the first domain via a peptide bond or via a peptide linker and a second dimerization polypeptide connected to the first C-terminus of the second domain via a peptide bond or via a peptide linker;

[0761] t) the first domain and / or the second domain is a transmembrane domain of ACE2 and / or a collection protein, the third domain and / or the fourth domain is not an ACE2 peptidase domain, and the first domain and the second domain are joined to each other by a non-covalent connection between

[0762] (1) between a first dimerization polypeptide connected to the first N-terminus of the first domain via a peptide bond or via a peptide linker and a second dimerization polypeptide connected to the first N-terminus of the second domain via a peptide bond or via a peptide linker, or

[0763] (2) between a first dimerization polypeptide connected to the first C-terminus of the first domain via a peptide bond or via a peptide linker and a second dimerization polypeptide connected to the first C-terminus of the second domain via a peptide bond or via a peptide linker;

[0764] u) the first domain and / or the second domain is an ACE2 transmembrane domain and / or a clumping protein, the first dimerization polypeptide and the second dimerization polypeptide are selected from a clumping protein-like domain (CLD) and a clumping protein domain (CD), the third domain and / or the fourth domain is not an ACE2 peptidase domain, and the first domain and the second domain are joined to each other by a non-covalent connection between

[0765] (1) between a first dimerization polypeptide connected to the first N-terminus of the first domain via a peptide bond or via a peptide linker and a second dimerization polypeptide connected to the first N-terminus of the second domain via a peptide bond or via a peptide linker, or

[0766] (2) between a first dimerization polypeptide connected to the first C-terminus of the first domain via a peptide bond or via a peptide linker and a second dimerization polypeptide connected to the first C-terminus of the second domain via a peptide bond or via a peptide linker;

[0767] v) the first dimerization polypeptide and the second dimerization polypeptide are selected from the group consisting of a collector protein-like domain (CLD) and a collector protein domain (CD), preferably a CLD, and the first domain is selected from the group consisting of a binding domain of a protein or a part thereof or a modified version thereof, a secreted protein or a part thereof or a modified version thereof, a transmembrane protein or a part thereof or a modified version thereof, an intracellular binding domain or a part thereof or a modified version thereof, and an antibody or a part thereof or a modified version thereof;

[0768] w) the first dimerization polypeptide and the second dimerization polypeptide are selected from the group consisting of a collector protein-like domain (CLD) and a collector protein domain (CD), preferably a CLD, and the second domain is selected from the group consisting of a binding domain of a protein or a portion thereof or a modified form thereof, a secreted protein or a portion thereof or a modified form thereof, a transmembrane protein or a portion thereof or a modified form thereof, an intracellular binding domain or a portion thereof or a modified form thereof, and an antibody or a portion thereof or a modified form thereof;

[0769] x) the first dimerization polypeptide and the second dimerization polypeptide are selected from the group consisting of a collector protein-like domain (CLD) and a collector protein domain (CD), preferably a CLD, and the third domain is selected from the group consisting of a binding domain of a protein or a portion thereof or a modified form thereof, a secreted protein or a portion thereof or a modified form thereof, a transmembrane protein or a portion thereof or a modified form thereof, an intracellular binding domain or a portion thereof or a modified form thereof, and an antibody or a portion thereof or a modified form thereof;

[0770] y) the first dimerization polypeptide and the second dimerization polypeptide are selected from a collection protein-like domain (CLD) and a collection protein domain (CD), preferably a CLD, and the fourth domain is selected from the group consisting of a binding domain of a protein or a portion thereof or a modified form thereof, a secreted protein or a portion thereof or a modified form thereof, a transmembrane protein or a portion thereof or a modified form thereof, an intracellular binding domain or a portion thereof or a modified form thereof, and an antibody or a portion thereof or a modified form thereof;

[0771] z) the first dimerization polypeptide and the second dimerization polypeptide are selected from the group consisting of a collector protein-like domain (CLD) and a collector protein domain (CD), preferably a CLD, and the fifth domain, if present, is selected from the group consisting of a binding domain of a protein or a portion thereof or a modified form thereof, a secreted protein or a portion thereof or a modified form thereof, a transmembrane protein or a portion thereof or a modified form thereof, an intracellular binding domain or a portion thereof or a modified form thereof, and an antibody or a portion thereof or a modified form thereof;

[0772] aa) the first dimerization polypeptide and the second dimerization polypeptide are selected from the group consisting of a collector protein-like domain (CLD) and a collector protein 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 portion thereof or a modified form thereof, a secreted protein or a portion thereof or a modified form thereof, a transmembrane protein or a portion thereof or a modified form thereof, an intracellular binding domain or a portion thereof or a modified form thereof, and an antibody or a portion thereof or a modified form thereof;

[0773] bb) the first dimerization polypeptide and the second dimerization polypeptide are selected from the group consisting of a collector protein-like domain (CLD) and a collector protein domain (CD), preferably a CLD, and the seventh domain, if present, is selected from the group consisting of a binding domain of a protein or a portion thereof or a modified form thereof, a secreted protein or a portion thereof or a modified form thereof, a transmembrane protein or a portion thereof or a modified form thereof, an intracellular binding domain or a portion thereof or a modified form thereof, and an antibody or a portion thereof or a modified form thereof;

[0774] cc) the first dimerization polypeptide and the second dimerization polypeptide are selected from the group consisting of a collector protein-like domain (CLD) and a collector protein domain (CD), preferably a CLD, and the eighth domain, if present, is selected from the group consisting of a binding domain of a protein or a portion thereof or a modified form thereof, a secreted protein or a portion thereof or a modified form thereof, a transmembrane protein or a portion thereof or a modified form thereof, an intracellular binding domain or a portion thereof or a modified form thereof, and an antibody or a portion thereof or a modified form thereof;

[0775] dd) the first dimerization polypeptide and the second dimerization polypeptide are selected from the group consisting of a collection protein-like domain (CLD) and a collection protein domain (CD), preferably a CLD, and the first domain is not any of the following: a binding domain of a protein or a portion thereof or a modified form thereof, a secreted protein or a portion thereof or a modified form thereof, a transmembrane protein or a portion thereof or a modified form thereof, an intracellular binding domain or a portion thereof or a modified form thereof, and an antibody or a portion thereof or a modified form thereof;

[0776] ee) the first dimerization polypeptide and the second dimerization polypeptide are selected from the group consisting of a collection protein-like domain (CLD) and a collection protein domain (CD), preferably a CLD, and the second domain is not any of the following: a binding domain of a protein or a portion thereof or a modified form thereof, a secreted protein or a portion thereof or a modified form thereof, a transmembrane protein or a portion thereof or a modified form thereof, an intracellular binding domain or a portion thereof or a modified form thereof, and an antibody or a portion thereof or a modified form thereof;

[0777] ff) the first dimerization polypeptide and the second dimerization polypeptide are selected from the group consisting of a collection protein-like domain (CLD) and a collection protein domain (CD), preferably a CLD, and the third domain is not any of the following: a binding domain of a protein or a portion thereof or a modified form thereof, a secreted protein or a portion thereof or a modified form thereof, a transmembrane protein or a portion thereof or a modified form thereof, an intracellular binding domain or a portion thereof or a modified form thereof, and an antibody or a portion thereof or a modified form thereof;

[0778] gg) the first dimerization polypeptide and the second dimerization polypeptide are selected from the group consisting of a collection protein-like domain (CLD) and a collection protein domain (CD), preferably a CLD, and the fourth domain is not any of the following: a binding domain of a protein or a portion thereof or a modified form thereof, a secreted protein or a portion thereof or a modified form thereof, a transmembrane protein or a portion thereof or a modified form thereof, an intracellular binding domain or a portion thereof or a modified form thereof, and an antibody or a portion thereof or a modified form thereof;

[0779] hh) the first dimerization polypeptide and the second dimerization polypeptide are selected from the group consisting of a collector protein-like domain (CLD) and a collector protein domain (CD), preferably a CLD, and the fifth domain, if present, is not any of the following: a binding domain of a protein or a portion thereof or a modified form thereof, a secreted protein or a portion thereof or a modified form thereof, a transmembrane protein or a portion thereof or a modified form thereof, an intracellular binding domain or a portion thereof or a modified form thereof, and an antibody or a portion thereof or a modified form thereof;

[0780] ii) the first dimerization polypeptide and the second dimerization polypeptide are selected from the group consisting of a collector protein-like domain (CLD) and a collector protein domain (CD), preferably a CLD, and the sixth domain, if present, is not any of the following: a binding domain of a protein or a portion thereof or a modified form thereof, a secreted protein or a portion thereof or a modified form thereof, a transmembrane protein or a portion thereof or a modified form thereof, an intracellular binding domain or a portion thereof or a modified form thereof, and an antibody or a portion thereof or a modified form thereof;

[0781] jj) the first dimerization polypeptide and the second dimerization polypeptide are selected from the group consisting of a collector protein-like domain (CLD) and a collector protein domain (CD), preferably a CLD, and the seventh domain, if present, is not any of the following: a binding domain of a protein or a portion thereof or a modified form thereof, a secreted protein or a portion thereof or a modified form thereof, a transmembrane protein or a portion thereof or a modified form thereof, an intracellular binding domain or a portion thereof or a modified form thereof, and an antibody or a portion thereof or a modified form thereof;

[0782] kk) the first dimerization polypeptide and the second dimerization polypeptide are selected from the group consisting of a collector protein-like domain (CLD) and a collector protein domain (CD), preferably a CLD, and the eighth domain, if present, is not any of the following: a binding domain of a protein or a portion thereof or a modified form thereof, a secreted protein or a portion thereof or a modified form thereof, a transmembrane protein or a portion thereof or a modified form thereof, an intracellular binding domain or a portion thereof or a modified form thereof, and an antibody or a portion thereof or a modified form thereof;

[0783] 11) the first domain, the second domain, the third domain and / or the fourth domain are CD3 ζ chain intracellular binding domain, CD28 intracellular binding domain or 4-1BB intracellular binding domain, CD3 ε chain intracellular binding domain, ICOS intracellular binding domain, OX40 intracellular binding domain or 4-1BB intracellular binding domain;

[0784] mm) the seventh domain and / or the eighth domain, if present, is a CD3 ζ chain intracellular binding domain, a CD28 intracellular binding domain, or a 4-1BB intracellular binding domain, a CD3 ε chain intracellular binding domain, an ICOS intracellular binding domain, an OX40 intracellular binding domain, or a 4-1BB intracellular binding domain;

[0785] nn) the first domain, the second domain, the third domain and the fourth domain are not ACE2 peptidase domains;

[0786] oo) the first domain, the second domain, the third domain and the fourth domain are not ACE2 peptidase domains, and the first dimerization polypeptide and the second dimerization polypeptide are each a collector protein-like domain (CLD);

[0787] pp) the first domain, the second domain, the third domain and the fourth domain are not ACE2 peptidase domains or ACE2 transmembrane domains;

[0788] qq) the first domain, the second domain, the third domain, and the fourth domain are not ACE2 peptidase domains or ACE2 transmembrane domains, and the first dimerization polypeptide and the second dimerization polypeptide are each a collector protein-like domain (CLD);

[0789] rr) the tetrahedral molecule comprises a first domain, a second domain, a third domain, a fourth domain, a seventh domain and an eighth domain, the first domain and the second domain being joined to each other by a non-covalent bond between a first dimerization polypeptide connected to a first N-terminus of the first domain by a peptide bond or by a peptide linker and a second dimerization polypeptide connected to a first N-terminus of the second domain by a peptide bond or by a peptide linker, and

[0790] i) the third domain and the fourth domain are each a binding domain of a protein or a portion thereof or a modified form thereof, preferably a binding domain of a secretory protein, an extracellular domain of a transmembrane protein, or an antibody or a portion thereof, more preferably a single chain portion of an antibody, more preferably a single chain or single-domain antibody molecule, more preferably a scFv domain;

[0791] ii) the first domain and the second domain 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, collection protein, CD8a, CD8b, CD3ζ, CD3ε, CD28, ICOS, OX40 or 4-1BB; and

[0792] iii) the seventh domain and the eighth domain are each an intracellular binding domain, preferably an intracellular binding domain of CD3ζ chain, CD3ε chain, CD28, ICOS, OX40 or 4-1BB;

[0793] ss) The tetrahedral molecule comprises a first domain, a second domain, a third domain, a fourth domain, a seventh domain and an eighth domain, the first domain and the second domain are joined to each other by a non-covalent connection between a first dimerization polypeptide connected to a first N-terminus of the first domain by a peptide bond or by a peptide linker and a second dimerization polypeptide connected to a first N-terminus of the second domain by a peptide bond or by a peptide linker, the third domain and the fourth domain are each a scFv domain, the first domain and the second domain are each a transmembrane domain of ACE2, collection protein, CD8a, CD8b, CD3ζ, CD3ε, CD28, ICOS, OX40 or 4-1BB, and the seventh domain and the eighth domain are each an intracellular binding domain of CD3ζ chain, CD3ε chain, CD28, ICOS, OX40 or 4-1BB;

[0794] tt) the tetrahedral molecule comprises a first domain, a second domain, a third domain, a fourth domain, a ninth domain and a tenth domain, the first domain and the second domain being joined to each other by a non-covalent connection between a first dimerization polypeptide connected to a first N-terminus of the first domain by a peptide bond or by a peptide linker and a second dimerization polypeptide connected to a first N-terminus of the second domain by a peptide bond or by a peptide linker, and

[0795] i) the ninth domain and the tenth domain are each a binding domain of a protein or a portion thereof or a modified form thereof, preferably a binding domain of a secretory protein, an extracellular domain of a transmembrane protein, or an antibody or a portion thereof, more preferably a single chain portion of an antibody, more preferably a single chain or single domain antibody molecule, more preferably a scFv domain;

[0796] ii) the third domain and the fourth domain 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, collection protein, CD8a, CD8b, CD3ζ, CD3ε, CD28, ICOS, OX40 or 4-1BB; and

[0797] iii) the first domain and the second domain are each an intracellular binding domain, preferably an intracellular binding domain of CD3ζ chain, CD3ε chain, CD28, ICOS, OX40 or 4-1BB;

[0798] uu) the tetrahedral molecule comprises a first domain, a second domain, a third domain, a fourth domain, a ninth domain and a tenth domain, the first domain and the second domain being joined to each other by a non-covalent connection between a first dimerization polypeptide connected to a first N-terminus of the first domain by a peptide bond or by a peptide linker and a second dimerization polypeptide connected to a first N-terminus of the second domain by a peptide bond or by a peptide linker, the ninth domain and the tenth domain are each a scFv domain, the third domain and the fourth domain are each a transmembrane domain of ACE2, collection protein, CD8a, CD8b, CD3ζ, CD3ε, CD28, ICOS, OX40 or 4-1BB, and the first domain and the second domain are each an intracellular binding domain of CD3ζ chain, CD3ε chain, CD28, ICOS, OX40 or 4-1BB;

[0799] vv) the tetrahedral molecule comprises a first domain, a second domain, a third domain, a fourth domain, a seventh domain and an eighth domain, the first domain and the second domain being joined to each other by a non-covalent bond between a first dimerization polypeptide connected to a first N-terminus of the first domain by a peptide bond or by a peptide linker and a second dimerization polypeptide connected to a first N-terminus of the second domain by a peptide bond or by a peptide linker, and

[0800] i) the third domain and the fourth domain are each a binding domain of a protein or a portion thereof or a modified form thereof, preferably a binding domain of a secretory protein, an extracellular domain of a transmembrane protein, or an antibody or a portion thereof, more preferably a single chain portion of an antibody, more preferably a single chain or single domain antibody molecule, more preferably a scFv domain;

[0801] ii) the first domain and the second domain 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, collection protein, CD8a, CD8b, CD3ζ, CD3ε, CD28, ICOS, OX40 or 4-1BB; and

[0802] iii) the seventh domain and the eighth domain are each an antigen or a neo-antigen;

[0803] ww) the tetrahedral molecule comprises a first domain, a second domain, a third domain, a fourth domain, a seventh domain and an eighth domain, the first domain and the second domain are joined to each other by a non-covalent connection between a first dimerization polypeptide connected to a first N-terminus of the first domain by a peptide bond or by a peptide linker and a second dimerization polypeptide connected to a first N-terminus of the second domain by a peptide bond or by a peptide linker, the third domain and the fourth domain are each a scFv domain, the first domain and the second domain are each a transmembrane domain of ACE2, collection protein, CD8a, CD8b, CD3ζ, CD3ε, CD28, ICOS, OX40 or 4-1BB, and the seventh domain and the eighth domain are each an antigen or a neoantigen;

[0804] xx) the tetrahedral molecule comprises a first domain, a second domain, a third domain, a fourth domain, a ninth domain and a tenth domain, the first domain and the second domain being joined to each other by a non-covalent bond between a first dimerization polypeptide connected to a first N-terminus of the first domain by a peptide bond or by a peptide linker and a second dimerization polypeptide connected to a first N-terminus of the second domain by a peptide bond or by a peptide linker, and

[0805] i) the ninth domain and the tenth domain are each a binding domain of a protein or a portion thereof or a modified form thereof, preferably a binding domain of a secretory protein, an extracellular domain of a transmembrane protein, or an antibody or a portion thereof, more preferably a single chain portion of an antibody, more preferably a single chain or single domain antibody molecule, more preferably a scFv domain;

[0806] ii) the third domain and the fourth domain 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, collection protein, CD8a, CD8b, CD3ζ, CD3ε, CD28, ICOS, OX40 or 4-1BB; and

[0807] iii) the first domain and the second domain are each an antigen or a neoantigen;

[0808] yy) The tetrahedral molecule comprises a first domain, a second domain, a third domain, a fourth domain, a ninth domain and a tenth domain, the first domain and the second domain are joined to each other by a non-covalent connection between a first dimerization polypeptide connected to a first N-terminus of the first domain by a peptide bond or by a peptide linker and a second dimerization polypeptide connected to a first N-terminus of the second domain by a peptide bond or by a peptide linker, the ninth domain and the tenth domain are each a scFv domain, the third domain and the fourth domain are each a transmembrane domain of ACE2, collection protein, CD8a, CD8b, CD3ζ, CD3ε, CD28, ICOS, OX40 or 4-1BB, and the first domain and the second domain are each an antigen or a neoantigen.

[0809] In an embodiment comprising a transmembrane domain as the first domain and the second domain, preferably, the tetrahedral molecule comprises a first dimerization polypeptide and a second dimerization polypeptide that are naturally associated with the transmembrane domain. For example, if the first domain and the second domain are the transmembrane domains of ACE2, the first dimerization polypeptide and the second dimerization polypeptide are collection protein-like domains (CLD). Therefore, in a preferred embodiment of any of the above embodiments, the first domain and the second domain are the transmembrane domains of ACE2, and the first dimerization polypeptide and the second dimerization polypeptide are collection protein-like domains (CLD).

[0810] In an embodiment of the invention, in particular in any of the embodiments of the preceding six paragraphs, the non-peptidyl linkage is a non-covalent linkage between a first dimerization polypeptide linked to the first domain and a second dimerization polypeptide linked to the second domain.

[0811] In an embodiment of the invention, in particular in any one of the embodiments of the preceding seven paragraphs, the first dimerization polypeptide and the second dimerization polypeptide are selected from the group consisting of:

[0812] a) a dimerization domain of an extracellular protein dimer, and

[0813] b) Dimerization domain of intracellular protein dimer.

[0814] In an embodiment of the invention, in particular in any one of the embodiments of the preceding eight paragraphs, the first dimerization polypeptide and the second dimerization polypeptide are selected from the group consisting of:

[0815] a) Leucine zipper domain,

[0816] b) Collector-like domain (CLD),

[0817] c) collecting protein domains (CD),

[0818] d) CD8α extracellular domain, and

[0819] e) CD8β extracellular domain.

[0820] In a preferred embodiment of the tetrahedral molecule of the present invention, in particular in any one of the embodiments of the preceding nine paragraphs, the first dimerization polypeptide and the second dimerization polypeptide are selected from a collector protein-like domain (CLD) and a collector protein domain (CD), preferably a collector protein-like domain (CLD).

[0821] In an embodiment of the present invention:

[0822] a) the first dimerization polypeptide is identical to the second dimerization polypeptide, and

[0823] b) The polypeptides dimerize to form homodimers.

[0824] In an embodiment of the present invention:

[0825] a) the first dimerization polypeptide is different from the second dimerization polypeptide, and

[0826] b) The first dimerization polypeptide and the second dimerization polypeptide form a heterodimer.

[0827] In an embodiment of the invention, wherein the first dimerizing polypeptide and the second dimerizing polypeptide form a heterodimer:

[0828] a) the first dimerization polypeptide and the second dimerization polypeptide are selected from the group consisting of:

[0829] i) T cell receptor alpha extracellular domain and T cell receptor beta extracellular domain,

[0830] ii) a T cell receptor gamma extracellular domain and a T cell receptor extracellular domain,

[0831] iii) MHC class I alpha extracellular domain and beta-2 microglobulin,

[0832] iv) an MHC class II alpha extracellular domain and an MHC class II beta extracellular domain, and

[0833] v) CD8α extracellular domain and CD8β extracellular domain,

[0834] b) the first dimerization polypeptide is different from the second dimerization polypeptide, and

[0835] c) the first dimerization polypeptide and the second dimerization polypeptide form a heterodimer.

[0836] In some embodiments of the invention, the first dimerizing polypeptide and the second dimerizing polypeptide form less than 30%, 20%, 10%, 5%, 4%, 3%, 2% or 1% homodimers when present with each other.

[0837] Dimeric fusion protein

[0838] The present invention also provides a non-naturally occurring fusion protein dimer, comprising a dimer of a first dimerizing polypeptide and a second dimerizing polypeptide, wherein:

[0839] a) the first dimerization polypeptide is linked at its N-terminus or C-terminus to the first domain via a peptide bond or via a peptide linker,

[0840] b) a second dimerization polypeptide is optionally linked to the second domain at its N-terminus or C-terminus via a peptide bond or via a peptide linker,

[0841] c) the first dimerization polypeptide and the second dimerization polypeptide are selected from the group consisting of:

[0842] i) a collector protein-like domain (CLD), and

[0843] ii) collecting protein domains (CD),

[0844] d) the first dimerization polypeptide is optionally linked at its remaining free N-terminus or C-terminus to the third domain via a peptide bond or via a peptide linker, and

[0845] e) The second dimerization polypeptide is optionally linked to the fourth domain at its remaining free N-terminus or C-terminus via a peptide bond or via a peptide linker.

[0846] In any of the above embodiments, the first dimerizing polypeptide and the second dimerizing polypeptide are collectin-like domains (CLDs).

[0847] In an embodiment of the invention, the tetrahedral molecule or non-naturally occurring fusion protein dimer:

[0848] a) Not included

[0849] i) ACE2 PD on the N-terminal side of either dimerization polypeptide; and / or

[0850] ii) an ACE2 transmembrane domain and / or a collection protein transmembrane domain at the C-terminal side of either dimerization polypeptide; or

[0851] b) Include

[0852] i) ACE2 PD on the N-terminal side of either dimerization polypeptide; and / or

[0853] ii) an ACE2 transmembrane domain and / or a harvesting protein transmembrane domain on the C-terminal side of either dimerization polypeptide.

[0854] In an embodiment of the present invention, wherein the first dimerization polypeptide and the second dimerization polypeptide form a heterodimer and the dimerization polypeptide is a collector protein-like domain (CLD), the CLD comprises a substitution that disrupts homodimer formation in the CLD dimerization polypeptide, preferably wherein the substitution is at Arg652, Arg710, Tyr641, Tyr633, Asn638, Glu639, Gln653, Asn636, Ser709, Asp713 and / or Arg716, more preferably wherein 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 positively charged amino acids lysine.

[0855] In an embodiment of the present invention, wherein the first dimerization polypeptide and the second dimerization polypeptide form a heterodimer, the dimerization polypeptide is a collection protein, and the collection protein dimerization polypeptide includes a substitution that destroys the homodimer formation in the collection protein dimerization polypeptide, preferably wherein the substitution is at Arg59, Arg111, Tyr48 and / or Tyr40, more preferably wherein Tyr48 and / or Tyr40 are substituted with positively charged amino acids lysine, arginine or histidine, and Arg59 and / or Arg111 are substituted with negatively charged amino acids glutamic acid or aspartic acid or positively charged amino acids lysine.

[0856] In embodiments where the dimerizing polypeptide is a collector protein-like domain (CLD), the CLD comprises substitutions that promote heterodimer formation in the CLD dimerizing polypeptide, preferably:

[0857] a) preferably, replacing Tyr633 on the first CLD dimerization polypeptide or the second CLD dimerization polypeptide with a positively charged amino acid or a negatively charged amino acid;

[0858] b) preferably, replacing Tyr641 on the first CLD dimerization polypeptide or the second CLD dimerization polypeptide with a positively charged amino acid or a negatively charged amino acid;

[0859] c) preferably, replacing Arg652 on the first CLD dimerization polypeptide or the second CLD dimerization polypeptide with a positively charged amino acid or a negatively charged amino acid;

[0860] d) preferably, replacing Arg710 on the first CLD dimerization polypeptide or the second CLD dimerization polypeptide with a positively charged amino acid or a negatively charged amino acid;

[0861] e) preferably replacing Ser709 on the first CLD dimerization polypeptide or the second CLD dimerization polypeptide with a positively charged amino acid or a negatively charged amino acid; and / or

[0862] f) preferably, replacing Asp713 on the first CLD dimerization polypeptide or the second CLD dimerization polypeptide with a positively charged amino acid or a negatively charged amino acid;

[0863] In embodiments where the dimerizing polypeptide is a gleanin, the gleanin dimerizing polypeptide comprises substitutions that promote heterodimer formation in the gleanin dimerizing polypeptide, preferably:

[0864] a) preferably, replacing Tyr40 on the first collection protein dimerization polypeptide or the second collection protein dimerization polypeptide with a positively charged amino acid or a negatively charged amino acid;

[0865] b) preferably, replacing Tyr48 on the first collection protein dimerization polypeptide or the second collection protein dimerization polypeptide with a positively charged amino acid or a negatively charged amino acid;

[0866] c) preferably, replacing Arg59 on the first sorbin dimerization polypeptide or the second sorbin dimerization polypeptide with a positively charged amino acid or a negatively charged amino acid; and / or

[0867] d) Preferably, Arg111 on the first harvest protein dimerization polypeptide or the second harvest protein dimerization polypeptide is substituted with a positively charged amino acid or a negatively charged amino acid.

[0868] In embodiments where the dimerizing polypeptide is a collector protein-like domain (CLD), the CLD comprises substitutions that promote heterodimer formation in the CLD dimerizing polypeptide, preferably:

[0869] a) replacing Tyr633 on the first CLD dimerization polypeptide with a positively charged amino acid or a negatively charged amino acid, and replacing Arg710 on the second CLD dimerization polypeptide with the other of a positively charged amino acid or a negatively charged amino acid;

[0870] b) replacing Tyr633 on the second CLD dimerization polypeptide with a positively charged amino acid or a negatively charged amino acid, and replacing Arg710 on the first CLD dimerization polypeptide with the other of a positively charged amino acid or a negatively charged amino acid;

[0871] c) replacing Tyr641 on the first CLD dimerization polypeptide with a positively charged amino acid or a negatively charged amino acid, and replacing Arg652 on the second CLD dimerization polypeptide with the other of the positively charged amino acid or the negatively charged amino acid;

[0872] d) replacing Tyr641 on the second CLD dimerization polypeptide with a positively charged amino acid or a negatively charged amino acid, and replacing Arg652 on the first CLD dimerization polypeptide with the other of a positively charged amino acid or a negatively charged amino acid;

[0873] e) replacing Arg652 on the first CLD dimerization polypeptide with a positively charged amino acid or a negatively charged amino acid, and replacing Asn638 on the second CLD dimerization polypeptide with the other of a positively charged amino acid or a negatively charged amino acid;

[0874] f) replacing Arg652 on the second CLD dimerization polypeptide with a positively charged amino acid or a negatively charged amino acid, and replacing Arg638 on the first CLD dimerization polypeptide with the other of a positively charged amino acid or a negatively charged amino acid;

[0875] g) replacing Arg710 on the first CLD dimerization polypeptide with a positively charged amino acid or a negatively charged amino acid, and replacing Glu639 on the second CLD dimerization polypeptide with the other of a positively charged amino acid or a negatively charged amino acid;

[0876] h) replacing Arg710 on the second CLD dimerization polypeptide with a positively charged amino acid or a negatively charged amino acid, and replacing Glu639 on the first CLD dimerization polypeptide with the other of a positively charged amino acid or a negatively charged amino acid;

[0877] i) replacing Ser709 on the first CLD dimerization polypeptide with a positively charged amino acid or a negatively charged amino acid, and replacing Arg716 on the second CLD dimerization polypeptide with the other of a positively charged amino acid or a negatively charged amino acid;

[0878] j) replacing Ser709 on the second CLD dimerization polypeptide with a positively charged amino acid or a negatively charged amino acid, and replacing Arg716 on the first CLD dimerization polypeptide with the other of a positively charged amino acid or a negatively charged amino acid;

[0879] k) replacing Asp713 on the first CLD dimerization polypeptide with a positively charged amino acid or a negatively charged amino acid, and replacing Arg716 on the second CLD dimerization polypeptide with the other of a positively charged amino acid or a negatively charged amino acid; and / or

[0880] 1) replacing Asp713 on the second CLD dimerization polypeptide with a positively charged amino acid or a negatively charged amino acid, and replacing Arg716 on the first CLD dimerization polypeptide with the other of a positively charged amino acid or a negatively charged amino acid.

[0881] In embodiments where the dimerizing polypeptide is a gleanin, the gleanin dimerizing polypeptide comprises substitutions that promote heterodimer formation in the gleanin dimerizing polypeptide, preferably:

[0882] a) replacing Tyr40 on the first collection protein dimerization polypeptide with a positively charged amino acid or a negatively charged amino acid, and replacing Arg111 on the second collection protein dimerization polypeptide with the other of a positively charged amino acid or a negatively charged amino acid;

[0883] b) replacing Tyr40 on the second collection protein dimerization polypeptide with a positively charged amino acid or a negatively charged amino acid, and replacing Arg111 on the first collection protein dimerization polypeptide with the other of a positively charged amino acid or a negatively charged amino acid;

[0884] c) replacing Tyr48 on the first collection protein dimerization polypeptide with a positively charged amino acid or a negatively charged amino acid, and replacing Arg59 on the second collection protein dimerization polypeptide with the other of a positively charged amino acid or a negatively charged amino acid; and / or

[0885] d) replacing Tyr48 on the second collection protein dimerization polypeptide with a positively charged amino acid or a negatively charged amino acid, and replacing Arg59 on the first collection protein dimerization polypeptide with the other of a positively charged amino acid or a negatively charged amino acid.

[0886] Octahedral antibody

[0887] The present invention also provides an octahedral antibody, which comprises a first domain, a second domain, a third domain, a fourth domain, a fifth domain and a sixth domain, wherein:

[0888] a) each of the first domain, the second domain and the third domain is selected from the group consisting of a Fab domain and an Fc domain,

[0889] b) each of the first domain, the second domain and the third domain comprises:

[0890] i) a first polypeptide chain comprising a first N-terminus of the domain, and

[0891] ii) a second polypeptide chain comprising the second N-terminus of the domain,

[0892] 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 joined to each other via a non-peptidyl linkage, wherein the non-peptidyl linkage is:

[0893] i) the side chains are covalently linked, or

[0894] ii) non-covalent bonding between

[0895] (1) a first trimerizing polypeptide connected to the first N-terminus of the first domain via a peptide bond or via a peptide linker,

[0896] (2) a second trimerizing polypeptide connected to the first N-terminus of the second domain via a peptide bond or via a peptide linker, and

[0897] (3) a third trimerizing polypeptide connected to the first N-terminus of the third domain via a peptide bond or via a peptide linker,

[0898] wherein the first trimerizing polypeptide, the second trimerizing polypeptide and the third trimerizing polypeptide are not immunoglobulin polypeptides,

[0899] d) the fourth domain is linked at its C-terminus via a peptide bond or via a peptide linker to:

[0900] i) the second N-terminus of the first domain, or

[0901] ii) the N-terminal end of the first trimerizing polypeptide,

[0902] e) the fifth domain is linked at its C-terminus via a peptide bond or via a peptide linker to:

[0903] i) the second N-terminus of the second domain, or

[0904] ii) the N-terminus of the second trimerizing polypeptide, and

[0905] f) the sixth domain is linked at its C-terminus via a peptide bond or via a peptide linker to:

[0906] i) the second N-terminus of the third domain, or

[0907] ii) the N-terminus of the third trimerizing polypeptide.

[0908] In an embodiment of the octahedral antibody of the invention, the non-peptidyl linkage is a non-covalent linkage between a first trimerizing polypeptide connected to a first N-terminus of the first domain, a second trimerizing polypeptide connected to a first N-terminus of the second domain, and a third trimerizing polypeptide connected to a first N-terminus of the third domain, wherein the first trimerizing polypeptide, the second trimerizing polypeptide and the third trimerizing polypeptide are selected from the group consisting of the following TNF ligand superfamily members: 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, EctodyplasinATNFLSF19, TNF / TNFLSF2, lymphotoxin α / TNFLSF1 and lymphotoxin β / TNFLSF3. In a preferred embodiment, the trimerizing polypeptide is selected from the group consisting of SEQ ID NOs: 787-790 (TNFSF1), SEQ ID NOs: 791-792 (TNFSF2), SEQ ID NOs: 793-795 (TNFSF3), SEQ ID NOs: 796-798 (TNFSF4), SEQ ID NOs: 799-802 (TNFSF5), SEQ ID NOs: 803-806, SEQ ID NOs: 807-809 (TNFSF7), SEQ ID NOs: 810-813 (TNFSF8), SEQ ID NOs: 814-816 (TNFSF9), SEQ ID NOs: 817-820 (TNFSF10), SEQ ID NOs: 821-822 (TNFSF11), SEQ ID NOs: 823-827 (TNFSF12), SEQ ID NOs: 828-831 (TNFSF13), SEQ ID NOs: 832-833 (TNFSF13B), SEQ ID NOs: 834-835 (TNFSF13C), SEQ ID NOs: 836-837 (TNFSF13D), SEQ ID NOs: 838-839 (TNFSF14), SEQ ID NOs: 840-841 (TNFSF14B), SEQ ID NOs: 842-843 (TNFSF14C), SEQ ID NOs: 844-845 (TNFSF14D), SEQ ID NOs: 845-846 (TNFSF14E), SEQ ID NOs: 847-848 (TNFSF14F), SEQ ID NOs: 849-850 (TNFSF14B), SEQ ID NOs: 851-852 ID NOs: 834-837 (TNFSF14), SEQ ID NOs: 838-841 (TNFSF15) and SEQ ID NOs: 842-843 (TNFSF18).

[0909] In an embodiment of the present invention, the octahedral antibody further comprises a seventh domain, an eighth domain and / or a ninth domain, wherein:

[0910] a) the seventh domain is linked at its C-terminus to the second N-terminus of the first domain via a peptide bond or via a peptide linker,

[0911] b) the eighth domain is linked at its C-terminus to the second N-terminus of the second domain via a peptide bond or via a peptide linker, and / or

[0912] c) The ninth domain is linked at its C-terminus to the second N-terminus of the third domain via a peptide bond or via a peptide linker.

[0913] In an embodiment of the present invention, the octahedral antibody further comprises a tenth domain, an eleventh domain and / or a twelfth domain, wherein:

[0914] a) the tenth domain is linked at its N-terminus via a peptide bond or via a peptide linker to:

[0915] i) the first C-terminus of the first domain, or

[0916] ii) the second C-terminus of the first domain,

[0917] b) the eleventh domain is linked at its N-terminus via a peptide bond or via a peptide linker to:

[0918] i) the first C-terminus of the second domain, or

[0919] ii) the second C-terminus of the second domain,

[0920] c) the twelfth domain is linked at its N-terminus via a peptide bond or via a peptide linker to:

[0921] i) the first C-terminus of the third domain, or

[0922] ii) the second C-terminus of the third domain.

[0923] In an embodiment, the first domain, the second domain and the third domain of the octahedral antibody of the present invention can be any domain of the first domain and the second domain as the tetrahedral antibody of the present invention described herein. In an embodiment, the fourth domain, the fifth domain and the sixth domain of the octahedral antibody of the present invention can be any domain of the third domain and the fourth domain as the tetrahedral antibody of the present invention described herein. In an embodiment, the seventh domain, the eighth domain and the ninth domain of the octahedral antibody of the present invention can be any domain of the fifth domain and the sixth domain as the tetrahedral antibody of the present invention described herein. In an embodiment, the tenth domain, the eleventh domain and the twelfth domain of the octahedral antibody of the present invention can be any domain of the seventh domain and the eighth domain as the tetrahedral antibody of the present invention described herein. In addition, all such domains can include any feature (e.g., mutation) described about the domain of the tetrahedral antibody of the present invention.

[0924] Octahedral molecule

[0925] The present invention also provides an octahedral molecule, which comprises a first domain, a second domain, a third domain, a fourth domain, a fifth domain and a sixth domain, wherein:

[0926] a) at least one of the first domain, the second domain and the third domain is not a Fab domain or an Fc domain, and the first domain, the second domain, the third domain, the fourth domain, the fifth domain and the sixth domain each independently comprise:

[0927] i) a first polypeptide chain comprising a first N-terminus and a first C-terminus of the domain, and

[0928] ii) optionally a second polypeptide chain comprising a second N-terminus and a second C-terminus of the domain,

[0929] 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 joined to each other via a non-covalent bond between:

[0930] (1) a first trimerizing polypeptide connected to the first N-terminus of the first domain via a peptide bond or via a peptide linker,

[0931] (2) a second trimerizing polypeptide connected to the first N-terminus of the second domain via a peptide bond or via a peptide linker, and

[0932] (3) a third trimerizing polypeptide connected to the first N-terminus of the third domain via a peptide bond or via a peptide linker,

[0933] wherein the first trimerizing polypeptide, the second trimerizing polypeptide and the third trimerizing polypeptide are not immunoglobulin polypeptides,

[0934] c) the fourth domain is linked at its C-terminus via a peptide bond or via a peptide linker to:

[0935] i) the N-terminal end of the first trimerizing polypeptide, or

[0936] ii) the second N-terminus of the first domain, if present,

[0937] d) the fifth domain is linked at its C-terminus via a peptide bond or via a peptide linker to:

[0938] i) the N-terminus of the second trimerizing polypeptide, or

[0939] ii) the second N-terminus of the second domain, if present, and

[0940] e) the sixth domain is linked at its C-terminus via a peptide bond or via a peptide linker to:

[0941] i) the N-terminus of the third trimerizing polypeptide, or

[0942] ii) the second N-terminus of the third domain, if present.

[0943] In an embodiment of the octahedral molecule of the invention, in particular in any of the embodiments of the preceding paragraphs, the first trimerizing polypeptide, the second trimerizing polypeptide and the third trimerizing polypeptide are selected from the group consisting of the following TNF ligand superfamily members: 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, EctodyplasinATNFLSF19, TNF / TNFLSF2, lymphotoxin alpha / TNFLSF1 and lymphotoxin beta / TNFLSF3. In a preferred embodiment, the trimerizing polypeptide is selected from the group consisting of SEQ ID NOs: 787-790 (TNFSF1), SEQ ID NOs: 791-792 (TNFSF2), SEQ ID NOs: 793-795 (TNFSF3), SEQ ID NOs: 796-798 (TNFSF4), SEQ ID NOs: 799-802 (TNFSF5), SEQ ID NOs: 803-806, SEQ ID NOs: 807-809 (TNFSF7), SEQ ID NOs: 810-813 (TNFSF8), SEQ ID NOs: 814-816 (TNFSF9), SEQ ID NOs: 817-820 (TNFSF10), SEQ ID NOs: 821-822 (TNFSF11), SEQ ID NOs: 823-827 (TNFSF12), SEQ ID NOs: 828-831 (TNFSF13), SEQ ID NOs: 832-833 (TNFSF13B), SEQ ID NOs: 834-835 (TNFSF13C), SEQ ID NOs: 836-837 (TNFSF13D), SEQ ID NOs: 838-839 (TNFSF14), SEQ ID NOs: 840-841 (TNFSF14B), SEQ ID NOs: 842-843 (TNFSF14C), SEQ ID NOs: 844-845 (TNFSF14D), SEQ ID NOs: 845-846 (TNFSF14E), SEQ ID NOs: 847-848 (TNFSF14F), SEQ ID NOs: 849-850 (TNFSF14B), SEQ ID NOs: 851-852 NO:834-837 (TNFSF14), SEQ ID NO:838-841 (TNFSF15) and SEQ ID NO:842-843 (TNFSF18).

[0944] In an embodiment of the invention, in particular in any of the embodiments of the preceding two paragraphs, the octahedral molecule further comprises a seventh domain, an eighth domain and / or a ninth domain, wherein:

[0945] a) the seventh domain is linked at its C-terminus via a peptide bond or via a peptide linker to the second N-terminus of the first domain, if present,

[0946] b) the eighth domain is linked at its C-terminus via a peptide bond or via a peptide linker to the second N-terminus of the second domain, if present, and / or

[0947] c) the ninth domain is linked at its C-terminus via a peptide bond or via a peptide linker to the second N-terminus of the third domain, if present.

[0948] In an embodiment of the present invention, in particular in any of the embodiments of the preceding three paragraphs, the octahedral molecule further comprises a tenth domain, an eleventh domain and / or a twelfth domain, wherein:

[0949] a) The tenth domain is connected as follows:

[0950] i) is linked at its N-terminus to the C-terminus of the first domain via a peptide bond or via a peptide linker, or

[0951] ii) is linked at its C-terminus to the N-terminus of the fourth domain via a peptide bond or via a peptide linker,

[0952] b) The eleventh domain is linked as follows:

[0953] i) is linked at its N-terminus to the first C-terminus of the second domain via a peptide bond or via a peptide linker, or

[0954] ii) is linked at its C-terminus to the N-terminus of the fifth domain via a peptide bond or via a peptide linker,

[0955] c) The twelfth domain is connected as follows:

[0956] i) is linked at its N-terminus to the first C-terminus of the third domain via a peptide bond or via a peptide linker, or

[0957] ii) is linked at its C-terminus to the N-terminus of the sixth domain via a peptide bond or via a peptide linker.

[0958] In an embodiment, in particular, in any of the embodiments of the aforementioned four paragraphs, the first domain, the second domain and the third domain of the octahedral molecule of the present invention may be any of the first and second domains of the tetrahedral antibody or molecule of the present invention described herein, preferably not an Fc domain or a Fab domain. In an embodiment, the fourth domain, the fifth domain and the sixth domain of the octahedral molecule of the present invention may be any of the third and fourth domains of the tetrahedral antibody or molecule of the present invention described herein, preferably not an Fc domain or a Fab domain. In an embodiment, the seventh domain, the eighth domain and the ninth domain of the octahedral molecule of the present invention may be any of the fifth and sixth domains of the tetrahedral antibody or molecule of the present invention described herein. In an embodiment, the tenth domain, the eleventh domain and the twelfth domain of the octahedral molecule of the present invention may be any of the seventh and eighth domains of the tetrahedral antibody or molecule of the present invention or the ninth and tenth domains of the tetrahedral molecule of the present invention described herein. In addition, all such domains may include any of the features (e.g., mutations) described for the domains of the tetrahedral antibodies of the present invention.

[0959] In any embodiment of the octahedral molecule of the present invention, in particular any embodiment of the five preceding paragraphs, the first domain, the second domain and the third domain are not Fc domains or Fab domains. In any embodiment of the octahedral molecule of the present invention, in particular any embodiment of the five preceding paragraphs, the first domain, the second domain, the third domain, the fourth domain, the fifth domain and the sixth domain are not Fc domains or Fab domains.

[0960] In any embodiment of the octahedral molecule of the present invention, in particular any embodiment of the preceding six paragraphs,

[0961] a) the first domain, the second domain and / or the third domain are selected from the group consisting of (i) secretory proteins and (ii) extracellular domains of transmembrane proteins,

[0962] b) the fourth domain, the fifth domain and / or the sixth domain are selected from the group consisting of (i) an extracellular domain of a secretory protein and (ii) a transmembrane protein,

[0963] c) the first, second and third trimerizing polypeptides are selected from the group consisting of the following TNF ligand superfamily members: 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, EctodyplasinATNFLSF19, TNF / TNFLSF2, Lymphotoxin alpha / TNFLSF1 and Lymphotoxin beta / TNFLSF3;

[0964] d) the first trimerization polypeptide, the second trimerization polypeptide and the third trimerization polypeptide are selected from the group consisting of SEQ ID NO: 787-790 (TNFSF1), SEQ ID NO: 791-792 (TNFSF2), SEQ ID NO: 793-795 (TNFSF3), SEQ ID NO: 796-798 (TNFSF4), SEQ ID NO: 799-802 (TNFSF5), SEQ ID NO: 803-806, SEQ ID NO: 807-809 (TNFSF7), SEQ ID NO: 810-813 (TNFSF8), SEQ ID NO: 814-816 (TNFSF9), SEQ ID NO: 817-820 (TNFSF10), SEQ ID NO: 821-822 (TNFSF11), SEQ ID NO: 823-827 (TNFSF12), SEQ ID NO: 828-831 (TNFSF13), SEQ ID NO: 832-833 (TNFSF14), SEQ ID NO: 834-835 (TNFSF15), SEQ ID NO: 836-837 (TNFSF16), SEQ ID NO: 838-839 (TNFSF17), SEQ ID NO: 840-841 (TNFSF18), SEQ ID NO: 842-843 (TNFSF19), SEQ ID NO: 844-845 NO: 832-833 (TNFSF13B), SEQ ID NO: 834-837 (TNFSF14), SEQ ID NO: 838-841 (TNFSF15) and SEQ ID NO: 842-843 (TNFSF18);

[0965] e) the first trimerizing polypeptide, the second trimerizing polypeptide and the third trimerizing polypeptide are selected from the group consisting of the following TNF ligand superfamily members: OX40L / TNFLSF4, CD40L / TNFLSF5, FASL / TNFLSF6, CD70L / TNFLSF7, CD3 0L / TNFLSF8, 4-1BBL / TNFLSF9, TRAIL / TNFLSF10, RANKL / TNFLSF11, TWEAK / TNFLSF12, APRIL / TNFLSF13, BAFF / TNFLSF13B, LIGHT / TNFLSF14, VEGI / TNFLSF15, GITRL / TNFLSF18, EctodyplasinATNFLSF19, TNF / TNFLSF2, lymphotoxin α / TNFLSF1 and lymphotoxin β / TNFLSF3, and the first domain, the second domain and / or the third domain are transmembrane domains that are not naturally associated with the selected first trimerization polypeptide, the second trimerization polypeptide and the third trimerization polypeptide;

[0966] f) the first trimerizing polypeptide, the second trimerizing polypeptide and the third trimerizing polypeptide are selected from the group consisting of SEQ ID NOs: 787-790 (TNFSF1), SEQ ID NOs: 791-792 (TNFSF2), SEQ ID NOs: 793-795 (TNFSF3), SEQ ID NOs: 796-798 (TNFSF4), SEQ ID NOs: 799-802 (TNFSF5), SEQ ID NOs: 803-806, SEQ ID NOs: 807-809 (TNFSF7), SEQ ID NOs: 810-813 (TNFSF8), SEQ ID NOs: 814-816 (TNFSF9), SEQ ID NOs: 817-820 (TNFSF10), SEQ ID NOs: 821-822 (TNFSF11), SEQ ID NOs: 823-827 (TNFSF12), SEQ ID NOs: 828-831 (TNFSF13), SEQ ID NOs: 832-833 (TNFSF14), SEQ ID NOs: 834-835 (TNFSF15), SEQ ID NOs: 836-837 (TNFSF16), SEQ ID NOs: 838-839 (TNFSF17), SEQ ID NOs: 840-841 (TNFSF18), SEQ ID NOs: 842-843 (TNFSF19), SEQ ID NOs: 844-845 NO: 832-833 (TNFSF13B), SEQ ID NO: 834-837 (TNFSF14), SEQ ID NO: 838-841 (TNFSF15) and SEQ ID NO: 842-843 (TNFSF18), the first domain, the second domain and / or the third domain is a transmembrane domain that is non-naturally associated with the selected first trimerization polypeptide, the second trimerization polypeptide and the third trimerization polypeptide;

[0967] g) the first domain is selected from the group consisting of: a binding domain of a protein or a portion thereof or a modified form thereof, a secreted protein or a portion thereof or a modified form thereof, a transmembrane protein or a portion thereof or a modified form thereof, an intracellular binding domain or a portion thereof or a modified form thereof, and an antibody or a portion thereof or a modified form thereof;

[0968] h) the second domain is selected from the group consisting of: a binding domain of a protein or a portion thereof or a modified form thereof, a secreted protein or a portion thereof or a modified form thereof, a transmembrane protein or a portion thereof or a modified form thereof, an intracellular binding domain or a portion thereof or a modified form thereof, and an antibody or a portion thereof or a modified form thereof;

[0969] i) the third domain is selected from the group consisting of: a binding domain of a protein or a portion thereof or a modified form thereof, a secreted protein or a portion thereof or a modified form thereof, a transmembrane protein or a portion thereof or a modified form thereof, an intracellular binding domain or a portion thereof or a modified form thereof, and an antibody or a portion thereof or a modified form thereof;

[0970] j) the fourth domain is selected from the group consisting of: a binding domain of a protein or a portion thereof or a modified form thereof, a secreted protein or a portion thereof or a modified form thereof, a transmembrane protein or a portion thereof or a modified form thereof, an intracellular binding domain or a portion thereof or a modified form thereof, and an antibody or a portion thereof or a modified form thereof;

[0971] k) the fifth domain is selected from the group consisting of: a binding domain of a protein or a portion thereof or a modified form thereof, a secreted protein or a portion thereof or a modified form thereof, a transmembrane protein or a portion thereof or a modified form thereof, an intracellular binding domain or a portion thereof or a modified form thereof, and an antibody or a portion thereof or a modified form thereof;

[0972] l) the sixth domain is selected from the group consisting of: a binding domain of a protein or a portion thereof or a modified form thereof, a secreted protein or a portion thereof or a modified form thereof, a transmembrane protein or a portion thereof or a modified form thereof, an intracellular binding domain or a portion thereof or a modified form thereof, and an antibody or a portion thereof or a modified form thereof;

[0973] m) the seventh domain, if present, is selected from the group consisting of: a binding domain of a protein or a portion thereof or a modified form thereof, a secreted protein or a portion thereof or a modified form thereof, a transmembrane protein or a portion thereof or a modified form thereof, an intracellular binding domain or a portion thereof or a modified form thereof, and an antibody or a portion thereof or a modified form thereof;

[0974] n) the eighth domain, if present, is selected from the group consisting of a binding domain of a protein or a portion thereof or a modified form thereof, a secreted protein or a portion thereof or a modified form thereof, a transmembrane protein or a portion thereof or a modified form thereof, an intracellular binding domain or a portion thereof or a modified form thereof, and an antibody or a portion thereof or a modified form thereof;

[0975] o) the ninth domain, if present, is selected from the group consisting of a binding domain of a protein or a portion thereof or a modified form thereof, a secreted protein or a portion thereof or a modified form thereof, a transmembrane protein or a portion thereof or a modified form thereof, an intracellular binding domain or a portion thereof or a modified form thereof, and an antibody or a portion thereof or a modified form thereof;

[0976] p) a tenth domain, if present, selected from the group consisting of a binding domain of a protein or a portion thereof or a modified form thereof, a secreted protein or a portion thereof or a modified form thereof, a transmembrane protein or a portion thereof or a modified form thereof, an intracellular binding domain or a portion thereof or a modified form thereof, and an antibody or a portion thereof or a modified form thereof;

[0977] q) an eleventh domain, if present, is selected from the group consisting of a binding domain of a protein or a portion thereof or a modified form thereof, a secreted protein or a portion thereof or a modified form thereof, a transmembrane protein or a portion thereof or a modified form thereof, an intracellular binding domain or a portion thereof or a modified form thereof, and an antibody or a portion thereof or a modified form thereof;

[0978] r) a twelfth domain, if present, selected from the group consisting of a binding domain of a protein or a portion thereof or a modified form thereof, a secreted protein or a portion thereof or a modified form thereof, a transmembrane protein or a portion thereof or a modified form thereof, an intracellular binding domain or a portion thereof or a modified form thereof, and an antibody or a portion thereof or a modified form thereof;

[0979] s) the first domain is not any of the following: a binding domain of a protein or a portion thereof or a modified form thereof, a secreted protein or a portion thereof or a modified form thereof, a transmembrane protein or a portion thereof or a modified form thereof, an intracellular binding domain or a portion thereof or a modified form thereof, and an antibody or a portion thereof or a modified form thereof;

[0980] t) the second domain is not any of the following: a binding domain of a protein or a portion thereof or a modified form thereof, a secreted protein or a portion thereof or a modified form thereof, a transmembrane protein or a portion thereof or a modified form thereof, an intracellular binding domain or a portion thereof or a modified form thereof, and an antibody or a portion thereof or a modified form thereof;

[0981] u) the third domain is not any of the following: a binding domain of a protein or a portion thereof or a modified form thereof, a secreted protein or a portion thereof or a modified form thereof, a transmembrane protein or a portion thereof or a modified form thereof, an intracellular binding domain or a portion thereof or a modified form thereof, and an antibody or a portion thereof or a modified form thereof;

[0982] v) the fourth domain is not any of the following: a binding domain of a protein or a portion thereof or a modified form thereof, a secreted protein or a portion thereof or a modified form thereof, a transmembrane protein or a portion thereof or a modified form thereof, an intracellular binding domain or a portion thereof or a modified form thereof, and an antibody or a portion thereof or a modified form thereof;

[0983] w) the fifth domain is not any of the following: a binding domain of a protein or a portion thereof or a modified form thereof, a secreted protein or a portion thereof or a modified form thereof, a transmembrane protein or a portion thereof or a modified form thereof, an intracellular binding domain or a portion thereof or a modified form thereof, and an antibody or a portion thereof or a modified form thereof;

[0984] x) the sixth domain is not any of the following: a binding domain of a protein or a portion thereof or a modified form thereof, a secreted protein or a portion thereof or a modified form thereof, a transmembrane protein or a portion thereof or a modified form thereof, an intracellular binding domain or a portion thereof or a modified form thereof, and an antibody or a portion thereof or a modified form thereof;

[0985] y) the seventh domain, if present, is not any of the following: a binding domain of a protein or a portion thereof or a modified form thereof, a secreted protein or a portion thereof or a modified form thereof, a transmembrane protein or a portion thereof or a modified form thereof, an intracellular binding domain or a portion thereof or a modified form thereof, and an antibody or a portion thereof or a modified form thereof;

[0986] z) the eighth domain, if present, is not any of the following: a binding domain of a protein or a portion thereof or a modified form thereof, a secreted protein or a portion thereof or a modified form thereof, a transmembrane protein or a portion thereof or a modified form thereof, an intracellular binding domain or a portion thereof or a modified form thereof, and an antibody or a portion thereof or a modified form thereof;

[0987] aa) the ninth domain, if present, is not any of the following: a binding domain of a protein or a portion thereof or a modified form thereof, a secreted protein or a portion thereof or a modified form thereof, a transmembrane protein or a portion thereof or a modified form thereof, an intracellular binding domain or a portion thereof or a modified form thereof, and an antibody or a portion thereof or a modified form thereof;

[0988] bb) the tenth domain, if present, is not any of the following: a binding domain of a protein or a portion thereof or a modified form thereof, a secreted protein or a portion thereof or a modified form thereof, a transmembrane protein or a portion thereof or a modified form thereof, an intracellular binding domain or a portion thereof or a modified form thereof, and an antibody or a portion thereof or a modified form thereof;

[0989] cc) the eleventh domain, if present, is not any of the following: a binding domain of a protein or a portion thereof or a modified form thereof, a secreted protein or a portion thereof or a modified form thereof, a transmembrane protein or a portion thereof or a modified form thereof, an intracellular binding domain or a portion thereof or a modified form thereof, and an antibody or a portion thereof or a modified form thereof;

[0990] dd) the twelfth domain, if present, is not any of the following: a binding domain of a protein or a portion thereof or a modified form thereof, a secreted protein or a portion thereof or a modified form thereof, a transmembrane protein or a portion thereof or a modified form thereof, an intracellular binding domain or a portion thereof or a modified form thereof, and an antibody or a portion thereof or a modified form thereof;

[0991] ee) the first domain, the second domain, the third domain, the fourth domain, the fifth domain and / or the sixth domain are CD3 ζ chain intracellular binding domain, CD28 intracellular binding domain or 4-1BB intracellular binding domain, CD3 ε chain intracellular binding domain, ICOS intracellular binding domain, OX40 intracellular binding domain or 4-1BB intracellular binding domain;

[0992] ff) the tenth domain, the eleventh domain and / or the twelfth domain, if present, is a CD3 ζ chain intracellular binding domain, a CD28 intracellular binding domain or a 4-1BB intracellular binding domain, a CD3 ε chain intracellular binding domain, an ICOS intracellular binding domain, an OX40 intracellular binding domain or a 4-1BB intracellular binding domain;

[0993] gg) the octahedral molecule comprises a first domain, a second domain, a third domain, a fourth domain, a fifth domain, a sixth domain, a tenth domain, an eleventh domain and a twelfth domain, and:

[0994] i) the fourth domain, the fifth domain and the sixth domain are each a binding domain of a protein or a portion thereof or a modified form thereof, preferably a binding domain of a secretory protein, an extracellular domain of a transmembrane protein, or an antibody or a portion thereof, more preferably a single chain portion of an antibody, more preferably a single chain or single domain antibody molecule, more preferably a scFv domain;

[0995] ii) the first domain, the second domain and the third domain 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, collection protein, 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; and

[0996] iii) the tenth domain, the eleventh domain and the twelfth domain are each connected to the C-terminus of the first domain, the second domain and the third domain at the N-terminus, respectively, and each is an intracellular binding domain, preferably an intracellular binding domain of CD3ζ chain, CD3ε chain, CD28, ICOS, OX40 or 4-1BB;

[0997] hh) the octahedral molecule comprises a first domain, a second domain, a third domain, a fourth domain, a fifth domain, a sixth domain, a tenth domain, an eleventh domain and a twelfth domain, the fourth domain, the fifth domain and the sixth domain are each a scFv domain, the first domain, the second domain and the third domain are each a transmembrane domain of ACE2, collection protein, CD8a, CD8b, CD3ζ, CD3ε, CD28, ICOS, OX40 or 4-1BB, the tenth domain, the eleventh domain and the twelfth domain are each connected at the N-terminus to the C-terminus of the first domain, the second domain and the third domain, respectively, and are each an intracellular binding domain of CD3ζ chain, CD3ε chain, CD28, ICOS, OX40 or 4-1BB;

[0998] ii) the octahedral molecule comprises a first domain, a second domain, a third domain, a fourth domain, a fifth domain, a sixth domain, a tenth domain, an eleventh domain and a twelfth domain, and:

[0999] i) the tenth domain, the eleventh domain and the twelfth domain are each connected at the C-terminus to the N-terminus of the fourth domain, the fifth domain and the sixth domain, respectively, and each is a binding domain of a protein or a portion thereof or a modified form thereof, preferably a binding domain of a secretory protein, an extracellular domain of a transmembrane protein or an antibody or a portion thereof, more preferably a single chain portion of an antibody, more preferably a single chain or single domain antibody molecule, more preferably an scFv domain;

[1000] ii) the fourth domain, the fifth domain and the sixth domain are each a transmembrane domain, preferably a transmembrane domain of TNFSF1, TNFSF2, TNFSF3, TNFSF4, TNFSF5, TNFSF6, TNFSF7, TNFSF8, TNFSF9, TNFSF10, TNFSF11, TNFSF12, TNFSF13, TNFSF13B, TNFSF14, TNFSF15 or TNFSF18, more preferably a transmembrane domain of ACE2, collection protein, CD8a, CD8b, CD3ζ, CD3ε, 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; and

[1001] iii) the first domain, the second domain and the third domain are each an intracellular binding domain, preferably an intracellular binding domain of CD3ζ chain, CD3ε chain, CD28, ICOS, OX40 or 4-1BB; or

[1002] jj) the octahedral molecule comprises a first domain, a second domain, a third domain, a fourth domain, a fifth domain, a sixth domain, a tenth domain, an eleventh domain and a twelfth domain, the tenth domain, the eleventh domain and the twelfth domain are each connected at the C-terminus to the N-terminus of the fourth domain, the fifth domain and the sixth domain, respectively, and each is a scFv domain, the fourth domain, the fifth domain and the sixth domain are each a transmembrane domain of ACE2, collection protein, CD8a, CD8b, CD3ζ, CD3ε, CD28, ICOS, OX40 or 4-1BB, and the first domain, the second domain and the third domain are each an intracellular binding domain of CD3ζ chain, CD3ε chain, CD28, ICOS, OX40 or 4-1BB;

[1003] kk) the octahedral molecule comprises a first domain, a second domain, a third domain, a fourth domain, a fifth domain, a sixth domain, a tenth domain, an eleventh domain and a twelfth domain, and:

[1004] i) the fourth domain, the fifth domain and the sixth domain are each a binding domain of a protein or a portion thereof or a modified form thereof, preferably a binding domain of a secretory protein, an extracellular domain of a transmembrane protein or an antibody or a portion thereof, more preferably a single chain portion of an antibody, more preferably a single chain or single domain antibody molecule, more preferably a scFv domain;

[1005] ii) the first domain, the second domain and the third domain 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, collection protein, 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; and

[1006] iii) the tenth domain, the eleventh domain, and the twelfth domain are each connected at the N-terminus to the C-terminus of the first domain, the second domain, and the third domain, respectively, and each is an antigen or a neo-antigen;

[1007] 11) the octahedral molecule comprises a first domain, a second domain, a third domain, a fourth domain, a fifth domain, a sixth domain, a tenth domain, an eleventh domain and a twelfth domain, the fourth domain, the fifth domain and the sixth domain are each a scFv domain, the first domain, the second domain and the third domain are each a transmembrane domain of ACE2, collection protein, CD8a, CD8b, CD3ζ, CD3ε, CD28, ICOS, OX40 or 4-1BB, the tenth domain, the eleventh domain and the twelveth domain are each connected to the C-terminus of the first domain, the second domain and the third domain at the N-terminus, respectively, and each is an antigen or a neoantigen;

[1008] mm) the octahedral molecule comprises a first domain, a second domain, a third domain, a fourth domain, a fifth domain, a sixth domain, a tenth domain, an eleventh domain and a twelfth domain, and:

[1009] i) the tenth domain, the eleventh domain and the twelfth domain are each connected at the C-terminus to the N-terminus of the fourth domain, the fifth domain and the sixth domain, respectively, and each is a binding domain of a protein or a portion thereof or a modified form thereof, preferably a binding domain of a secretory protein, an extracellular domain of a transmembrane protein or an antibody or a portion thereof, more preferably a single chain portion of an antibody, more preferably a single chain or single domain antibody molecule, more preferably an scFv domain;

[1010] ii) the fourth domain, the fifth domain and the sixth domain are respectively transmembrane domains, preferably the transmembrane domains of TNFSF1, TNFSF2, TNFSF3, TNFSF4, TNFSF5, TNFSF6, TNFSF7, TNFSF8, TNFSF9, TNFSF10, TNFSF11, TNFSF12, TNFSF13, TNFSF13B, TNFSF14, TNFSF15 or TNFSF18, more preferably the transmembrane domains of ACE2, collection protein, CD8a, CD8b, CD3ζ, CD3ε, 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; and

[1011] iii) the first domain, the second domain and the third domain are each an antigen or a neoantigen; or

[1012] nn) The octahedral molecule includes a first domain, a second domain, a third domain, a fourth domain, a fifth domain, a sixth domain, a tenth domain, an eleventh domain and a twelfth domain, the tenth domain, the eleventh domain and the twelfth domain are each connected at the C-terminus to the N-terminus of the fourth domain, the fifth domain and the sixth domain, respectively, and each is a scFv domain, the fourth domain, the fifth domain and the sixth domain are each a transmembrane domain of ACE2, collection protein, CD8a, CD8b, CD3ζ, CD3ε, CD28, ICOS, OX40 or 4-1BB, and the first domain, the second domain and the third domain are each an antigen or a neo-antigen.

[1013] In embodiments of the invention comprising a transmembrane domain as the first domain, the second domain and the third domain, preferably the octahedral molecule comprises a first trimerizing polypeptide, a second trimerizing polypeptide and a third trimerizing polypeptide that are naturally associated with the transmembrane domain. For example, if the first domain, the second domain and the third domain are the transmembrane domain of TNFSF1, the first trimerizing polypeptide, the second trimerizing polypeptide and the third trimerizing polypeptide are the extracellular domains of TNFSF1.

[1014] In a preferred embodiment of any embodiment of the octahedral molecule of the present invention, in particular in any embodiment of the aforementioned eight paragraphs, the first domain, the second domain and the third domain are each a transmembrane domain. Alternatively, in a preferred embodiment of any embodiment of the octahedral molecule of the present invention, in particular in any embodiment of the aforementioned seven paragraphs, the fourth domain, the fifth domain and the sixth domain are each a transmembrane domain.

[1015] Tetrahedral and octahedral antibodies or molecules

[1016] In an embodiment of the present invention:

[1017] a) one or more of the first, second, third, fourth, fifth, sixth, seventh and eighth domains of the 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 the octahedral antibody or molecule is an Fc domain, wherein one or more of the Fc domains are independently selected from any one of the Fc domains disclosed herein,

[1018] b) one or more of the first, second, third, fourth, fifth, sixth, seventh and eighth domains of the tetrahedral antibody or molecule, or one or more of the first, second, third, fourth, fifth, sixth, seventh and eighth, ninth, tenth, eleventh and twelfth domains of the octahedral antibody or molecule is a Fab domain, wherein one or more of the Fab domains are independently selected from any one of the Fab domains disclosed herein,

[1019] c) one or more of the third domain, the fourth domain, the fifth domain, the sixth domain, the seventh domain, and the eighth domain of the tetrahedral antibody or molecule, or one or more of the fourth domain, the fifth domain, the sixth domain, the seventh domain, the eighth domain, the ninth domain, the tenth domain, the eleventh domain, and the twelfth domain of the octahedral antibody or molecule is a secreted protein, wherein the one or more secreted proteins are independently selected from any secreted protein disclosed herein,

[1020] d) one or more of the third domain, the fourth domain, the fifth domain, the sixth domain, the seventh domain and the eighth domain of the tetrahedral antibody or molecule, or one or more of the fourth domain, the fifth domain, the sixth domain, the seventh domain, the eighth domain, the ninth domain, the tenth domain, the eleventh domain and the twelfth domain of the octahedral antibody or molecule is an extracellular domain of a transmembrane protein, wherein the extracellular domains of the one or more transmembrane proteins are independently selected from any extracellular domain of the transmembrane proteins disclosed herein,

[1021] e) one or more of the third, fourth, fifth, sixth, seventh and eighth domains of a tetrahedral antibody or molecule, or one or more of the fourth, fifth, sixth, seventh and eighth, ninth, tenth, eleventh and twelfth domains of an octahedral antibody or molecule:

[1022] i) includes the structure of a compound that is a drug approved for treating an individual suffering from a disease,

[1023] ii) a structure comprising an organic compound with a molecular weight of less than 1000 Dalton, a DNA aptamer, an RNA aptamer, an oligonucleotide or a protein with biological activity,

[1024] iii) comprises a primary or secondary amine,

[1025] iv) is aripiprazole or oseltamivir,

[1026] v) is a respiratory drug, an antiasthmatic, analgesic, antidepressant, antianginal, antiarrhythmic, antihypertensive, antidiabetic, antihistamine, anti-infective, antibiotic, anti-inflammatory, anti-Parkinson's disease drug, antipsychotic, antipyretic, anti-ulcer, attention deficit hyperactivity disorder (ADHD) drug, central nervous system stimulant, decongestant or psychostimulant,

[1027] vi) alprenolol, acebutolol, amidephrine, amineptine, amosulalol, amoxapine, amphetamine, atenolol, atomoxetine, balofloxacin, bamethan, befunolol, benazepril, benfluorex, benzotamine benzoctamine, betahistine, betaxolol, bevantolol, bifemelane, bisoprolol, brinzolamide, bufeniode, butethamine, camylofine, carazolol, carticaine, carvedilol, cephaeline, ciprofloxacin ofloxacin, cloZapine, clobenZorex, clorprenaline, cyclopentamine, delapril, demexiptiline, denopamine, desipramine, desloratadine, diclofenac, dimetofrine, dioxadrol, dobutamine, dopexamine, doripenem, dorzolamide, droprenilamine, duloxetine, eltopraZine, enalapril, enoxacin, epinephrine, ertapenem, esapraZole, esmolol, etoxadrol, fasudil, fendiline,Fenethylline, fenfluramine, fenoldopam, fenoterol, fenproporex, flecamide, fluoxetine, formoterol, frovatriptan, gaboxadol, garenoxacin, gatifloxacin, grepafloxacin, hexoprenaline, imidapril, indalpine, indecainide, indeloxazine hydrochloride hydrochloride), isoxsuprine, ispronicline, labetalol, landiolol, lapatinib, levophacetoperane, lisinopril, lomefloxacin, lotrafiban, maprotiline, mecamylamine, mefloquine, mepindolol, meropenem, metapramine, metaproterenol, methoxyphenamine, dextrorotary methylphenidate, methylphenidate, metipranolol, metoprolol, mitoxantrone, mivazerol, moexipril, moprolol, moxifloxacin, nebivolol, nifenalol, nipradilol, norfloxacin, nortriptyline, nylidrin, olanZapine, oxamniquine, oxprenolol, oxyfedrine,paroxetine, perhexyline, phenmetrazine, phenylephrine, phenylpropylmethylamine, pholedrine, picilorex, pimethylline, pindolol, pipemidicacid, piridocaine, practolol, pradofloxacin, pramipexole, pramiverin, prenalterol, prenylamine, prilocalne, procaterol, pronethalol, propafenone, propranolol, propylhexedrine, protokylol, protriptyline, pseudoephedrine, reboxetine tine), rasagiline, (r)-rasagiline, repinotan, reproterol, rimiterol, ritodrine, safinamide, salbutamol / albuterol, salmeterol, sarizotan, sertraline, silodosin, sotalol, soterol enol), sparfloxacin, spirapril, sulfinalol, synephrine, tamsulosin, tebanicline, tianeptine, tirofiban, tretoquinol, trimetazidine, troxipide, varenicline, vildagliptin, viloxazine,viquidil or xamoterol;

[1028] vii) contains biologically active proteins,

[1029] viii) having biological activity such that it has target binding activity,

[1030] ix) is an independently folded protein or a portion thereof,

[1031] x) is a glycosylated protein,

[1032] xi) includes intrachain disulfide bonds,

[1033] xii) binding to cytokines,

[1034] xiii) binding to a cytokine, wherein the cytokine is TNFα,

[1035] xiv) includes atrial natriuretic peptide (ANP), calcitonin, corticotropin-releasing hormone (CRH), endothelin, exenatide, gastric inhibitory peptide (GIP), glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 (GLP-2), GLP-1 or GLP-2 analogs, glucagon vasoactive intestinal polypeptide (GVIP), ghrelin, peptide YY or secretin or a portion thereof,

[1036] xv) comprising a stretch of consecutive amino acids in the sequence HGEGTFTSDVSSYLEEQAAKEFLAWLVKGRG (SEQ ID NO: 4657),

[1037] xvi) comprises at least one stretch of consecutive amino acids that is identical to a stretch of consecutive amino acids present in the heavy chain of Fab or Fab' of an antibody,

[1038] xvii) comprises at least one continuous stretch of amino acids that is identical to a continuous stretch of amino acids present in the light chain of Fab or Fab' of an antibody,

[1039] xviii) comprises at least one Fab or Fab' or at least a portion of a Fab or Fab' of an antibody,

[1040] xix) comprising Fab-1 or Fab'1 of an antibody or a portion thereof,

[1041] xx) comprises Fab-2 or Fab'2 of an antibody or a portion thereof,

[1042] xxi) comprises two Fab or Fab' hands of an antibody,

[1043] xxii) comprises at least one stretch of consecutive amino acids that is identical to a stretch of consecutive amino acids present in a single-chain antibody, or

[1044] xxiii) comprises at least one consecutive stretch of amino acids which is identical to a consecutive stretch of amino acids present in TNFα receptor.

[1045] f) the tetrahedral antibody or the octahedral antibody comprises a covalent linkage, wherein the covalent linkage is selected from any covalent linkage disclosed herein or comprises any heterobifunctional crosslinker disclosed herein, and / or

[1046] g) the tetrahedral antibody or octahedral antibody or molecule comprises more than one peptide linker, wherein the more than one peptide linker is independently selected from:

[1047] i) as the sequence TSTSPTRSMAGAVHLPQPVSTRSQHTQPTPEPSTAPSTSFLLPMGPSPPAEGSTGD (SEQ ID NO: 3227) or a stretch of consecutive amino acids present in said sequence,

[1048] ii) as the sequence GGGGAGGGGAGGGGAGGGGAGGGGAGGG (SEQ ID NO: 3226) or a stretch of consecutive amino acids present in said sequence, or

[1049] iii) any peptide linker disclosed herein.

[1050] Figures 1 to 14 and FIG. 29A to FIG. 42 Various non-limiting examples of tetrahedral antibodies and octahedral antibodies of the present invention are schematically described. Descriptions of various types of domains of these tetrahedral antibodies and octahedral antibodies (such as represented by ellipses or ellipse groups of various colors and / or patterns) are provided in the brief description of the drawings. Each figure represents an embodiment of the present invention. In addition, the examples of the present application provide specific tetrahedral antibodies, and each antibody is an embodiment of the present invention. The present invention contemplates the production of each variant of these specific tetrahedral antibodies. Specifically, in the case where the tetrahedral antibodies disclosed in the examples include mutants or modified sequences, the present invention particularly contemplates the substitution of mutants or modified sequences with wild-type sequences. Conversely, the present invention particularly contemplates the substitution of wild-type sequences (if present) with mutant counterpart sequences (mutant counterpart sequences) comprising any relevant mutation described herein to modify any tetrahedral antibody.

[1051] The present invention also provides a composition comprising 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%, 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 %, 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% of the tetrahedral antibody or octahedral antibody of the present invention as the ratio (w / w) of the peptide-containing molecules in the composition.

[1052] Preparation method

[1053] The present invention also provides a method for preparing a tetrahedral antibody comprising four domains of the present invention, wherein the non-peptidyl linkage of the tetrahedral antibody is a non-covalent linkage between a first dimerization polypeptide linked to a first N-terminus of the first domain and a second dimerization polypeptide linked to a first N-terminus of the second domain, the method comprising:

[1054] a) recombinantly expressing in a host cell each of the following polypeptides:

[1055] i) a first polypeptide comprising, from its N-terminus to its C-terminus,

[1056] (1) Optionally, a third domain, the third domain is connected at its C-terminus via a peptide bond or via a peptide linker

[1057] (2) the N-terminus of the first dimerization polypeptide, the first dimerization polypeptide is connected to the

[1058] (3) the N-terminus of the first polypeptide chain of the first domain,

[1059] ii) a second polypeptide, the second polypeptide comprising, from its N-terminus to its C-terminus,

[1060] (1) Optionally, the fourth domain is connected at its C-terminus to

[1061] (2) the N-terminus of the second dimerization polypeptide, the second dimerization polypeptide is connected to the N-terminus of the second dimerization polypeptide via a peptide bond or a peptide linker

[1062] (3) the N-terminus of the first polypeptide chain of the second domain,

[1063] iii) a third polypeptide, the third polypeptide comprising, from its N-terminus to its C-terminus,

[1064] (1) The third domain, if not present on the first polypeptide, is linked at its C-terminus via a peptide bond or via a peptide linker to the

[1065] a. the N-terminus of the third dimerization polypeptide, the third dimerization polypeptide is connected at its C-terminus to the N-terminus of the second polypeptide chain of the first domain by a peptide bond or by a peptide linker, or

[1066] b. the N-terminus of the second polypeptide chain of the first domain,

[1067] iv) a fourth polypeptide, the fourth polypeptide comprising, from its N-terminus to its C-terminus,

[1068] (1) The fourth domain, if not present on the second polypeptide, is linked at its C-terminus via a peptide bond or via a peptide linker to the

[1069] a. the N-terminus of the fourth dimerization polypeptide, the fourth dimerization polypeptide is connected at its C-terminus to the N-terminus of the second polypeptide chain of the first domain by a peptide bond or by a peptide linker, or

[1070] b. the N-terminus of the second polypeptide chain of the first domain, and

[1071] v) optionally, one or more additional polypeptides comprising the second polypeptide chain of the third domain and / or the fourth domain, if the second polypeptide chain is present.

[1072] The present invention also provides a method for preparing a tetrahedral antibody comprising four domains of the present invention, wherein the non-peptidyl linkage of the tetrahedral antibody is a non-covalent linkage between a first dimerization polypeptide linked to a first C-terminus of the first domain and a second dimerization polypeptide linked to a first N-terminus of the second domain, the method comprising:

[1073] a) recombinantly expressing in a host cell each of the following polypeptides:

[1074] i) a first polypeptide, the first polypeptide comprising, from its N-terminus to its C-terminus,

[1075] (1) a first polypeptide chain of the first domain, the first polypeptide chain being connected at its C-terminus via a peptide bond or via a peptide linker

[1076] (2) the N-terminus of the first dimerization polypeptide, the first dimerization polypeptide is optionally connected to the C-terminus of the first dimerization polypeptide via a peptide bond or a peptide linker

[1077] (3) N-terminus of the third domain,

[1078] ii) a second polypeptide, the second polypeptide comprising, from its N-terminus to its C-terminus,

[1079] (1) Optionally, the fourth domain is connected at its C-terminus to

[1080] (2) the N-terminus of the second dimerization polypeptide, the second dimerization polypeptide is connected to the N-terminus of the second dimerization polypeptide via a peptide bond or a peptide linker

[1081] (3) the N-terminus of the first polypeptide chain of the second domain,

[1082] iii) a third polypeptide, the third polypeptide comprising, from its N-terminus to its C-terminus,

[1083] (1) a second polypeptide chain of the first domain, the second polypeptide chain being connected at its C-terminus via a peptide bond or via a peptide linker

[1084] a. the N-terminus of the third dimerization polypeptide, if the third dimerization polypeptide is not present on the first polypeptide, the third dimerization polypeptide is linked to the N-terminus of the third domain at its C-terminus by a peptide bond or by a peptide linker, or

[1085] b. the N-terminus of the third domain, if the third domain is not present on the first polypeptide,

[1086] iv) a fourth polypeptide, the fourth polypeptide comprising, from its N-terminus to its C-terminus,

[1087] (1) The fourth domain, if not present on the second polypeptide, is linked at its C-terminus via a peptide bond or via a peptide linker to the

[1088] a. the N-terminus of the fourth dimerization polypeptide, which is in turn connected at its C-terminus to the N-terminus of the second polypeptide chain of the first domain via a peptide bond or via a peptide linker, or

[1089] b. the N-terminus of the second polypeptide chain of the first domain, and

[1090] v) optionally, one or more additional polypeptides comprising the second polypeptide chain of the third domain and / or the fourth domain, if present.

[1091] The present invention also provides a method for preparing a tetrahedral antibody comprising four domains of the present invention, wherein the non-peptidyl linkage of the tetrahedral antibody is a non-covalent linkage between a first dimerization polypeptide linked to a first N-terminus of the first domain and a second dimerization polypeptide linked to a first C-terminus of the second domain, the method comprising:

[1092] a) recombinantly expressing in a host cell each of the following polypeptides:

[1093] i) a first polypeptide, the first polypeptide comprising, from its N-terminus to its C-terminus,

[1094] (1) Optionally, a third domain, the third domain is connected at its C-terminus via a peptide bond or via a peptide linker

[1095] (2) the N-terminus of the first dimerization polypeptide, the first dimerization polypeptide is connected to the

[1096] (3) the N-terminus of the first polypeptide chain of the first domain,

[1097] ii) a second polypeptide, the second polypeptide comprising, from its N-terminus to its C-terminus,

[1098] (1) a first polypeptide chain of the second domain, the first polypeptide chain being connected at its C-terminus via a peptide bond or via a peptide linker

[1099] (2) the N-terminus of a second dimerization polypeptide, which is optionally linked at its C-terminus to the

[1100] (3) N-terminus of the third domain,

[1101] iii) a third polypeptide, the third polypeptide comprising, from its N-terminus to its C-terminus,

[1102] (1) The third domain, if not present on the first polypeptide, is linked at its C-terminus via a peptide bond or via a peptide linker to the

[1103] a. the N-terminus of the third dimerization polypeptide, which is in turn connected at its C-terminus to the N-terminus of the second polypeptide chain of the first domain via a peptide bond or via a peptide linker, or

[1104] b. the N-terminus of the second polypeptide chain of the first domain,

[1105] iv) a fourth polypeptide, the fourth polypeptide comprising, from its N-terminus to its C-terminus,

[1106] (1) a second polypeptide chain of the first domain, the second polypeptide chain being connected at its C-terminus via a peptide bond or via a peptide linker

[1107] a. the N-terminus of the fourth dimerization polypeptide, if the fourth dimerization polypeptide is not present on the second polypeptide, the fourth dimerization polypeptide is linked to the N-terminus of the fourth domain at its C-terminus by a peptide bond or by a peptide linker; or

[1108] b. the N-terminus of the fourth domain, if the fourth domain is not present on the second polypeptide, and

[1109] v) optionally, one or more additional polypeptides comprising the second polypeptide chain of the third domain and / or the fourth domain, if present.

[1110] The present invention also provides a method for preparing a tetrahedral antibody comprising four domains of the present invention, wherein the non-peptidyl linkage of the tetrahedral antibody is a non-covalent linkage between a first dimerization polypeptide linked to the first C-terminus of the first domain and a second dimerization polypeptide linked to the first C-terminus of the second domain, the method comprising:

[1111] a) recombinantly expressing in a host cell each of the following polypeptides:

[1112] i) a first polypeptide, the first polypeptide comprising, from its N-terminus to its C-terminus,

[1113] (1) a first polypeptide chain of the first domain, the first polypeptide chain being connected at its C-terminus via a peptide bond or via a peptide linker

[1114] (2) the N-terminus of the first dimerization polypeptide, which is optionally linked at its C-terminus to the

[1115] (3) N-terminus of the third domain,

[1116] ii) a second polypeptide, the second polypeptide comprising, from its N-terminus to its C-terminus,

[1117] (1) a first polypeptide chain of the second domain, the first polypeptide chain being connected at its C-terminus via a peptide bond or via a peptide linker

[1118] (2) the N-terminus of a second dimerization polypeptide, which is optionally linked at its C-terminus to the

[1119] (3) N-terminus of the third domain,

[1120] iii) a third polypeptide, the third polypeptide comprising, from its N-terminus to its C-terminus,

[1121] (1) a second polypeptide chain of the first domain, the second polypeptide chain being connected at its C-terminus via a peptide bond or via a peptide linker

[1122] a. the N-terminus of the third dimerization polypeptide, if the third dimerization polypeptide is not present on the first polypeptide, the third dimerization polypeptide is linked to the N-terminus of the third domain at its C-terminus by a peptide bond or by a peptide linker, or

[1123] b. the N-terminus of the third domain, if the third domain is not present on the first polypeptide,

[1124] iv) a fourth polypeptide, the fourth polypeptide comprising, from its N-terminus to its C-terminus,

[1125] (1) a second polypeptide chain of the first domain, the second polypeptide chain being connected at its C-terminus via a peptide bond or via a peptide linker

[1126] a. the N-terminus of the fourth dimerization polypeptide, if the fourth dimerization polypeptide is not present on the second polypeptide, the fourth dimerization polypeptide is connected to the N-terminus of the fourth domain at its C-terminus by a peptide bond or by a peptide linker; or

[1127] b. the N-terminus of the fourth domain, if the fourth domain is not present on the second polypeptide, and

[1128] v) optionally one or more additional polypeptides comprising the second polypeptide chain of the third domain and / or the fourth domain, if present.

[1129] The present invention also provides a method for preparing a tetrahedral antibody comprising a fifth domain and / or a sixth domain of the present invention, wherein the non-peptidyl linkage of the tetrahedral antibody is a non-covalent linkage between a first dimerization polypeptide linked to a first N-terminus of the first domain and a second dimerization polypeptide linked to a first N-terminus of the second domain, the method comprising:

[1130] a) recombinantly expressing in a host cell each of the following polypeptides:

[1131] i) a first polypeptide, the first polypeptide comprising, from its N-terminus to its C-terminus,

[1132] (1) the third domain, or the fifth domain, if present, is linked at its C-terminus to

[1133] (2) the N-terminus of the first dimerization polypeptide, the first dimerization polypeptide is connected to the

[1134] (3) the N-terminus of the first polypeptide chain of the first domain,

[1135] ii) a second polypeptide, the second polypeptide comprising, from its N-terminus to its C-terminus,

[1136] (1) the fourth domain, or the sixth domain, if present, is linked at its C-terminus to

[1137] (2) the N-terminus of the second dimerization polypeptide, the second dimerization polypeptide is connected to the N-terminus of the second dimerization polypeptide via a peptide bond or a peptide linker

[1138] (3) the N-terminus of the first polypeptide chain of the second domain,

[1139] iii) a third polypeptide, the third polypeptide comprising, from its N-terminus to its C-terminus,

[1140] (1) the third domain, if the third domain is not present on the first polypeptide, or the fifth domain, if the fifth domain is present, the third domain or the fifth domain is linked at its C-terminus to

[1141] a. the N-terminus of the third dimerization polypeptide, which is in turn connected at its C-terminus to the N-terminus of the second polypeptide chain of the first domain via a peptide bond or via a peptide linker, or

[1142] b. the N-terminus of the second polypeptide chain of the first domain,

[1143] iv) a fourth polypeptide, the fourth polypeptide comprising, from its N-terminus to its C-terminus,

[1144] (1) the fourth domain, if the fourth domain is not present on the second polypeptide, or the sixth domain, if the sixth domain is present, the fourth domain or the sixth domain is linked at its C-terminus to the

[1145] a. the N-terminus of the fourth dimerization polypeptide, which is in turn connected at its C-terminus to the N-terminus of the second polypeptide chain of the first domain via a peptide bond or via a peptide linker, or

[1146] b. the N-terminus of the second polypeptide chain of the first domain, and

[1147] v) optionally, one or more additional polypeptides comprising the second polypeptide chain of the third, fourth, fifth and / or sixth domain, if present.

[1148] The present invention also provides a method for preparing a tetrahedral antibody comprising a fifth domain and / or a sixth domain of the present invention, wherein the non-peptidyl linkage of the tetrahedral antibody is a non-covalent linkage between a first dimerization polypeptide linked to a first C-terminus of the first domain and a second dimerization polypeptide linked to a first N-terminus of the second domain, the method comprising:

[1149] a) recombinantly expressing in a host cell each of the following polypeptides:

[1150] i) a first polypeptide, the first polypeptide comprising, from its N-terminus to its C-terminus,

[1151] (1) a first polypeptide chain of the first domain, the first polypeptide chain being connected at its C-terminus via a peptide bond or via a peptide linker

[1152] (2) the N-terminus of the first dimerization polypeptide, the first dimerization polypeptide is connected to the

[1153] (3) the N-terminus of the third domain, or the N-terminus of the fifth domain, if the fifth domain is present,

[1154] ii) a second polypeptide, the second polypeptide comprising, from its N-terminus to its C-terminus,

[1155] (1) the fourth domain, or the sixth domain, if the sixth domain is present, is linked at its C-terminus to

[1156] (2) the N-terminus of the second dimerization polypeptide, the second dimerization polypeptide is connected to the N-terminus of the second dimerization polypeptide via a peptide bond or a peptide linker

[1157] (3) the N-terminus of the first polypeptide chain of the second domain,

[1158] iii) a third polypeptide, the third polypeptide comprising, from its N-terminus to its C-terminus,

[1159] (1) a second polypeptide chain of the first domain, the second polypeptide chain being connected at its C-terminus via a peptide bond or via a peptide linker

[1160] a. the N-terminus of the third dimerization polypeptide, if the third dimerization polypeptide is not present on the first polypeptide, the third dimerization polypeptide is linked at its C-terminus to the N-terminus of the third domain, or to the N-terminus of the fifth domain, if the fifth domain is present, by a peptide bond or by a peptide linker, or

[1161] b. the N-terminus of the third domain, if the third domain is not present on the first polypeptide, or the N-terminus of the fifth domain, if the fifth domain is present,

[1162] iv) a fourth polypeptide, the fourth polypeptide comprising, from its N-terminus to its C-terminus,

[1163] (1) the fourth domain, if the fourth domain is not present on the second polypeptide, or the sixth domain, if the sixth domain is present, the fourth domain or the sixth domain is linked at its C-terminus to the

[1164] a. the N-terminus of the fourth dimerization polypeptide, which is in turn connected at its C-terminus to the N-terminus of the second polypeptide chain of the first domain via a peptide bond or via a peptide linker, or

[1165] b. the N-terminus of the second polypeptide chain of the first domain, and

[1166] v) optionally one or more additional polypeptides comprising the second polypeptide chain of the third, fourth, fifth and / or sixth domain, if present.

[1167] The present invention also provides a method for preparing a tetrahedral antibody comprising a fifth domain and / or a sixth domain of the present invention, wherein the non-peptidyl linkage of the tetrahedral antibody is a non-covalent linkage between a first dimerization polypeptide linked to a first N-terminus of the first domain and a second dimerization polypeptide linked to a first C-terminus of the second domain, the method comprising:

[1168] a) recombinantly expressing in a host cell each of the following polypeptides:

[1169] i) a first polypeptide, the first polypeptide comprising, from its N-terminus to its C-terminus,

[1170] (1) the third domain or the fifth domain, if the fifth domain is present, is linked at its C-terminus to the

[1171] (2) the N-terminus of the first dimerization polypeptide, the first dimerization polypeptide is connected to the

[1172] (3) the N-terminus of the first polypeptide chain of the first domain,

[1173] ii) a second polypeptide, the second polypeptide comprising, from its N-terminus to its C-terminus,

[1174] (1) a first polypeptide chain of the second domain, the first polypeptide chain being connected at its C-terminus via a peptide bond or via a peptide linker

[1175] (2) the N-terminus of the second dimerization polypeptide, the second dimerization polypeptide is connected to the N-terminus of the second dimerization polypeptide via a peptide bond or a peptide linker

[1176] (3) the N-terminus of the fourth domain or the N-terminus of the sixth domain, if the sixth domain is present,

[1177] iii) a third polypeptide, the third polypeptide comprising, from its N-terminus to its C-terminus,

[1178] (1) the third domain, if the third domain is not present on the first polypeptide, or the fifth domain, if the fifth domain is present, the third domain or the fifth domain is linked at its C-terminus to the

[1179] (a) the N-terminus of the third dimerization polypeptide, which in turn is linked at its C-terminus to the N-terminus of the second polypeptide chain of the first domain via a peptide bond or via a peptide linker, or

[1180] (b) the N-terminus of the second polypeptide chain of the first domain, and

[1181] iv) a fourth polypeptide, the fourth polypeptide comprising, from its N-terminus to its C-terminus,

[1182] (1) a second polypeptide chain of the first domain, the second polypeptide chain being connected at its C-terminus via a peptide bond or via a peptide linker

[1183] (a) the N-terminus of the fourth dimeric polypeptide, if the fourth dimeric polypeptide is not present on the second polypeptide, the fourth dimeric polypeptide is in turn linked at its C-terminus via a peptide bond or via a peptide linker to the N-terminus of the fourth domain, or to the N-terminus of the sixth domain, if the sixth domain is present, or

[1184] (b) the N-terminus of the fourth domain, if the fourth domain is not present on the second polypeptide, or the N-terminus of the sixth domain, if the sixth domain is present, and

[1185] v) optionally, one or more additional polypeptides comprising the second polypeptide chain of the third, fourth, fifth and / or sixth domain, if present.

[1186] The present invention also provides a method for preparing a tetrahedral antibody comprising a fifth domain and / or a sixth domain of the present invention, wherein the non-peptidyl linkage of the tetrahedral antibody is a non-covalent linkage between a first dimerization polypeptide linked to the first C-terminus of the first domain and a second dimerization polypeptide linked to the first C-terminus of the second domain, the method comprising:

[1187] a) recombinantly expressing in a host cell each of the following polypeptides:

[1188] i) a first polypeptide, the first polypeptide comprising, from its N-terminus to its C-terminus,

[1189] (1) a first polypeptide chain of the first domain, the first polypeptide chain being connected at its C-terminus via a peptide bond or via a peptide linker

[1190] (2) the N-terminus of the first dimerization polypeptide, the first dimerization polypeptide is connected to the

[1191] (3) the N-terminus of the third domain or the N-terminus of the fifth domain, if the fifth domain is present,

[1192] ii) a second polypeptide, the second polypeptide comprising, from its N-terminus to its C-terminus,

[1193] (1) a first polypeptide chain of a second domain, the second domain being linked at its C-terminus via a peptide bond or via a peptide linker

[1194] (2) the N-terminus of the second dimerization polypeptide, the second dimerization polypeptide is connected to the N-terminus of the second dimerization polypeptide via a peptide bond or a peptide linker

[1195] (3) the N-terminus of the fourth domain or the N-terminus of the sixth domain, if the sixth domain is present,

[1196] iii) a third polypeptide, the third polypeptide comprising, from its N-terminus to its C-terminus,

[1197] (1) a second polypeptide chain of the first domain, the second polypeptide chain being connected at its C-terminus via a peptide bond or via a peptide linker

[1198] a. the N-terminus of the third dimerization polypeptide, if the third dimerization polypeptide is not present on the first polypeptide, the third dimerization polypeptide is linked at its C-terminus to the N-terminus of the third domain, or to the N-terminus of the fifth domain, if the fifth domain is present, by a peptide bond or by a peptide linker, or

[1199] b. the N-terminus of the third domain, if the third domain is not present on the first polypeptide, or the N-terminus of the fifth domain, if the fifth domain is present, and

[1200] iv) a fourth polypeptide, the fourth polypeptide comprising, from its N-terminus to its C-terminus,

[1201] (1) a second polypeptide chain of the first domain, the second polypeptide chain being connected at its C-terminus via a peptide bond or via a peptide linker

[1202] a. the N-terminus of the fourth dimerization polypeptide, if the fourth dimerization polypeptide is not present on the second polypeptide, the fourth dimerization polypeptide is linked at its C-terminus to the N-terminus of the fourth domain, or to the N-terminus of the sixth domain, if the sixth domain is present, by a peptide bond or by a peptide linker, or

[1203] b. the N-terminus of the fourth domain, if the fourth domain is not present on the second polypeptide, or the N-terminus of the sixth domain, if the sixth domain is present, and

[1204] c) optionally, one or more additional polypeptides comprising the polypeptide of the second polypeptide chain of the third, fourth, fifth and / or sixth domain, if present.

[1205] Domain

[1206] The domains of the tetrahedral antibodies and octahedral antibodies herein are numbered to facilitate description and identification of each domain. The first domain may be referred to herein as "D1" or "domain 1". The same principle applies to all other domains of the present invention (i.e., the second domain may be referred to herein as "D2" or "domain 2", etc.). In addition, unless otherwise indicated, the tetrahedral antibodies of the present invention may lack more than one domain without affecting the numbering of other domains. For example, the tetrahedral antibodies of the present invention may include domain 1, domain 2, domain 3, domain 4, and domain 6, but not domain 5. As another example, the tetrahedral antibodies of the present invention may include domain 1, domain 2, domain 3, domain 4, domain 7, and domain 8, but not domain 5 and domain 6 (see, e.g. Fig.42 ).

[1207] In principle, the first domain and the second domain of the tetrahedral antibody of the present invention are interchangeable, i.e., in some embodiments, the features described as being applied to the first domain can be equally applied to the second domain. Similarly, the third domain and the fourth domain of the tetrahedral antibody of the present invention are interchangeable, the fifth domain and the sixth domain of the present invention are interchangeable, and the seventh domain and the eighth domain are interchangeable.

[1208] Similarly, with respect to the octahedral antibodies of the present invention, the first domain, the second domain and the third domain of the present invention are interchangeable, the fourth domain, the fifth domain and the sixth domain are interchangeable, the seventh domain, the eighth domain and the ninth domain are interchangeable, and the tenth domain, the eleventh domain and the twelfth domain are interchangeable. As mentioned above, in this context, interchangeable means that any feature described herein as being applied to one of the domains can also be applied to any other domain.

[1209] In the same manner, it should be understood by those skilled in the art that domains 1 and 2 of the tetrahedral antibody of the present invention and domains 1, 2, and 3 of the octahedral antibody of the present invention have similar structural purposes and are therefore equivalent, because any description applied to domains 1 and 2 of the tetrahedral antibody of the present invention can also be applied to domains 1, 2, and 3 of the octahedral antibody of the present invention. Similar equivalence applies between domains 3 and 4 of the tetrahedral antibody of the present invention and domains 4, 5, and 6 of the octahedral antibody of the present invention. In addition, similar equivalence applies between domains 5 and 6 of the tetrahedral antibody of the present invention and domains 7, 8, and 9 of the octahedral antibody of the present invention. Further, similar equivalence applies between domains 7 and 8 of the tetrahedral antibody of the present invention and domains 10, 11, and 12 of the octahedral antibody of the present invention.

[1210] chain

[1211] Various embodiments of the present invention include domains consisting of a "heavy chain" and a "light chain". The heavy chain of the present invention may be referred to herein as an "H chain" or "H1", "H2", "H3", etc. Similarly, the light chain of the present invention may be referred to herein as an "L chain" or "L1", "L2", "L3", etc. Each of these chains is an embodiment of the present invention. In addition, when each of these chains is combined with their corresponding heavy chain or light chain, they are all embodiments of the present invention.

[1212] In an embodiment of the tetrahedral antibody of the present invention, it comprises a first heavy chain ("H1") and a second heavy chain ("H2"). The H1 and H2 chains can be paired with each other to form domain 1 and domain 2. H1 can also be paired with a light chain to form domain 3 and domain 4, and H2 can also be paired with a heavy chain to form domain 5 and domain 6. The H1 and H2 chains can also homodimerize. In this case, the dimerization polypeptide on the H1 chain homodimerizes with the dimerization polypeptide on the H2 chain. The H1 chain or the H2 chain can also include additional domains 7 and 8 as described herein. The H1 chain and / or the H2 chain can also include a dimerization polypeptide between domain 1 and domain 3 and / or between domain 2 and domain 4. In each tetrahedral antibody of the present invention, the H1 chain and the H2 chain can include more than one peptide connector. If the H1 chain and / or the H2 chain comprises a dimerizing polypeptide, a peptide linker may be present between domain 1 or domain 2 and the dimerizing polypeptide, between the dimerizing polypeptide and domain 3 or domain 4, or between the two. A peptide linker may also be present between domain 1 or domain 2 and the dimerizing polypeptide, between the dimerizing polypeptide and domain 5 or domain 6, or both.

[1213] Similar principles apply to the octahedral antibodies of the present invention. The H1 chain and the H2 chain are paired with each other to form domain 1, domain 2, and domain 3. H1 can also be paired with a light chain to form domain 4, domain 5, and domain 6, while H2 can be paired with a light chain to form domain 7, domain 8, and domain 9. The H1 chain or the H2 chain can also include additional domains 10, 11, and 12 as described herein.

[1214] Various embodiments of the present invention include Fc fusion proteins. In such embodiments, a portion of an "Fc fusion chain" can be paired with an "Fc chain" to form an Fc domain. The Fc domain of the present invention is typically domain 1 and / or domain 2 of a tetrahedral antibody of the present invention and domain 1, domain 2, and / or domain 3 of an octahedral antibody of the present invention. An "Fc fusion chain" typically also includes a portion that forms domain 3, domain 4, domain 5, and / or domain 6 of a tetrahedral antibody of the present invention and domain 4, domain 5, domain 6, domain 7, domain 8, domain 9, domain 10, domain 11, and / or domain 12 of an octahedral antibody of the present invention.

[1215] In the tetrahedral antibodies of the present invention, the "Fc fusion chain" may include a dimerization polypeptide between a portion forming a portion of domain 1 and domain 2 and a portion forming domain 3 and domain 4. In alternative embodiments, the "Fc fusion chain" may lack a dimerization polypeptide because the "Fc chains" of domain 1 and domain 2 each include a dimerization polypeptide at their respective N-termini. In an alternative to this embodiment, the "Fc chains" of domain 1 and domain 2 are linked at their respective N-termini by a covalent bond.

[1216] The present invention specifically cont...

Claims

1. A tetrahedral antibody comprising a first domain, a second domain, a third domain and a fourth domain, wherein: a) each of the first domain and the second domain is selected from the group consisting of a Fab domain and an Fc domain, b) each of the first structural domain and the second structural domain comprises: 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 the domain, c) the first domain and the second domain are joined to each other via a non-peptidyl linkage, wherein the non-peptidyl linkage is: i) Covalent Linking (1) connected to the first N-terminus of the first domain and the first N-terminus of the second domain, (2) connected to the first C-terminus of the first domain and the first C-terminus of the second domain, (3) connected to the first N-terminus of the first domain and the first C-terminus of the second domain, or (4) connected to the first C-terminus of the first domain and the first N-terminus of the second domain, or ii) Non-covalent attachment (1) between a first dimerization polypeptide connected to the first N-terminus of the first domain via a peptide bond or via a peptide linker and a second dimerization polypeptide connected to the first N-terminus of the second domain via a peptide bond or via a peptide linker, (2) between a first dimerization polypeptide connected to the first C-terminus of the first domain via a peptide bond or via a peptide linker and a second dimerization polypeptide connected to the first C-terminus of the second domain via a peptide bond or via a peptide linker, (3) between a first dimerization polypeptide connected to the first N-terminus of the first domain via a peptide bond or via a peptide linker and a second dimerization polypeptide connected to the first C-terminus of the second domain via a peptide bond or via a peptide linker, or (4) between a first dimerization polypeptide connected to the first C-terminus of the first domain by a peptide bond or by a peptide linker and a second dimerization polypeptide connected to the first N-terminus of the second domain by a peptide bond or by a peptide linker, wherein the first dimerization polypeptide and the second dimerization polypeptide are not immunoglobulin polypeptides, d) if the first domain is joined to the second domain by a covalent link to a first N-terminus of the first domain, the third domain is linked at its C-terminus to the second N-terminus of the first domain by a peptide bond or by a peptide linker, e) if the first domain is joined to the second domain by a covalent link to a first C-terminus of the first domain, the third domain is linked at its N-terminus to the second C-terminus of the first domain by a peptide bond or by a peptide linker, f) if the first domain is joined to the second domain via a first dimerization polypeptide linked to a first N-terminus of the first domain, the third domain is linked at its C-terminus via a peptide bond or via a peptide linker i) the N-terminus of the first dimerization polypeptide, ii) the second N-terminus of the first domain, or iii) an N-terminus of a third dimerization polypeptide, wherein the third dimerization polypeptide is linked at its C-terminus to the second N-terminus of the first domain via a peptide bond or via a peptide linker, g) if the first domain is joined to the second domain via a first dimerization polypeptide linked to a first C-terminus of the first domain, the third domain is linked at its N-terminus via a peptide bond or via a peptide linker i) the C-terminus of the first dimerization polypeptide, ii) the second C-terminus of the first domain, or iii) a C-terminus of a third dimerization polypeptide, wherein the third dimerization polypeptide is linked at its N-terminus to the second C-terminus of the first domain via a peptide bond or via a peptide linker, h) if the second domain is joined to the first domain by a covalent link to the first N-terminus of the second domain, the fourth domain is linked at its C-terminus to the second N-terminus of the second domain by a peptide bond or by a peptide linker, i) if the second domain is joined to the first domain by a covalent link to the first C-terminus of the second domain, the fourth domain is linked at its N-terminus to the second C-terminus of the second domain by a peptide bond or by a peptide linker, j) if the second domain is joined to the first domain via a second dimerization polypeptide linked to a first N-terminus of the second domain, the fourth domain is linked at its C-terminus via a peptide bond or via a peptide linker i) the N-terminus of the second dimerization polypeptide, ii) a second N-terminus of the second domain, or iii) the N-terminus of a fourth dimerization polypeptide, wherein the third dimerization polypeptide is linked at its C-terminus to the second N-terminus of the second domain via a peptide bond or via a peptide linker, k) if the second domain is joined to the first domain via a second dimerization polypeptide linked to the first C-terminus of the second domain, the fourth domain is linked at its N-terminus via a peptide bond or via a peptide linker i) the C-terminus of the second dimerization polypeptide, ii) the second C-terminus of the second domain, or iii) the C-terminus of a fourth dimerization polypeptide, wherein the fourth dimerization polypeptide is linked at its N-terminus to the second C-terminus of the second domain via a peptide bond or via a peptide linker.

2. The tetrahedral antibody according to claim 1, wherein: a) the first domain is an Fc domain, and the second domain is a Fab domain, b) the first domain and the second domain are Fc domains, c) the first domain and the second domain are Fab domains, d) the third domain and the fourth domain are Fab domains, e) the third domain and / or the fourth domain are selected from the group consisting of (i) secretory proteins and (ii) extracellular domains of transmembrane proteins, f) the third domain is selected from the group consisting of (i) a secretory protein and (ii) an extracellular domain of a transmembrane protein, and the fourth domain is Fab, g) the third domain is IL-15, h) the third domain is IL-15, and the fourth domain is the IL-15Rαsushi domain, i) the third domain is IL-15, and the fourth domain is Fab, j) the third domain and the fourth domain are each an ACE2 peptidase domain (PD), k) the first domain and the second domain are Fc domains, the third domain and the fourth domain are selected from the group consisting of (i) secretory proteins and (ii) extracellular domains of transmembrane proteins, l) the first domain and the second domain are Fc domains, the third domain is selected from the group consisting of (i) secretory proteins and (ii) extracellular domains of transmembrane proteins, and the fourth domain is Fab, m) the first domain and the second domain are Fc domains, the third domain and the fourth domain are Fab domains, n) the first domain and the second domain are Fc domains, the third domain and the fourth domain are each an ACE2 peptidase domain (PD), o) the first domain is an Fc domain, the second domain, the third domain and the fourth domain 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-15Rαsushi 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 Fab.

3. The tetrahedral antibody according to claim 1 or claim 1.k) iii), wherein the non-peptidyl linkage between the first domain and the second domain is a covalent linkage.

4. The tetrahedral antibody according to claim 3, wherein the covalent linkage comprises the following structure: a) b) or c) wherein R2 represents an organic structure connected to the first domain or the second domain, R4 represents an organic structure connected to the other of the first domain or the second domain, wherein R1 is H or is part of an additional structure that is a cyclic structure, wherein the additional cyclic structure includes R1 or a part of R1, and may also include R2 or a part of R2 and a carbon between R2 and the olefin double bond.

5. The tetrahedral antibody according to claim 4, wherein R1 and R2 are connected by at least one direct bond to form a ring structure, wherein the ring structure comprises a) a portion of R1, b) a portion of R2, c) a carbon between R2 and the olefin double bond, and d) the olefinic double bond.

6. The tetrahedral antibody according to claim 5, wherein R1 is selected from the group consisting of: a) b) as well as c) It is optionally substituted at any position.

7. The tetrahedral antibody according to any one of claims 4 to 6, wherein the carbon between R2 and the olefin double bond is directly bonded to R2 via a double bond and a single bond.

8. The tetrahedral antibody of claim 7, wherein R2 is a) b) or c) which is optionally substituted at any position, wherein R2 is connected to R1 via the nitrogen atom of R2, and wherein 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 glycols, polyoxyalkylated polyols, polyvinyl alcohols, polyvinyl alkyl ethers, poly(lactic acid), poly(lactic-co-glycolic acid), polysaccharides, branched residues, C1-C4 alkyl, amines, sulfur, oxygen, succinimide, maleimide, glycerol, triazole, isoxazolidine, C1-C4 acyl, succinyl, malonyl, glutaryl, phthaloyl, adipoyl, and amino acids, where [PEG(y)]z is: Where y=1-100, z=1-10.

9. The tetrahedral antibody according to claim 7, wherein R1 and R2 taken together are: which is optionally substituted at any position, wherein 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 glycols, polyoxyalkylated polyols, polyvinyl alcohols, polyvinyl alkyl ethers, poly(lactic acid), poly(lactic-co-glycolic acid), polysaccharides, branched residues, C1-C4 alkyl, amines, sulfur, oxygen, succinimide, maleimide, glycerol, triazole, isoxazolidine, C1-C4 acyl, succinyl, malonyl, glutaryl, phthaloyl, adipoyl, and amino acids, where [PEG(y)]z is: Where y=1-100, z=1-10.

10. The tetrahedral antibody according to any one of claims 4 to 7 or claim 9, wherein the covalent linkage comprises the following structure: which is optionally substituted at any position, wherein 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 glycols, polyoxyalkylated polyols, polyvinyl alcohols, polyvinyl alkyl ethers, poly(lactic acid), poly(lactic-co-glycolic acid), polysaccharides, branched residues, C1-C4 alkyl, amines, sulfur, oxygen, succinimide, maleimide, glycerol, triazole, isoxazolidine, C1-C4 acyl, succinyl, malonyl, glutaryl, phthaloyl, adipoyl, and amino acids, where [PEG(y)]z is: Where y=1-100, z=1-10.

11. The tetrahedral antibody of claim 3, wherein the covalent linkage comprises the following structure: in: a)X a is a chemical structure selected from the group consisting of: i) a chemical structure comprising a cyclooctane fused to a dihydropyridazine, ii) a chemical structure comprising a cyclooctene fused to a pyridazine, b) R a Is X a a bond or chemical structure connected to the first N-terminus of the first domain, and c) R b Is X a A bond or chemical structure connected to the first N-terminus of the second domain.

12. The tetrahedral antibody according to claim 11, wherein X a Includes the following structures: Where R c is H, alkyl or aryl, or a tautomer thereof.

13. The tetrahedral antibody according to any one of claims 11 to 12, wherein the covalent linkage comprises the following structure: Where R c is H, alkyl or aryl, or a tautomer thereof.

14. The tetrahedral antibody according to any one of claims 11 to 13, wherein 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, wherein each moiety is independently selected from the group consisting of: [PEG(y)]z, polyalkylene glycol, polyoxyalkylene glycol, polyvinyl alcohol, polyvinyl alkyl ether, poly(lactic acid), poly(lactic-co-glycolic acid), polysaccharides, branched residues, C1-C 10 Alkyl, C3-C 10 Cycloalkanes, C2-C 10 Olefins, C5-C 10 Cycloolefins, amines, sulfur, oxygen, succinimide, maleimide, glycerol, triazole, isoxazolidine, C2-C5 acyl, C2-C5 amide, C2-C5 acyloxy, succinyl, malonyl, glutaryl, phthaloyl, adipoyl, amino acids, aryl, heteroaryl, carbamate, chemical structures containing cyclooctane fused to dihydropyridazine, chemical structures containing cyclooctene fused to triazole, chemical structures containing cyclooctene fused to isoxazolidine, dibenzocyclooctenes, dibenzoazacyclooctenes, wherein X1 is CH or N, X2 is CH2 or carbonyl, R5 is aryl or alkyl, and wherein [PEG(y)]z is: Where y=1-100, z=1-10.

15. The tetrahedral antibody according to claim 14, wherein R a and / or R b Each independently: a) comprising a [PEG(y)]z group; b) comprises a polyalkylene glycol, a polyoxyalkylated polyol, a polyvinyl alcohol, a polyvinyl alkyl ether, a poly(lactic acid), a poly(lactic-glycolic acid) or a polysaccharide group; c) contains C1-C4 alkyl; d) contains succinimide; e) contains an amine; f) contains succinyl, malonyl, glutaryl, phthaloyl or adipoyl groups; g) contains a malonyl group; h) contains amino acids; i) contains cysteine; j) contains lysine; k) consists of a chain of 3 parts selected from the group consisting of: [PEG(y)]z, polyalkylene glycol, polyoxyalkyl 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 Olefins, C5-C 10 Cycloolefins, amines, sulfur, oxygen, succinimide, maleimide, glycerol, triazole, isoxazolidine, C2-C5 acyl, C2-C5 amide, C2-C5 acyloxy, succinyl, malonyl, glutaryl, phthaloyl, adipoyl, amino acids, aryl, heteroaryl, carbamate, chemical structures containing cyclooctane fused to dihydropyridazine, chemical structures containing cyclooctene fused to triazole, chemical structures containing cyclooctene fused to isoxazolidine, dibenzocyclooctenes, dibenzoazacyclooctenes, l) is composed of a chain of 4 moieties selected from the group consisting of: [PEG(y)]z, polyalkylene glycol, polyoxyalkyl 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 Olefins, C5-C 10 Cycloolefins, amines, sulfur, oxygen, succinimide, maleimide, glycerol, triazole, isoxazolidine, C2-C5 acyl, C2-C5 amide, C2-C5 acyloxy, succinyl, malonyl, glutaryl, phthaloyl, adipoyl, amino acids, aryl, heteroaryl, carbamate, chemical structures containing cyclooctane fused to dihydropyridazine, chemical structures containing cyclooctene fused to triazole, chemical structures containing cyclooctene fused to isoxazolidine, dibenzocyclooctenes, dibenzoazacyclooctenes, m) is composed of a chain of 5 moieties selected from the group consisting of: [PEG(y)]z, polyalkylene glycol, polyoxyalkyl 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 Olefins, C5-C 10 Cycloolefins, amines, sulfur, oxygen, succinimide, maleimide, glycerol, triazole, isoxazolidine, C2-C5 acyl, C2-C5 amide, C2-C5 acyloxy, succinyl, malonyl, glutaryl, phthaloyl, adipoyl, amino acids, aryl, heteroaryl, carbamate, chemical structures containing cyclooctane fused to dihydropyridazine, chemical structures containing cyclooctene fused to triazole, chemical structures containing cyclooctene fused to isoxazolidine, dibenzocyclooctenes, dibenzoazacyclooctenes, n) comprising a [PEG(y)]z group bonded to a lysine; o) comprising a C1-C4 acyl group bonded to a succinimide group; p) comprising lysine bonded to a C1-C4 acyl group; q) comprising a [PEG(y)]z group bonded to a glutaryl group; r) is composed of a chain of three, four or five moieties selected from the group consisting of: [PEG(y)]z, C2-C5 acyl, succinyl, malonyl, glutaryl, amino acids, chemical structures containing cyclooctane fused to dihydropyridazine, chemical structures containing cyclooctene fused to triazole, chemical structures containing cyclooctene fused to isoxazolidine, dibenzocyclooctene, dibenzoazacyclooctene, wherein X1 is CH or N, X2 is CH2 or carbonyl, R5 is aryl or alkyl, and wherein [PEG(y)]z is: Where y = 1-100, z = 1-10; s) is a key; t) is cysteine; u) has a linear structure; or v) having a branched structure; w) has the following structure: x) is: wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 1-30, 1-40 or 1-50; y) is: wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 1-30, 1-40, or 1-50, x is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 1-30, 1-40, or 1-50, and z is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 1-30, 1-40, or 1-50; z) is: wherein x is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 1-30, 1-40, or 1-50 and z is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 1-30, 1-40, or 1-50; or aa) is: wherein n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 1-30, 1-40, or 1-50.

16. The tetrahedral antibody according to claim 14 or claim 15, wherein R a and / or R b Include part, wherein X1 is CH or N, and X2 is CH2 or a carbonyl group.

17. The tetrahedral antibody of claim 1 or claim 1.k) iii), wherein the non-peptidyl linkage is a non-covalent linkage between a first dimerization polypeptide linked to the first domain and a second dimerization polypeptide linked to the second domain.

18. The tetrahedral antibody according to claim 17, wherein the first dimerization polypeptide and the second dimerization polypeptide are selected from the group consisting of: a) a dimerization domain of an extracellular protein dimer, and b) Dimerization domain of intracellular protein dimer.

19. The tetrahedral antibody according to claim 17, wherein the first dimerization polypeptide and the second dimerization polypeptide are selected from the group consisting of: a) Leucine zipper domain, b) Collector-like domain (CLD), c) collecting protein domains (CD), d) CD8α extracellular domain, and e) CD8β extracellular domain.

20. The tetrahedral antibody according to any one of claims 17 to 19, wherein: a) the first dimerization polypeptide is identical to the second dimerization polypeptide, and b) the dimerized polypeptide forms a homodimer.

21. The tetrahedral antibody according to any one of claims 17 to 19, wherein: a) the first dimerization polypeptide is different from the second dimerization polypeptide, and b) The first dimerization polypeptide and the second dimerization polypeptide form a heterodimer.

22. The tetrahedral antibody according to claim 21, wherein: a) the dimerizing polypeptide is a collector-like domain (CLD), wherein: i) the CLD comprises a substitution that disrupts homodimer formation in the CLD dimerization polypeptide, preferably wherein the substitution is at Arg652, Arg710, Tyr641, Tyr633, Asn638, Glu639, Gln653, Asn636, Ser709, Asp713 and / or Arg716, more preferably wherein 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 positively charged amino acids lysine; or b) the dimerizing polypeptide is a collection protein, wherein: i) the collector protein dimerization polypeptide comprises a substitution that disrupts homodimer formation in the collector protein dimerization polypeptide, preferably wherein the substitution is at Arg59, Arg111, Tyr48 and / or Tyr40, more preferably wherein Tyr48 and / or Tyr40 are substituted with positively charged amino acids lysine, arginine or histidine, and Arg59 and / or Arg111 are substituted with negatively charged amino acids glutamic acid or aspartic acid or positively charged amino acids lysine.

23. The tetrahedral antibody according to claim 22, wherein: a) the dimerizing polypeptide is a collector-like domain (CLD), wherein: i) the CLD comprises substitutions that promote heterodimer formation in the CLD dimerization polypeptide, preferably wherein: (1) replacing Tyr633 on the first CLD dimerization polypeptide with a positively charged amino acid or a negatively charged amino acid, and replacing Arg710 on the second CLD dimerization polypeptide with the other of a positively charged amino acid or a negatively charged amino acid; (2) replacing Tyr633 on the second CLD dimerization polypeptide with a positively charged amino acid or a negatively charged amino acid, and replacing Arg710 on the first CLD dimerization polypeptide with the other of a positively charged amino acid or a negatively charged amino acid; (3) replacing Tyr641 on the first CLD dimerization polypeptide with a positively charged amino acid or a negatively charged amino acid, and replacing Arg652 on the second CLD dimerization polypeptide with the other of a positively charged amino acid or a negatively charged amino acid; (4) replacing Tyr641 on the second CLD dimerization polypeptide with a positively charged amino acid or a negatively charged amino acid, and replacing Arg652 on the first CLD dimerization polypeptide with the other of a positively charged amino acid or a negatively charged amino acid; (5) replacing Arg652 on the first CLD dimerization polypeptide with a positively charged amino acid or a negatively charged amino acid, and replacing Asn638 on the second CLD dimerization polypeptide with the other of a positively charged amino acid or a negatively charged amino acid; (6) replacing Arg652 on the second CLD dimerization polypeptide with a positively charged amino acid or a negatively charged amino acid, and replacing Arg638 on the first CLD dimerization polypeptide with the other of a positively charged amino acid or a negatively charged amino acid; (7) replacing Arg710 on the first CLD dimerization polypeptide with a positively charged amino acid or a negatively charged amino acid, and replacing Glu639 on the second CLD dimerization polypeptide with the other of a positively charged amino acid or a negatively charged amino acid; (8) replacing Arg710 on the second CLD dimerization polypeptide with a positively charged amino acid or a negatively charged amino acid, and replacing Glu639 on the first CLD dimerization polypeptide with the other of a positively charged amino acid or a negatively charged amino acid; (9) replacing Ser709 on the first CLD dimerization polypeptide with a positively charged amino acid or a negatively charged amino acid, and replacing Arg716 on the second CLD dimerization polypeptide with the other of a positively charged amino acid or a negatively charged amino acid; (10) replacing Ser709 on the second CLD dimerization polypeptide with a positively charged amino acid or a negatively charged amino acid, and replacing Arg716 on the first CLD dimerization polypeptide with the other of a positively charged amino acid or a negatively charged amino acid; (11) replacing Asp713 on the first CLD dimerization polypeptide with a positively charged amino acid or a negatively charged amino acid, and replacing Arg716 on the second CLD dimerization polypeptide with the other of a positively charged amino acid or a negatively charged amino acid; and / or (12) replacing Asp713 on the second CLD dimerization polypeptide with a positively charged amino acid or a negatively charged amino acid, and replacing Arg716 on the first CLD dimerization polypeptide with the other of a positively charged amino acid or a negatively charged amino acid; or b) the dimerizing polypeptide is a collection protein, wherein: i) the collection protein dimerization polypeptide comprises substitutions that promote heterodimer formation in the collection protein dimerization polypeptide, preferably wherein: (1) replacing Tyr40 on the first collection protein dimerization polypeptide with a positively charged amino acid or a negatively charged amino acid, and replacing Arg111 on the second collection protein dimerization polypeptide with the other of a positively charged amino acid or a negatively charged amino acid; (2) replacing Tyr40 on the second collection protein dimerization polypeptide with a positively charged amino acid or a negatively charged amino acid, and replacing Arg111 on the first collection protein dimerization polypeptide with the other of a positively charged amino acid or a negatively charged amino acid; (3) replacing Tyr48 on the first collection protein dimerization polypeptide with a positively charged amino acid or a negatively charged amino acid, and replacing Arg59 on the second collection protein dimerization polypeptide with the other of a positively charged amino acid or a negatively charged amino acid; and / or (4) replacing Tyr48 on the second collection protein dimerization polypeptide with a positively charged amino acid or a negatively charged amino acid, and replacing Arg59 on the first collection protein dimerization polypeptide with the other of a positively charged amino acid or a negatively charged amino acid.

24. The tetrahedral antibody according to claim 17, wherein: a) the first dimerization polypeptide and the second dimerization polypeptide are selected from the group consisting of: i) T cell receptor alpha extracellular domain and T cell receptor beta extracellular domain, ii) a T cell receptor gamma extracellular domain and a T cell receptor extracellular domain, iii) MHC class I alpha extracellular domain and beta-2 microglobulin, iv) an MHC class II alpha extracellular domain and an MHC class II beta extracellular domain, and v) CD8α extracellular domain and CD8β extracellular domain, b) the first dimerization polypeptide is different from the second dimerization polypeptide, and c) the first dimerization polypeptide and the second dimerization polypeptide form a heterodimer.

25. The tetrahedral antibody of any one of claims 21 to 24, wherein the first dimerization polypeptide and the second dimerization polypeptide form less than 30%, 20%, 10%, 5%, 4%, 3%, 2% or 1% homodimers when present with each other.

26. The tetrahedral antibody according to any one of claims 17 to claim 25, wherein the first dimerization polypeptide comprises one or more disulfide bonds formed with the second dimerization polypeptide, preferably wherein: a) the one or more disulfide bonds are at the interface between the first dimerization polypeptide and the second dimerization polypeptide, more preferably wherein: i) if the first dimerization polypeptide and the second dimerization polypeptide are a accretin-like domain or a accretin, the one or more disulfide bonds are in the second helix and the fourth helix of the accretin-like domain or in the corresponding regions of the accretin, or b) the one or more disulfide bonds are located between an immunoglobulin hinge region or a portion thereof comprising at least one cysteine ​​attached to the N-terminus and / or C-terminus of the first dimerization polypeptide and the second dimerization polypeptide, wherein the hinge region is attached to the first dimerization polypeptide and the second dimerization polypeptide directly or via a peptide linker, preferably wherein the first dimerization polypeptide and the second dimerization polypeptide are collector protein-like domains or collector proteins.

27. The tetrahedral antibody according to any one of claims 17 to 20, wherein: a) the third domain and the fourth domain are each an ACE2 peptidase domain (PD), and b) the first dimerization polypeptide and the second dimerization polypeptide are each an ACE2 recruitment protein-like domain (CLD), Preferably, the first domain and the second domain are Fc domains, and each polypeptide chain of the tetrahedral antibody comprises an amino acid sequence listed in any one of SEQ ID NO: 74 to SEQ ID NO: 119, more preferably an amino acid sequence listed in SEQ ID NO:

78.

28. The tetrahedral antibody according to any one of claims 17 to claim 27, wherein the first domain and the second domain are Fc domains.

29. The tetrahedral antibody according to any one of claims 17 to 27, wherein: a) the first domain and the second domain are Fc domains, and the third domain is a first type of Fab domain, b) the first domain and the second domain are Fc domains, the third domain and the fourth domain 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, the second domain and the third domain 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 domain, the third domain and the fourth domain 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.

30. The tetrahedral antibody according to any one of claims 17 to claim 29, which additionally comprises a fifth domain, wherein the fifth domain is linked at its C-terminus via a peptide bond or via a peptide linker to: a) the N-terminus of the first dimerization polypeptide, b) the second N-terminus of the first domain, or c) an N-terminus of a third dimerization polypeptide, wherein the third dimerization polypeptide is linked at its C-terminus to the second N-terminus of the first domain via a peptide bond or via a peptide linker.

31. The tetrahedral antibody according to claim 30, wherein: a) the first domain and the second domain are Fc domains, and the fifth domain is a first type of Fab domain, b) the first domain and the second domain are Fc domains, the third domain and the fifth domain 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 and the second domain are Fc domains, the fourth domain and the fifth domain are independently selected from the group consisting of a first type of Fab domain and a second type of Fab domain, d) the first domain and the second domain are Fc domains, and the third domain, the fourth domain and the fifth domain 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, the second domain and the fifth domain 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, the second domain, the third domain and the fifth domain 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 domain, the fourth domain and the fifth domain 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.

32. The tetrahedral antibody according to any one of claims 17 to claim 31, additionally comprising a fifth domain and / or a sixth domain, wherein: a) the first domain is joined to the second domain via a first dimerization polypeptide linked to a first N-terminus of the first domain, wherein i) the fifth domain is connected at its C-terminus via a peptide bond or via a peptide linker to: (1) the N-terminus of the first dimerization polypeptide, (2) the second N-terminus of the first domain, or (3) an N-terminus of a third dimerization polypeptide, wherein the third dimerization polypeptide is connected at its C-terminus to the second N-terminus of the first domain via a peptide bond or via a peptide linker, b) the first domain is joined to the second domain via a first dimerization polypeptide linked to a first C-terminus of the first domain, wherein i) the fifth domain is connected at its N-terminus via a peptide bond or via a peptide linker to: (1) the C-terminus of the first dimerization polypeptide, (2) the second C-terminus of the first domain, or (3) a C-terminus of a third dimerization polypeptide, wherein the third dimerization polypeptide is connected at its N-terminus to the second C-terminus of the first domain via a peptide bond or via a peptide linker, c) the second domain is joined to the first domain via a second dimerization polypeptide linked to a first N-terminus of the second domain, wherein i) the sixth domain is connected at its C-terminus via a peptide bond or via a peptide linker to: (1) the N-terminus of the second dimerization polypeptide, (2) the second N-terminus of the second domain, or (3) the N-terminus of a fourth dimerization polypeptide, wherein the fourth dimerization polypeptide is connected at its C-terminus to the second N-terminus of the second domain via a peptide bond or via a peptide linker, or d) the second domain is joined to the first domain via a second dimerization polypeptide linked to a first C-terminus of the second domain, wherein i) the sixth domain is connected at its N-terminus via a peptide bond or via a peptide linker to: (1) the C-terminus of the second dimerization polypeptide, (2) the second C-terminus of the second domain, or (3) the C-terminus of a fourth dimerization polypeptide, wherein the fourth dimerization polypeptide is connected at its N-terminus to the second C-terminus of the second domain via a peptide bond or via a peptide linker.

33. The tetrahedral antibody according to claim 32, wherein: 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 fifth 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 domain and the second domain are Fc domains, and the third domain, the fourth domain and the fifth domain 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, the second domain and the fifth domain 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, the second domain, the third domain and the fifth domain 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, the second domain, the fourth domain and the fifth domain 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 domain and the second domain are Fc domains, the third domain and the fourth domain are ACE2 peptidase domains (PD), and the fifth domain and the sixth domain are Fab domains.

34. The tetrahedral antibody according to claim 32, wherein: a) the third domain, the fourth domain, the fifth domain and the sixth domain are each ACE2 PD, and the dimerization polypeptide is each ACE2 CLD, b) the first and second domains are Fc domains, the third, fourth, fifth and sixth domains are each ACE2 PD, and the dimerization polypeptides are each ACE2 CLD, preferably wherein the first and second domains are each connected to their respective dimerization polypeptides via a peptide linker, c) the third domain and the fourth domain are each ACE2 PD, the fifth domain and the sixth domain are each a Fab domain, and the dimerization polypeptide is each ACE2 CLD, d) the first and second domains are Fc domains, the third and fourth domains are each ACE2 PD, the fifth and sixth domains are each Fab domains, and the dimerization polypeptides are each ACE2 CLD, preferably wherein the first and second domains are each connected to their respective dimerization polypeptides via a peptide linker, e) the third domain and the fourth domain are each a Fab domain, the fifth domain and the sixth domain are each an ACE2 PD, and the dimerization polypeptide is each an ACE2 CLD, f) the first and second domains are Fc domains, the third and fourth domains are each Fab domains, the fifth and sixth domains are each ACE2 PD, and the dimerization polypeptides are each ACE2 CLD, preferably wherein the first and second domains are each connected to their respective dimerization polypeptides via a peptide linker, or g) the first and second domains are Fc domains, the third and fourth domains are ACE2PD, the fifth and sixth domains are Fab domains, the dimerization polypeptides are each ACE2 CLD, and the first and second domains are each connected to their respective dimerization polypeptides via a peptide linker, Preferably, if such domains and linkers are present, they are characterized by one or more or all of the following characteristics: i) the Fc domain is characterized by one or more or all of the following features: (1) is a heterodimer, (2) is the IgG1 Fc domain, (3) comprising a silent mutation so that the Fc domain lacks Fcγ receptor binding activity, preferably wherein such mutation is one of the following mutation combinations: (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 FcRn activity, preferably wherein such mutation extends the half-life of the tetrahedral antibody, preferably wherein the mutation is: (a) The combination of the following mutations: L309D / Q311H / N434S (DHS), (b) The combination of the following mutations: S239D / I298E, (c) S239D, preferably wherein the other Fc domain of the tetrahedral antibody, if present, comprises an I298E mutation, or (d) I298E, preferably wherein the other Fc domain of the tetrahedral antibody, if present, comprises an S239D mutation, and (5) comprising mutations that eliminate their protein A binding sites, preferably wherein such mutations are H435R / Y436F (HY / RF), ii) said ACE2 peptidase domain comprises a mutation that blocks its angiotensin converting enzyme activity, preferably wherein such mutation is a H378A mutation, iii) the Fab domain is a chimeric Fab domain comprising a murine variable region, and iv) each of the peptide linkers has a length of 23 amino acids and is derived from the stem region of a TNF receptor, preferably wherein the TNF receptor is TNF receptor 1B, more preferably wherein the peptide linker consists of the amino acid sequence set forth in SEQ ID NO: 4468, and v) Such domains and peptide linkers are formed from two or three different types of polypeptide chains.

35. The tetrahedral antibody according to claim 32, wherein: a) the third domain and the fourth domain are each ACE2 PD, b) the fifth domain, if present, is linked at its C-terminus to the N-terminus of a third dimeric polypeptide via a peptide bond or via a peptide linker, wherein the third dimeric polypeptide is linked at its C-terminus to the second N-terminus of the first domain via a peptide bond or via a peptide linker, c) the sixth domain, if present, is linked at its C-terminus to the N-terminus of a fourth dimeric polypeptide via a peptide bond or via a peptide linker, wherein the fourth dimeric polypeptide is linked at its C-terminus to the second N-terminus of the second domain via a peptide bond or via a peptide linker, and d) the first dimerization polypeptide, the second dimerization polypeptide, the third dimerization polypeptide and the fourth dimerization polypeptide are each ACE2 CLD.

36. The tetrahedral antibody according to any one of claims 27 and claims 34 to 35, wherein the ACE2 PD comprises or consists of amino acids 18-615 of the ACE2 protein or a portion thereof.

37. The tetrahedral antibody according to any one of claims 27 and claims 34 to 35, wherein the ACE2 CLD comprises or consists of amino acids 616-740 or a portion thereof of the ACE2 protein.

38. The tetrahedral antibody of any one of claims 27 and claims 34 to 37, wherein the ACE2 PD has catalytic activity.

39. The tetrahedral antibody according to any one of claims 27 and claims 34 to claim 37, wherein ACE2 PD is catalytically inactive.

40. The tetrahedral antibody of claim 39, wherein the ACE2 PD comprises a R273Q or H378A mutation.

41. The tetrahedral antibody according to any one of claims 28, 29, 31 and 33 to 40, wherein the Fc domain lacks Fcγ receptor binding activity.

42. The tetrahedral antibody of claim 41, wherein the Fc domain comprises: a) P329G mutation, L234A mutation and L235A mutation (PGLALA); b) L234A mutation and L235A mutation (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.

43. The tetrahedral antibody according to any one of claims 27 to claim 42, wherein the tetrahedral antibody comprises one or more Fab domains, and the one or more Fab domains comprise the complementarity determining regions (CDRs) of the Fab domain of the B13A antibody.

44. The tetrahedral antibody according to claim 43, wherein the one or more Fab domains comprise VH and VL regions from the B13A antibody, preferably wherein the VH and VL regions comprise the amino acid sequences listed in SEQ ID NO: 463 and SEQ ID NO: 464 or variants thereof, said variants having at least 90%, preferably at least 95%, more preferably at least 98% identity with said sequences.

45. The tetrahedral antibody of claim 43 or claim 44, wherein the one or more Fab domains are humanized.

46. ​​The tetrahedral antibody according to claim 34, wherein the first and second domains are Fc domains, the third and fourth domains are ACE2 PD, the fifth and sixth domains are Fab domains, the dimerization polypeptides are each ACE2CLD, and the first and second domains are each connected to their respective dimerization polypeptides via a peptide linker, wherein the domains and peptide linkers of the tetrahedral antibody are formed by three different types of polypeptide chains.

47. The tetrahedral antibody of claim 46, wherein the three different types of polypeptide chains are denoted H1, L2 and H2, wherein: 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 wherein the H1 chain, L2 chain and H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 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 wherein the H1 chain, L2 chain and H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 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 wherein the H1 chain, L2 chain and H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 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 wherein the H1 chain, L2 chain and H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 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 wherein the H1 chain, L2 chain and H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 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 wherein the H1 chain, L2 chain and H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 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 wherein the H1 chain, L2 chain and H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 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, the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 534, or wherein the H1 chain, L2 chain and H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences.

48. The tetrahedral antibody of claim 34, wherein the first domain and the second domain are Fc domains, the third domain, the fourth domain, the fifth domain, and the sixth domain are each ACE2 PD, and the dimerization polypeptide is each ACE2 CLD, wherein the first domain and the second domain are each connected to their respective dimerization polypeptides via a peptide linker, wherein the domains and the peptide linker of the tetrahedral antibody are formed by two different types of polypeptide chains.

49. The tetrahedral antibody of claim 48, wherein the two different types of polypeptide chains are denoted H1 and H2, wherein: a) the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 509, the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 510, or wherein the H1 chain and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences; b) the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 512, the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 513, or wherein the H1 chain and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences; c) the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 516, the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 517, or wherein the H1 chain and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences; d) the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 520, the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 521, or wherein the H1 chain and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences; e) the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 542, the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 543, or wherein the H1 chain and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences; f) the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 545, the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 546, or wherein the H1 chain and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 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 wherein the H1 chain and the H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences; or h) the H1 chain comprises the amino acid sequence set forth in SEQ ID NO: 551, the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 552, or wherein the H1 chain and H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences.

50. The tetrahedral antibody of claim 35, wherein: a) the third domain, the first dimerization polypeptide and the first polypeptide chain of the first domain are part of a first stretch of consecutive amino acids, b) the fourth domain, the second dimerization polypeptide and the first polypeptide chain of the second domain are part of a second stretch of consecutive amino acids, c) the fifth domain, the third dimerization polypeptide and the second polypeptide chain of the first domain are part of a third stretch of consecutive amino acids, and d) the sixth domain, the fourth dimerization polypeptide and the second polypeptide chain of the second domain are part of a fourth stretch of consecutive amino acids, wherein each stretch of consecutive amino acids consists of an amino acid sequence selected from the group consisting of SEQ ID NO: 74 to SEQ ID NO: 119, or wherein such each stretch of consecutive amino acids is a variant having at least 90%, preferably at least 95%, more preferably at least 98% identity with said sequence.

51. A polynucleotide encoding the polypeptide of claim 27, wherein the polypeptide comprises the amino acid sequence listed in any one of SEQ ID NO: 74 to SEQ ID NO:

119.

52. A polynucleotide encoding a polypeptide comprising any one of the polypeptide chains of claim 47 or claim 49.

53. A polynucleotide encoding a polypeptide comprising any stretch of consecutive amino acids as described in claim 50.

54. A vector comprising a polynucleotide encoding a polypeptide comprising three different types of polypeptide chains as described in claim 47, wherein each polynucleotide is operably linked to a promoter that directs the expression of the polynucleotide in a host cell.

55. A vector comprising a polynucleotide encoding a polypeptide comprising two different types of polypeptide chains as described in claim 49, wherein each polynucleotide is operably linked to a promoter that directs the expression of the polynucleotide in a host cell.

56. A vector comprising one or more polynucleotides of any one of claims 51 to 53, wherein each polynucleotide is operably linked to a promoter that directs expression of the polynucleotide in a host cell.

57. A host cell comprising the vector of any one of claims 54 to 56.

58. Use of the host cell of claim 57 in a method for preparing a tetrahedral antibody.

59. A method for producing a tetrahedral antibody, the method comprising recombinantly expressing the two different types of polypeptide chains of claim 47 in a host cell.

60. A method for producing a tetrahedral antibody, the method comprising recombinantly expressing the two different types of polypeptide chains of claim 49 in a host cell.

61. A method for producing a tetrahedral antibody, the method comprising recombinantly expressing the vector of any one of claims 54 to 56 in a host cell.

62. A method for producing a tetrahedral antibody comprising two, three or four different types of polypeptide chains, the method comprising expressing the two, three or four different types of polypeptide chains in the host cell of claim 57.

63. A pharmaceutical composition comprising any one of the tetrahedral antibodies of claim 27 and claims 34 to claim 49 and one or more pharmaceutically acceptable excipients.

64. A method of treating Covid-19 in an individual, the method comprising administering to the individual a therapeutically effective amount of the pharmaceutical composition of claim 63.

65. The tetrahedral antibody according to any one of claims 1 to claim 33, further comprising a seventh domain and / or an eighth domain, wherein: a) the first domain is joined to the second domain via a covalent link to a first N-terminus of the first domain or via a first dimerization polypeptide linked to a first N-terminus of the first domain, wherein i) the seventh domain is connected at its N-terminus via a peptide bond or via a peptide linker to: (1) the first C-terminus of the first domain, or (2) the second C-terminus of the first domain, b) the first domain is joined to the second domain via a covalent link to a first C-terminus of the first domain or via a first dimerization polypeptide linked to a first C-terminus of the first domain, wherein i) the seventh domain is connected at its C-terminus via a peptide bond or via a peptide linker to: (1) the first N-terminus of the first domain, or (2) the second N-terminus of the first domain, c) the second domain is joined to the first domain via a covalent link to the first N-terminus of the second domain or via a second dimerization polypeptide linked to the first N-terminus of the second domain, wherein i) the eighth domain is connected at its N-terminus via a peptide bond or via a peptide linker to: (1) the first C-terminus of the second domain, or (2) the second C-terminus of the second domain, or d) the second domain is joined to the first domain via a covalent link to the first C-terminus of the second domain or via a second dimerization polypeptide linked to the first C-terminus of the second domain, wherein i) the eighth domain is connected at its C-terminus via a peptide bond or via a peptide linker to: (1) the first N-terminus of the second domain, or (2) The second N-terminus of the second domain.

66. The tetrahedral antibody of claim 32, wherein: a) the first domain and the second domain are Fc domains, the third domain and the fourth domain are anti-CD20 Fab domains, and the fifth domain and the sixth domain are anti-CD19 Fab domains; b) the first domain and the second domain are Fc domains, the third domain and the fourth domain are anti-CD19 Fab domains, and the fifth domain and the sixth domain are anti-CD20 Fab domains; c) the first domain and the second domain are Fc domains, the third domain and the fourth domain are anti-CD20 Fab domains, the fifth domain and the sixth domain are anti-CD19 Fab domains, and each dimerization polypeptide is ACE2 CLD; d) the first domain and the second domain are Fc domains, the third domain and the fourth domain are anti-CD19 Fab domains, the fifth domain and the sixth domain are anti-CD20 Fab domains, and each dimerization polypeptide is ACE2 CLD; e) the first domain and the second domain are Fc domains, the third domain and the fourth domain are anti-CD20 Fab domains, the fifth domain and the sixth domain are anti-CD19 Fab domains, and each dimerization polypeptide is ACE2 CLD, and the first domain and the second domain are each connected to their respective dimerization polypeptides by a peptide linker; f) the first domain and the second domain are Fc domains, the third domain and the fourth domain are anti-CD19 Fab domains, the fifth domain and the sixth domain are anti-CD20 Fab domains, and each dimerization polypeptide is ACE2 CLD, and the first domain and the second domain are each connected to their respective dimerization polypeptides via a peptide linker.

67. The tetrahedral antibody of claim 66, wherein: a) the first domain and the second domain are Fc domains, the third domain and the fourth domain are anti-CD20 Fab domains, the fifth domain and the sixth domain are anti-CD19 Fab domains, and the seventh domain and the eighth domain are single-chain 4-1BB ligands; b) the first domain and the second domain are Fc domains, the third domain and the fourth domain are anti-CD19 Fab domains, the fifth domain and the sixth domain are anti-CD20 Fab domains, and the seventh domain and the eighth domain are single-chain 4-1BB ligands; c) the first domain and the second domain are Fc domains, the third domain and the fourth domain are anti-CD20 Fab domains, the fifth domain and the sixth domain are anti-CD19 Fab domains, the seventh domain and the eighth domain are single-chain 4-1BB ligands, and each dimerization polypeptide is ACE2 CLD; d) the first domain and the second domain are Fc domains, the third domain and the fourth domain are anti-CD19 Fab domains, the fifth domain and the sixth domain are anti-CD20 Fab domains, the seventh domain and the eighth domain are single-chain 4-1BB ligands, and each dimerization polypeptide is ACE2 CLD; e) the first domain and the second domain are Fc domains, the third domain and the fourth domain are anti-CD20 Fab domains, the fifth domain and the sixth domain are anti-CD19 Fab domains, the seventh domain and the eighth domain are single-chain 4-1BB ligands, and each dimerization polypeptide is ACE2 CLD, and the first domain and the second domain are each connected to their respective dimerization polypeptides by a peptide linker; or f) the first domain and the second domain are Fc domains, the third domain and the fourth domain are anti-CD19 Fab domains, the fifth domain and the sixth domain are anti-CD20 Fab domains, the seventh domain and the eighth domain are single-chain 4-1BB ligands, and each dimerization polypeptide is ACE2 CLD, and the first domain and the second domain are each connected to their respective dimerization polypeptides by a peptide linker.

68. The tetrahedral antibody of claim 66 or claim 67, wherein: a) the anti-CD19 Fab domain comprises i) CDRs of both the heavy and light chains of FMC63, preferably wherein the anti-CD19 Fab is the Fab domain of FMC63; ii) CDRs of both the heavy and light chains of FMC60, preferably wherein the anti-CD19 Fab is the Fab domain of FMC60; or iii) CDRs of both the heavy and light chains of FMC59, preferably wherein the anti-CD19 Fab is the Fab domain of FMC59; and / or b) the anti-CD20 Fab domain comprises the CDRs of rituximab, preferably wherein the anti-CD20 Fab is the Fab domain of rituximab.

69. The tetrahedral antibody of any one of claims 66 to 68, wherein the Fc domain is characterized by one or more or all of the following features: a) is a heterodimer, b) is an IgG1 Fc domain, c) comprises a silent mutation such that the Fc domain lacks Fcγ receptor binding activity, preferably wherein such mutation is 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) comprises mutations that enhance FcRn activity, preferably wherein such mutations extend the half-life of said tetrahedral antibody, preferably wherein said mutations are a combination of the following mutations: L309D / Q311H / N434S (DHS), and e) comprising mutations that eliminate their protein A binding sites, preferably wherein such mutations are H435R / Y436F (HY / RF).

70. The tetrahedral antibody according to any one of claims 66 to claim 69, wherein the peptide linkers each have a length of 23 amino acids and are derived from the stem region of a TNF receptor, preferably wherein the TNF receptor is TNF receptor 1B, and more preferably wherein the peptide linker consists of the amino acid sequence listed in SEQ ID NO: 4468.

71. The tetrahedral antibody of any one of claims 66 to claim 70, wherein each of the dimerizing polypeptides is an ACE2 CLD, wherein each ACE2 CLD comprises or consists of amino acids 616-740 of the ACE2 protein.

72. The tetrahedral antibody according to claim 66, wherein the domains and peptide linkers are formed by four different types of polypeptide chains, preferably wherein the four different types of polypeptide chains are denoted L1, H1, L2 and H2, wherein: 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 wherein the L1 chain, H1 chain, L2 chain and H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 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 wherein the L1 chain, H1 chain, L2 chain and H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 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 wherein the L1 chain, H1 chain, L2 chain and H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 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 wherein the L1 chain, H1 chain, L2 chain and H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 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 wherein the L1 chain, H1 chain, L2 chain and H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 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 wherein the L1 chain, H1 chain, L2 chain and H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 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 wherein the L1 chain, H1 chain, L2 chain and H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 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 wherein the L1 chain, H1 chain, L2 chain and H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 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 wherein the L1 chain, H1 chain, L2 chain and H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 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 wherein the L1 chain, H1 chain, L2 chain and H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 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 wherein the L1 chain, H1 chain, L2 chain and H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 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 wherein the L1 chain, H1 chain, L2 chain and H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 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 wherein the L1 chain, H1 chain, L2 chain and H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 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 wherein the L1 chain, H1 chain, L2 chain and H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 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 wherein the L1 chain, H1 chain, L2 chain and H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 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 wherein the L1 chain, H1 chain, L2 chain and H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 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 wherein the L1 chain, H1 chain, L2 chain and H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 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 wherein the L1 chain, H1 chain, L2 chain and H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 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 wherein the L1 chain, H1 chain, L2 chain and H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences; t) the L1 chain comprises the amino acid sequence set forth in SEQ D 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 wherein the L1 chain, H1 chain, L2 chain and H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 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 wherein the L1 chain, H1 chain, L2 chain and H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 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 wherein the L1 chain, H1 chain, L2 chain and H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 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 wherein the L1 chain, H1 chain, L2 chain and H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 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 wherein the L1 chain, H1 chain, L2 chain and H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 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 wherein the L1 chain, H1 chain, L2 chain and H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 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 wherein the L1 chain, H1 chain, L2 chain and H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 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 wherein the L1 chain, H1 chain, L2 chain and H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity with said sequences.

73. The tetrahedral antibody according to claim 67, wherein the domains and peptide linkers are formed by four different types of polypeptide chains, preferably wherein the four different types of polypeptide chains are denoted L1, H1, L2 and H2, wherein: 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 wherein the L1 chain, H1 chain, L2 chain and H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 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 wherein the L1 chain, H1 chain, L2 chain and H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 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 wherein the L1 chain, H1 chain, L2 chain and H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 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 wherein the L1 chain, H1 chain, L2 chain and H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 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 wherein the L1 chain, H1 chain, L2 chain and H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 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 wherein the L1 chain, H1 chain, L2 chain and H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 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 wherein the L1 chain, H1 chain, L2 chain and H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 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, the H2 chain comprises the amino acid sequence set forth in SEQ ID NO: 726, or wherein the L1 chain, H1 chain, L2 chain and H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 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 wherein the L1 chain, H1 chain, L2 chain and H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 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 wherein the L1 chain, H1 chain, L2 chain and H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 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 wherein the L1 chain, H1 chain, L2 chain and H2 chain are variants having at least 90%, preferably at least 95%, more preferably at least 98% identity to said sequences; or l) the L1 chain comprises the amino acid sequence listed in SEQ ID NO: 740, the H1 chain comprises the amino acid sequence listed in SEQ ID NO: 730, the L2 chain comprises the amino acid sequence listed in SEQ ID NO: 742, and the H2 chain comprises the amino acid sequence listed in SEQ ID NO: 732, or wherein the L1 chain, H1 chain, L2 chain and H2 chain are variants having at least 90%, preferably at least 95%, and more preferably at least 98% identity with said sequences.

74. A polynucleotide encoding a polypeptide comprising any one of the polypeptide chains of claim 72 or claim 73.

75. A vector comprising a polynucleotide encoding a polypeptide comprising four different types of polypeptide chains as described in claim 72 or claim 73, wherein each polynucleotide is operably linked to a promoter that directs the expression of the polynucleotide in a host cell.

76. A vector comprising one or more polynucleotides of claim 74, wherein each polynucleotide is operably linked to a promoter that directs expression of the polynucleotide in a host cell.

77. A host cell comprising the vector of claim 75 or claim 76.

78. Use of the host cell of claim 77 in a method for preparing a tetrahedral antibody.

79. A method for producing a tetrahedral antibody, the method comprising recombinantly expressing four different types of polypeptide chains according to claim 72 or claim 73 in a host cell.

80. A method for producing a tetrahedral antibody, the method comprising recombinantly expressing the vector of claim 75 or claim 76 in a host cell.

81. A method for producing a tetrahedral antibody comprising four different types of polypeptide chains, the method comprising expressing the four different types of polypeptide chains in the host cell of claim 77.

82. A pharmaceutical composition comprising any one of the tetrahedral antibodies of claim 66 to claim 73 and one or more pharmaceutically acceptable excipients.

83. A method of treating cancer or an inflammatory disease in an individual, the method comprising administering to the individual a therapeutically effective amount of the pharmaceutical composition of claim 82, preferably wherein the cancer is a B cell cancer.

84. A tetrahedral molecule comprising a first domain, a second domain, a third domain and a fourth domain, wherein: a) the first structural domain and the second structural domain 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 the domain, b) the first domain and the second domain are joined to each other by a non-covalent bond, the non-covalent bond (1) between a first dimerization polypeptide connected to the first N-terminus of the first domain via a peptide bond or via a peptide linker and a second dimerization polypeptide connected to the first N-terminus of the second domain via a peptide bond or via a peptide linker, (2) between a first dimerization polypeptide connected to the first C-terminus of the first domain via a peptide bond or via a peptide linker and a second dimerization polypeptide connected to the first C-terminus of the second domain via a peptide bond or via a peptide linker, (3) between a first dimerization polypeptide connected to the first N-terminus of the first domain by a peptide bond or by a peptide linker and a second dimerization polypeptide connected to the first C-terminus of the second domain by a peptide bond or by a peptide linker, or (4) between a first dimerization polypeptide connected to the first C-terminus of the first domain by a peptide bond or by a peptide linker and a second dimerization polypeptide connected to the first N-terminus of the second domain by a peptide bond or by a peptide linker, wherein the first dimerization polypeptide and the second dimerization polypeptide are not immunoglobulin polypeptides, c) if the first domain is joined to the second domain via a first dimerization polypeptide linked to a first N-terminus of the first domain, the third domain is linked at its C-terminus via a peptide bond or via a peptide linker i) the N-terminus of the first dimerization polypeptide, ii) the second N-terminus of the first domain, if present, or iii) the N-terminus of a third dimerization polypeptide, wherein the third dimerization polypeptide is linked at its C-terminus to the second N-terminus of the first domain, if the second N-terminus of the first domain exists, via a peptide bond or via a peptide linker, d) if the first domain is joined to the second domain via a first dimerization polypeptide linked to a first C-terminus of the first domain, the third domain is linked at its N-terminus to the second domain via a peptide bond or via a peptide linker i) the C-terminus of the first dimerization polypeptide, ii) the second C-terminus of the first domain, if present, or iii) the C-terminus of a third dimeric polypeptide, wherein the third dimeric polypeptide is linked at its N-terminus to the second C-terminus of the first domain, if the second C-terminus of the first domain exists, via a peptide bond or via a peptide linker, e) if the second domain is linked to the first domain via a second dimerization polypeptide linked to a first N-terminus of the second domain, the fourth domain is linked at its C-terminus via a peptide bond or via a peptide linker i) the N-terminus of the second dimerization polypeptide, ii) if present, the second N-terminus of the second domain, or iii) the N-terminus of the fourth dimerization polypeptide, wherein the third dimerization polypeptide is linked at its C-terminus to the second N-terminus of the second domain, if the second N-terminus of the second domain exists, via a peptide bond or via a peptide linker, and f) if the second domain is joined to the first domain via a second dimerization polypeptide linked to the first C-terminus of the second domain, the fourth domain is linked at its N-terminus via a peptide bond or via a peptide linker i) the C-terminus of the second dimerization polypeptide, ii) the second C-terminus of the second domain, if present, or iii) the C-terminus of a fourth dimerization polypeptide, wherein the fourth dimerization polypeptide is linked at its N-terminus to the second C-terminus of the second domain, if the second C-terminus of the second domain exists, via a peptide bond or via a peptide linker.

85. The tetrahedral molecule of claim 84, wherein a) the first domain is an Fc domain or a Fab domain, b) the first domain is an Fc domain or a Fab domain, and 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 domain and the second domain are Fc domains, e) the first domain and the second domain are Fab domains, f) the second domain, the third domain and / or the fourth domain are selected from the group consisting of (i) secretory proteins and (ii) extracellular domains of transmembrane proteins, g) the third domain is selected from the group consisting of (i) a secretory protein and (ii) an extracellular domain of a transmembrane protein, and the fourth domain is Fab, h) the third domain is IL-15, i) the third domain is IL-15, and the fourth domain is the IL-15Rαsushi domain, j) the third domain is IL-15, the fourth domain is Fab, k) the third domain and the fourth domain are each an ACE2 peptidase domain (PD), l) the first domain and the second domain are Fc domains, the third domain and the fourth domain are selected from the group consisting of (i) secretory proteins and (ii) extracellular domains of transmembrane proteins, m) the first domain and the second domain are Fc domains, the third domain is selected from the group consisting of (i) secretory proteins and (ii) extracellular domains of transmembrane proteins, and the fourth domain is Fab, n) the first domain and the second domain are Fc domains, the third domain and the fourth domain are Fab domains, o) the first domain and the second domain are Fc domains, the third domain and the fourth domain are each an ACE2 peptidase domain (PD), p) the first domain is an Fc domain, the second domain, the third domain and the fourth domain 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-15Rαsushi 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 Fab.

86. The tetrahedral molecule of claim 84 or claim 85, wherein the first dimerizing polypeptide and the second dimerizing polypeptide are selected from the group consisting of: a) a dimerization domain of an extracellular protein dimer, and b) Dimerization domain of intracellular protein dimer.

87. The tetrahedral molecule of claim 84 or claim 85, wherein the first dimerizing polypeptide and the second dimerizing polypeptide are selected from the group consisting of: a) Leucine zipper domain, b) Collector-like domain (CLD), c) collecting protein domains (CD), d) CD8α extracellular domain, and e) CD8β extracellular domain.

88. The tetrahedral molecule of any one of claims 84 to 87, wherein: a) the first dimerization polypeptide is identical to the second dimerization polypeptide, and b) the dimerized polypeptide forms a homodimer.

89. The tetrahedral molecule of any one of claims 84 to 87, wherein: a) the first dimerization polypeptide is different from the second dimerization polypeptide, and b) The first dimerization polypeptide and the second dimerization polypeptide form a heterodimer.

90. The tetrahedral molecule of claim 84 or claim 85, wherein: a) the first dimerization polypeptide and the second dimerization polypeptide are selected from the group consisting of: i) T cell receptor alpha extracellular domain and T cell receptor beta extracellular domain, ii) a T cell receptor gamma extracellular domain and a T cell receptor extracellular domain, iii) MHC class I alpha extracellular domain and beta-2 microglobulin, iv) an MHC class II alpha extracellular domain and an MHC class II beta extracellular domain, and v) CD8α extracellular domain and CD8β extracellular domain, b) the first dimerization polypeptide is different from the second dimerization polypeptide, and c) the first dimerization polypeptide and the second dimerization polypeptide form a heterodimer.

91. The tetrahedral molecule of claim 89 or claim 90, wherein the first dimerizing polypeptide and the second dimerizing polypeptide form less than 30%, 20%, 10%, 5%, 4%, 3%, 2% or 1% homodimers when present with each other.

92. A non-naturally occurring fusion protein dimer comprising a dimer of a first dimerizing polypeptide and a second dimerizing polypeptide, wherein: a) the first dimerization polypeptide is linked to the first domain at its N-terminus or C-terminus via a peptide bond or via a peptide linker, and the second dimerization polypeptide is optionally linked to the second domain at its N-terminus or C-terminus via a peptide bond or via a peptide linker, b) the first dimerization polypeptide and the second dimerization polypeptide are selected from the group consisting of: i) a collector protein-like domain (CLD), and ii) collecting protein domains (CD), c) said first dimerization polypeptide is optionally linked to a third domain at its remaining free N-terminus or C-terminus via a peptide bond or via a peptide linker, and d) said second dimerization polypeptide is optionally linked at its remaining free N-terminus or C-terminus to the fourth domain via a peptide bond or via a peptide linker.

93. The tetrahedral molecule of any one of claims 84 to 91, or the non-naturally occurring fusion protein dimer of claim 92, which: i) does not contain ACE2 PD on the N-terminal side of either dimerization polypeptide; and / or ii) does not contain an ACE2 transmembrane domain on the C-terminal side of either dimerization polypeptide.

94. An octahedral antibody comprising a first domain, a second domain, a third domain, a fourth domain, a fifth domain and a sixth domain, wherein: a) each of the first domain, the second domain and the third domain is selected from the group consisting of a Fab domain and an Fc domain, b) Each of the first domain, the second domain and the third domain comprises: 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 the domain, 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 joined to each other via a non-peptidyl linkage, wherein the non-peptidyl linkage is: i) the side chains are covalently linked, or ii) non-covalent bonding between (1) a first trimerizing polypeptide connected to the first N-terminus of the first domain via a peptide bond or via a peptide linker, (2) a second trimerizing polypeptide connected to the first N-terminus of the second domain via a peptide bond or via a peptide linker, (3) a third trimerizing polypeptide connected to the first N-terminus of the third domain via a peptide bond or via a peptide linker, wherein the first trimerizing polypeptide, the second trimerizing polypeptide and the third trimerizing polypeptide are not immunoglobulin polypeptides, d) the fourth domain is linked at its C-terminus via a peptide bond or via a peptide linker to: i) the second N-terminus of the first domain, or ii) the N-terminus of said first trimerizing polypeptide, e) the fifth domain is connected at its C-terminus via a peptide bond or via a peptide linker to: i) the second N-terminus of the second domain, or ii) the N-terminus of the second trimerizing polypeptide, and f) the sixth domain is connected at its C-terminus via a peptide bond or via a peptide linker to: i) the second N-terminus of the third domain, or ii) the N-terminus of the third trimerizing polypeptide.

95. The octahedral antibody of claim 94, wherein the non-peptidyl linkage is a non-covalent linkage between a first trimerizing polypeptide linked to a first N-terminus of the first domain, a second trimerizing polypeptide linked to a first N-terminus of the second domain, and a third trimerizing polypeptide linked to a first N-terminus of the third domain, wherein the first trimerizing polypeptide, the second trimerizing polypeptide, and the third trimerizing polypeptide are selected from the group consisting of the following TNF ligand superfamily members: OX40L / TNFLSF4, CD40L / TNFLSF5, FASL / TNFLSF6, CD70L / TNFLSF 7, CD30L / TNFLSF8, 4-1BBL / TNFLSF9, TRAIL / TNFLSF10, RANKL / TNFLSF11, TWEAK / TNFLSF12, APRIL / TNFLSF13, BAFF / TNFLSF13B, LIGHT / TNFLSF14, VEGI / TNFLSF15, GITRL / TNFLSF18, EctodyplasinATNFLSF19, TNF / TNFLSF2, lymphotoxin α / TNFLSF1 and lymphotoxin β / TNFLSF3.

96. The octahedral antibody of claim 94 or claim 95, further comprising a seventh domain, an eighth domain and / or a ninth domain, wherein: a) the seventh domain is connected at its C-terminus to the second N-terminus of the first domain via a peptide bond or via a peptide linker, b) the eighth domain is connected at its C-terminus to the second N-terminus of the second domain via a peptide bond or via a peptide linker, and / or c) the ninth domain is connected at its C-terminus to the second N-terminus of the third domain via a peptide bond or via a peptide linker.

97. The octahedral antibody according to any one of claims 94 to 96, further comprising a tenth domain, an eleventh domain and / or a twelfth domain, wherein: a) the tenth domain is connected at its N-terminus via a peptide bond or via a peptide linker to: i) a first C-terminus of the first domain, or ii) a second C-terminus of the first domain, b) the eleventh domain is linked at its N-terminus via a peptide bond or via a peptide linker to: i) a first C-terminus of the second domain, or ii) a second C-terminus of the second domain, c) the twelfth domain is connected at its N-terminus via a peptide bond or via a peptide linker to: i) a first C-terminus of the third domain, or ii) a second C-terminus of the third domain.

98. The tetrahedral antibody or octahedral antibody, non-naturally occurring fusion protein dimer or tetrahedral molecule according to any one of claims 1 to claim 97, wherein: a) one or more of the first domain, the second domain, the third domain, the fourth domain, the fifth domain, the sixth domain, the seventh domain, and the eighth domain of the tetrahedral antibody, or one or more of the first domain, the second domain, the third domain, the fourth domain, the fifth domain, the sixth domain, the seventh domain, the eighth domain, the ninth domain, the tenth domain, the eleventh domain, and the twelfth domain of the octahedral antibody is an Fc domain, wherein the one or more Fc domains are independently selected from any Fc domain disclosed herein, b) one or more of the first domain, the second domain, the third domain, the fourth domain, the fifth domain, the sixth domain, the seventh domain, and the eighth domain of the tetrahedral antibody, or one or more of the first domain, the second domain, the third domain, the fourth domain, the fifth domain, the sixth domain, the seventh domain, the eighth domain, the ninth domain, the tenth domain, the eleventh domain, and the twelfth domain of the octahedral antibody is a Fab domain, wherein the one or more Fab domains are independently selected from any Fab domain disclosed herein, c) one or more of the third domain, the fourth domain, the fifth domain, the sixth domain, the seventh domain, and the eighth domain of the tetrahedral antibody, or one or more of the fourth domain, the fifth domain, the sixth domain, the seventh domain, the eighth domain, the ninth domain, the tenth domain, the eleventh domain, and the twelfth domain of the octahedral antibody is a secreted protein, wherein the one or more secreted proteins are independently selected from any secreted protein disclosed herein, d) one or more of the third domain, the fourth domain, the fifth domain, the sixth domain, the seventh domain, and the eighth domain of the tetrahedral antibody, or one or more of the fourth domain, the fifth domain, the sixth domain, the seventh domain, the eighth domain, the ninth domain, the tenth domain, the eleventh domain, and the twelfth domain of the octahedral antibody is an extracellular domain of a transmembrane protein, wherein the extracellular domains of the one or more transmembrane proteins are independently selected from the extracellular domains of any transmembrane protein disclosed herein, e) one or more of the third domain, the fourth domain, the fifth domain, the sixth domain, the seventh domain and the eighth domain of the tetrahedral antibody, or one or more of the fourth domain, the fifth domain, the sixth domain, the seventh domain, the eighth domain, the ninth domain, the tenth domain, the eleventh domain and the twelfth domain of the octahedral antibody: i) includes the structure of a compound that is a drug approved for treating an individual suffering from a disease, ii) a structure comprising an organic compound with a molecular weight of less than 1000 Daltons, a DNA aptamer, an RNA aptamer, an oligonucleotide or a biologically active protein, iii) comprises a primary or secondary amine, iv) is aripiprazole or oseltamivir, v) is a respiratory drug, an antiasthmatic, analgesic, antidepressant, antianginal, antiarrhythmic, antihypertensive, antidiabetic, antihistamine, anti-infective, antibiotic, anti-inflammatory, anti-Parkinson's disease drug, antipsychotic, antipyretic, anti-ulcer, attention deficit hyperactivity disorder (ADHD) drug, central nervous system stimulant, decongestant or psychostimulant, vi) alprenolol, acebutolol, amidephrine, amineptine, amosulalol, amoxapine, amphetamine, atenolol, atomoxetine, balofloxacin, bamethan, befunolol, benazepril, benfluorex, benzotamine benzoctamine, betahistine, betaxolol, bevantolol, bifemelane, bisoprolol, brinzolamide, bufeniode, butethamine, camylofine, carazolol, carticaine, carvedilol, cephaeline, ciprofloxacin ofloxacin, cloZapine, clobenZorex, clorprenaline, cyclopentamine, delapril, demexiptiline, denopamine, desipramine, desloratadine, diclofenac, dimetofrine, dioxadrol, dobutamine, dopexamine, doripenem, dorzolamide, droprenilamine, duloxetine, eltopraZine, enalapril, enoxacin, epinephrine, ertapenem, esapraZole, esmolol, etoxadrol, fasudil, fendiline,Fenethylline, fenfluramine, fenoldopam, fenoterol, fenproporex, flecamide, fluoxetine, formoterol, frovatriptan, gaboxadol, garenoxacin, gatifloxacin, grepafloxacin, hexoprenaline, imidapril, indalpine, indecainide, indeloxazine hydrochloride hydrochloride), isoxsuprine, ispronicline, labetalol, landiolol, lapatinib, levophacetoperane, lisinopril, lomefloxacin, lotrafiban, maprotiline, mecamylamine, mefloquine, mepindolol, meropenem, metapramine, metaproterenol, methoxyphenamine, dextrorotary methylphenidate, methylphenidate, metipranolol, metoprolol, mitoxantrone, mivazerol, moexipril, moprolol, moxifloxacin, nebivolol, nifenalol, nipradilol, norfloxacin, nortriptyline, nylidrin, olanZapine, oxamniquine, oxprenolol, oxyfedrine,paroxetine, perhexyline, phenmetrazine, phenylephrine, phenylpropylmethylamine, pholedrine, picilorex, pimethylline, pindolol, pipemidicacid, piridocaine, practolol, pradofloxacin, pramipexole, pramiverin, prenalterol, prenylamine, prilocalne, procaterol, pronethalol, propafenone, propranolol, propylhexedrine, protokylol, protriptyline, pseudoephedrine, reboxetine tine), rasagiline, (r)-rasagiline, repinotan, reproterol, rimiterol, ritodrine, safinamide, salbutamol / albuterol, salmeterol, sarizotan, sertraline, silodosin, sotalol, soterol enol), sparfloxacin, spirapril, sulfinalol, synephrine, tamsulosin, tebanicline, tianeptine, tirofiban, tretoquinol, trimetazidine, troxipide, varenicline, vildagliptin, viloxazine,viquidil or xamoterol, vii) contains biologically active proteins, viii) having biological activity such that it has target binding activity, ix) is an independently folded protein or a portion thereof, x) is a glycosylated protein, xi) includes intrachain disulfide bonds, xii) binding to cytokines, xiii) binding to a cytokine, wherein the cytokine is TNFα, xiv) includes atrial natriuretic peptide (ANP), calcitonin, corticotropin-releasing hormone (CRH), endothelin, exenatide, gastric inhibitory peptide (GIP), glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 (GLP-2), GLP-1 or GLP-2 analogs, glucagon vasoactive intestinal polypeptide (GVIP), ghrelin, peptide YY or secretin or a portion thereof, xv) comprising a stretch of consecutive amino acids in the sequence HGEGTFTSDVSSYLEEQAAKEFIAWLVKGRG (SEQ ID NO: 4657), xvi) comprises at least one continuous stretch of amino acids that is identical to a continuous stretch of amino acids present in the heavy chain of Fab or Fab' of an antibody, xvii) comprises at least one continuous stretch of amino acids that is identical to a continuous stretch of amino acids present in the light chain of Fab or Fab' of an antibody, xviii) comprises at least one Fab or Fab' or at least a portion of a Fab or Fab' of an antibody, xix) comprising Fab-1 or Fab'1 of an antibody or a portion thereof, xx) comprises Fab-2 or Fab'2 of an antibody or a portion thereof, xxi) comprises two Fab or Fab' hands of an antibody, xxii) comprises at least one stretch of consecutive amino acids that is identical to a stretch of consecutive amino acids present in a single-chain antibody, or xxiii) comprises at least one consecutive stretch of amino acids that is identical to a consecutive stretch of amino acids present in TNFα receptor, f) the tetrahedral antibody or octahedral antibody comprises a covalent linkage, wherein the covalent linkage is selected from any covalent linkage disclosed herein or comprises any heterobifunctional cross-linker disclosed herein, and / or g) the tetrahedral antibody or octahedral antibody comprises one or more peptide linkers, wherein the one or more peptide linkers are independently selected from: i) as the sequence TSTSPTRSMAGAVHLPQPVSTRSQHTQPTPEPSTAPSTSFLLPMGPSPPAEGSTGD (SEQ ID NO: 3227) or a stretch of consecutive amino acids present in said sequence, ii) as the sequence GGGGAGGGGAGGGGAGGGGAGGGGAGGG (SEQ ID NO: 3226) or a stretch of consecutive amino acids present in said sequence, or iii) any peptide linker disclosed herein.

99. A composition comprising 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 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%, 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 %, 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% of the tetrahedral antibody or octahedral antibody of any one of claims 1 to claim 98 as the ratio (w / w) of peptide-containing molecules in the composition.

100. A pharmaceutical composition comprising the composition of claim 99 and one or more pharmaceutically acceptable excipients.

101. A method for preparing the tetrahedral antibody of any one of claims 17 to claim 31, wherein the non-peptidyl linkage of the tetrahedral antibody is a non-covalent linkage between a first dimerization polypeptide linked to the first N-terminus of the first domain and a second dimerization polypeptide linked to the first N-terminus of the second domain, the method comprising: a) recombinantly expressing in a host cell each of the following polypeptides: i) a first polypeptide, the first polypeptide comprising, from its N-terminus to its C-terminus, (1) Optionally, the third domain is connected at its C-terminus to (2) the N-terminus of the first dimerization polypeptide, the first dimerization polypeptide is connected at its C-terminus via a peptide bond or a peptide linker (3) the N-terminus of the first polypeptide chain of the first domain, ii) a second polypeptide, said second polypeptide comprising, from its N-terminus to its C-terminus, (1) Optionally, the fourth domain is connected at its C-terminus to (2) the N-terminus of the second dimerization polypeptide, the second dimerization polypeptide is connected at its C-terminus via a peptide bond or a peptide linker (3) the N-terminus of the first polypeptide chain of the second domain, iii) a third polypeptide, said third polypeptide comprising, from its N-terminus to its C-terminus, (1) the third domain, if the third domain is not present on the first polypeptide, the third domain is connected at its C-terminus via a peptide bond or via a peptide linker (a) the N-terminus of a third dimerization polypeptide, said third dimerization polypeptide being linked at its C-terminus to the N-terminus of the second polypeptide chain of the first domain via a peptide bond or via a peptide linker, or (b) the N-terminus of the second polypeptide chain of the first domain, iv) a fourth polypeptide, said fourth polypeptide comprising, from its N-terminus to its C-terminus, (1) the fourth domain, if the fourth domain is not present on the second polypeptide, the fourth domain is connected at its C-terminus via a peptide bond or via a peptide linker (a) the N-terminus of a fourth dimerization polypeptide, said fourth dimerization polypeptide being linked at its C-terminus to the N-terminus of the second polypeptide chain of the first domain via a peptide bond or via a peptide linker, or (b) the N-terminus of the second polypeptide chain of the first domain, and v) optionally one or more additional polypeptides comprising the second polypeptide chain of the third domain and / or the fourth domain, if the second polypeptide chain is present.

102. A method for preparing the tetrahedral antibody of any one of claims 17 to claim 31, wherein the non-peptidyl linkage of the tetrahedral antibody is a non-covalent linkage between a first dimerization polypeptide linked to a first C-terminus of the first domain and a second dimerization polypeptide linked 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) a first polypeptide, said first polypeptide comprising, from its N-terminus to its C-terminus, (1) the first polypeptide chain of the first domain, the first polypeptide chain being connected at its C-terminus to (2) the N-terminus of the first dimerization polypeptide, the first dimerization polypeptide is optionally connected to the C-terminus of the first dimerization polypeptide via a peptide bond or a peptide linker (3) the N-terminus of the third domain, ii) a second polypeptide, said second polypeptide comprising, from its N-terminus to its C-terminus, (1) Optionally, the fourth domain is connected at its C-terminus to (2) the N-terminus of the second dimerization polypeptide, the second dimerization polypeptide is connected at its C-terminus via a peptide bond or a peptide linker (3) the N-terminus of the first polypeptide chain of the second domain, iii) a third polypeptide, said third polypeptide comprising, from its N-terminus to its C-terminus, (1) the second polypeptide chain of the first domain, the second polypeptide chain being connected at its C-terminus via a peptide bond or a peptide linker (a) the N-terminus of a third dimerization polypeptide, which in turn is linked at its C-terminus to the N-terminus of the third domain via a peptide bond or via a peptide linker, if the third domain is not present on the first polypeptide, or (b) the N-terminus of the third domain, if the third domain is not present on the first polypeptide, iv) a fourth polypeptide, said fourth polypeptide comprising, from its N-terminus to its C-terminus, (1) the fourth domain, if the fourth domain is not present on the second polypeptide, the fourth domain is connected at its C-terminus via a peptide bond or via a peptide linker (a) the N-terminus of a fourth dimerization polypeptide, which in turn is linked at its C-terminus to the N-terminus of the second polypeptide chain of the first domain via a peptide bond or via a peptide linker, or (b) the N-terminus of the second polypeptide chain of the first domain, and v) optionally one or more additional polypeptides comprising the second polypeptide chain of the third domain and / or the fourth domain, if the second polypeptide chain is present.

103. A method for preparing the tetrahedral antibody of any one of claims 17 to claim 31, wherein the non-peptidyl linkage of the tetrahedral antibody is a non-covalent linkage between a first dimerization polypeptide linked to a first N-terminus of the first domain and a second dimerization polypeptide linked 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) a first polypeptide, said first polypeptide comprising, from its N-terminus to its C-terminus, (1) Optionally, the third domain is connected at its C-terminus to (2) the N-terminus of the first dimerization polypeptide, the first dimerization polypeptide is connected at its C-terminus via a peptide bond or a peptide linker (3) the N-terminus of the first polypeptide chain of the first domain, ii) a second polypeptide, said second polypeptide comprising, from its N-terminus to its C-terminus, (1) the first polypeptide chain of the second domain, the first polypeptide chain is connected at its C-terminus via a peptide bond or a peptide linker (2) the N-terminus of the second dimerization polypeptide, which is optionally linked at its C-terminus to the (3) the N-terminus of the third domain, iii) a third polypeptide, said third polypeptide comprising, from its N-terminus to its C-terminus, (1) the third domain, if the third domain is not present on the first polypeptide, the third domain is connected at its C-terminus via a peptide bond or via a peptide linker (a) the N-terminus of a third dimerization polypeptide, which in turn is linked at its C-terminus to the N-terminus of the second polypeptide chain of the first domain via a peptide bond or via a peptide linker, or (b) the N-terminus of the second polypeptide chain of the first domain, iv) a fourth polypeptide, said fourth polypeptide comprising, from its N-terminus to its C-terminus, (1) the second polypeptide chain of the first domain, the second polypeptide chain being connected at its C-terminus via a peptide bond or a peptide linker (a) the N-terminus of a fourth dimerization polypeptide, which in turn is linked at its C-terminus to the N-terminus of the fourth domain by a peptide bond or by a peptide linker if the fourth domain is not present on the second polypeptide; or (b) the N-terminus of the fourth domain, if the fourth domain is not present on the second polypeptide, and v) optionally, one or more additional polypeptides comprising the second polypeptide chain of the third domain and / or the fourth domain, if the second polypeptide chain is present.

104. A method for preparing the tetrahedral antibody of any one of claims 17 to claim 31, wherein the non-peptidyl linkage of the tetrahedral antibody is a non-covalent linkage between a first dimerization polypeptide linked to the first C-terminus of the first domain and a second dimerization polypeptide linked to the first C-terminus of the second domain, the method comprising: a) recombinantly expressing in a host cell each of the following polypeptides: i) a first polypeptide, said first polypeptide comprising, from its N-terminus to its C-terminus, (1) the first polypeptide chain of the first domain, the first polypeptide chain being connected at its C-terminus to (2) the N-terminus of the first dimerization polypeptide, which is optionally connected at its C-terminus to the (3) the N-terminus of the third domain, ii) a second polypeptide, said second polypeptide comprising, from its N-terminus to its C-terminus, (1) the first polypeptide chain of the second domain, the first polypeptide chain being connected at its C-terminus to (2) the N-terminus of the second dimerization polypeptide, which is optionally linked at its C-terminus to the (3) the N-terminus of the third domain, iii) a third polypeptide, said third polypeptide comprising, from its N-terminus to its C-terminus, (1) the second polypeptide chain of the first domain, the second polypeptide chain being connected at its C-terminus via a peptide bond or a peptide linker (a) the N-terminus of a third dimerization polypeptide, which in turn is linked at its C-terminus to the N-terminus of the third domain via a peptide bond or via a peptide linker, if the third domain is not present on the first polypeptide, or (b) the N-terminus of the third domain, if the third domain is not present on the first polypeptide, iv) a fourth polypeptide, said fourth polypeptide comprising, from its N-terminus to its C-terminus, (1) the second polypeptide chain of the first domain, the second polypeptide chain being connected at its C-terminus via a peptide bond or a peptide linker (a) the N-terminus of a fourth dimerization polypeptide, which in turn is linked at its C-terminus to the N-terminus of the fourth domain by a peptide bond or by a peptide linker if the fourth domain is not present on the second polypeptide; or (b) the N-terminus of the fourth domain, if the fourth domain is not present on the second polypeptide, and v) optionally one or more additional polypeptides comprising the second polypeptide chain of the third domain and / or the fourth domain, if the second polypeptide chain is present.

105. A method for preparing the tetrahedral antibody of any one of claims 32 to 50, wherein the non-peptidyl linkage of the tetrahedral antibody is a non-covalent linkage between a first dimerization polypeptide linked to the first N-terminus of the first domain and a second dimerization polypeptide linked to the first N-terminus of the second domain, the method comprising: a) recombinantly expressing in a host cell each of the following polypeptides: i) a first polypeptide, said first polypeptide comprising, from its N-terminus to its C-terminus, (1) the third domain or the fifth domain, if the fifth domain exists, is connected at its C-terminus to (2) the N-terminus of the first dimerization polypeptide, the first dimerization polypeptide is connected at its C-terminus via a peptide bond or a peptide linker (3) the N-terminus of the first polypeptide chain of the first domain, ii) a second polypeptide, said second polypeptide comprising, from its N-terminus to its C-terminus, (1) the fourth domain or the sixth domain, if the sixth domain exists, is connected at its C-terminus to (2) the N-terminus of the second dimerization polypeptide, the second dimerization polypeptide is connected at its C-terminus via a peptide bond or a peptide linker (3) the N-terminus of the first polypeptide chain of the second domain, iii) a third polypeptide, said third polypeptide comprising, from its N-terminus to its C-terminus, (1) the third domain, if the third domain is not present on the first polypeptide, or the fifth domain, if the fifth domain is present, the third domain or the fifth domain is linked at its C-terminus via a peptide bond or via a peptide linker to (a) the N-terminus of a third dimerization polypeptide, which in turn is linked at its C-terminus to the N-terminus of the second polypeptide chain of the first domain via a peptide bond or via a peptide linker, or (b) the N-terminus of the second polypeptide chain of the first domain, iv) a fourth polypeptide, said fourth polypeptide comprising, from its N-terminus to its C-terminus, (1) the fourth domain, if the fourth domain is not present on the second polypeptide, or the sixth domain, if the sixth domain is present, the fourth domain or the sixth domain is linked at its C-terminus via a peptide bond or via a peptide linker to (a) the N-terminus of a fourth dimerization polypeptide, which in turn is linked at its C-terminus to the N-terminus of the second polypeptide chain of the first domain via a peptide bond or via a peptide linker, or (b) the N-terminus of the second polypeptide chain of the first domain, and v) optionally one or more additional polypeptides comprising the second polypeptide chain of the third, fourth, fifth and / or sixth domain, if present.

106. A method for preparing the tetrahedral antibody of any one of claims 32 to 46, wherein the non-peptidyl linkage of the tetrahedral antibody is a non-covalent linkage between a first dimerization polypeptide linked to a first C-terminus of the first domain and a second dimerization polypeptide linked 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) a first polypeptide, said first polypeptide comprising, from its N-terminus to its C-terminus, (1) the first polypeptide chain of the first domain, the first polypeptide chain being connected at its C-terminus to (2) the N-terminus of the first dimerization polypeptide, the first dimerization polypeptide is connected at its C-terminus via a peptide bond or a peptide linker (3) the N-terminus of the third domain or the N-terminus of the fifth domain, if the fifth domain exists, ii) a second polypeptide, said second polypeptide comprising, from its N-terminus to its C-terminus, (1) the fourth domain or the sixth domain, if the sixth domain exists, is connected at its C-terminus to (2) the N-terminus of the second dimerization polypeptide, the second dimerization polypeptide is connected at its C-terminus via a peptide bond or a peptide linker (3) the N-terminus of the first polypeptide chain of the second domain, iii) a third polypeptide, said third polypeptide comprising, from its N-terminus to its C-terminus, (1) the second polypeptide chain of the first domain, the second polypeptide chain being connected at its C-terminus via a peptide bond or a peptide linker (a) the N-terminus of the third dimerization polypeptide, which in turn is linked at its C-terminus via a peptide bond or via a peptide linker to the N-terminus of the third domain, if the third domain is not present on the first polypeptide, or to the N-terminus of the fifth domain, if the fifth domain is present, or (b) the N-terminus of the third domain, if the third domain is not present on the first polypeptide, or the N-terminus of the fifth domain, if present, iv) a fourth polypeptide, said fourth polypeptide comprising, from its N-terminus to its C-terminus, (1) the fourth domain, if the fourth domain is not present on the second polypeptide, or the sixth domain, if the sixth domain is present, the fourth domain or the sixth domain is linked at its C-terminus to (a) the N-terminus of a fourth dimerization polypeptide, which in turn is linked at its C-terminus to the N-terminus of the second polypeptide chain of the first domain via a peptide bond or via a peptide linker, or (b) the N-terminus of the second polypeptide chain of the first domain, and v) optionally one or more additional polypeptides comprising the second polypeptide chain of the third, fourth, fifth and / or sixth domain, if present.

107. A method for preparing the tetrahedral antibody of any one of claims 32 to 46, wherein the non-peptidyl linkage of the tetrahedral antibody is a non-covalent linkage between a first dimerization polypeptide linked to a first N-terminus of the first domain and a second dimerization polypeptide linked 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) a first polypeptide, said first polypeptide comprising, from its N-terminus to its C-terminus, (1) the third domain or the fifth domain, if the fifth domain exists, is connected at its C-terminus to (2) the N-terminus of a first dimerization polypeptide, wherein the first dimerization polypeptide is connected at its C-terminus to (3) the N-terminus of the first polypeptide chain of the first domain, ii) a second polypeptide, said second polypeptide comprising, from its N-terminus to its C-terminus, (1) the first polypeptide chain of the second domain, the first polypeptide chain being connected at its C-terminus to (2) the N-terminus of the second dimerization polypeptide, the second dimerization polypeptide is connected at its C-terminus via a peptide bond or a peptide linker (3) the N-terminus of the fourth domain or the N-terminus of the sixth domain, if the sixth domain exists, iii) a third polypeptide, said third polypeptide comprising, from its N-terminus to its C-terminus, (1) the third domain, if the third domain is not present on the first polypeptide, or the fifth domain, if the fifth domain is present, the third domain or the fifth domain is linked at its C-terminus to (a) the N-terminus of a third dimerization polypeptide, which in turn is linked at its C-terminus to the N-terminus of the second polypeptide chain of the first domain via a peptide bond or via a peptide linker, or (b) the N-terminus of the second polypeptide chain of the first domain, and iv) a fourth polypeptide, said fourth polypeptide comprising, from its N-terminus to its C-terminus, (1) the second polypeptide chain of the first domain, the second polypeptide chain being connected at its C-terminus via a peptide bond or a peptide linker (a) the N-terminus of the fourth dimerization polypeptide, which in turn is linked at its C-terminus via a peptide bond or via a peptide linker to the N-terminus of the fourth domain, if the fourth domain is not present on the second polypeptide, or to the N-terminus of the sixth domain, if the sixth domain is present, or (b) the N-terminus of the fourth domain, if the fourth domain is not present on the second polypeptide, or the N-terminus of the sixth domain, if the sixth domain is present, and v) optionally one or more additional polypeptides comprising the second polypeptide chain of said third, fourth, fifth and / or sixth domain, if present.

108. A method for preparing the tetrahedral antibody of any one of claims 32 to 46, wherein the non-peptidyl linkage of the tetrahedral antibody is a non-covalent linkage between a first dimerization polypeptide linked to the first C-terminus of the first domain and a second dimerization polypeptide linked to the first C-terminus of the second domain, the method comprising: a) recombinantly expressing in a host cell each of the following polypeptides: i) a first polypeptide, said first polypeptide comprising, from its N-terminus to its C-terminus, (1) the first polypeptide chain of the first domain, the first polypeptide chain being connected at its C-terminus to (2) the N-terminus of a first dimerization polypeptide, wherein the first dimerization polypeptide is connected at its C-terminus to (3) the N-terminus of the third domain, or the N-terminus of the fifth domain, if the fifth domain exists, ii) a second polypeptide, said second polypeptide comprising, from its N-terminus to its C-terminus, (1) the first polypeptide chain of the second domain, the first polypeptide chain being connected at its C-terminus to (2) the N-terminus of the second dimerization polypeptide, the second dimerization polypeptide is connected at its C-terminus via a peptide bond or a peptide linker (3) the N-terminus of the fourth domain, or the N-terminus of the sixth domain, if the sixth domain exists, iii) a third polypeptide, said third polypeptide comprising, from its N-terminus to its C-terminus, (1) the second polypeptide chain of the first domain, the second polypeptide chain being connected at its C-terminus via a peptide bond or a peptide linker (a) the N-terminus of the third dimerization polypeptide, which in turn is linked at its C-terminus via a peptide bond or via a peptide linker to the N-terminus of the third domain, if the third domain is not present on the first polypeptide, or to the N-terminus of the fifth domain, if the fifth domain is present, or (b) the N-terminus of the third domain, if the third domain is not present on the first polypeptide, or the N-terminus of the fifth domain, if the fifth domain is present, and iv) a fourth polypeptide, said fourth polypeptide comprising, from its N-terminus to its C-terminus, (1) the second polypeptide chain of the first domain, the second polypeptide chain being connected at its C-terminus via a peptide bond or a peptide linker (a) the N-terminus of the fourth dimerization polypeptide, which in turn is linked at its C-terminus via a peptide bond or via a peptide linker to the N-terminus of the fourth domain, if the fourth domain is not present on the second polypeptide, or to the N-terminus of the sixth domain, if the sixth domain is present, or (b) the N-terminus of the fourth domain, if the fourth domain is not present on the second polypeptide, or the N-terminus of the sixth domain, if the sixth domain is present, and v) optionally one or more additional polypeptides comprising the polypeptide of the second polypeptide chain of the third, fourth, fifth and / or sixth domain, if the second polypeptide chain is present.

109. The tetrahedral antibody of any one of claims 17 to 25, wherein the first domain is an Fc domain, the second domain, the third domain and the fourth domain are Fab domains, wherein: a) the third domain and the fourth domain comprise a first type of Fab, and the second domain comprises a second type of Fab, i) the first type of Fab is formed by VH-CH on the H1 or H2 chain and VL-CL on the L1 chain, and the second type of Fab is formed by VL-CH on the H1 chain and VH-CL domain on the L2 chain; ii) the first type of Fab is formed by the VL-CH domain on the H1 or H2 chain and the VH-CL domain on the L1 chain, and the second type of Fab is formed by the VH-CH domain on the H2 chain and the VL-CL domain on the L2 chain, or iii) the first type of Fab is formed by VH-CH on the H1 or H2 chain and VL-CL on the L1 chain, and the second type of Fab is formed by VH-CH on the H2 chain and VL-CL on the L2 chain, wherein VL is a kappa and / or lambda light chain V region.

110. The tetrahedral antibody of claim 32, wherein the third domain, the fourth domain, the fifth domain and the sixth domain are Fab domains, wherein a) the third domain and the fourth domain comprise a first type of Fab, the fifth domain and / or the sixth domain comprise a second type of Fab, and i) the first type of Fab is formed by the VH-CH domain on the H1 chain and the VL-CL domain on the L1 chain, and the second type of Fab is formed by the VL-CH domain on the H2 chain and the VH-CL domain on the L2 chain; ii) the first type of Fab is formed by the VL-CH domain on the H1 chain and the VH-CL domain on the L1 chain, and the second type of Fab is formed by the VH-CH domain on the H2 chain and the VL-CL domain on the L2 chain; or iii) the first type of Fab is formed by the VH-CH domains on the H1 chain and the VL-CL domains on the L1 chain, and the second type of Fab is formed by the VH-CH domains on the H2 chain and the VL-CL domains on the L2 chain, wherein VL is a kappa and / or lambda light chain V region.

111. The tetrahedral antibody of claim 109 or claim 110, wherein: a) one type of Fab comprises a Q39K mutation and an S183E mutation in its heavy chain portion, and a Q38E mutation and a V133K mutation in its light chain portion, and another type of Fab comprises an S183K mutation and a Q38E mutation in its heavy chain portion, and a V133E mutation and a Q39K mutation in its light chain portion; b) one type of Fab comprises Q39K mutation and S183E mutation in its heavy chain portion, and Q38E mutation and V133K mutation in its light chain portion, and another type of Fab comprises S183K mutation and Q38K mutation in its heavy chain portion, and V133E mutation and Q39E mutation in its light chain portion; c) one type of Fab comprises Q39E mutation and S183E mutation in its heavy chain portion, and Q38E mutation and V133K mutation in its light chain portion, and another type of Fab comprises S183K mutation and Q38E mutation in its heavy chain portion, and V133E mutation and Q39K mutation in its light chain portion; d) one type of Fab comprises Q39E mutation and S183E mutation in its heavy chain portion, and Q38K mutation and V133K mutation in its light chain portion, and another type of Fab comprises S183K mutation and Q38K mutation in its heavy chain portion, and S176E mutation and Q39E mutation in its light chain portion; e) one type of Fab comprises a Q39K mutation and an S183E mutation in its heavy chain portion, and a Q38E mutation and an S176K mutation in its light chain portion, and another type of Fab comprises an S183K mutation and a Q38E mutation in its heavy chain portion, and an S176E mutation and a Q39K mutation in its light chain portion; f) one type of Fab comprises a Q39K mutation and an S183E mutation in its heavy chain portion, and a Q38E mutation and an S176K mutation in its light chain portion, and another type of Fab comprises an S183K mutation and a Q38K mutation in its heavy chain portion, and an S176E mutation and a Q39E mutation in its light chain portion; g) one type of Fab comprises a Q39E mutation and a S183E mutation in its heavy chain portion, and a Q38E mutation and a S176K mutation in its light chain portion, and the other type of Fab comprises a S183K mutation and a Q38E mutation in its heavy chain portion, and a S176E mutation and a Q39K mutation in its light chain portion; or h) One type of Fab comprises Q39E mutation and S183E mutation in its heavy chain portion, and Q38K mutation and S176K mutation in its light chain portion, and another type of Fab comprises S183K mutation and Q38K mutation in its heavy chain portion, and S176E mutation and Q39E mutation in its light chain portion.

Images