NZ789212A - Anti-c5 antibodies and methods of use - Google Patents

Abstract

The invention provides anti-C5 antibodies and methods of using the same. In some embodiments, an isolated anti-C5 antibody of the present invention binds to an epitope within the beta chain of C5 with a higher affinity at neutral pH than at acidic pH. The invention also provides isolated nucleic acids encoding an anti-C5 antibody of the present invention. The invention also provides host cells comprising a nucleic acid of the present invention. The invention also provides a method of producing an antibody comprising culturing a host cell of the present invention so that the antibody is produced. The invention further provides a method of producing an anti-C5 antibody comprising immunizing an animal against a polypeptide which comprises the MG1-MG2 domain of the beta chain of C5. Anti-C5 antibodies of the present invention may be for use as a medicament. ds encoding an anti-C5 antibody of the present invention. The invention also provides host cells comprising a nucleic acid of the present invention. The invention also provides a method of producing an antibody comprising culturing a host cell of the present invention so that the antibody is produced. The invention further provides a method of producing an anti-C5 antibody comprising immunizing an animal against a polypeptide which comprises the MG1-MG2 domain of the beta chain of C5. Anti-C5 antibodies of the present invention may be for use as a medicament.

Description

[DESCRIPTION] [Title of Invention] ANTI-C5 ANTIBODIES AND S OF USE This application is a divisional of New Zealand patent application 748003, which is the al phase entry in New Zealand of PCT international application (published as WO2017/217524) filed 16 June 2017, all of which are incorporated herein by reference in their entireties.

[Technical Field] The present invention relates to anti-C5 antibodies and methods of using the same.

[Background Art] The complement system plays a central role in the clearance of immune complexes and in immune responses to infectious agents, foreign antigens, virus-infected cells and tumor cells. There are about 25-30 complement proteins, which are found as a complex collection of plasma ns and membrane cofactors. Complement components achieve their immune defensive ons by cting in a series of intricate enzymatic cleavages and membrane binding events. The resulting complement cascades lead to the production of products with opsonic, immunoregulatory, and lytic functions.

Currently, it is widely accepted that the complement system can be activated through three distinct pathways: the classical pathway, the lectin y, and the alternative pathway. These pathways share many components, and while they differ in their initial steps, they converge and share the same terminal complement components (C5 through C9) responsible for the activation and ction of target cells.

The classical pathway is normally activated by the formation of antigen-antibody complexes. Independently, the first step in activation of the lectin pathway is the binding of specific lectins such as mannan-binding lectin (MBL), H-ficolin, M-ficolin, lin and C-type lectin CL-11. In st, the ative pathway spontaneously undergoes a low level of turnover tion, which can be readily amplified on foreign or other abnormal surfaces (bacteria, yeast, virally infected cells, or damaged tissue).

These pathways converge at a point where ment ent C3 is cleaved by an active protease to yield C3a and C3b.

C3a is an anaphylatoxin. C3b binds to bacterial and other cells, as well as to certain viruses and immune complexes, and tags them for removal from the ation (the role known as opsonin). C3b also forms a complex with other components to form C5 convertase, which cleaves C5 into C5a and C5b.

C5 is a 190 kDa protein found in normal serum at approximately 80 micro g/ml (0.4 micro M). C5 is glycosylated with about 1.5-3% of its mass attributed to carbohydrate.

Mature C5 is a heterodimer of 115 kDa alpha chain that is disulfide linked to 75 kDa beta chain. C5 is synthesized as a single chain precursor protein (pro-C5 precursor) of 1676 amino acids (see, e.g., PTL 1 and PTL 2). The pro-C5 precursor is d to yield the beta chain as an amino terminal fragment and the alpha chain as a carboxyl terminal fragment. The alpha chain and the beta chain polypeptide fragments are connected to each other via a disulfide bond and constitute the mature C5 protein.

Mature C5 is cleaved into the C5a and C5b nts during activation of the complement pathways. C5a is cleaved from the alpha chain of C5 by C5 tase as an amino terminal fragment sing the first 74 amino acids of the alpha chain. The remaining portion of mature C5 is nt C5b, which contains the rest of the alpha chain disulfide bonded to the beta chain. Approximately 20% of the 11 kDa mass of C5a is attributed to carbohydrate.

C5a is another anaphylatoxin. C5b combines with C6, C7, C8 and C9 to form the membrane attack complex (MAC, C5b-9, terminal complement complex (TCC)) at the surface of the target cell. When sufficient numbers of MACs are inserted into target cell membranes, MAC pores are formed to e rapid osmotic lysis of the target cells.

As mentioned above, C3a and C5a are anaphylatoxins. They can trigger mast cell degranulation, which releases histamine and other mediators of inflammation, resulting in smooth muscle contraction, increased vascular bility, leukocyte activation, and other inflammatory phenomena ing cellular proliferation resulting in hypercellularity. C5a also functions as a chemotactic peptide that serves to attract granulocytes such as neutrophils, eosinophils, basophils and monocytes to the site of complement tion.

The activity of C5a is regulated by the plasma enzyme carboxypeptidase N that removes the carboxy-terminal arginine from C5a forming C5a-des-Arg derivative. C5a-des-Arg exhibits only 1% of the anaphylactic activity and polymorphonuclear chemotactic activity of unmodified C5a.

While a properly functioning complement system provides a robust defense t ing microbes, inappropriate regulation or activation of complement has been implicated in the pathogenesis of a variety of disorders including, e.g., rheumatoid arthritis (RA); lupus nephritis; ischemia-reperfusion injury; paroxysmal nocturnal hemoglobinuria (PNH); atypical hemolytic uremic syndrome (aHUS); dense deposit e (DDD); macular degeneration (e.g., age-related macular degeneration ; hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome; thrombotic thrombocytopenic purpura (TTP); spontaneous fetal loss; Pauci-immune itis; molysis bullosa; recurrent fetal loss; multiple sclerosis (MS); traumatic brain injury; and injury resulting from myocardial infarction, cardiopulmonary bypass and hemodialysis (see, e.g., NPL 1). ore, inhibition of excessive or uncontrolled activations of the ment e can provide clinical benefits to patients with such disorders.

Paroxysmal nocturnal hemoglobinuria (PNH) is an uncommon blood disorder, wherein red blood cells are compromised and are thus destroyed more rapidly than normal red blood cells. PNH results from the clonal expansion of hematopoietic stem cells with somatic ons in the PIG-A (phosphatidylinositol glycan class A) gene which is d on the X chromosome. Mutations in PIG-A lead to an early block in the synthesis of glycosylphosphatidylinositol (GPI), a molecule which is required for the anchor of many proteins to cell surfaces. Consequently, PNH blood cells are deficient in GPI-anchored proteins, which include complement-regulatory proteins CD55 and CD59.

Under normal stances, these complement-regulatory proteins block the formation of MAC on cell surfaces, thereby preventing erythrocyte lysis. The absence of the GPI- anchored proteins causes complement-mediated hemolysis in PNH.

PNH is characterized by hemolytic anemia (a decreased number of red blood cells), hemoglobinuria (the presence of hemoglobin in urine, particularly t after sleeping), and hemoglobinemia (the presence of hemoglobin in the bloodstream). PNH- afflicted individuals are known to have paroxysms, which are defined here as incidences of dark-colored urine. Hemolytic anemia is due to intravascular destruction of red blood cells by complement ents. Other known symptoms include dysphasia, fatigue, erectile dysfunction, thrombosis and recurrent abdominal pain.

Eculizumab is a humanized monoclonal antibody directed against the complement protein C5, and the first therapy approved for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS) (see, e.g., NPL 2). Eculizumab inhibits the cleavage of C5 into C5a and C5b by C5 convertase, which prevents the generation of the terminal complement complex C5b-9. Both C5a and C5b- 9 cause the terminal complement-mediated events that are characteristic of PNH and aHUS (see also, PTL 3, PTL 4, PTL 5, and PTL 6).

Several s have described anti-C5 antibodies. For example, PTL 7 described an anti-C5 dy which binds to the alpha chain of C5 but does not bind to C5a, and blocks the activation of C5, while PTL 8 described an anti-C5 monoclonal antibody which inhibits C5a ion. On the other hand, PTL 9 described an anti-C5 antibody which recognizes the proteolytic site for C5 tase on the alpha chain of C5, and ts the conversion of C5 to C5a and C5b. PTL 10 described an anti-C5 antibody which has an affinity constant of at least 1 x107 M-1.

Antibodies (IgGs) bind to neonatal Fc or (FcRn), and have long plasma retention times. The binding of IgGs to FcRn is typically observed under acidic ions (e.g., pH 6.0), and it is rarely ed under neutral conditions (e.g., pH 7.4). Typically, IgGs are nonspecifically incorporated into cells via endocytosis, and return to the cell surfaces by binding to endosomal FcRn under the acidic conditions in the endosomes.

Then, IgGs dissociate from FcRn under the neutral conditions in plasma. IgGs that have failed to bind to FcRn are degraded in lysosomes. When the FcRn binding ability of an IgG under acidic conditions is eliminated by ucing mutations into its Fc region, the IgG is not recycled from the endosomes into the plasma, g to marked ment of the plasma retention of the IgG. To improve the plasma retention of IgGs, a method that enhances their FcRn binding under acidic conditions has been reported.

When the FcRn binding of an IgG under acidic conditions is improved by introducing an amino acid tution into its Fc region, the IgG is more efficiently recycled from the endosomes to the plasma, and thereby shows improved plasma retention. Meanwhile, it has also been reported that an IgG with enhanced FcRn binding under neutral ions does not dissociate from FcRn under the l conditions in plasma even when it returns to the cell surface via its binding to FcRn under the acidic conditions in the mes, and consequently its plasma retention remains unaltered, or rather, is worsened (see, e.g., NPL 3; NPL 4; NPL 5).

Recently, antibodies that bind to antigens in a pH-dependent manner have been ed (see, e.g., PTL 11and PTL 12). These antibodies strongly bind to antigens under the plasma l conditions and dissociate from the antigens under the endosomal acidic conditions. After dissociating from the antigens, the antibodies become capable once again of g to antigens when recycled to the plasma via FcRn. Thus, a single antibody molecule can repeatedly bind to le antigen les. In general, the plasma retention of an antigen is much shorter than that of an antibody that has the above-mentioned FcRn-mediated recycling ism. Therefore, when an antigen is bound to an dy, the antigen normally shows prolonged plasma retention, resulting in an increase of the plasma concentration of the antigen. On the other hand, it has been reported that the above-described antibodies, which bind to antigens in a pH-dependent manner, eliminate antigens from plasma more rapidly than typical antibodies because they dissociate from the antigens within the endosomes during the FcRn-mediated recycling process. PTL 13 also described computer modeling analysis showing that an antibody with pH-dependent binding directed against C5 could extend antigen knockdown.

[Citation List] [Patent Literature] [PTL 1] U.S. Patent No. 6,355,245 [PTL 2] U.S. Patent No. 7,432,356 [PTL 3] [PTL 4] [PTL 5] [PTL 6] [PTL 7] WO 95/29697 [PTL 8] WO 02/30985 [PTL 9] [PTL 10] [PTL 11] [PTL 12] [PTL 13] [Non Patent Literature] [NPL 1] Holers et al., Immunol. Rev. 0-316 (2008) [NPL 2] Dmytrijuk et al., The Oncologist 13(9):993-1000 (2008) [NPL 3] Yeung et al., J Immunol. 182(12): 7663-7671 (2009) [NPL 4] Datta-Mannan et al., J Biol. Chem. 282(3):1709-1717 (2007) [NPL 5] Dall'Acqua et al., J. Immunol. :5171-5180 (2002) [Summary of Invention] [Technical Problem] An ive of the ion is to provide anti-C5 antibodies and methods of using the same.

[Solution to Problem] The invention provides anti-C5 antibodies and methods of using the same.

In some embodiments, an isolated anti-C5 antibody of the present ion binds to an epitope within the beta chain of C5. In some embodiments, an ed anti-C5 antibody of the present invention binds to an epitope within the MG1-MG2 domain of the beta chain of C5. In some embodiments, an ed 5 antibody of the present invention binds to an epitope within a fragment consisting of amino acids 33-124 of the beta chain (SEQ ID NO: 40) of C5. In some embodiments, an isolated anti-C5 antibody of the present invention binds to an epitope within the beta chain (SEQ ID NO: 40) of C5 which comprises at least one fragment selected from the group consisting of amino acids 47-57, 70-76, and 107-110. In some embodiments, an isolated anti-C5 antibody of the present invention binds to an epitope within a fragment of the beta chain (SEQ ID NO: 40) of C5 which comprises at least one amino acid residue selected from the group consisting of Glu48, Asp51, His70, His72, Lys109, and His110 of SEQ ID NO: 40. In further embodiments, the antibody binds to C5 with a higher affinity at neutral pH than at acidic pH. In r embodiments, the antibody binds to C5 with a higher affinity at pH7.4 than at pH5.8. In another embodiment, an isolated anti-C5 antibody of the present invention binds to the same epitope as an antibody described in Table 2. In r embodiments, the antibody binds to the same epitope as an antibody described in Table 2 with a higher ty at pH7.4 than at pH5.8. In a further embodiment, the anti- C5 antibody of the present invention binds to the same epitope as an antibody described in Tables 7 or 8. In further embodiments, the antibody binds to the same epitope as an antibody described in Tables 7 or 8 with a higher affinity at pH7.4 than at pH5.8.

In certain embodiments, an anti-C5 antibody of the present invention es for binding C5 with an antibody comprising a VH and VL pair selected from: (a) a VH of SEQ ID NO:1 and a VL of SEQ ID NO:11; (b) a VH of SEQ ID NO: 5 and a VL of SEQ ID NO:15; (c) a VH of SEQ ID NO:4 and a VL of SEQ ID NO:14; (d) a VH of SEQ ID NO: 6 and a VL of SEQ ID NO: 16; (e) a VH of SEQ ID NO:2 and a VL of SEQ ID NO:12; (f) a VH of SEQ ID NO: 3 and a VL of SEQ ID NO: 13; (g) a VH of SEQ ID NO:9 and a VL of SEQ ID NO:19; (h) a VH of SEQ ID NO:7 and a VL of SEQ ID NO: 17; (i) aVH of SEQ ID NO:8 and a VL of SEQ ID NO:18; and (j) a VH of SEQ ID NO:10 and a VL of SEQ ID NO:20. In further ments, the anti-C5 antibody binds to C5 with a higher affinity at neutral pH than at acidic pH. In r embodiments, the anti-C5 antibody binds to C5 with a higher affinity at pH7.4 than at pH5.8.

In some embodiments, an isolated anti-C5 antibody of the present invention has a characteristic selected from the group consisting of: (a) the antibody contacts amino acids D51 and K109 of C5 (SEQ ID NO:39); (b) the affinity of the antibody for C5 (SEQ ID NO:39) is r than the affinity of the antibody for a C5 mutant consisting of an E48A substitution of SEQ ID NO:39; or (c) the antibody binds to a C5 protein consisting of the amino acid sequence of SEQ ID NO:39 at pH7.4, but does not bind to a C5 protein consisting of the amino acid sequence of SEQ ID NO:39 with a H72Y substitution at pH7.4. In r embodiments, the antibody binds to C5 with a higher affinity at neutral pH than at acidic pH. In further embodiments, the antibody binds to C5 with a higher affinity at pH7.4 than at pH5.8.

In some embodiments, an isolated anti-C5 antibody of the present invention inhibits activation of C5. In some embodiments, an isolated anti-C5 dy of the present invention inhibits tion of C5 variant R885H. In some embodiments, an isolated anti-C5 antibody of the present invention is a monoclonal dy. In some embodiments, an isolated anti-C5 antibody of the present invention is a human, humanized, or ic antibody. In some embodiments, an isolated anti-C5 antibody of the present ion is an antibody fragment that binds to C5. In some embodiments, an isolated anti-C5 antibody of the present invention is a full length IgG1 or IgG4 antibody.

In some embodiments, an isolated anti-C5 antibody of the present ion comprises (a) a HVR-H3 comprising the amino acid sequence DX1GYX2X3PTHAMX4X5, wherein X1 is G or A, X2 is V, Q or D, X3 is T or Y, X4 is Y or H, X5 is L or Y (SEQ ID NO: 128), (b) a HVR-L3 comprising the amino acid sequence QX1TX2VGSSYGNX3, wherein X1 is S, C, N or T, X2 is F or K, X3 is A, T or H (SEQ ID NO: 131), and (c) a HVR-H2 comprising the amino acid sequence X1IX2TGSGAX3YX4AX5WX6KG, wherein X1 is C, A or G, X2 is Y or F, X3 is T, D or E, X4 is Y, K or Q, X5 is S, D or E, X6 is A or V (SEQ ID NO: 127).

In some embodiments, an isolated 5 antibody of the present invention comprises (a) a HVR-H1 comprising the amino acid sequence X2, n X1 is M or V, X2 is C or A (SEQ ID NO: 126), (b) a HVR-H2 comprising the amino acid sequence X1IX2TGSGAX3YX4AX5WX6KG, wherein X1 is C, A or G, X2 is Y or F, X3 is T, D or E, X4 is Y, K or Q, X5 is S, D or E, X6 is A or V (SEQ ID NO: 127), and (c) a HVR-H3 sing the amino acid sequence DX1GYX2X3PTHAMX4X5, wherein X1 is G or A, X2 is V, Q or D, X3 is T or Y, X4 is Y or H, X5 is L or Y (SEQ ID NO: 128). In further embodiments, the dy comprises (a) a HVR-L1 comprising the amino acid sequence X1ASQX2IX3SX4LA, wherein X1 is Q or R, X2 is N, Q or G, X3 is G or S, X4 is D, K or S (SEQ ID NO: 129); (b) a HVR-L2 comprising the amino acid sequence GASX1X2X3S, wherein X1 is K, E or T, X2 is L or T, X3 is A, H, E or Q (SEQ ID NO: 130); and (c) a HVR-L3 comprising the amino acid ce QX1TX2VGSSYGNX3, wherein X1 is S, C, N or T, X2 is F or K, X3 is A, T or H (SEQ ID NO: 131).

In some embodiments, an isolated anti-C5 antibody of the present invention comprises (a) a HVR-L1 comprising the amino acid ce X1ASQX2IX3SX4LA, wherein X1 is Q or R, X2 is N, Q or G, X3 is G or S, X4 is D, K or S (SEQ ID NO: 129); (b) a HVR-L2 comprising the amino acid sequence GASX1X2X3S, wherein X1 is K, E or T, X2 is L or T, X3 is A, H, E or Q (SEQ ID NO: 130); and (c) a HVR-L3 comprising the amino acid sequence QX1TX2VGSSYGNX3, wherein X1 is S, C, N or T, X2 is F or K, X3 is A, T or H (SEQ ID NO: 131).

In some embodiments, an ed anti-C5 antibody of the present invention comprises a heavy chain variable domain framework FR1 comprising the amino acid sequence of any one of SEQ ID NOs: 132-134; FR2 comprising the amino acid sequence of any one of SEQ ID NOs: 135-136; FR3 comprising the amino acid sequence of any one of SEQ ID NOs: 137-139; and FR4 comprising the amino acid sequence of any one of SEQ ID NOs: 140-141. In some embodiments, an isolated anti-C5 antibody of the present invention comprises a light chain variable domain framework FR1 comprising the amino acid sequence of any one of SEQ ID NOs: 142-143; FR2 comprising the amino

Claims (29)

[CLAIMS]

1. [Claim 1] An antibody that binds to C5 for use in treating a complement-mediated disease or condition which involves excessive or uncontrolled activation of C5, wherein the antibody binds to an epitope within the beta chain of C5 with a higher affinity at neutral pH than at acidic pH.

2. [Claim 2] An antibody that binds to C5 for use in enhancing the clearance of C5 from plasma, wherein the antibody binds to an epitope within the beta chain of C5 with a higher affinity at neutral pH than at acidic pH.

3. [Claim 3] Use of an antibody that binds to C5 in the manufacture of a medicament for treatment of a complement-mediated disease or condition which involves excessive or uncontrolled activation of C5, wherein the antibody binds to an epitope within the beta chain of C5 with a higher affinity at neutral pH than at acidic pH.

4. [Claim 4] Use of an antibody that binds to C5 in the manufacture of a medicament for enhancing the clearance of C5 from plasma, wherein the antibody binds to an epitope within the beta chain of C5 with a higher affinity at neutral pH than at acidic pH.

5. [Claim 5] A method of treating an individual having a complement-mediated disease or condition which involves excessive or uncontrolled activation of C5, the method comprising administering to the individual an effective amount of an antibody that binds to C5, wherein the antibody binds to an epitope within the beta chain of C5 with a higher affinity at neutral pH than at acidic pH.

6. [Claim 6] A method of enhancing the clearance of C5 from plasma in an individual comprising administering to the individual an effective amount of an antibody that binds to C5 to enhance the clearance of C5 from plasma, wherein the antibody binds to an epitope within the beta chain of C5 with a higher affinity at neutral pH than at acidic pH. 132

7. [Claim 7] The antibody for use, the use, or the method according to any one of claims 1 to 6, wherein the antibody has a characteristic selected from the group consisting of: (a) the antibody contacts amino acids D51 and K109 of C5 (SEQ ID NO:39); (b) the affinity of the antibody for C5 (SEQ ID NO:39) is greater than the affinity of the antibody for a C5 mutant consisting of an E48A substitution of SEQ ID NO:39; and (c) the antibody binds to a C5 protein consisting of the amino acid sequence of SEQ ID NO:40 at pH7.4, but does not bind to a C5 protein consisting of the amino acid sequence of SEQ ID NO:39 with a H72Y substitution at pH7.4.

8. [Claim 8] The antibody for use, the use, or the method according to any one of claims 1 to 6, wherein the antibody competes for binding to C5 with an antibody comprising a VH and VL pair selected from: (a) a VH of SEQ ID NO:1 and a VL of SEQ ID NO:11; (b) a VH of SEQ ID NO: 5 and a VL of SEQ ID NO:15; (c) a VH of SEQ ID NO:4 and a VL of SEQ ID NO:14; (d) a VH of SEQ ID NO: 6 and a VL of SEQ ID NO: 16; (e) a VH of SEQ ID NO:2 and a VL of SEQ ID NO:12; (f) a VH of SEQ ID NO: 3 and a VL of SEQ ID NO: 13; (g) a VH of SEQ ID NO:9 and a VL of SEQ ID NO:19; (h) a VH of SEQ ID NO:7 and a VL of SEQ ID NO: 17; (i) aVH of SEQ ID NO:8 and a VL of SEQ ID NO:18; and (j) a VH of SEQ ID NO: 10 and a VL of SEQ ID NO:20.

9. [Claim 9] The antibody for use, the use, or the method according to any one of claims 1 to 8, wherein the antibody binds to an epitope within the MG1-MG2 domain of the beta chain of C5.

10. [Claim 10] The antibody for use, the use, or the method according to any one of claims 1 to 9, wherein the antibody binds to an epitope within a fragment consisting of amino acids 33-124 of the beta chain (SEQ ID NO: 40) of C5.

11. [Claim 11] 133 The antibody for use, the use, or the method according to any one of claims 1 to 10, wherein the antibody binds to an epitope within the beta chain (SEQ ID NO: 40) of C5 which comprises at least one fragment selected from the group consisting of amino acids 47-57, 70-76, and 107-110.

12. [Claim 12] The antibody for use, the use, or the method according to any one of claims 1 to 11, wherein the antibody binds to an epitope within a fragment of the beta chain (SEQ ID NO: 40) of C5 which comprises at least one amino acid selected from the group consisting of Glu48, Asp51, His70, His72, Lys109, and His110.

13. [Claim 13] The antibody for use, the use, or the method according to any one of claims 1 to 12, wherein the antibody binds to the same epitope as an antibody described in Tables 2, 7 or 8.

14. [Claim 14] The antibody for use, the use, or the method according to any one of claims 1 to 13, wherein the antibody inhibits activation of C5.

15. [Claim 15] The antibody for use, the use, or the method according to any one of claims 1 to 14, wherein the antibody inhibits activation of C5 variant R885H.

16. [Claim 16] The antibody for use, the use, or the method according to any one of claims 1 to 15, wherein the abtibody is a monoclonal antibody.

17. [Claim 17] The antibody for use, the use, or the method according to any one of claims 1 to 16, wherein the antibody is a human, humanized, or chimeric antibody.

18. [Claim 18] The antibody for use, the use, or the method according to any one of claims 1 to 17, wherein the antibody is an antibody fragment that binds to C5.

19. [Claim 19] The antibody for use, the use, or the method according to any one of claims 1 to 18, wherein the antibody comprises (a) a HVR-H3 comprising the amino acid sequence DX1GYX2X3PTHAMX4X5, wherein X1 is G or A, X2 is V, Q or D, X3 is T or Y, X4 is 134 Y or H, X5 is L or Y (SEQ ID NO: 128), (b) a HVR-L3 comprising the amino acid sequence QX1TX2VGSSYGNX3, wherein X1 is S, C, N or T, X2 is F or K, X3 is A, T or H (SEQ ID NO: 131), and (c) a HVR-H2 comprising the amino acid sequence X1IX2TGSGAX3YX4AX5WX6KG, wherein X1 is C, A or G, X2 is Y or F, X3 is T, D or E, X4 is Y, K or Q, X5 is S, D or E, X6 is A or V (SEQ ID NO: 127).

20. [Claim 20] The antibody for use, the use, or the method according to any one of claims 1 to 18, wherein the antibody comprises (a) a HVR-H1 comprising the amino acid sequence SSYYX1X2, wherein X1 is M or V, X2 is C or A (SEQ ID NO: 126), (b) a HVR-H2 comprising the amino acid sequence X1IX2TGSGAX3YX4AX5WX6KG, wherein X1 is C, A or G, X2 is Y or F, X3 is T, D or E, X4 is Y, K or Q, X5 is S, D or E, X6 is A or V (SEQ ID NO: 127), and (c) a HVR-H3 comprising the amino acid sequence DX1GYX2X3PTHAMX4X5, wherein X1 is G or A, X2 is V, Q or D, X3 is T or Y, X4 is Y or H, X5 is L or Y (SEQ ID NO: 128).

21. [Claim 21] The antibody for use, the use, or the method according to claim 20, wherein the antibody further comprises (a) a HVR-L1 comprising the amino acid sequence X1ASQX2IX3SX4LA, wherein X1 is Q or R, X2 is N, Q or G, X3 is G or S, X4 is D, K or S (SEQ ID NO: 129); (b) a HVR-L2 comprising the amino acid sequence GASX1X2X3S, wherein X1 is K, E or T, X2 is L or T, X3 is A, H, E or Q (SEQ ID NO: 130); and (c) a HVR-L3 comprising the amino acid sequence QX1TX2VGSSYGNX3, wherein X1 is S, C, N or T, X2 is F or K, X3 is A, T or H (SEQ ID NO: 131).

22. [Claim 22] The antibody for use, the use, or the method according to any one of claims 1 to 18, wherein the antibody comprises (a) a HVR-L1 comprising the amino acid sequence X1ASQX2IX3SX4LA, wherein X1 is Q or R, X2 is N, Q or G, X3 is G or S, X4 is D, K or S (SEQ ID NO: 129); (b) a HVR-L2 comprising the amino acid sequence GASX1X2X3S, wherein X1 is K, E or T, X2 is L or T, X3 is A, H, E or Q (SEQ ID NO: 130); and (c) a HVR-L3 comprising the amino acid sequence QX1TX2VGSSYGNX3, wherein X1 is S, C, N or T, X2 is F or K, X3 is A, T or H (SEQ ID NO: 131).

23. [Claim 23] The antibody for use, the use, or the method according to claim 20, wherein the 135 antibody further comprises a heavy chain variable domain framework FR1 comprising the amino acid sequence of any one of SEQ ID NOs: 132-134; a heavy chain variable domain framework FR2 comprising the amino acid sequence of any one of SEQ ID NOs: 135-136; a heavy chain variable domain framework FR3 comprising the amino acid sequence of any one of SEQ ID NOs: 137-139; and a heavy chain variable domain framework FR4 comprising the amino acid sequence of any one of SEQ ID NOs: 140- 141.

24. [Claim 24] The antibody for use, the use, or the method according to claim 22, wherein the antibody further comprises a light chain variable domain framework FR1 comprising the amino acid sequence of any one of SEQ ID NOs: 142-143; a light chain variable domain framework FR2 comprising the amino acid sequence of any one of SEQ ID NOs: 144-145; a light chain variable domain framework FR3 comprising the amino acid sequence of any one of SEQ ID NOs: 146-147; and a light chain variable domain framework FR4 comprising the amino acid sequence of SEQ ID NO: 148.

25. [Claim 25] The antibody for use, the use, or the method according to any one of claims 1 to 18, wherein the antibody comprises (a) a VH sequence having at least 95% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 10, 106-110; (b) a VL sequence having at least 95% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 20, 111-113; or (c) a VH sequence as in (a) and a VL sequence as in (b).

26. [Claim 26] The antibody for use, the use, or the method according to claim 25, wherein the antibody comprises a VH sequence of any one of SEQ ID NOs: 10, 106-110.

27. [Claim 27] The antibody for use, the use, or the method according to claim 25, wherein the antibody comprises a VL sequence of any one of SEQ ID NOs: 20, 111-113.

28. [Claim 28] The antibody for use, the use, or the method according to claim 26 or 27, wherein the antibody comprises a VH sequence of any one of SEQ ID NOs: 10, 106-110 and a VL sequence of any one of SEQ ID NOs: 20, 111-113. 136

29. [Claim 29] The antibody for use, the use, or the method according to any one of claims 1 to 28, wherein the antibody is a full length IgG1 or IgG4 antibody.