ANTI-C1s ANTIBODY

Abstract

The present invention provides antibodies that include an antigen-binding region and a constant region of the antibody and bind to C1s in a pH-dependent manner. The present invention provides pharmaceutical compositions containing any of said antibodies, and methods for treating an individual who has a complement-mediated disease or disorder, or preventing an individual who has the potential to have a complement-mediated disease or disorder, the method comprising administering one of the antibodies to the individual.

Description

ANTI-C1s ANTIBODY Invention Engineering Field The present invention relates to antibodies such as antibodies anti-Cls, and methods for using them. Background of the Invention The C1 complex is a large functional protein complex as a key initiator of the classical pathway cascade. Complex C1 consists of of three components, Clg, Clr and Cls, each of which has molar ratio 1:2:2 (NPL 1). The classical pathway begins when the Cl complex binds to the target bound by the antibody. Clg, which has 6 globular heads, mediates the binding of Cl complexes on antibodies through avidity interactions with the Fc region. After tightly bound to the target, Clr in the C1 complex automatically active and becomes enzymatically active. Activated Clr then breaks down and activates the Cls proenzyme in the complex C1 (NPL 2). Next, C1 actively breaks down its substrate, complementing the C2 and C4 components into the C2a / C2b fragment, and C4a / C4b. This causes the assembly of C4b2a, the C3 convertase, in target surface that breaks down C3 to form C3b. C3b on in turn breaks down C5 to initiate the formation of the attack complex terminal membrane, C5b, C6, C1, C8 and C9, which lyse the target through pore formation. The C1 and Clr proteins have identical domain arrangements, namely CUBI-EGF-CUB2-CCP1-CCP2-Serine Protease (NPL 3). CUBl- domain EGF-CUB2 mediates the interaction between Clr and Cls to form tetramer C1r2s2 (NPL 4), and also between C1lr2s2 and Clg (NPL 5). In contrast, the CCP1-CCP2-Serine Protease domains of Clr and Cl responsible for the proteolytic breakdown of each its substrate (NPL 6, NPL 7). The C1r2s2 tetramer interacts 4d with six stems in Clg through six binding sites in the CUB1- Domain EGF-CUB2 from tetramer (NPL 5). While the complement system functions with s protect the host from pathogens, dysregulation or activation suit Which misalignment of the classical pathway results in various disorders that complement-mediated such as, and not limited to, a autoimmune hemolytic anemia (AIHA), Behcet's disease, bullous pemphigus immune thrombocytopenic purpura (ITP), and so on. By k anemia (BP), arena that is, excessive or insufficient inhibition of classical pathway activation controlled can provide clinical benefits for patients 4d the disturbance. with H1532, an antibody that binds to the beta domain of Cls, reported to be able to inhibit the interaction of C1r2s2 with Clg (NPL 8). However, these antibodies cannot completely neutralize the activity of human serum hemolytic and 308 activity persists even after 24 hours incubation of serum with antibodies. Antibodies are pharmaceutical substances of great interest because they are stable. in plasma, is highly specific for its target, and is generally showed a superior pharmacokinetic profile. However, k Due to its large molecular size, therapeutic antibody doses can be high. In the case of a large number of targets, arena Sanya dose therapeutic antibody requirements are even higher. As a result, methods that improve the pharmacokinetics of antibodies, pharmacodin and the nature of antigen binding is an interesting way Amika, For reduce the dosage and high production costs associated with therapeutic antibodies. It has been reported antigen in a way that this is also known as that the antibody that binds 4d depends on pH (further in "pH dependent antibodies" with lower or “pH-dependent antibody binding”) allows one antibody molecules to neutralize several antigen molecules. (NPL 9, PTL 1). pH-dependent antibodies bind strongly to its antigen at neutral pH conditions in plasma, but dissociates from antigens under acidic pH conditions in endosomes cells. After being separated from the antigen, the antibody is recycled returned to the plasma by the FcRn receptor while the antigen that separated and degraded in the cell's lysosomes. Antibodies that are recycled repeat then free to bind with and neutralize the molecule antigen again and this process continues to repeat as long as the antibodies remain in circulation. List of Citations Patent Literature IPTL 1) International Patent Application No. WO2009 / 125825 Non-Patent Literature INPL 1| Wang and friends. Mole Cell. 2016 Jul 1:63(1):135-45 INPL 21) Mortensen and friends. Proc Natil Acad Sci US A. 2017 Jan 317114(5) :986-991 INPL 3) Gal and friends. Mol Immunol. 2009 Sep:46(14):21745-52 INPL 4 | Almitairi et al. Proc Natil Acad Sci U S A 2018 Jan 237115 (4) :768-773 (NPL 5) Bally and friends. J Biol Chem. 2009 Jul 17:284(29):19340-8 INPL €6M| Rossi and friends. 1998 J Biol Chem. 1998 Jan 9:213(2):11232-9 INPL 7) Lacroix et al. J Biol Chen. 2001 Sep 281216 (39) :36233-40 INPL 8) Tseng and friends. Mol Immunol. 1997 Jun:34(8-9) :671- (NPL 9| Igawa and friends. Nat Biotechnol. 2010 Nov:28 (11) :1203-7 Brief Description of the Invention Technical issues The present invention provides anti-complement component antibodies such as anti-Cls antibodies, pharmaceutical compositions containing antibodies and the methods for using them. Solution to the Problem In one embodiment, the present invention provides antibodies that includes the antigen-binding region and the constant region of the antibody, which has the function of encouraging dissociation (displacement function) so that antibodies bind to the Clgrs complex and promote its dissociation Clg from the Clgrs complex and / or blocking function so that antibodies bind to C1r2s2 and inhibit Clg binding on C1r2s2, and binds to Cls in a manner that depends on at pH. In certain embodiments, the antibodies of the present invention have a mutant constant region that includes at least one amino acid changes that decrease FcyR binding activity and / or at least one amino acid change that decreases isoelectric point (pI) of the Fc region. In particular, the present invention relates to the following: Il) Isolated antibodies that include the antigen-binding region and antibody constant region, where the antibody promotes the dissociation of Clg from the Clgrs complex and / or inhibits the binding of Clg to C1r2s2, and where the antigen binding region includes the HVR-HIl combination, HVR-H2, HVR-H3, HVR-Ll, HVR-L2, and HVR-L3 were selected from the group consisting of 1) to 6) below: 1) HVR-H1I, HVR-H2, HVR-H3, HVR-LI1, HVR-L2, and HVR-L3 which includes amino acid sequence consisting of SEO ID NO: 25, 26, 21, 60, 61, and 62, respectively: 2) HVR-H1, HVR-H2, HVR-H3, HVR-LI, HVR-L2, and HVR-L3 which include amino acid sequence consisting of SEO ID NO: 37, 38, 39, 56, 57, and 58, respectively: 3) HVR-H1, HVR-H2, HVR-H3, HVR-LI1, HVR-L2, and HVR-L3 which includes amino acid sequence consisting of SEO ID NO: 25, 26, 21, 56, 57, and 58, respectively: 4) HVR-H1, HVR-H2, HVR-H3, HVR- Ll, HVR-L2, and HVR-L13 which includes the amino acid sequence consisting of SEO ID NO: 25, 26, 21, 48, 49, and 50, respectively: 5) HVR-H1, HVR-H2, HVR-H3, HVR-LI1, HVR-L2, and HVR-L3 which includes amino acid sequence consisting of SEO ID NO: 29, 30, 31, 52, 53, and 54, respectively: and 6) HVR-H1, HVR-H2, HVR-H3, HVR-LI1, HVR-L2, and HVR-L3 which includes amino acid sequence consisting of SEO ID NO: 33, 34, 35, 56, 57, and 58, respectively. I21 Antibodies from item Il), where the antibodies cover the region heavy chain variable (VH) and light chain variable (VL) regions selected from the group consisting of 1) to 6) below This: 1) VH and VL which include amino acid sequences consisting of SEO ID NO: 24 and 59, respectively: 2) NH and VL which include amino acid sequences consisting of SEO ID NO: 36 and 55, respectively: 3) VH and VL which include amino acid sequences consisting of SEO ID NO: 24 and 55, respectively: 4) VH and VL which include amino acid sequences consisting of SEO ID NO: 24 and 47, respectively: 5) VH and VL which include amino acid sequences consisting of SEO ID NO: 28 and 51, respectively: and 6) VH and VL which include amino acid sequences consisting of SEO ID NO: 32 and 55, respectively. (3) Antibodies from the grains (lJ| or (2), where the ratio of the KD values ​​in acidic pH range to KD value in the neutral pH range, the ratio Acid KD / neutral KD, is 107 or more. (41 Antibodies from one of points (1) to (3), where antigen binding region can specifically bind to CUBI1-EGF-CUB2 domain of human C1. (5) Antibodies from one of points (1) to (4)J, where antibodies have a mutant constant region that covers at least one amino acid change that decreases binding activity Fcy receptor. (6) Antibodies from item (5), wherein the mutant constant region includes amino acid change in at least one of positions 235 and 236 according to EU numbering. (71 Antibodies from any of the items (1) to (|6J, where antibodies have a mutant constant region that covers at least one amino acid change, and where the amino acid change is lowering the isoelectric point (pl) from the constant region of the mutant compared to the parent constant area. (8) Antibodies from item |7|, where the mutant constant region includes amino acid changes in at least one of positions 137, 268, 214, 355, and 419 according to EU numbering. (9) Antibodies from any of points (Ill) to (8)|, where pl is 7.8 or less. (10) Antibodies to any one of the items (1l| to (8|, where the constant region includes the constant region of the heavy chain which includes amino acid sequence consisting of SEO ID NO: 45 and the region light chain constants that include amino acid sequences consisting of from SEO ID NO: 23. Ill) Antibodies that have binding activity on Cl, where antibodies include combinations of HVR-Hl, HVR-H2, HVR-H3, HVR-Ll, HVR- L2, and HVR-L3 selected from a group consisting of 1) up to 6) under 1ni: 1) HVR-H1I, HVR-H2, HVR-H3, HVR-LI1, HVR-L2, and HVR-L3 which includes amino acid sequence consisting of SEO ID NO: 25, 26, 21, 60, 61, and 62, respectively: 2) HVR-H1, HVR-H2, HVR-H3, HVR-LI, HVR-L2, and HVR-L3 which include amino acid sequence consisting of SEO ID NO: 37, 38, 39, 56, 57, and 58, respectively: 3) HVR-H1, HVR-H2, HVR-H3, HVR-LI1, HVR-L2, and HVR-L3 which includes amino acid sequence consisting of SEO ID NO: 25, 26, 21, 56, 57, and 58, respectively: 4) HVR-H1l, HVR-H2, HVR-H3, HVR- Ll, HVR-L2, and HVR-L3 includes the amino acid sequence consisting of SEO ID NO: 25, 26, 21, 48, 49, and 50, respectively: 5) HVR-H1, HVR-H2, HVR-H3, HVR-LI1, HVR-L2, and HVR-L3 which includes amino acid sequence consisting of SEO ID NO: 53, 29, 30, 31, 52, and 54, respectively: and 6) HVR-H1, HVR-H2, HVR-H3, HVR-LI1, HVR-L2, and HVR-L3 which includes amino acid sequence consisting of SEO ID NO: 33, 34, 35, 56, 57, and 58, respectively. (12) Antibodies from item Ill), where the antibodies cover the region heavy chain variable (VH) and light chain variable (VL) regions selected from the group consisting of 1) to 6) below This: 1) VH and VL which include amino acid sequences consisting of SEO ID NO: 24 and 59, respectively: 2) NH and VL which include amino acid sequences consisting of SEO ID NO: 36 and 55, respectively: 3) VH and VL which include amino acid sequences consisting of SEO ID NO: 24 and 55, respectively: 4) VH and VL which include amino acid sequences consisting of SEO ID NO: 24 and 47, respectively: 5) VH and VL which include amino acid sequences consisting of SEO ID NO: 28 and 51, respectively: and 6) VH and VL which include amino acid sequences consisting of SEO ID NO: 32 and 55, respectively. (13) Antibodies from item I(11| or (12), where the constant region antibodies encompass the constant region of the H chain which includes the sequence amino acids consisting of SEO ID NO: 45 and constant region L chain which includes the amino acid sequence consisting of SEO ID NO: 23. (14) Antibodies containing heavy chains (H chains) and chains light (L chain) is selected from the group consisting of 1) to 6) below: 1) H chain and L chain which include the amino acid sequences that each consisting of SEO ID NO: 66 and 61: 2) H chain and L chain which include the amino acid sequences that each consisting of SEO ID NO: 68 and 69: 3) H chain and L chain which include the amino acid sequences each consisting of SEO ID NO: 70 and 71: 4) H chain and L chain which include the amino acid sequences that each consisting of SEO ID NO: 72 and 73j 5) H chain and L chain which include amino acid sequences that each consisting of SEO ID NO: 74 and 1 / 5: and 6) H chain and L chain which include amino acid sequences that each consisting of SEO ID NO: 76 and 77. (15) Pharmaceutical compositions containing antibodies from one of the from points (1) to (14) and at least one carrier that can pharmaceutically acceptable. (16) Pharmaceutical composition of item (15), namely for use to treat individuals who have diseases or disorders that complement-mediated, or prevent potentially harmful individuals have a complement-mediated disease or disorder. (17) Methods for treating individuals who have a disease or complement-mediated disorders, or prevent individuals who potentially have a disease or disorder that is mediated complement, the method involves providing an effective amount from antibodies from any of (1) to (14). (18) Antibodies from one of points (1) to (14), namely for use in treating or preventing disease or complement-mediated disorders. (19) Therapeutic or prophylactic substances for diseases or disorders complement-mediated, substances that include antibodies from one of the one of points (1) to (14). (201 Use of antibodies from one of the items (Il) to (14) in the manufacture of therapeutic or prophylactic substances for complement-mediated diseases or disorders. (21) Isolated antibodies that include the antigen-binding region and antibody constant region, where the ratio of the KD value in the acidic pH range to the acidic value KD in the neutral pH range, the ratio of acid KD / neutral KD, is 107 or more, and where the constant region of the antibody includes at least one amino acid changes that decrease receptor binding activity Fcy and at least one amino acid change that lowers the boiling point isoelectric (pl). Short Description of Image Figure 1-1 shows the changes in antibody concentration in plasma of male sinomolgus monkeys after receiving a single dose COS0637pHv2-FcgSil, C0OS0637pHv2-SG1077R, COS0637pHv3-SG1077R, and COS0637 / pHv8-SG1077R antibody (log-linear). Data are shown with mean t standard deviation (N - 3). Figure 1-2 shows the change in the concentration ratio of Cls in plasma of male sinomolgus monkeys after receiving administration single intravenous antibody CO0S0637pHv2-FcgSil, COS0637pHv2- SG1077R, COS0637pHv3-SG1077R, and COS0637pHv8-SG1077R against Cls concentration in plasma before administration (log-linear). Data indicated by the mean t standard deviation (N — 3). Figure 2-1 shows the evaluation of anti-Cl1s antibodies. COS0637pHv8-TT9IR for Clg shift function. Solid line shows the sensorgram obtained when hClg was injected into hC1r2s2 and then buffer is injected (C1r2s2#tCl1g): sensorgram 1: dotted line shows the sensorgram obtained when hClg is injected into hClr2s2 and then antibodies injected (C1r2s2#tClgtAb): sensorgram 2: and dotted line shows the sensorgram obtained when hClg was not injected into hClr2s2 and only injected antibody (C1r2s2-Ab): sensorgram 3. COS0637pHv8-TT9IR is injected as Ab. Figure 2-2 shows the evaluation of anti-Cl1s antibodies. COS0637pHvV15-TT9IR for Clg shift function. Solid line shows the sensorgram obtained when hClg was injected into hC1r2s2 and then buffer is injected (C1r2s2#tCl1g): sensorgram 1: dotted line shows the sensorgram obtained when hClg is injected into hClr2s2 and then antibodies injected (C1r2s2#tClgtAb): sensorgram 2: and dotted line shows the sensorgram obtained when hClg was not injected into hClr2s2 and only injected antibody (C1r2s2-Ab): sensorgram 3. COS0637pHv15-TT9IR is injected as Ab. Figure 2-3 shows the evaluation of anti-Cls antibodies. COS0637pHvl1e-TT9IR for Clg shift function. Solid line shows the sensorgram obtained when hClg was injected into hC1r2s2 and then buffer is injected (C1r2s2#tCl1g): sensorgram 1: dotted line shows the sensorgram obtained when hClg is injected into hClr2s2 and then antibodies injected (C1r2s2#tClgtAb): sensorgram 2: and dotted line shows the sensorgram obtained when hClg was not injected into hClr2s2 and only injected antibody (C1r2s2-Ab): sensorgram 3. COS0637pHv16-TT9IR is injected as Ab. Figure 2-4 shows the evaluation of anti-Cl1s antibodies. COS0637pHv17-TT9IR for Clg shift function. Solid line shows the sensorgram obtained when hClg was injected into hC1r2s2 and then buffer is injected (C1r2s2#tCl1g): sensorgram 1: dotted line shows the sensorgram obtained when hClg is injected into hClr2s2 and then antibodies injected (C1r2s2#tClgtAb): sensorgram 2: and dotted line shows the sensorgram obtained when hClg was not injected into hClr2s2 and only injected antibody (C1r2s2-Ab): sensorgram 3. COS0637pHv17-TT9IR was injected as Ab. Figure 2-5 shows the evaluation of anti-Cl1s antibodies. COS0637pHv21-TT9IR for Clg shift function. Solid line shows the sensorgram obtained when hClg was injected into hC1r2s2 and then buffer is injected (C1r2s2#tCl1g): sensorgram 1: dotted line shows the sensorgram obtained when hClg is injected into hClr2s2 and then antibodies injected (C1r2s2#tClgtAb): sensorgram 2: and dotted line shows the sensorgram obtained when hClg was not injected into hClr2s2 and only injected antibody (C1r2s2-Ab): sensorgram 3. COS0637pHv21-TT9IR was injected as Ab. Figure 2-6 shows the evaluation of anti-Cls antibodies. COS0637pHv23-TT9IR for Clg shift function. Solid line shows the sensorgram obtained when hClg was injected into hC1r2s2 and then buffer is injected (C1r2s2#tCl1g): sensorgram 1: dotted line shows the sensorgram obtained when hClg is injected into hClr2s2 and then antibodies injected (C1r2s2#tClgtAb): sensorgram 2: and dotted line shows the sensorgram obtained when hClg was not injected into hClr2s2 and only injected antibody (C1r2s2-#Ab): sensorgram 3. COS0637pHv23-TT9IR was injected as Ab. Figure 2-1 shows the evaluation of anti-Cl1s antibodies. COS0637pHv25-TT9IR for Clg shift function. Solid line shows the sensorgram obtained when hClg was injected into hC1r2s2 and then buffer is injected (C1r2s2#tCl1g): sensorgram 1: dotted line shows the sensorgram obtained when hClg is injected into hClr2s2 and then antibodies injected (C1r2s2#tClgtAb): sensorgram 2: and dotted line shows the sensorgram obtained when hClg was not injected into hClr2s2 and only injected antibody (C1r2s2-Ab): sensorgram 3. COS0637pHv25-TT9IR was injected as Ab. Figure 2-8 shows the evaluation of anti-Cls antibodies. COS0637pHv8-G1A3FcgSiltLowpI for Clg. Line displacement function The solid shows the sensorgram obtained when hClg was injected. to hC1r2s2 and then can be injected (C1r2s21C19): sensorgram 1: dotted line indicates sensorgram obtained when hClg is injected into hClr2s2 and then injected antibody (C1r2s2tClgtAb): sensorgram 2: and line The dashed line indicates the sensorgram obtained when hClg was not present. injected into hC1r2s2 and only antibodies were injected (C1r2s2-Ab): sensorgram 3. COS0637pHv8-G1A3FcgSil-LowpiI injected as Ab. Figure 2-9 shows the evaluation of anti-Cls antibodies. COS0637pHv15-G1A3FcgSiltLowpI for Clg. Line displacement function The solid shows the sensorgram obtained when hClg was injected. to hC1r2s2 and then can be injected (C1r2s21C19): sensorgram 1: dotted line indicates sensorgram obtained when hClg is injected into hClr2s2 and then injected antibody (C1r2s2tClgtAb): sensorgram 2: and line The dashed line indicates the sensorgram obtained when hClg was not present. injected into hC1r2s2 and only antibodies were injected (C1r2s2-Ab): sensorgram 3. COS0637pHv15-G1A3FcgSil-LowpiI injected as Ab. Figure 2-10 shows the evaluation of anti-Cls antibodies. COS0637pHv16-G1A3FcgSiltLowpI for Clg. Line displacement function The solid shows the sensorgram obtained when hClg was injected. to hClr2s2 and then can be injected (C1r2s21C19): sensorgram 1: dotted line indicates sensorgram obtained when hClg is injected into hClr2s2 and then injected antibody (C1r2s2tClgtAb): sensorgram 2: and line The dashed line indicates the sensorgram obtained when hClg was not present. injected into hC1r2s2 and only antibodies were injected (C1r2s2-Ab): sensorgram 3. COS0637pHv16-G1IA3FcgSil-LowpiI injected as Ab. Figure 2-11 shows the evaluation of anti-C1s antibodies. COS0637pHv17-G1A3FcgSiltLowpI for Clg. Line displacement function The solid shows the sensorgram obtained when hClg was injected. to hClr2s2 and then can be injected (C1r2s21C19): sensorgram 1: dotted line indicates sensorgram obtained when hClg is injected into hClr2s2 and then injected antibody (C1r2s2tClgtAb): sensorgram 2: and line The dashed line indicates the sensorgram obtained when hClg was not present. injected into hC1r2s2 and only antibodies were injected (C1r2s2-Ab): sensorgram 3. COS0637pHv17-G1A3FcgSil-LowpiI injected as Ab. Figure 2-12 shows the evaluation of anti-C1s antibodies. COS0637pHv21-G1A3FcgSiltLowpI for Clg. Line displacement function The solid shows the sensorgram obtained when hClg was injected. to hClr2s2 and then can be injected (C1r2s21C19): sensorgram 1: dotted line indicates sensorgram obtained when hClg is injected into hClr2s2 and then injected antibody (C1r2s2tClgtAb): sensorgram 2: and line The dashed line indicates the sensorgram obtained when hClg was not present. injected into hC1r2s2 and only antibodies were injected (C1r2s2-Ab): sensorgram 3. COS0637pHv21-G1IA3FcgSil-LowpiI injected as Ab. Figure 2-13 shows the evaluation of anti-C1s antibodies. COS0637pHv23-G1A3FcgSiltLowpI for Clg. Line displacement function The solid shows the sensorgram obtained when hClg was injected. to hClr2s2 and then can be injected (C1r2s21C19): sensorgram 1: dotted line indicates sensorgram obtained when hClg is injected into hClr2s2 and then injected antibody (C1r2s2tClgtAb): sensorgram 2: and line The dashed line indicates the sensorgram obtained when hClg was not present. injected into hC1r2s2 and only antibodies were injected (C1r2s2-Ab): sensorgram 3. COS0637pHv23-G1A3FcgSil-LowpiI injected as Ab. Figure 2-14 shows the evaluation of anti-C1s antibodies. COS0637pHv25-G1A3FcgSiltLowpI for Clg. Line displacement function The solid shows the sensorgram obtained when hClg was injected. to hClr2s2 and then can be injected (C1r2s21C19): sensorgram 1: dotted line indicates sensorgram obtained when hClg is injected into hClr2s2 and then injected antibody (C1r2s2tClgtAb): sensorgram 2: and line The dashed line indicates the sensorgram obtained when hClg was not present. injected into hC1r2s2 and only antibodies were injected (C1r2s2-Ab): sensorgram 3. COS0637pHv25-G1A3FcgSil-LowpiI injected as Ab. Figure 3-1 shows the changes in antibody concentration in plasma of male sinomolgus monkeys after receiving a single dose antibodies COS0637pHv16-G1IA3FcgSil-LowpiI and COS0637pHv21- GIA3FcgSil-LowpI intravenous (log-linear). Data are shown with mean t standard deviation (Antibody COS0637pHv1e-G1A3FcgSil-tLowpI1: N — 3, Antibody COS0637pHv21-G1A3FcgSiltLowpI: N -— 2). Figure 3-2 shows the change in the concentration ratio of Cls in plasma of male sinomolgus monkeys after receiving a single dose antibodies COS0637pHv16-G1IA3FcgSil-LowpiI and COS0637pHv21- Intravenous GIA3FcgSil-LowpI on plasma Cls concentration before administration (log-linear). Data are shown with the mean t standard deviation (Antibody COS0637pHvle-G1A3FcgSil-tLowpI / N — 3, Antibody COS0637pHv21-G1A3FcgSil-tLowpI, N — 2). Figure 4 shows the evaluation of anti-Cls antibodies for function. Complement neutralization in monkeys. Complement neutralization activity in monkeys, anti-C1ls antibodies (C0OS0637pHv2-FcgSil, C0S0637pHv2- SG1077R, CO0S0637pHv3-SG1077R, CO0S0637pHv8-SG1077R, COS0637pHv1le- G1A3FcgSil-LowpI, COS06 37pHv21-G1A3FcgSiltLowp1) are indicated. All specimens suppressed red blood cell lysis immediately after administration. Suppression of red blood cell lysis was observed for up to 56 days after administration of COS0637pHv16e-G1A3FcgSiltLow pI and COS0637pHv21- G1A3FcgSiltLow pl. Complete Description of the Invention The techniques and procedures described or referred to herein generally well understood and commonly used using conventional methodology by people who are experts in this field, such as, for example, the widely used methodology that described in Sambrook and colleagues, Molecular Cloning: A Laboratory Manual 3rd edition (2001) Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, Current Protocols in Molecular Biology (FM Ausubel, and friends eds., (2003)): the series Methods in Enzymology (Academic Press, Inc.): PCR 2: A Practical Approach (M.J. MacPherson, B.D. Hames dan G.R. Taylor eds. (1995)), Harlow dan Lane, eds. (1988) Antibodies, A Laboratory Manual, and Animal Cell Culture (R.I. Freshney, ed. (1987)): Oligonucleotide Synthesis (M.J. Gait, ed., 1984): Methods in Molecular Biology, Humana Press: Cell Biology: A Laboratory Notebook (J.E. Cellis, ed., 1998) Academic Press: Animal Cell Culture (R.I. Freshney), ed., 1987): Introduction to Cell and Tissue Culture (J. P. Mather dan P.E. Roberts, 1998) Plenum Press, Cell and Tissue Culture: Laboratory Procedures (A. Doyle, J.B. Griffiths, and D.G. Newell, eds., 1993-8) J. Wiley and Sons: Handbook of Experimental Immunology (D.M. Weir dan C.C. Blackwell, eds.): Gene Transfer Vectors for Mammalian Cells (J.M. Miller dan M.P. Calos, eds., 1987): PCR: The Polymerase Chain Reaction, (Mullis dan kawan-kawan, eds., 1994): Current Protocols in Immunology (J.E. Coligan dan kawan-kawan, eds., 1991): Short Protocols in Molecular Biology (Wiley and Sons, 1999): Immunobiology (C.A. Janeway and P. Travers, 1997): Antibodies (P. Finch, 1997): Antibodies: A Practical Approach (D. Catty., ed., IRL Press, 1988-1989): Monoclonal Antibodies: A Practical Approach (P. Shepherd dan C. Dean, eds., Oxford University Press, 2000): Using Antibodies: A Laboratory Manual (BE. Harlow dan D. Lane (Cold Spring Harbor Laboratory Press, 1999): The Antibodies (M. Zanetti dan J. D. Capra, eds., Harwood Academic Publishers, 1995): dan Cancer: Principles and Practice of Oncology (V.T. Devita dan kawan-kawan, eds., J.B. Lippincott Company, 1993). I. Definisi Unless otherwise specified, technical and scientific terms used here has the same meaning as usual understood by a person skilled in the field in which the invention is is at. Singleton and friends, Dictionary of Microbiology and Molecular Biology 2nd ed., J. Wiley & Sons (New York, NY 1994), and March, Advanced Organic Chemistry Reactions, Mechanisms and Structure 4th ed., John Wiley & Sons (New York, NY 13992), provides those skilled in the field with general guidance for Many terms are used in this application. All references cited herein, including patent applications and publications, combined as a reference as a whole. For the purposes of interpreting this specification, the following definitions apply. will apply and where appropriate, the terms used in the form The singular will also include the plural and vice versa. Need it is understood that the terminology used here is for the purpose of describing certain embodiments only, and is not intended to limit. If definition as set out below contrary to the documents incorporated herein by reference, the definitions set forth below apply. "Acceptor human skeleton" for the purpose here is framework that includes the amino acid sequences of the domain framework light chain variable weight (VH) human consensus framework, this. Framework immunoglobulin includes sequences changes in amino acid sequences. (VL) or chain variable domain framework derived from the human immunoglobulin framework or man man or consensus framework the same amino acids, as defined below acceptors that "come from" the framework humans can or may contain amino acid changes are 10 or less, 9 or less, 7 or less, 3 or less, 6 or less, or 2 or less. 5 or less, In some embodiments, the number of less than 8 or 4 or less, In some embodiments, the human skeleton of the VL acceptor is identical in sequence to the sequence human immunoglobulin VL framework or consensus framework sequence man. “Affinity” refers to the strength of the total number of interactions. noncovalent bonds between single-molecule binding sites (e.g., antibodies) and their binding partners (e.g., antigens). Except otherwise stated, as used herein, "affinity "binding" refers to reflect (for example, its partner Y can generally be shown or KD). in this field, antibody on binding affinity interaction And 1:1 between members antigen). Affinity intrinsic that binding pair molecule X for by the dissociation constant (Kd) Affinity can be measured by commonly known methods. including those described herein. Embodiment illustrative and specific examples for measuring binding affinity explained following This. "Affinity", "affinity binding", "binding ability", and "binding activity" can be used alternately. The term "binding activity" refers to the strength of the total number of noncovalent interactions between one or more binding site of a molecule (e.g., an antibody) and a partner binding (e.g. antigen). Here, the binding activity not limited to activities that reflect 1:1 interactions between members of a binding pair (e.g., antibody and antigen). When members of a binding pair can bind to each other by means of monovalent and multivalent binding, activity binding is the strength of the total number of these bindings. The binding activity of molecule X for its partner Y can generally be indicated by the dissociation constant (KD). Alternatively, the degree of association and dissociation (Kon and Koff) can be used to binding assessment. Binding activity can be measured by general methods known in the art, including those described here. Illustrative embodiments and specific examples to measure binding affinity is explained below. “Affinity-matured” antibodies refer to antibodies with one or more changes in one or more areas hypervariable (HVR), compared to the non-hypervariable parent antibody have those changes, those changes result in increased affinity of antibodies for antigens. The terms "anti-Cls antibodies", "antibodies that bind to Cls", and "antibodies that have binding activity to Cls" refers to antibodies that are capable of binding Cls with high affinity. enough so that antibodies are useful as diagnostic substances and / or therapeutic in targeting Cl. In one embodiment, the level of binding of anti-Cls antibodies to non-Cls proteins that do not related is less than about 108 of antibody binding on Cls as measured, for example by radioimmunoassay (RIA). In certain embodiments, antibodies that bind to C1 has a dissociation constant (Kd) of 1 micromolar (micro M) or less, 100 nM or less, 10nM or less, 1 nM or less, 0.1 nM or less, 0.01 nM or less, or 0.001 nM or less (e.g. 10 “M or less, e.g. from 10'M to 10-»M, for example, from 10”? M to 10-28 M). In certain embodiments, anti-Cls antibodies bind to conserved Cls epitopes among Cls of different species. The term "antibody" is used here in a broad sense and covers a variety of antibody structures, including but not limited to limited to monoclonal antibodies, polyclonal antibodies, antibodies multispecific (e.g., bispecific antibodies), and fragments antibodies as long as they show antigen binding activity desired. “Antibody fragment” refers to molecules other than intact antibodies. which includes the intact antibody portion that binds to the antigen bound by intact antibodies. Examples of antibody fragments include but not limited to Fv, Fab, Fab', Fab'-SH, F(ab') » : diabodij linear antibodies, single-chain antibody molecules (e.g. scFv): and multispecific antibodies formed from antibody fragments. "Antibodies that bind to the same epitope" as reference antibody refers to an antibody that blocks binding reference antibody to its antigen in determining the competition amount 50&8 or more, and vice versa, the reference antibody blocks binding of antibodies to their antigens in a competition test of 508 or more. An example of a competition setting is provided here. The term "chimeric" antibody refers to an antibody where parts of the heavy and / or light chains are derived from the source or certain species, while the remaining heavy and / or light chains come from different sources or species. The "class" of an antibody refers to the type of constant or constant region owned by its heavy chain. There are five classes main antibodies: IGgA, IgD, IgE, IGgG, and IgM, and some in among them can be divided again into subclasses (isotypes), for example, IgGi, 19G2, 1gGG3, IgGa, IGAL, and IGgA2. Constant domain of heavy chain which correspond to different immunoglobulin classes respectively each called alpha, delta, epsilon, gamma, and mu. The term "cytotoxic agent" as used herein refers to substances that inhibit or prevent cellular function and / or cause cell death or destruction. cytotoxic substances including, but not limited to, radioactive isotopes (e.g., 211At, 1317, 125T, 90y, 180Re, 188Re, 153Sm, 212Bi, 320p, 212ph and isotopes radioactive from Lu): chemotherapy substances or drugs (for example, methotrexate, adriamycin, vinca alkaloids (vincristine, vinblastine, etoposide), doxorubicin, melphalan, mitomycin C, chlorambucil, daunorubicin or other intercalating agent): inhibitory agent growth: enzymes and their fragments such as nucleolytic enzymesj: antibiotics: toxins such as small molecule toxins or toxins that enzymatically active from bacteria, fungi, plants or animals, including fragments and / or variants thereof, and various antitumor agents or anticancer as described below. "Effector function" refers to the biological activity that caused by the Fc region of the antibody, which varies with antibody isotypes. Examples of antibody effector functions include: Clg binding and complement-dependent cytotoxicity (CDC): Fc receptor binding, mediated cytotoxicity antibody-dependent cell division (ADCC): phagocytosis, regulation down cell surface receptors (e.g. B cell receptors): and B cell activation. "Effective amount" of a substance, e.g. a pharmaceutical formulation, refers to the effective amount, at the dose and over the period the time required to achieve therapeutic results or desired prophylaxis. The term "epitope" encompasses any determinant capable of bound by antibodies. An epitope is an antigen-bound region by antibodies that target the antigen, and include amino acids specific amino acids that directly contact antibodies. Epitope determinants can include surface groupings of molecules chemically active substances such as amino acids, sugar side chains, phosphoryl or sulfonyl groups, and can have characteristics certain three-dimensional structural, and / or load characteristics specific. Generally, antibodies that are specific to the target antigen certain will recognize epitopes on the target antigen in the mixture protein and / or macromolecular complexes. The term "area Fc" is used here to define the C-terminal region of the immunoglobulin heavy chain containing at least part of the constant region. This term includes the Fc region of the native sequence and the Fc region of the variant. In one embodiment, The Fc region of the human IgG heavy chain extends from Cys226, or from Pro230, to the carboxyl terminal of the heavy chain. However, lysine C-terminal (Lys447) or glycine-lysine (residues 446-447) of the region Fc may or may not be present. Unless otherwise specified herein, numbering of amino acid residues in the Fc region or constant region according to the EU numbering system, also called the EU index, as described in Kabat and colleagues, Seguences of Proteins of Immunological Interest, 5th Edition. Public Health Services, National Institutes of Health, Bethesda, MD, 1991. “Framework” or “FR” refers to the variable domain residues besides the hypervariable region residue (HVR). FR variable domain generally consists of four FR domains: FR1, FR2, FR3, and FR4. Thus, FR and HVR sequences commonly appear in sequences following in VH (or VL): FRI-H1(L1)-FR2-H2(L2)-FR3-H3(L3) -FR4. The terms "full-length antibody" and "intact antibody" used here interchangeably to refer to antibodies which has a structure that is basically similar to the structure native antibodies or have heavy chains containing the Fc region as defined here. The terms "host cell", "host cell line", and "host cell culture" used interchangeably and refers to cells where the acid exogenous nucleic acids have been introduced, including the progeny of the cells Host cells include "transformants" and "transformed cells". transformed,” which includes primary and secondary transformed cells. its descendants without regard to the number of parts. The descendants can not completely identical in nucleic acid content to the cell parent, but may contain mutations. Mutant offspring have the same biological function or activity as selected or selected in the cells that were originally changed including in here. "Human antibodies" are antibodies that have the sequence amino acids that correspond to the antibodies produced by humans or human cells or derived from non-human sources that use a human antibody repertoire or sequences that encodes other human antibodies. This definition of human antibodies specifically excludes humanized antibodies that include residues that bind nonhuman antigens. The "human consensus framework" is a framework that shows the most frequently occurring amino acid residues in choice of human immunoglobulin VL or VH frame sequences. Generally, selection of human immunoglobulin VL or VH sequences is from variable domain sequence subgroups. In general, subgroups sequences are subgroups as in Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, NIH Publication 91-3242, Bethesda MD (1991), vols. 1-3. In one embodiment, for VL, the subgroup is the kappa subgroup I as in Kabat and friends, supra. In one embodiment, for VH, the subgroup is subgroup III as in Kabat and friends, supra. “Humanized” antibodies refer to chimeric antibodies that includes amino acid residues from non-human HVR and amino acid residues amino acids from human FR. In certain embodiments, the antibodies humanized will include essentially all at least one, and usually two, variable domains, where all or most of HVR (e.g., CDR) corresponds to nonhuman antibodies, and all or essentially all FRs correspond to antibodies man. Humanized antibodies may optionally include at least part of the constant region of the antibody is derived from human antibodies. “Humanized forms” of antibodies, for example, non-human antibodies, referring to antibodies that have undergone humanization. The term "hypervariable region" or "HVR" as it is used here refers to each domain area hypervariable antibody variables in the sequence ("regions complementary determinant" or "CDR") and / or form an ansa structurally defined ("hypervariable ansa") and / or containing residues that come into contact with the antigen ("antigen contact"). In general, antibodies cover six HVRs, that is, a total of six HVRs, three in VH (Hl, H2, H3), and three in VL (Ll, L2, L3). Example of HVR here includes: (a) hypervariable loop that occurs at amino acid residues 26-32 (L1), 50-52 (L2), 91-96 (L3), 26-32 (H1), 53-55 (H2), and 96-101 (H3) (Chothia and Lesk, J. Mol. Biol. 196:901-917 (1987)): (b) CDR that occurs at amino acid residues 24-34 (L1), 50-56 (L2), 89-97 (13), 31-35b6b (H1), 50-65 (H2), and 95-102 (H3) (Kabat and friends, Sequences of Proteins of Immunological Interest, 5th Edition. Public Health Service, National Institutes of Health, Bethesda, MD (1991)): (c) antigen contact that occurs at amino acid residues 27c-36 (L1), 46-55 (L2), 89-96 (L3), 30-35b (H1), 47-58 (H2), and 93-101 (H3) (MacCallum and colleagues J. Mol. Biol. 262: 132-145 (1996)): and (d) a combination of (a), (b), and / or (c), including acid residues amino HVR 46-56 (L2), 41-56 (L2), 48-56 (L2), 49-56 (L2), 26-35 (H1), 26-35b (H1), 49-65 (H2), 93-102 (H3), and 94-102 (H3). Unless otherwise stated, HVR residues and other residues in variable domains (e.g. FR residues) are numbered here according to Kabat and friends, supra. An "immunoconjugate" is an antibody conjugated to one or more heterologous molecules, including but not limited to cytotoxic substances. The "individual" or "subject" is a mammal. Mammals include, but not limited to, domestic animals (e.g., cows, sheep, cats, dogs, and horses), primates (e.g., humans and non-human primates such as monkeys), rabbits, and rodents (e.g., mice and rats). In certain embodiments, individuals or the subject is human. "Isolated" antibodies are antibodies that have been separated from the components of its natural environment. In some embodiments, antibodies are purified to a purity greater than 958 or 998 as determined by, for example, electrophoresis (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatography (e.g., ion exchange or liquid phase HPLC) reversed). To review the method of assessing antibody purity, see, for example, Flatman and colleagues, J. Chromatogr. B 848:179- 81 (2007). "Isolated" nucleic acid refers to nucleic acid molecules which has been separated from its natural environmental components. Acid isolated nucleic acid includes nucleic acid molecules contained in cells that usually contain nucleic acid molecules, but nucleic acid molecules exist extrachromosomally or at sites chromosomes that differ from their natural chromosome location. "Isolated nucleic acid encoding anti-Cls antibody" or "isolated nucleic acid encoding anti-Clr antibodies" refers to one or more nucleic acid molecules that encode heavy and light chains of antibodies (or fragments thereof), including nucleic acid molecules.) in a single vector or vector separate, and the nucleic acid molecules are found in one or more locations within the host cell. The term “monoclonal antibody” as used herein refers to antibodies obtained from a population of antibodies that essentially homogeneous, that is, the individual antibodies that make up populations are identical and / or bind the same epitopes, except for antibody variants which may, for example, contain mutations that occur naturally or arise during the production of production of monoclonal antibodies, these variants are generally present in small amounts. In contrast to polyclonal antibody preparations, which usually includes different antibodies directed against different determinants (epitopes), each monoclonal antibody from monoclonal antibody preparations directed against determinants single antigen. Thus, the "monoclonal" modifier shows the characteristics of antibodies obtained from the population antibodies that are essentially homogeneous, and are not interpreted as requires the production of antibodies by certain methods. For example, monoclonal antibodies to be used in accordance with the present invention can be made using various techniques, including but not limited to limited to hybridoma methods, recombinant DNA methods, methods phage display, and methods using transgenic animals that containing all or part of the human immunoglobulin locus, these methods and other example methods for making antibodies monoclonal is described here. "Naive antibodies" refers to antibodies that are not conjugated to heterologous moieties (e.g., cytotoxic moieties) or radiolabeled. Plain antibodies may be present in pharmaceutical formulations. "Native antibodies" refers to naturally occurring immunoglobulin molecules. with various structures. For example, native IgG antibodies are heterotetrameric glycoprotein of about 150,000 daltons, consisting of two identical light chains and two identical heavy chains disulfide bonded. From the N- to the C-terminus, each chain weight has a variable region (VH), also called the weight domain variable or variable domain of the heavy chain, followed by three constant domains (CHl, CH2, and CH3). Similarly, from N- to C- terminus, each light chain has a variable region (VL), also called variable light domain or variable domain light chain, followed by the constant light domain (CL). The light chain Mild antibodies can be assigned to one of two types, called kappa and lambda, based on the amino acid sequence of its constant domain. The term "packaging insert" is used to refer to instructions that are usually included in the product's commercial packaging therapeutic, which contains information about indications, uses, dosage, administration, combination therapy, contraindications and / or warning regarding use of the therapeutic product. "Percent (8) amino acid sequence identity" in relation to with the reference polypeptide sequence defined as the percentage amino acid residues in the candidate sequence that are identical to the residues amino acids in the reference polypeptide sequence, after alignment sequence and insert gaps, if necessary, to achieve the percentage maximum sequence identity, and does not take into account Conservative substitution as part of sequence identity. Alignment for the purpose of determining the percent identicality of amino acid sequences Amino can be achieved in a variety of ways that suit the individual. who are experts in this field, for example, using software publicly available computers such as BLAST software, BLAST-2, ALIGN, Megalign (DNASTAR), or GENETYX (trademarks registered) (Genetyx Co., Ltd.). People who are experts in this field can determine the appropriate parameters for aligning sequences, including any algorithms necessary to achieve maximum alignment across the compared sequences. The ALIGN-2 sequence comparison computer program is owned by Genentech, Inc., and its source code have been filed together user documentation at the United States Copyright Office, Washington DC, 20559, registered under Copyright Registration United States No. TXU510087. The ALIGN-2 program is publicly available. of Genentech, Inc., South San Francisco, California, or can be compiled from source code. The ALIGN-2 program must compiled for use on UNIX operating systems, including UNIX V4.0D digital. All sequence comparison parameters are set by the ALIGN-2 program and does not vary. In situations where ALIGN-2 is used for amino acid sequence comparison, $ the identicalness of the amino acid sequence of a particular amino acid sequence A to, with, or against a particular amino acid sequence B (which can expressed as a specific amino acid sequence A which has or includes $ the identity of a particular amino acid sequence to, with, or against a particular amino acid sequence B) is calculated as following: 100 times the X / Y fraction where X is the number of amino acid residues scored as identical matches by the ALIGN-2 sequence alignment program in alignment of programs A and B, and where Y is the total number of residues amino acids in B. It will be understood that where the length of the sequence amino acid A is not the same length as amino acid sequence B, $ the identicalness of the amino acid sequence from A to B will not be the same as $ identicality of amino acid sequences from B to A. Unless otherwise stated in particular, all $ values ​​of amino acid sequence identity used here were obtained as described in the previous paragraph using the computer program ALIGN-2. The term "pharmaceutical formulation" refers to a preparation that in such a way as to allow the biological activity of the active ingredients contained in it are effective, and which does not contain additional components that are highly toxic to the subject whose formulation will be managed. "Pharmaceutically acceptable carrier" refers to ingredients in a pharmaceutical formulation, other than the active ingredient, that are not toxic to the subject. Pharmaceutically acceptable carrier including, but not limited to, buffers, excipients, stabilizers, or preservatives. The phrase "specifically related to", as used here, refers to the activity or characteristic antibodies to bind to unintended antigens at the binding level which includes background binding (i.e., non-specific) but does not include binding that significant (i.e., specific). In other words, "specifically "tied to" refers to the activity or characteristics of antibodies to bind to the desired antigen on level of engagement that includes significant engagement (i.e., specific) in addition to or in place of background binding (i.e., non-specific). Specificity can be measured by the method anything mentioned in this specification or known in this field. Non-specific or background binding levels the above mentioned can be zero, or can be non-zero but close to zero, or can be low enough to be ignored. technical by someone who is an expert in this field. For example, when an expert cannot detect or observe the signal significant (or relatively strong) binding between antibodies and antigens not intended in the binding determination accordingly, it can be said that antibodies are "not specifically bind to unwanted antigens. On the other hand, when an expert can detect or observe a signal that significant (or relatively strong) binding between antibodies and the desired antigen in the appropriate binding assay, it can be said that antibodies "specifically bind to" desired antigen. The term "C1", as used herein, refers to C1 is native to any vertebrate source, including mammals such as primates (e.g. humans) and rodents (e.g. mice and mice), unless otherwise stated. This term includes C1 that has not been processed "full length" as well as any resulting form of C1 from processing within the cell. This term also includes Cl variants that occur naturally, for example splice variants or splice variants allelic. The amino acid sequence of the human C1 sample is shown in SEO ID NO: 1. Amino acid sequence of the Cls sample of the synomolgus monkey shown in SEO ID NO: 3. The term "C1lr", as used herein, refers to any native Clr from any vertebrate source, including mammals such as primates (e.g. humans) and rodents (e.g. mice and rats), unless otherwise stated. This term includes Unprocessed "full length" Clr as well as all forms of Clr resulting from processing within the cell. This term is also includes naturally occurring Clr variants, for example the variant splice or allelic variant. Human Clr amino acid sequence example is shown in SEO ID NO: 2. Example amino acid sequence The synomolgus monkey Clr is shown in SEO ID NO: 4. As used herein, "treatment" (and variations thereof) grammatically like "treat") refers to clinical intervention in an attempt to alter the natural course of the individual being treated, and can be done either for prophylaxis or during travel clinical pathology. The desired effects of treatment include, but not limited to, preventing the occurrence or recurrence of disease, reduce symptoms, reduce pathological consequences directly or indirectly from the disease, preventing metastasis, reduce the rate of disease progression, improvement or palliative from disease. disease state, and remission or improvement prognosis. In some embodiments, the antibodies of the present invention used to delay the progression of the disease or to slow down the progression of the disease. The term "variable region" or "variable domain" refers to on the heavy or light chain domain of the antibody involved in binding of antibodies to antigens. Variable domains of the α-chain heavy and light chains (VH and VL, respectively) of antibodies The original generally has a similar structure, with each The domain includes four conserved framework regions (FRs) and three hypervariable regions (HVR). (See, for example, Kindt and Kuby Immunology friends, 6th edition, WH Freeman and Co., page 91 (2007).) A single VH or VL domain may be sufficient for provide antigen binding specificity. Furthermore, antibodies that bind to a specific antigen can be isolated using the domain The VH or VL of the antibody that binds to the antigen to perform complementary VL or VH domain library screening. See, for example, Portolano and colleagues, J. Immunol. 150:880-887 (1993) : Clarkson and colleagues, Nature 352:6241-628 (1991). The term "vector", as used here, refers to in nucleic acid molecules that are capable of spreading other nucleic acids that is linked to it. This term includes vectors as self-replicating nucleic acid structures and vectors inserted into the genome of the host cell into which it has been inserted. Certain vectors are capable of directing the expression of nucleic acids that operatively linked. The vectors are referred to here as "expression vector". II. Antibodies In one aspect, the invention is based, in part, on antibodies that include antigen-binding regions and constant regions antibodies. In certain embodiments, antibodies that bind with C1 provided. In certain embodiments, the antibodies are which specifically binds to C1 is provided. Antibodies from This invention is useful, for example, for the diagnosis or treatment of complement-mediated diseases or disorders. In one embodiment, the Cl species may be selected from one species or more. human animals species is human, rhesus monkeys, marmosets, In certain embodiments, the species is and not human. In certain embodiments, rats, and monkeys (e.g., synomolgus, chimpanzees, and baboons). In the embodiment certain species are humans and monkeys (e.g., synomolgus, rhesus monkeys, marmosets, chimpanzees, and baboons). In the embodiment In particular, the species are humans and synomolgus. In embodiment, Antibodies include various types of antibodies which include antibody fragments, chimeric and humanized antibodies, human antibodies, library-derived antibodies, and antibodies multispecific. In an embodiment, the antibody may be an antibody full length, for example, or class or isotype defined here. (Antibody Fragment) intact IGGI, I1gG2, IgGG3 or IgGG4 antibodies other antibodies such as those In certain embodiments, antibodies are provided herein is an antibody fragment. limited to, Fab fragments, Antibody fragments include, but are not Fab', Fab'-SH, Flab')» Fv, and scFv, and other fragments described below. For review certain antibody fragments, 9:129-134 (2003). look at Hudson and friends Nat. Med. For an overview of the scF$v fragment, see, for example, Pluckthun, in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., (Springer-Verlag, New York), p. 269-315 (1994): see also International Patent Application No. WO 93 / 16185: and United States Patent Nos. 5,571,894 and 5,587,458. For a discussion of the Fab and Fl(ab')» fragments which include receptor binding epitope residues and have increased in vivo half-life, see United States Patent No. 5,869,016. Diabodies are antibody fragments with two binding sites. antigens that can be bivalent or bispecific. See, for example, European Patent No. EP 404,097: International Patent Application No. WO 1993 / 01161l: Hudson and friends, Nat. Med. 9:129-134 (2003): and Hollinger and colleagues, Proc. Natl. Acad. Sci. USA 90: 6444- 6448 (1993). Tribodies and tetrabodies are also described in Hudson and friends, Nat. Med. 9:129-134 (2003). Single domain antibodies are antibody fragments that contain all or part of the heavy chain variable domain or all or part of the light chain variable domain of an antibody. In certain embodiments, the single domain antibody is an antibody human single domain (Domantis, Inc., Waltham, MA: see, for example, United States Patent No. 6,248,516 Bl). Antibody fragments can be prepared by various techniques, including but not limited to proteolytic digestion of intact antibodies as well as production by recombinant host cells (e.g. E. coli or phages), as described here. (Chimeric and Humanized Antibodies) In certain embodiments, antibodies are provided herein are chimeric antibodies. Certain chimeric antibodies are described, for example, in United States Patent No. 4,816,567: and Morrison and friends, Proc. Natl. Acad. Sci. USA, 81:6851-6855 (1984)). In one example, the chimeric antibody covers a variable region instead humans (e.g., variable regions derived from mice, rats, hamsters, rabbits, or non-human primates, such as monkeys) and human constant area. In a further example, antibodies Chimeric antibodies are "class-switched" antibodies where the class or subclass has been changed from its parent antibody. Chimeric antibodies includes its antigen-binding fragment. In certain embodiments, the chimeric antibody is an antibody humanized. Typically, nonhuman antibodies are humanized to reduce immunogenicity in humans, while still maintain the specificity and affinity of non-human antibodies parent. Generally, humanized antibodies include one or more variable domain where HVR, for example, CDR, (or part thereof) derived from non-human antibodies, and FR (or parts thereof) derived from human antibody sequences. Humanized antibodies freely chosen will also include at least part of human constant area. In some embodiments, some residues The FR in the humanized antibody is replaced with the corresponding residue from non-human antibodies (e.g., antibodies from which residues HVR originates), for example, to restore or improve specificity or affinity of antibodies. Humanized antibodies and their manufacturing methods are reviewed, for example in Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008), and further explained, for example, in Riechmann and friends, Nature 332:323-329 (1988): Oueen and friends, Proc. Nat'1 Acad. Sci. USA 86:10029-10033 (1989): American Patents Union No. 5, 821,337, 1,521,191, 6,982,321, and 1,087,409: Kashmiri and colleagues, Methods 36:25-34 (2005) (describing specificity determining region (SDR) grafting): Padlan, Mol. Immunol. 28:489-498 (1991) (describing "resurfacing"): Dall'Acgua and friends, Methods 36:43-60 (2005) (describing "FR shuffling"): and Osbourn and colleagues, Methods 36:61-68 (2005) and Klimka and friends, Br. J Cancer, 83:252-260 (2000) (describes a “guided selection” approach to shuffling) FR). Areas of the human skeleton that can be used for humanization includes but is not limited to: framework areas selected using the “best fit” method (see, for example, Sims and colleagues J. Immunol. 151:2296 (1993)): skeletal regions derived from the human antibody consensus sequence from specific subgroups of the variable regions of the light or heavy chains (see, for example, Carter and colleagues Proc. Natl. Acad. Sci. USA, 89:4285 (1992): and Presta and friends J. Immunol., 151:2623 (1993)): human adult skeletal region (somatic mutation) or the human germline skeletal region (see, for example, Almagro and Fransson, Front. Biosci. 13:1619-1633 (2008)): and framework area derived from FR library screening (see, for example, Read and friends, J. Biol. Chem. 212:10678-10684 (1997) and Rosok and friends, J. Biol. Chem. 2171:22611-22618 (1996) ). (Human Antibody) In certain embodiments, antibodies are provided herein are human antibodies. Human antibodies can be produced by using various techniques known in this field. Human antibodies are described in general terms in van Dijk and van de Winkel, Curr. Opinion. Pharmacol. 5: 368-74 (2001) and Lonberg, Curr. Opinion. Immunol. 20:450-459 (2008). Human antibodies can be made by administering 1 immunogen in transgenic animals that have been modified to produce whole human antibodies or whole antibodies with variable regions humans in response to antigenic challenges. Animals These usually contain all or part of the locus human immunoglobulin, which replaces the immunoglobulin 1 locus endogenous, or existing extrachromosomally or integrated randomly into the animal's chromosomes. In these transgenic mice, endogenous immunoglobulin loci have generally been inactivated. For review of methods for obtaining human antibodies from transgenic animals, see Lonberg, Nat. Biotech. 23:1117-1125 (2005). See also, for example, United States Patents Nos. 6,075,181 and 6,150,584 which describes the XENOMOUSE technology (registered trademark), Patent United States Patent No. 5,770,429 describes HUMAB technology (trademark registered trademark): United States Patent No. 1,041,870 describes KM MOUSE technology (registered trademark), and Publications United States Patent Application No. US 2007 / 0061900, describes VELOCIMOUSE technology (registered trademark)). Variable area humans from intact antibodies produced by the animal can be further modified, for example by combining with different human constant areas. Human antibodies can also be made by methods based on hybridoma. Human myeloma cell lines and mouse heteromyeloma humans for the production of human monoclonal antibodies have explained. (See, for example, Kozbor J. Immunol., 133: 3001 (1984): Brodeur and friends, Monoclonal Antibody Production Technigues and Applications, p. 51-63 (Marcel Dekker, Inc., New York, 1987): and Boerner and colleagues, J. Immunol., 1417: 86 (1991).) Human antibodies produced through technology Human B cell hybridomas were also described in Li and colleagues, Proc. Natl. Acad. Sci. USA, 103:3557-3562 (2006). Additional methods including those described, for example, in United States Patent No. No. 1,189,826 (describing the production of human IgM antibodies) monoclonal hybridoma cell lines) and Ni, Xiandai Mianyixue, 26(4):265-268 (2006) (describing hybridoma humans). Human hybridoma technology (Trioma technology) is also described in Vollmers and Brandlein, Histology and Histopathology, 20(3):927-937 (2005) and Vollmers and Brandlein, Methods and Findings in Experimental and Clinical Pharmacology, 21(3):185-91 (2005). Human antibodies can also be produced by isolating variable domain sequences of Fv clones selected from the display library phages of human origin. The variable domain sequences then can be combined with the constant human domain which desired. Techniques for selecting human antibodies from a library antibodies are described below. (Library-derived Antibodies) The antibodies of the invention can be isolated by performing combination library screening for antibodies with activity or desired activity. For example, various methods are known in this field to generate phage display libraries and screen the library for antibodies that have desired binding characteristics. The method is reviewed, for example, in Hoogenboom and colleagues in Methods in Molecular Biology 118:1-37 (O'Brien and colleagues, ed., Human Press, Totowa, NJ, 2001) and further explained, for example, in McCafferty and colleagues, Nature 348:552-554: Clackson and friends, Nature 352: 624-628 (1991): Marks and friends, J. Mol. Biol. 222: 581-597 (1992): Marks and Bradbury, in Methods in Molecular Biology 248:161-175 (Lo, ed., Human Press, Totowa, NJ, 2003): Sidhu and friends, J. Mol. Biol. 338(2): 299-310 (2004): Lee and friends, J. Mol. Biol. 340(5): 1073-1093 (2004): Felouse, Proc. Natl. Acad. Sci. USA 101(34): 12467-12472 (2004): and Lee and colleagues, J. Immunol. Methods 284(1-2): 119-132 (2004). In certain phage display methods, the repertoire of VH and VL genes separately cloned by polymerase chain reaction (PCR) and randomly recombined in a phage library, which then can be screened for antigen-binding phages such as those described in Winter and colleagues, Ann. Reverend Immunol., 12: 433-455 (1994). Phages typically display antibody fragments, either as a single chain Fv fragment (scFv) or as a fragment Fab. Library from immunized sources provides antibodies high affinity for immunogens without the requirement to build hybridoma. Alternatively, the naive repertoire can be cloned (e.g., from humans) to provide a single source of antibodies to various non-self antigens as well as self antigens without any immunization as described by Griffiths and colleagues Comrade, EMBO J, 12: 125 -134 (1993). Finally, naive libraries too can be made synthetically by cloning the V gene segment not rearranged from stem cells, and using PCR primers that contains random sequences to encode highly conserved CDR3 regions. vary and to achieve in vitro rearrangements, such as as described by Hoogenboom and Winter, J. Mol. Biol., 221: 381-388 (1992). Publication of a patent describing a phage library human antibodies include, for example: United States Patent No. 5,750,373, and United States Patent Publication No. 2005 / 0079574, 2005 / 0119455, 2005 / 0266000, 2007 / 0117126, 2001 / 0160598, 2001 / 023776 4, 2001 / 0292936, and 2009 / 0002360. Antibodies or antibody fragments isolated from a library human antibodies are considered as human antibodies or fragments human antibodies here. (Multispecific Antibodies) In certain embodiments, antibodies are provided herein are multispecific antibodies, for example bispecific antibodies. Multispecific antibodies are monoclonal antibodies that have binding specificity for at least two different sites. In certain embodiments, one of the binding specificities is for C1 and the others are for other antigens. In In certain embodiments, bispecific antibodies can bind to two different Cl epitopes. Bispecific antibodies can also used to localize cytotoxic substances to the cells expressing Cl. Bispecific antibodies can be made as full-length antibodies or antibody fragments. Techniques for making multispecific antibodies include, but not limited to, recombinant co-expression of two partners immunoglobulin heavy-light chains that have specificity different (see Milstein and Cuello, Nature 305: 537 (1983)), International Patent Application No. WO 93 / 08829, and Traunecker and colleagues, EMBO J. 10: 3655 (1991)), and "knob-in- hole" (see, e.g., United States Patent No. 5,731,168). Multi-specific antibodies can also be made by engineering the effects of electrostatic steering to create Fc-antibody molecules heterodimeric (International Patent Application No. WO 2009 / 089004A1): cross-linking two or more antibodies or fragments (see, e.g., United States Patent Nos. 4,676,980, and Brennan and colleagues, Science, 229: 81 (1985)): uses leucine zipper to produce bi-specific antibodies (see, for example, Kostelny and colleagues, J. Immunol., 148(5):1547-1553 (1992)): using "diabody" technology to create fragments bispecific antibodies (see, for example, Hollinger et al., Proc. Natl. Acad. Sci. USA, 90:6444-6448 (1993)): and using single-chain dimer Fv (scFrv) (see, for example, Gruber and co- bro, JJ. Immunol., 152:5368 (1994)): and making antibodies trispecific as described, for example in Tutt and colleagues friend J. Immunol. 147: 60 (1991). Antibodies engineered with three or more sites functional antigen binding, including "Octopus Antibodies", also included here (see, for example, American Patent Application Union No. US 2006 / 0025576A1). Antibodies or fragments here also include "Dual-acting Fabs" or "DAF" which includes the antigen binding site that binds with C1 as well as other different antigens (see, Patent Application United States No. US 2008 / 0069820, for example). A. Isolated antibodies In certain embodiments, the antibody is an antibody isolated. In an embodiment, the isolated antibody covers the region antigen binding and antibody constant regions. In an embodiment, the isolated antibody may have a function movement in such a way that the antibodies are specific binds to Cls and promotes the dissociation of Clg from the complex Clgrs. In an embodiment, the isolated antibody may have a function blockade so that antibodies that specifically bind to Cls and inhibits the binding of Clg to Cl1r2s2. Antibodies that isolated can have one or both of the transfer functions and blocking function. Antibodies preferably have both the function. In one embodiment, the isolated antibody is specifically binds to C1 in a pH-dependent manner. As specific examples of embodiment, in cases where the activity antibody binding to human C1 and / or sinomolgus was measured with surface plasmon resonance, 1) the value of the dissociation constant (KD) in the neutral pH range can be calculated reliably, and the KD value in the acidic pH range is not can be calculated reliably because there is no binding activity or very low binding activity, or i1) ratio of KD value in the acidic pH range to KD value in neutral pH range, acid KD / neutral KD ratio, more than 10 provided both KD values ​​in the neutral pH range and the acidic pH range can be can be calculated reliably. It is hoped that these antibodies will be superior as anti-inflammatory substances. pharmacy, because the dose and frequency of administration to patients can reduced and as a result the total dose can be reduced. Antibodies anti-Cls is expected to have a superior safety profile compared to antibodies that bind to and remove the Clgrs complexes from the plasma, as they will only removes Cl1lr2s2 (via binding to Cls) from plasma but not Clg from plasma. As a result, the side effects associated with with Clg depletion can be avoided. In addition, antibodies with rapid Clg displacement is expected to have neutralization faster complement activity, which can be translated to be faster treatment efficacy. (al) BIACORE (registered trademark) / Displacement concept In one embodiment, an isolated antibody that inhibits the interaction between the Clg complex and Cl1r2s2 is an antibody that binding of Clgrs complexes on a chip for resonance determination surface plasmons, for example, BIACORE chips (registered trademark) and promotes the dissociation of Clg from the Clgrs complex. In some embodiment, binding function on the Clgrs complex and promotes dissociation of Clg from the Clgrs complex mentioned above is called here as "movement function / activity" or "Clg transfer function / activity". Function / activity can be assessed precisely qualitatively or quantitatively using surface plasmon resonance determination, for example, BIACORE determination (registered trademark) as described herein. In In further embodiments, antibodies may be defined as antibodies that have a displacement function when the unit value response (RU) in the presence of antibodies lower than the unit value response (RU) in the absence of antibodies as determined. with surface plasmon resonance determination, for example BIACORE determination (registered trademark), when sufficient time has passed. In sensorgram obtained from the determination, the expert person can identify that the curve in the presence of Clg and antibodies approaching the curve in the presence of Clg in the absence of antibodies. In further embodiments, the skilled person may identify the "crossover time point" where the curve with the presence of Clg in the absence of antibodies crosses the curve with the presence of Clg and antibodies (see Example for details). In order to further tight, some crossover points can be observed even in one sensorgram due to noise or oscillation of the last curve when crossing the previous curve. In that case, whichever from several points in time the crossing can be selected as "points crossing time". “Passing sufficient time” means the point the measurement time of the response unit (RU) value is sufficient after the “point crossing time” for measurement purposes. In some embodiment, time point of measurement of response unit (RU) value is at least 60 seconds, 100 seconds, 150 seconds, 200 seconds, 500 seconds seconds, 700 seconds, 1000 seconds, 1500 seconds, or 2000 seconds after the time point at which the antibody injection begins. Alternatively, the time point measurement time can be at least 100 seconds, 200 seconds, 300 seconds, 400 seconds, 500 seconds, 600 seconds, 700 seconds, 800 seconds, 900 seconds, 1000 seconds, 3000 seconds, 5000 seconds, 7000 seconds, or 10000 seconds after the crossing point. In one embodiment, an isolated antibody that inhibits The interaction between the Clg and C1r2s2 complexes can be defined as antibodies that have a transfer function at a given time point crossing (for example, in the designation of BIACORE (trademark registered)) in 60 seconds, 100 seconds, 150 seconds, 200 seconds, 500 seconds, 700 seconds, 1000 seconds, 1500 seconds, or 2000 seconds after the time point at which the antibody injection begins, as specified by, for example, the designation of BIACORE (registered trademark) using the following conditions: The capture rate of the C1r2s2 complex and C1lg each at 200 resonance units (RU) and 200 resonance units (RU) resonance (RU), and antibodies as analytes were injected at 500 nM at 10 microliters (micro L) / min. In one embodiment, an isolated antibody that inhibits The interaction between the Clg and C1r2s2 complexes can be defined as antibodies that have a transfer function when almost all (or all) Clg is dissociated from the Clgrs complex within a short time. 100 seconds, 300 seconds, 500 seconds, 700 seconds, 1000 seconds, 1500 seconds, 2000 seconds, 3000 seconds, 5000 seconds, 7000 seconds, or 10000 seconds after the time point of initiation of antibody injection, as determined by, for example, the designation of BIACORE (trademark registered) using the following conditions: Complex catch rate C1r2s2 and Clg are at 200 resonance units (RU) and 200 resonance units (RU). resonance (RU), respectively, and antibody as analyte injected at 500 nM at 10 micro L / min. For example, in sensorgram obtained from the determination, can it was determined that "almost all (or all) Clg was separated from Clgrs complex" when the value (RU) in the presence of Clg and antibodies approaching or reaching the value (RU) in the presence of antibodies with absence of Clg. Here, "almost all (of C1lg)" refers to percentage 708, 718, 1728, 138, 148, 1758, 168, 1178, 188, 198, 808, 818, 8285, 8385, 848, 8585, 868, 8785, 8885, 8985, 908, 918, 9285, 938, 9485, 9585, 9685, 978, 98 8, 995, or more: and "all (of Clg)" refers to the percentage of 1008. The percentage of dissociated Clg can be determined quantitatively by any determination that described herein. In some embodiments, 1this invention provide a screening method for antibodies that substitute for Clg from the C1r2s2 complex, using the measurement method the above mentioned "movement function / activity" of the antibodies. In one embodiment, the screening method includes select antibodies that inhibit the interaction between the Clg complex and C1lr2s2: that is, selecting antibodies that bind to the complex Clgrs and induces the dissociation of Clg from the Clgrs complex. Antibodies which has a transfer function / activity can be selected with precisely using surface plasmon resonance determination, for example, BIACORE (registered trademark) designation as described here. In some embodiments, the screening method includes determine (1) the response unit (RU) value in the presence of antibodies and (11) the response unit (RU) value in the absence of antibodies, with surface plasmon resonance determination, for example BIACORE determination (registered trademark), when sufficient time has passed. Method screening may include comparing the value (1) above and the value (11) above. Screening methods may include selecting antibodies when the value of (1) above is lower than the value of (ii) above. Screening methods may include identifying “points in time” "crossing" where the curve with the presence of Clg with the absence of antibodies cross the curve in the presence of Clg and antibodies. As mentioned above, several points in time of crossing can be observed even in one sensorgram, and one of several points the crossover time can be selected as the "crossover time point". In some embodiments, the screening method may include measuring response unit (RU) values ​​of at least 60 seconds, 100 seconds, 150 seconds, 200 seconds, 500 seconds, 700 seconds, 1000 seconds, 1500 seconds or 2000 seconds after the time point of initiation of antibody injection. As Alternatively, screening methods may include measuring unit values response (RU) at least 100 seconds, 200 seconds, 300 seconds, 400 seconds, 500 seconds, 600 seconds, 700 seconds, 800 seconds, 900 seconds, 1000 seconds, 3000 seconds, 5000 seconds, 7000 seconds, or 10000 seconds after the time the intersection point. In some embodiments, the method screening may include selecting antibodies that inhibit interactions between the Clg and C1r2s2 complexes or antibodies that have a function displacement, when the time point of antibody crossing is within 60 seconds, 100 seconds, 150 seconds, 200 seconds, 500 seconds, 700 seconds, 1000 seconds, 1500 seconds, or 2000 seconds after the time point initiation of antibody injection, as determined by, for example, the designation of BIACORE (a registered trademark) using the following conditions: The capture levels of the C1r2s2 and Clg complexes are at 200 resonance units (RU) and 200 resonance units (RU), respectively respectively, and antibodies as analytes were injected at 500 nM at 10 microliters (micro L) / minute. In some embodiments, the method screening may include selecting antibodies that inhibit interactions between the Clg and C1r2s2 complexes or antibodies that have a function displacement, when almost all (or all) of the Clg is separated from Clgrs complex in 100 seconds, 300 seconds, 500 seconds, 700 seconds seconds, 1000 seconds, 1500 seconds, 2000 seconds, 3000 seconds, 5000 seconds, 1000 seconds, or 10000 seconds after the point in time the injection started antibodies, as determined by, for example, the BIACORE assay (registered trademark) using the following conditions: Level The capture of the complex C1lr2s2 and Clg is at 200, respectively. resonance units (RU) and 200 resonance units (RU), and antibodies as an analyte injected at 500 nM at 10 micro L / min. As mentioned above, "almost all (of Clg)" refers to percentage 708, 718, 1728, 138, 148, 1758, 168, 1178, 188, 198, 808, 818, 828, 838, 848, 858, 868, 878, 8885, 898, 908, 918, 9285, 938, 9485, 9585, 9685, 9785, 988, 998, or more, and "all (of Clg)" refers to 1008, and the percentage of dissociated Clg can be determined quantitatively by any determination that described herein including the designation of BIACORE (trademark) registered). (a2) BIACORE (registered trademark) / Blocking concept In one embodiment, the invention provides antibodies isolated that inhibits the interaction between the Clg complex and C1lr2s2, where the antibody has a blocking function so that antibodies bind to C1r2s2 and inhibit Clg binding on C1r2s2. In a further embodiment, the antibody has blocking ratio of at least 608, 658, 108, 158, 8085, 858, 908, 958 or more. Blocking function / activity or ratio blocking can be determined using the BIACORE determination (registered trademark). The following conditions may apply to evaluate Clg blocking level: Cl1r2s2 capture level aimed at 50, 100, 200, 400 resonance units (RU). Variants antibodies were injected at 250, 500, 1000, 2000 nM for saturate antibody binding, followed by injection of Clg humans at 50, 100, 200 nM with or without antibody variants at 250, 500, 1000, 2000 nM. The blocking ratio was calculated by the following formula: (1- (human Clg binding response in the presence of human Cl1g antibody / binding response variants without variants antibodies)| x 1005. (a3) pH dependence In one embodiment, the isolated antibody is specifically binds to C1 in a pH-dependent manner. In preferred embodiment, antibody binding activity to C1 is lower in the acidic pH range (e.g. at pH 6.0) compared to the neutral pH range (e.g., at pH 71.4). In an embodiment, the antibody may have a binding very low at C1 in the acidic pH range so that, when binding activity was measured by surface plasmon resonance and dissociation constant (KD) value is calculated from the data, the KD value in acidic pH ranges have lower reliability or activity binding at C1 in the acidic pH range was not detected, i.e., in cases where the antibody binding activity against Cl human and / or synomolgus measured by plasmon resonance surface, 1) KD values ​​in the neutral pH range can be calculated reliably, and the KD value in the acidic pH range cannot be calculated accurately. reliable because there is no binding activity or activity very low binding, or i1) ratio of KD value in the acidic pH range to KD value in neutral pH range, acid KD / neutral KD ratio, more than 10 provided both KD values ​​in the neutral pH range and the acidic pH range can be can be calculated reliably. In the embodiment, the acid KD / neutral KD ratio of ii) is more preferred 14 or more, 44 or more, 45 or more, 72 or more, 99 or more, 100 or more, 107 or more, 110 or more, 117 or more, 120 or more, 138 or more, 181 or more, 209 or more, 225 or more, 278 or more. In an embodiment, the ratio Acid KD / neutral KD of ii) preferably 44 or more, 45 or more, 72 or more, 99 or more, 100 or more, 107 or more, 110 or more, 117 or more, 120 or more, 138 or more, 181 or more, 209 or more, 225 or more, 278 or more. The meaning of the word 'reliable' in this case is explained as follows. The KD value of each sample at pH 71.4 and pH 6.0 was determined. at a temperature of 37 degrees C using BIACORE (registered trademark) T200 instrument (Cytiva). Anti-mouse Ig kappa light chain Purified Human (GE Healthcare) can be immobilized to all CM5 sensor chip flow cells use a coupling kit amine (GE Healthcare). Buffer includes 20 mM ACES, 150 mM NaCl, 1,2 mM CaCl», 1 mg / mL bovine serum albumin (BSA) (IgG6G free), 1 mg / mL CMD (CM-Dextran sodium salt), 0.058 Tween (registered trademark) 20, and 0.0058 NaN3 (pH 7.4 or pH 6.0) was used as a running buffer. Each antibody can be captured onto the sensor surface through the Anti-Human Ig kappa light chain. Capture rate antibodies were adjusted to 50 resonance units (RU). For the value KD at pH7.4, the human Cl1r2s2 complex is made in such a way so that the protein complex can be injected at 0, 25, 40, 100, 200, 400 nM, 0, 12.5, 25, 40, 100, 200 nM, or 0, 6.3, 12.5, 25, 50, 100 nM, at 30 micro L / mmt. For KD values ​​at pH6.0, the human or sino Cl1r2s2 complex is made in such a way that protein complexes can be injected at O, 200, 400, 800, 1600, 3200 nM, or O, 50, 100, 200, 400, 800 nM, at 30 micro L / min with, for example, Glycine pH 2.0 (GE Healthcare). The sensor surface is made repeat each cycle with, for example, Glycine pH 2.0 (GE Healthcare). KD values ​​are obtained using BIACORE (trademark registered) T200 Evaluation software, version 2.0 (Cytiva). The KD value at pH6.0 was compared with the KD value at pH7.4 (ratio Acid KD / Neutral KD). If the results of software quality control BIACORE (registered trademark) states "kinetic constant cannot be uniquely determined" for an antibody, we assume that the KD value of antibodies cannot be calculated with reliable. In one case embodiment, the binding activity with surface plasmon resonance was measured at 37 degrees C using sensor chip where each antibody is captured by a chain human kappa Ig light at 50 resonance units and running buffer which includes 20 mM ACES (N-(2-Acetamido)-2-acid) aminoethanesulfonate), 150 mM NaCl, 1.2 mM Call», 1 mg / mL albumin bovine serum (BSA), 1 mg / mL CM-Dextran sodium salt (CMD), 0.058 polysorbate 20, 0.0058 NaN3 . In an embodiment, the antibody does not include an antibody that The KD value in the neutral pH range cannot be calculated directly. reliable because there is no binding activity or activity quite low binding. In addition to binding to C1 in a pH-dependent manner, the effect calcium on the pH-dependent affinity of antibodies to Cl can be another important property. Cls forms dimers in high calcium concentration but dissociates into monomers at low calcium concentrations. When Cls is in the dimeric state, bivalent antibodies are able to form immune complexes by linking Crosslinking of several Cls molecules. This allows the antibody to binds the C1 molecule in the complex through affinity interactions and avidity, thereby increasing the apparent antibody affinity. In contrast, when Cls is in the monomeric state, antibodies only binds through affinity interactions with Cls. This means that pH-dependent Cls antibodies can form immune complexes with dimeric Cls in plasma, but once inside acidic endosomes, Cls will dissociate into monomers. This causes the breakdown of immune complexes which then increases pH-dependent dissociation of antibodies from antigens. In one aspect, in isolated anti-Cls antibodies, the ratio KD value for Cls binding activity at acidic pH with a value KD for Cls binding activity at neutral pH (KD (pH acid) / KD (neutral) pH)) more than 10 when measured at a concentration High calcium at neutral and acidic pH. In one aspect, deep isolated anti-Cls antibodies, the ratio of KD values ​​to activity Cls binding at acidic pH with KD value for activity Cls binding at neutral pH (KD(acidic pH) / KD(neutral) pH)) is higher 148 of 10 when measured at high calcium concentrations at neutral pH and at low calcium concentrations at acidic pH. In some embodiment, in isolated anti-Cls antibodies, the ratio of KD values for Cls binding activity at acidic pH with KD value for Cls binding activity at neutral pH (KD(acidic pH) / KD(neutral) pH)) more than 10 when measured at low calcium concentrations at neutral and acidic pH, where anti-Cls antibodies bind to Cls dimer state. Without being bound by a particular theory, in case 1) structure The C1 epitope bound by the antibody can be changed conformational by the absence of calcium thus changing antibody affinity or 2) interaction (affinity or avidity) antibodies can vary depending on the Cls condition (state of monomeric or dimeric state), measurements using certain conditions (at high calcium concentrations at neutral pH and at low calcium concentrations at acidic pH) can be used for evaluation of the KD value ratio (KD(acidic pH) / KD(neutral pH)). In other words, the antibody binds to C1 with higher affinity at neutral pH than at acidic pH as described in (1) or (ii) below: (1) when measured at high calcium concentrations at neutral pH and acid, the ratio of KD values ​​to Cls binding activity at acidic pH with the KD value of Cls binding activity at neutral pH (KD(pH acid) / KD (neutral pH)) more than 10, (11) when measured at high calcium concentrations at neutral pH and at low calcium concentrations at acidic pH, the ratio of KD values for Cls binding activity at acidic pH with KD value Cls binding activity at neutral pH (KD (acidic pH) / KD (acidic pH) neutral)) more than 10. More generally, without being tied to a particular theory, in case 1) the structure of a particular antigen epitope that is bound by antibodies can be conformationally altered by the absence of calcium thus changing the affinity of the antibody or 2) interaction (affinity or avidity) of antibodies can vary depending on the condition antigen (monomeric or dimeric state), measurement by using certain conditions (at high calcium concentrations in Neutral pH and at low calcium concentrations in acidic conditions). pH) can be used to evaluate the ratio of KD values ​​(KD(pH acid) / KD (neutral pH)). Therefore, antibodies bind to antigens with higher affinity at neutral pH than at acidic pH as following: when measured at high calcium concentrations at neutral pH and at low calcium concentrations at acidic pH, the ratio of KD values for antigen binding activity at acidic pH against KD value for antigen binding activity at neutral pH (KD (pH acid) / KD(neutral pH)) more than 10. The KD ratio mentioned above, namely, KD (acidic pH) / KD (acidic pH) neutral) can be compared between the parent antibodies (i.e., the antibodies original before modification of the present invention) and antibodies wherein one or more amino acid mutations (e.g. additions, insertions, deletions, or substitution) has been introduced in relation to the original antibody (parent). The original (parent) antibody can be an antibody that known or newly isolated as long as it is specifically binds to Cl. Thus, in one aspect, in isolated anti-Cls antibodies, the ratio of KD values ​​to activity Cls binding at acidic pH with KD value for activity Cls binding at neutral pH (KD(acidic pH) / KD(neutral pH)) is minimal 1.2 times, 1.4 times, 1.6 times, 1.8 times, 2 times, 2.5 times, 3 times, 3.5 times, 4 times, 5 times, 8 times, l10 times higher than the ratio KD value of Cls binding activity at acidic pH with KD value Cls binding activity at neutral pH (KD(acidic pH) / KD(acidic pH) neutral)) of the original (parent) antibody. In other words, this invention provide isolated anti-Cls antibodies where anti-Cls antibodies isolated have been introduced with one or more amino acid mutations amino acid (e.g. addition, insertion, deletion, or substitution) of parent (original) antibody, and the ratio of (1) to (ii) below minimum 1.2, 1.4, 1.6, 1.8, 2, 2.5, 3, 3.5, 4, 5, 8, or 10: (Ci) ratio of the KD value for Cls binding activity at acidic pH to the value KD for Cls binding activity at neutral pH (KD(acidic pH) / KD (acidic pH) neutral)) of isolated anti-Cls antibodies, (i1) comparison KD value of Cls binding activity at acidic pH against KD value Cls binding activity at neutral pH (KD(acidic pH) / KD(acidic pH) neutral)) parent (original) antibody. This KD ratio can be measured in any calcium concentration (high or low), for example measured at high calcium concentrations at neutral and acidic pH, or measured at high calcium concentrations at neutral pH and at low calcium concentration at acidic pH. In one aspect, antibodies have binding activity. antigens that differ between intracellular and extracellular conditions. Intracellular and extracellular conditions refer to conditions that differ between inside and outside the cell. Condition categories include, for example, ion concentration, more specifically, ion concentration metal, hydrogen 10n concentration (pH), and calcium ion concentration. “Intracellular conditions” is preferred to refer to the characteristics environment in the environment inside the endosome, while "conditions "extracellular" is preferred to refer to environmental characteristics in the environment in plasma. Antibodies with the property of having antigen binding activity that changes according to ion concentration can be obtained by screening a large number of antibodies for domains that have these properties. For example, antibodies with the properties described above can be obtained by produce large numbers of antibodies whose sequences differ from one another each other with the hybridoma method or antibody library method, and measure its antigen binding activity at ion concentrations different. The B cell cloning method is one example of a method antibody screening. Furthermore, as explained below, at least one specific amino acid residue that can provide antibodies with the property of having binding activity antigens that change according to the concentration of a specified ion, to create a library of a large number of antibodies that have different sequences while sharing amino acid residues which is typical as a general structure. The library can be screened to efficiently isolate antibodies that have the properties explained above. In one aspect, the present invention provides antibodies that binds to C1 with higher affinity at pH neutral rather than acidic pH. In another aspect, 1 the present invention provided an anti-C1ls antibody that demonstrated binding pH dependent on Cls. As used here, the expression "pH-dependent binding" means "binding that reduced at acidic pH compared to neutral pH", and both expressions are interchangeable. For example, anti-Cls antibodies "with binding characteristics that depend on at pH" including antibodies that bind to Cls with higher affinity at neutral pH than at acidic pH. In certain embodiments, the ratio of the KD value to the activity Cls binding at acidic pH on KD value for activity Cls binding at neutral pH (KD(acidic pH) / KD(neutral pH)) is more than 10 when measured at high calcium concentrations at neutral and acidic pH. In certain embodiments, antibodies binds C1 with at least 11, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 400, 1000, 10000, or more times higher affinity at neutral pH than at acidic pH. In certain embodiments, the ratio of the KD value to the activity Cls binding at acidic pH on KD value for activity Cls binding at neutral pH (KD(acidic pH) / KD(neutral pH)) is more than 10 when measured at high calcium concentrations at pH neutral and at low calcium concentrations at acidic pH. In In certain embodiments, the antibody binds C1 with at least 11, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 15, 80, 85, 90, 95, 100, 200, 400, 1000, 10000, or more times affinity higher at neutral pH than at acidic pH. In the case mentioned above, for example, the acidic pH is 6.0 and neutral pH is 7.4, so KD(acid pH) / KD(neutral pH) is KD (pH 6.0) / KD (pH 7.4). In this connection, examples of pH acidic and neutral pH are explained in detail later. In some embodiments, KD(acidic pH) / KD(neutral pH) such as KD(pH 6.0) / KD (pH 7.4) maybe 11 to 10,000. When the antigen is a soluble protein, binding antibodies to antigens can result in prolonged time half-life of antigen in plasma (i.e., reduced antigen clearance from plasma), because antibodies can have a longer half-life longer in plasma than the antigen itself and can function as an antigen carrier. This is due to the recycling of the complex antigen-antibody by FcRn via the endosomal pathway in cells (Roopenian and Akilesh (2007) Nat Rev Immunol 17(9): 115-725). However, antibodies with pH-dependent binding characteristics, which binds its antigen in a neutral extracellular environment while releases antigens into the acidic endosomal compartment after enter the cell, it is expected to have superior properties in the case of neutralization and clearance of antigens relative to them. the pair that binds in a pH-independent manner (Igawa and friends (2010) Nature Biotechnol 2811): 1203-1201: Devanaboyina and colleagues (2013) mAbs 5(6): 851-859: Publication International Patent Application No: WO 2009 / 125825). In one aspect, the invention provides antibodies that bind with C1 with higher affinity under conditions high calcium concentration than in low concentration conditions low calcium. In one embodiment, preferred metal ions include, for example, calcium ions. Calcium ions are involved in the modulation of many biological phenomena, including muscle contractions such as skeletal muscle, smooth muscle, and heart: activation of movement, phagocytosis, and leukocyte-like: activation of changes in shape, secretion, and similar to platelets: lymphocyte activation: mast cell activation including histamine secretion: a cell-mediated response1 by alpha catecholamine receptor or acetylcholine receptor: exocytosis:j release of transmitter substances from neuron terminals, and axoplasmic flow in neurons. Known intracellular calcium ion receptors including troponin C, calmodulin, parvalbumin, and light chains myosin, which has several calcium ion binding sites and believed to have come from the same origin in the case of molecular evolution. There are also many known calcium binding motifs. The motifs that These well-known domains include, for example, the cadherin domain, KEF-hand of calmodulin, C2 domain Protein kinase C, Gla domain blood clotting protein Factor IX, C-type lectin of the receptor acyaroglycoprotein and mannose binding receptor, domain A LDL receptor, annexin, thrombospondin type 3 domain, and β-domain similar to EGF. In one embodiment, when the metal ion is a calcium ion, it is desirable that the antigen binding activity is lower in conditions of low calcium ion concentration than in conditions high concentration of calcium ions. While the concentration of calcium ions intracellular calcium concentration is lower compared to the extracellular calcium ions. In contrast, the concentration of calcium ions extracellular concentration is higher than the concentration of calcium ions intracellular . In one embodiment, the concentration of calcium ions that low preferably 0.1 micromolar (micro M) to 30 micro M, preferably 0.5 micro M to 10 micro M, and especially preferably 1 micro M to 5 micro M which is close to the ion concentration calcium. in early endosomes in vivo. Meanwhile, in one embodiment, high calcium ion concentration is preferred 100 micro M to 10 micro M, preferably 200 micro M to 5 mM, and especially preferably 0.5 mM to 2.5 mM approaching the concentration of calcium ions in plasma (in blood). In one embodiment, it is preferred that the calcium ion concentration the low is the concentration of calcium ions in endosomes, and high concentration of calcium ions is the concentration of calcium ions in plasma. When the level of antigen binding activity compared between low and high calcium ion concentrations, preferably stronger antibody binding at higher ion concentrations high calcium than at low calcium ion concentrations. In other words, it is preferable that the antigen binding activity of an antibody lower in calcium ion concentration lower than at high concentrations of 10on calcium. When the level of binding activity is expressed by a constant dissociation (KD), KD value (low calcium ion concentration) / KD (high calcium ion concentration) greater than 1, is preferred 2 or more, still preferred 10 or more, and more preferred again 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 400, 1000, 10000 or more. The upper limit of the KD value (ion concentration) low calcium) / KD (high calcium ion concentration) no is specifically limited, and can be any value such as 100, 400, 1000, or 10000, as long as it can be produced by the technique by expert person. It is possible to use a constant rate dissociation (kd) as a substitute for KD. When it is difficult to calculate the value KD, activity can be assessed based on the level of binding response in BIACORE (registered trademark) when the analyte is passed through the same concentration. When the antigen is passed over the chip immobilized with antibodies, the binding response at the concentration low calcium is preferred 1 / 2 or less of the binding response at high calcium concentrations, preferably 1 / 3 or less, preferably 1 / 5 or less, and especially preferably 1 / 10 or less. It is known that in general the ion concentration extracellular calcium in vivo (e.g. in plasma) is high, and intracellular calcium ion concentration (e.g. in endosomes) low. Thus, in one embodiment, it is preferred that the condition extracellular is a high concentration of calcium ions, and intracellular conditions are low calcium ion concentrations. When the property that the antigen binding activity is lower in conditions of intracellular calcium ion concentration than in extracellular calcium ion concentration conditions are given to antibodies, antigens that have bound to antibodies outside the cell dissociates from antibodies within the cell, thereby increasing the incorporation of antigens into cells from outside the cells. These antibodies, when administered to a living body, it can reduce the concentration antigen in plasma and reduce the physiological activity of the antigen in vivo . Thus, antibodies are useful. Screening methods for antigen or antibody binding regions that have antigen binding activity is lower at higher concentration conditions low calcium ions than in conditions of calcium ion concentration high includes, for example, the methods described in the Application International Patent No. WO2012 / 0173992 (e.g., paragraphs 0200- 0213). Method for providing an antigen-binding region with weaker binding properties to antigens under conditions lower calcium ion concentration than in conditions of high concentration high calcium ions are not specifically restricted, and can done by any method. In particular, the method includes, for example, a method for substituting at least one amino acid residues in the antigen-binding region with amino acid residues amino acids that have metal chelating activity, and / or include into the antigen-binding domain at least one amino acid residue have metal chelating activity. Antibodies where at least one amino acid residue of the antigen-binding region has been replaced with amino acid residues that have metal chelating activity and / or at least one amino acid residue that has activity Metal chelators have been introduced into the antigen binding domain is the preferred manifestation of antibodies. Amino acid residues that have metal chelating activity preferably include, for example, serine, threonine, asparagine, glutamine, aspartic acid, and glutamic acid. Furthermore, the residue Amino acids that alter the antigen-binding activity of the region antigen binder according to the concentration of 10on calcium is preferred includes, for example, amino acid residues that form the motif calcium binding. The calcium binding motif is well known by people who are experts in this field, and have been explained in detail detailed (e.g., Springer and colleagues, (Cell (2000) 102, 215- 211): Kawasaki and Kretsinger (Protein Prof. (1995) ) 2, 305- 490):Moncrief and friends, (J. Mol. Evol. (1990) 30, 522- 562):Chauvaux and friends, (Biochem. J. (1990) 265, 261-265): Bairoch and Cox (FEBS Lett. (1990) 269, 454-456): Davis (New Biol. (1990) 2, 410-419): Schaefer and colleagues, (Genomics (1995) 25, 638 to 643): Economou and friends, (EMBO J. (1990) 9, 349- 354):Wurzburg and friends, (Structure. (2006) 14, 6, 1049- 1058)). EF hand in troponin C light chain, calmodulin, parvalbumin, and myosin: Domain C2 in protein kinase C, Domain gla in blood clotting protein factor IX: C-type lectin of acyaroglycoprotein receptor and mannose-binding receptor, ASGPR, CD23, and DC-SIGN: Domains in the LDL receptor: annexinj domain cadherin domain: thrombospondin type 3 domain: and EGF-like domain preferably used as a calcium binding motif. The antigen-binding region may contain amino acid residues. which changes antigen binding activity according to ion concentration calcium, such as the amino acid residues described above with metal chelating activity and amino acid residues that form calcium binding motif. The location of these amino acid residues is in antigen-binding regions are not specifically restricted, and can placed at any position during antigen binding activity changes according to the concentration of calcium ions. Meanwhile, the residue These amino acids can be contained alone or in combination two or more, provided that the antigen binding activity changes according to the calcium ion concentration. Amino acid residues are preferred include, for example, serine, threonine, asparagine, glutamine, arginine, aspartate, and glutamic acid. When the antigen-binding region is antibody variable region, amino acid residues may be contained in heavy chain variable region and / or heavy chain variable region light. In a preferred embodiment, the amino acid residues can be contained in the CDR3 of the heavy chain variable region, preferably at positions 95, 96, 100a, and / or 101 according to Kabat numbering in CDR3 of the heavy chain variable region. In another preferred embodiment, the amino acid residue can be contained in the CDR1 of the light chain variable region, preferably in positions 30, 31, and / or 32 according to Kabat numbering in CDR! of the light chain variable region. In yet another preferred embodiment, the amino acid residue can be contained in the CDR2 of the light chain variable region, more preferably at position 50 according to Kabat's numbering in CDR2 of the light chain variable region. Still in development preferably, amino acid residues may be contained in CDR3 of the light chain variable region, preferably on position 92 according to Kabat numbering in CDR3 of the variable region light chain. Furthermore, it is possible to combine the embodiments described above. For example, amino acid residues can contained in two or three CDRs selected from CDRI, CDR2, and CDR3 of the light chain variable region, preferably on one or more positions 30, 31, 32, 50, and / or 92 according to Kabat numbering in the light chain variable region. A large number of antigen-binding regions that have sequences which differ while sharing as a common structure the acid residues the amino acids described above that alter the binding activity antigen according to calcium ion concentration, made as a library. Libraries can be screened to efficiently obtain areas antigen binder with binding activity on the antigen desired, where the antigen binding activity changes according to calcium ion concentration. The "affinity" of an antibody for Cl, for the purposes of this disclosure, expressed in KD of antibody. KD of antibody refers to equilibrium dissociation constant of antibody-antigen interaction. The greater the KD value for the antibody that binds the antigen, the the weaker its binding affinity for the antigen. Therefore therefore, as used here, the expression "affinity" higher at neutral pH than at acidic pH" (or the expression equivalent to "pH-dependent binding") means that KD antibodies at acidic pH are greater than the KD of antibodies at pH neutral. For example, in the context of the present invention, antibodies are considered binds C1 with higher affinity at neutral pH than at acidic pH if the KD antibody binds to C1 at pH acid more than 10 times compared to KD. antibody binding to C1 at neutral pH. Thus, the present invention includes antibodies that bind to C1 at acidic pH with a KD of at least 11, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 15, 80, 85, 90, 95, 100, 200, 400, 1000, 10000, or greater than KD antibodies that bind to C1 at neutral pH. In this embodiment In other words, the KD value of antibodies at neutral pH can be 10”M, 108M, 10”mM, 1010M, 101 M, 1012 M, or less. In other embodiments, the value KD of antibodies at acidic pH can be 10"M, 108M, 10"M, 10-"mMm, or larger. The binding properties of antibodies to a particular antigen can also be expressed in kd of antibody. The kd of an antibody refers to the constant the rate of dissociation of antibodies against a particular antigen and is expressed in units of reciprocal seconds (i.e., seconds). The increase in value kd indicates weaker antibody binding to the antigen. Therefore, the present invention includes antibodies that binds to C1 with a higher kd value at acidic pH than at neutral pH. The present invention includes antibodies that binds to C1 at acidic pH with kd of at least 11, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 400, 1000, 10000, or more times greater than kd antibodies that bind to C1 at neutral pH. In this embodiment On the other hand, the kd value of antibodies at neutral pH can be 10” 1 / second, 10- 3 1 / sec, 10-# 1 / sec, 10” 1 / sec, 10“ 1 / sec, or less. In another embodiment, the kd value of the antibody at acidic pH may be 10-53 1 / sec, 10-22 1 / sec, 101 1 / sec, or greater. In certain cases, "reduced binding at acidic pH" compared to that at neutral pH" is expressed in the ratio of the values KD of antibody at acidic pH with KD value of antibody at neutral pH (or vice versa) . As an example, antibodies can be considered showed "reduced binding at C1 at acidic pH" compared to its binding at neutral pH", for the purpose of this invention, if the antibody shows an acid / neutral KD ratio of 10 or more. In certain exemplary embodiments, the acid / neutral KD ratio for antibodies can be 11, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 15, 80, 85, 90, 95, 100, 200, 400, 1000, 10000, or more. In another embodiment, the KD value of the antibody at neutral pH can be 10” M, 108 M, 10” M, 10 M 10HM 1022 M, or less. In another embodiment, the KD value of the antibody at acidic pH may be 102?M, 108M, 10”M, 10-M, or larger. In certain cases, "reduced binding at acidic pH" compared to that at neutral pH" is expressed in the ratio of the values kd antibody at acidic pH with kd antibody value at neutral pH (or vice versa). For example, an antibody can be considered showed "reduced binding at C1 at acidic pH" compared to its binding at neutral pH", for the purpose, if the antibody shows an acid / neutral kd ratio of 2 or greater. In certain exemplary embodiments, the acid / neutral kd ratio for antibodies can be 11, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 170, 715, 80, 85, 90, 95, 100, 200, 400, 1000, 10000, or more. In another embodiment, the kd value of the antibody at neutral pH may be 10-2 1 / second, 10-? 1 / second, 10” 1 / second, 10” 1 / second, 10” 1 / second, or less. In another embodiment, the kd value of the antibody at pH acid can be 10“ 1 / second, 10” 1 / second, 101 1 / second, or greater. As used herein, the term "acidic pH" means pH 4.0 to 6.5. The expression "acidic pH" includes pH values ​​4.0, 4.1, 4.2, D3 AA 45 46 AT AB AI, 5.0, 5.1, 5.2, 535, 514, 5.5, 5965 5.9, 5.8, 5.9, 6.0, El, 6.2, 6.3, 6.4, and 6.5. In aspect certain, “acidic pH” is 6.0. As used herein, the term "neutral pH" means a pH of 6.7 to about 10.0. The expression "neutral pH" includes pH value 6.17, 6.8, 679, T.05 Tlp ND, 39 NA, NS, IN, NN, 1185 NI, 870, Bl 8.2, B3 SA 8.5, 816, SI, 8.8, 8.9, 9.0, dl 9.2, 9.3, 9, 9.3, 9.6, 9.1, 9.8, 9.9, and 10.0. In aspect In particular, a "neutral pH" is 7.4. As used here, the expression "in condition high calcium concentration" or "at high calcium concentration" means 100 micro M to 10 mM, preferably 200 micro M to 5 mM, and especially preferably 0.5 mM to 2.5 mM approaching the concentration of calcium ions in plasma (in blood). The terms "in conditions of high calcium concentration" or "in high calcium concentration" includes a calcium concentration value of 100 micro M, 200 micro M, 300 micro M, 400 micro M, 500 micro M, 600 micro M, 700 micro M, 800 micro M, 900 micro M, 0.5 mM, 0.7 mm, 0.9 mM, 1 mM, 1.2 mM, 1.4 mM, 1.6 mM, 1.8 mM, 2.0 mM, 2.2 mM, 2.4 mM, 2.5 mM, 3 mM, 4 mM, 5 mM, 6 mM, 7 mM, 8 mM, 9 mM, and 10 mM Ca 2? . In certain aspects, "under conditions of calcium concentration el high" or "at high calcium concentration" refers to 1.2 mM Ca & As used here, the expression "in the condition low calcium concentration" or "at low calcium concentration" means 0.1 micro M to 30 micro M, preferably 0.5 micro M M to 10 micro M, and especially preferably 1 micro M to 5 micro M which is close to the calcium ion concentration in endosomes early in vivo . The expression "under conditions of low calcium concentration" or "at low calcium concentrations" includes the concentration values calcium 0.1 micro M, 0.5 micro M, 1 micro M, 1.5 micro M, 2.0 micro M, 2.5 micro M, 2.6 micro M, 2.1 micro M, 2.8 micro M, 2.9 micro M, 3.0 micro M, 3.1 micro M, 3.2 micro M, 3.3 micro M, 3.4 micro M, 3.5 micro M, 4.0 micro M, 5.0 micro M, 6.0 micro M, 7.0 micro M, 8.0 micro M, 9.0 micro M, 10 micro M, 15 micro M, 20 micro M, 25 micro M, and 30 micro M Ca 2, In certain aspects, "under conditions low calcium concentration" or "at low calcium concentration" refers to 3.0 micro M Ca “ . The KD value and kd value, as stated here, can be determined using a plasmon resonance-based biosensor surfaces to characterize antibody-antigen interactions. (See, for example, Example 5, here). The KD value and kd value can be determined at a temperature of 25 degrees Celsius (C) or 37 degrees C. This determination can be done in the presence of 150 mM NaCl. In In some embodiments, this determination can be made by using surface plasmon resonance techniques where antibodies immobilized, the antigen serves as the analyte, and the conditions the following were used: 20 mM ACES and 150 mM Nall at 37 degrees Celsius (C). In one aspect, the invention provides a method for increases the clearance of Cls from plasma in individuals. In some embodiment, the method includes providing to an individual a specified amount effective of anti-Cls antibodies to increase Cls clearance from plasma. The present invention also provides a method for increasing clearance of Clr and Cls complexes from plasma in an individual. In some embodiments, the method includes providing to individual effective amount of anti-Cls antibodies for increases the clearance of Clr and Cls complexes from plasma. In some embodiments, the method includes providing to an individual effective amount of anti-Cls antibodies to increase clearance of Cl1lr2s2 from plasma. In some embodiments, the method includes providing individuals with an effective amount of anti-Cls antibodies to increase the clearance of Clr2s2 from plasma but not Clg from plasma. In another aspect, the invention provides a method for removing C1 from plasma, methods including: (a) identify individuals who require C1 to be removed from individual plasma: (b) provides antibodies that bind with Cls via the antigen-binding domain (Cls binding) of antibodies and have a KD(pH6.0) / KD(pH7.4) value, defined as the ratio of KD for Cls at pH 6.0 and KD for C1 at pH 7.4, from 11 to 10,000, when KD is determined using the technique surface plasmon resonance, where the antibody binds to Cl in plasma in vivo and dissociates from C1 bound in conditions that exist in endosomes in vivo, and where the antibodies is human IgG or human 1gG, and (c) provides antibodies to individuals. In the next aspect, the plasmon resonance technique the surface can be used at temperatures of 37 degrees C and 150 degrees mM NaCl. In a further aspect, the plasmon resonance technique such surfaces can be used where antibodies are immobilized, antigens serve as analytes, and the following conditions are used: 20 mM ACES and 150 mM NaCl at 37 degrees C. In another aspect, the present invention provides a method for remove C1 from plasma in subjects, the method includes: (a) identifying the first antibody that binds with C1 through the antigen-binding region of the first antibody, (b) identify a second antibody that: (1) binds to Cl via the antigen binding (Cl binding) domain of the antibody second, (2) identical in amino acid sequence to the first antibody except having at least one amino acid from the variable region from the first antibody substituted with histidine and / or at least one histidine inserted into the variable region from the first antibody, (3) has a KD(pH6.0) / KD(pH7.4) value that is, higher than the KD(pH6.0) / KD(pH7.4) value of the first antibody, and between 11 and 10,000, where KD (pH€6.0) / KD (pH7.4) is defined as the ratio of KD for Cls at pH 6.0 and KD for Cls at pH 1.4 when KD was determined using the plasmon resonance technique surface, (4) binds to Cls in plasma in vivo, (5) dissociates from the Cls bond under conditions present in endosomes in vivo, and (6) is human IgG or humanized 1g6,: (c) identify subjects requiring Cl level reduction plasma: and (d) administration of a second antibody to the subject so that plasma C1 levels in the subjects were reduced. In the next aspect, The surface plasmon resonance technique can be used in temperature of 37 degrees C and 150 mM NaCl. In the next aspect, the technique the surface plasmon resonance can be used at a temperature of 37 degrees C and 150 mM NaCl. In the next aspect, the technique surface plasmon resonance can be used where antibodies are immobilized, antigens function as analytes, and the following conditions were used: 20 mM ACES buffer and 150 mM NaCl at 3 / 7 degree C. In another aspect, the invention provides a method for removing C1 from plasma in subjects, the method includes: (a) identify the first antibody that: (1) binds to C1 through the antigen binding region of the first antibody, (2 ) identical in amino acid sequence to the antibody binds to Cls via the antigen-binding domain the second one (binding C1ls) of the second antibody, except that at least one region the variable of the first antibody has at least one residue histidine more than whether the corresponding variable region of the second antibody, (3) has a KD(pH6.0) / KD(pH7.4) value which is higher than the KD(pH6.0) / KD(pH7.4) value of the second antibody, and between 11 and 10,000, where KD (pH€6.0) / KD (pH7.4) is defined as the ratio of KD to C1 at pH 6.0 and KD to C1 at pH 7.4 when KD is determined using surface plasmon resonance technique, (4) binds to Cls in plasma in vivo, (5) dissociates from bound Cls under the conditions present in endosomes in vivo, and (6) is humanized IgG or humanized I1IgG:j (b) identify subjects who require reduction of Cl levels. plasma: and (c) provide the first antibody of at least one times in the subject so that the C1 level in the plasma in the subject reduced. In the next aspect, the plasmon resonance technique the surface can be used at temperatures of 37 degrees C and 150 degrees mM NaCl. In a further aspect, the plasmon resonance technique the surface can be used at temperatures of 37 degrees C and 150 degrees mM NaCl. In a further aspect, the plasmon resonance technique such surfaces can be used where antibodies are immobilized, antigens serve as analytes, and the following conditions are used: 20 mM ACES and 150 mM NaCl at 37 degrees C. In some In some cases, antibodies inhibit components of the classical complement pathway, in In some cases, the components of the classical complement pathway are Cls. (a4) pI of isolated antibody In one embodiment, the isoelectric point (pl) of the antibody isolated reduced by constant area changes. In In this embodiment, the isolated antibodies with reduced p1 include at least one amino acid change (e.g., addition, insertion, deletion, or amino acid substitution) in the constant region compared with the parent constant area. In further embodiments, each each amino acid change lowers the isoelectric point (pI) of the constant area compared to the parent constant area. In In further embodiments, amino acids may be exposed on the surface area. pI can be compared between the parent antibody (original antibody) before the change of this invention) and antibodies after the change the present invention wherein one or more amino acid mutations (e.g., addition, insertion, deletion, or substitution) is entered into antibody constant region (parent constant region) of the original antibody (parent). Amino acid changes lower the isoelectric point (pI) mutant constant region compared to the parent constant region. That is, the antibodies of the present invention have a mutant constant region which includes at least one amino acid change, where amino acid changes lower the isoelectric point (pI) of the region mutant constant compared to the parent constant region. Antibodies The original (parent) can be a known antibody or a new one. isolated as long as it specifically binds to C1. In one aspect, pI of anti-Cls antibody is changed at least O,l, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0 lower than the pI of the native antibody (parent). The pI of the modified anti-Cls antibody is preferably 0.6, 0.7, 0.8, 0.9, or 1.0 lower, preferably 1.1, 1.2, 1.3, 1.4, or 1.5 is lower, and then preferably 1.6, 1.71, 1.8, 1.9, or 2.0 lower than the pI of the native (parent) antibody. In a further embodiment, the isolated antibody covers the region constant and antigen-binding domains. In further embodiments, antigen binding activity of the antigen binding domain varies depending on the concentration conditions of 1on. In a further embodiment, the constant area with pI reduction of the present invention includes at least one change an amino acid at at least one selected position of the group consisting of: 137, 268, 214, 285, 311, 312, 315, 318, 333, 335, 337, 341, 342, 343, 355, 384, 385, 388, 390, 399, 400, 401, 402, 413, 419, 420, 422, and 431 according to EU numbering. More preferred, constant region mutants with decreasing pI covers amino acid changes in at least one of positions 137, 268, 214, 355, and 419 according to EU numbering. In further embodiments, in the constant region with decreasing pl, amino acids at each the selected position is replaced with one of arginine, amino acid glutamate, serine, and glutamine. In a particular embodiment, in a constant region with decreasing PI, amino acids at positions 137, 268, 214, 355, and 419 (all numbers according to the EU numbering system) is replaced by one of arginine, glutamic acid, serine, and glutamine. In one embodiment, the isoelectric point (pl) of Isolation can also be reduced by changing the area antibody variables heavy chain and / or light chain variable region. In embodiment, isolated antibodies with decreased pl covers at least one amino acid change in the variable region of the chain weight and / or variable region of the light chain compared to the parent region. The decrease in pI is accompanied by changes in the region heavy chain variable and / or light chain variable regions and / or a decrease in pI with a constant area change can contribute to the increase in PK of the isolated antibodies. In one embodiment of isolated antibodies, pI is 1.8 or less, 1.7! or less, 1.6 or less, antibody or 1.5 or less. pI preferably 7.7 or less, preferably 7.6 or less, then preferably 7.5 or less. When pI less than or equal to both values, half-life antibody in the blood will be extended. On the other hand, the minimum value that perhaps the pI is 4.28 or more normally. In one embodiment, the pI of the antibody may be measured by capillary isoelectric focusing (cIEF). As an example embodiment, CIEF was performed on a Simple Protein intact capillary imaging system The iCE3 uses a fluorocarbon-coated capillary cartridge. Solution The anolyte and catholyte are 0.08 M phosphoric acid in 0.18 m / v methyl cellulose (MC) and 0.1 M sodium hydroxide in 0.18 m / v MC. All samples analyzed contained working antibodies 0.2 mg / mL, 0.358 m / v MC, 6 mM IDA (iminodiacetic acid), 10mM arginine, 0.5 $ w / v pI marker (5.85) and 0.5 $ w / v pI marker (9.99), and 2 $ vol pharmacologic 8-10.5, and 2 $ vol pharmalyte 5- 8. All samples were vortexed and centrifuged briefly before inserted into the automatic sampling compartment. The sample incubated in an automatic sampler for 2 hours before start measurement. Focus at 1.5 kV for 1 minute followed by 3.0 kV for 7 minutes. Sampling compartment automatically maintained at a temperature of 10 degrees C. The measurement was repeated twice. times for each sample, and the p1I value of each The sample is obtained by calculating the average of n-—2 measurements. Alternatively, in one embodiment, the pI of the antibody can be measured by capillary isoelectric focusing (cIEF). As example embodiment, cIEF is performed on a capillary imaging system Whole Protein Simple 1CE3 using coated capillary cartridges fluorocarbons. The anolyte and catholyte solutions are each acidic. 0.08 M phosphate in 0.18 m / v methyl cellulose (MC) and sodium 0.1 M hydroxide in 0.18 m / v MC. All samples analyzed contains 0.358 m / v working MC, 4 mM IDA (iminodiacetic acid), 10 mM arginine, pI marker (3.21 or 4.22 or 4.65 or 5.12 or 5.85 or 6.14 or 6.el or 1.05 or 1.65 or 8.140 or 8.79 or 9.46 or 9.77 or 10.1), and one of the following v / v mixtures from 4$ pharmalyte 3-10. All samples were vortexed and centrifuged briefly before inserting into the sampling compartment automatic. Focusing at 1.5 kV conditions for 1 minute followed by by 3.0 kV for 8 minutes. Automatic sampling compartment maintained at a temperature of 10 degrees C. The measurement was repeated twice for each sample, and the pI value of each sample obtained by calculating the average of n-—2 measurements. In one case embodiment, the pI is measured by focusing capillary isoelectric, where the solution contains 0.08 M acid phosphate in 0.18 m / v methyl cellulose (MC) was used as the solution anolyte, a solution containing 0.1 M sodium hydroxide in 0.18 m / v MC was used as the catholyte solution, and the solution contains 0.5 mg / mL antibody, 0.38 m / v MC, 6.0 mM acid iminodiacetate (IDA), 10mM arginine, 4 M urea, and pI marker (71.65 and 9.77) is used as a solution that functions to lyse antibody. (a5) Antigen binding region In one embodiment, the antibody includes a binding region antigen. In a preferred embodiment, the binding region antigens can specifically bind to epitopes in the domain C1-EGF-CUB2 Cl. In a further preferred embodiment, antigen binding region can specifically bind to the Cl domain CUB1-EGF-CUB2. In this embodiment, C1 is included but not limited to human C1. C1 is preferred to human C1. In one embodiment, the antigen-binding region may be antibody variable region. The antibody variable region can all or part of the antibody variable region during the antigen binding region does not damage the properties of the antibody isolated, such as displacement function and / or blocking function, and subsequent binding activity of the antibody, in cases where the antibody binding activity against Cl human and / or synomolgus measured by plasmon resonance surface, 1) the value of the dissociation constant (KD) in the neutral pH range can be calculated reliably, and the KD value in the acidic pH range is not can be calculated reliably because there is no binding activity or very low binding activity, or i1) ratio of KD value in the acidic pH range to KD value in neutral pH range, acid KD / neutral KD ratio, more than 10 provided both KD values ​​in the neutral pH range and the acidic pH range can be can be calculated reliably. In an embodiment, the variable region of the antibody is humanized. The preferred antigen binding region is the variable region. humanized antibodies. It is hoped that side effects can be avoided compared with nonhumanized antibodies when such humanized antibodies are used for treatment. In one embodiment, the antigen-binding region of the antibody isolated anti-Cls which include the combination of HVR-Hl, HVR-H2, HVR- H3, HVR-L1, HVR-L2, and HVR-L3 were selected from the group consists of 1) to 6) below: 1) HVR-H1I, HVR-H2, HVR-H3, HVR-LI1, HVR-L2, and HVR-L3 which includes amino acid sequence consisting of SEO ID NO: 25, 26, 21, 60, 61, and 62, respectively: 2) HVR-H1, HVR-H2, HVR-H3, HVR-LI, HVR-L2, and HVR-L3 which include amino acid sequence consisting of SEO ID NO: 37, 38, 39, 56, 57, and 58, respectively: 3) HVR-H1, HVR-H2, HVR-H3, HVR-LI1, HVR-L2, and HVR-L3 which includes amino acid sequence consisting of SEO ID NO: 25, 26, 21, 56, 57, and 58, respectively: 4) HVR-H1l, HVR-H2, HVR-H3, HVR- Ll, HVR-L2, and HVR-L3 includes the amino acid sequence consisting of SEO ID NO: 25, 26, 21, 48, 49, and 50, respectively: 5) HVR-H1, HVR-H2, HVR-H3, HVR-LI1, HVR-L2, and HVR-L3 which includes amino acid sequence consisting of SEO ID NO: 29, 30, 31, 52, 53, and 54, respectively: and 6) HVR-H1, HVR-H2, HVR-H3, HVR-LI1, HVR-L2, and HVR-L3 which includes amino acid sequence consisting of SEO ID NO: 33, 34, 35, 56, 57, and 58, respectively. In another embodiment of the present invention, anti-Cls antibodies isolated includes the variable region of the heavy chain, the variable region light chain and constant region of the antibody. In this embodiment, The isolated anti-Cls antibodies cover the variable region of the α chain. heavy (VH) and variable regions of the light chain (VL) are selected from the group consisting of 1) to 6) below: 1) VH and VL which include amino acid sequences consisting of SEO ID NO: 24 and 59, respectively: 2) NH and VL which include amino acid sequences consisting of SEO ID NO: 36 and 55, respectively: 3) VH and VL which include amino acid sequences consisting of SEO ID NO: 24 and 55, respectively: 4) VH and VL which include amino acid sequences consisting of SEO ID NO: 24 and 47, respectively: 5) VH and VL which include amino acid sequences consisting of SEO ID NO: 28 and 51, respectively: and 6) VH and VL which include amino acid sequences consisting of SEO ID NO: 32 and 55, respectively. (a6) Constant region of antibodies In one embodiment, the constant region of the antibody in Isolated antibodies include but are not limited to areas human antibody constant region. The human antibody constant region can includes heavy chains and light chains. Human antibodies include but not limited to human IgGl. Human antibodies are more preferred by human IgGl. In one embodiment, the constant region of the antibody includes at least one amino acid that can increase the ability binding of isolated antibodies to FcRn in the acidic pH range compared to antibodies isolated without at least one the amino acids. In the embodiment, the constant region includes (a) Ala at position 434: Glu, Arg, Ser, or Lys at position 438: and Glu, Asp, or Gln at position 440, according to EU numbering: (b) Ala at position 434: Arg or Lys at position 438: and Glu or Asp at position 440, according to EU numbering: (c) Ile or Leu at position 1428: Ala at position 434) Ile, Leu, Val, Thr, or Phe at position 436: Glu, Arg, Ser, or Lys at position 438: and Glu, Asp, or Gln at position 440, according to EU numbering: (d) Ile or Leu at position 1428: Ala at position 434) Ile, Leu, Val, Thr, or Phe at position 436: Arg or Lys at position 438: and Glu or Asp at position 440, according to EU numbering: (e) Leu at position 428: Ala at position 434: Val or Thr at position 436: Glu, Arg, Ser, or Lys at position 438: and Glu, Asp, or Gln at position 440, according to EU numbering: or (£) Leu at position 428: Ala at position 434: Val or Thr at position 436: Arg or Lys at position 438: and Glu or Asp at position 439: position 440, according to EU numbering. International Patent Application No. WO2013 / 046704 specifically reported the double amino acid residue substitution 0438R / S440E, 0438R / S440D, 0438K / S440E, and 0438K / S440D according to EU numbering, which results in a significant reduction in factor binding rheumatoid arthritis when combined with amino acid substitutions can increase FcRn binding under acidic conditions. Dalam perwujudan, daerah konstante lebih disukai sakla kombinazione substitusi asam amino yang selected dari kelokom yang consists of: (I) (a) N434A / 0438R / S440E: (b) N434A / 0438R / S440D: (c) N434A / 0438K / S440E: (d) N434A / 0438K / S440D: (e) N434A / Y436T / 0438R / S440E: (£) N434A / Y436T / 0438R / S440D: (9g) N434A / Y436T / 0438K / S440E: (h) N434A / Y436T / 0438K / S440D: (1) N434A / Y436vV / 0438R / S440E: (3) N434A / Y436V / 0438R / S440D: (k) N434A / Y436V / 0438K / S440E: (1) N434A / Y436V / 0438K / S440D: (m) N434A / R435H / F436T / 0438R / S440E: (n) N434A / R435H / F436T / 0438R / S440D: (o) N434A / R435H / F436T / 0438K / S440E: (p) N434A / R435H / F436T / 0438K / S440D: (g) N434A / R435H / F436V / 0438R / S440E: (r) N434A / R435H / F436V / 0438R / S440D: (s) N434A / R435H / F436V / 0438K / S440E: (t) N434A / R435H / F436V / 0438K / S440D: (u) M428L / N434A / 0438R / S440E: (v) M428L / N434A / 0438R / S440D: (w) M428L / N434A / 0438K / S440E: (x) M428L / N434A / 0438K / S440D: (y) M428L / N434A / Y43€6T / 0438R / S440E: (2) M428L / N434A / Y436T / 0438R / S440D: (aa) M428L / N434A / Y436T / 0438K / S440E: (ab) M428L / N434A / Y436T / 0438K / S440D: (ac) M428L / N434A / Y436V / 0438R / S440E: (iklan) M428L / N434A / Y436V / 0438R / S440D: (ae) M428L / N434A / Y436V / 0438K / S440E: (af) M428L / N434A / Y436V / 0438K / S440D: (ag) L235R / G236R / S239K / M428L / N434A / Y436T / 0438R / S440Ej (ah) L235R / G236R / A321G / A330S / P3315 / M428L / N434A / Y436T / 0438R / S440E, according to the UE numbering, or (II) (a) N434A / 0438R / S440E: (b) N434A / Y43€T / 0438R / S440E: (ec) N434A / Y43€V / 0438R / S440E: (d) M428L / N434A / 0438R / S440E: (e) M428L / N434A / Y436T / 0438R / S440E: (£) M428L / N434A / Y436V / 0438R / S440E: (g) L235R / G236R / S239K / M428L / N434A / Y43€6T / 0438R / S440Ej day (h) L235R / G236R / A321G / A330S / P3315 / M428L / N434A / Y436T / 0438R / S440E, according to EU numbering. In another embodiment, the constant region preferably includes at least one amino acid selected from the group consisting of from leucine at position 428, alanine at position 434 and threonine at position 436 (all numbers conform to the EU numbering system). In an embodiment, the constant region preferably comprises leucine at position 428, alanine at position 434 and threonine at position 436 (all numbers according to the EU numbering system). Regional variant €£c (Sweeping technology) In certain embodiments, one or more acid modifications amino acids can be inserted into the Fc region of the antibody provided here, resulting in a regional variant of Fc. The variant The Fc region may include human Fc region sequences (e.g., Fc region of human IgGl, 1IgG2, 1IgG3 or 1IgG4) which includes amino acid modification (e.g. substitution) in one or more amino acid positions. In some embodiments, the Fc region is Fc region of human IgGl. To increase the decrease in plasma antigen concentration and / or enhance the pharmacokinetics of antibodies, amino acid residues in the FcRn binding site in the Fc region of IgG can be modified to increase its uptake into cells. When antibodies with pH dependence is modified in this way, the mutant will be "sweeping" antibodies that can more strongly bind FcRn and allows antigens to be transferred efficiently into endosomes (where the pH is acidic) and then degrades, but itself can be more efficiently recycled to the cell surface. These modified "sweeper" antibodies can strongly binds FcRn at neutral pH and on the cell surface and enhance antigen uptake and degradation, compared to with native (parent) antibodies without modification. (Semin Immunopathol. 20187 40(1): 125-140). In some aspects, antibodies include Fc regions that have at least one amino acid modification in the Fc region for increase the decrease in plasma antigen concentration and / or enhance antibody pharmacokinetics. Regions with decreased Fcy receptor binding activity particularly preferred as a constant region of antigens of this invention. For example, the antibodies of this invention have mutant constant region that includes at least one acid change amino acids that decrease the binding activity of Fcy receptors. Here, Fcy receptor (here, also denoted as Fecy receptor, FCyR, or FcgR) refers to receptors that can bind to Fc region of IgGl, Ig6G2, IgG3, or IgG4, and includes all members of the protein family. are essentially encoded by genes Fcy receptor. In humans, this family is included, but not limited to, FcyRI (CD64) including 1isoforms FcyRIa, FcyRIb, and FcCYRIcC: FcyRII (CD32) including the FcyRIla isoform (including allotypes H131 (H type) and R131 (R type), FcyRIIb (including FcyRIIb-1 and FcyRIIb-2), and FcyRIIc: and FcyRIII (CD16) including 1isoform FcyRIIlIla (including allotypes V158 and F158) and FcyRIlIb (including allotypes FcyRIIIb-NA1 and FcyRIIIb-NA2): as well as human FcyR have not been discovered, and the isoforms or allotypes of FcyR. FcyR includes, but not limited to, those originating from humans, mice, mice, rabbits, and monkeys, and can originate from any organism. Mouse FcCyRs include, but are not limited to, FcyRI (CD64), FcCyRII (CD32), FcCYRIII (CD16), and FcyRIII-2 (CD16-2), as well as all Mouse FcyRs have not been discovered, and FcYR isoforms or allotypes. Examples of suitable Fcy receptors include human FcyRI (CD64), FcyRIla (CD32), FcyRIIb (CD32), FcyRIIIla (CD16) and / or FcyRIlIb (CD16) . Activation receptors carrying activation motifs based on tyrosine immunoreceptors (ITAM) and inhibitory receptors that carry immunoreceptor tyrosine-based inhibitory motif (ITIM) is present in between FcyRs. FcyRs are categorized into activating FcyRs: FCYRI, FcyRIla R, FcyRIla H, FcyRITla, and FcyRIIIb, and FcyR inhibition: FcyRIIb. The polynucleotide sequence and amino acid sequence of FcyRI are respectively respectively shown in NM 000566.3 and NP 000557.1: sequences polynucleotide and amino acid sequences of FcyRIla respectively shown in BC020823.1 and AAH20823.1: polynucleotide sequences and the amino acid sequence of FcyRIIb are shown in Fig. BC146678.1 and AAI46679.1: polynucleotide sequence and amino acid sequence amino FcyRIIla are shown in BC033678.1 and AAH33678.1: and the polynucleotide sequence and amino acid sequence of FcCyRIIlIb is indicated in BC128562.1 and AAI128563.1, respectively (RefSeg accession number). There are two types of gene polymorphisms for FcyRIIa, where the amino acid at position 131 of FcyRIla substituted with histidine (H type) or arginine (R type) (J. Exp. Med, 1172, 19-25, 1990). In addition, there are two types of gene polymorphisms for FcyRIIb, where the amino acid at position 232 of FcyRIIb is substituted with isoleucine (type I) or threonine (type T) (Arthritis. Rheum. 46: 1242-1254 (2002)). In addition, there are two types of gene polymorphisms for FcyRIIla, where the amino acid is at position 158 of FcyRIlIIa substituted with valine (type V) or phenylalanine (type FP) (J. Clin. Invest. 100(5): 1059-1070 (1997)). There are also two types gene polymorphism for FcyRIIIb, namely type NA1 and type NA2 (Jl. Clin. Invest. 85: 1287-1295 (1990)). Can decreased binding activity of the Fcy receptor be confirmed by well-known methods such as FACS, ELISA format, screening with Amplified Luminescent Proximity Homogeneous Assay (ALPHA), BIACORE method resonance-based surface plasmon (SPR), etc. (Proc.Natl.Acad.Sci.USA (2006) 103(11), 4005-4010). For example, the binding properties of each sample to FcyRs at pH 7.4 determined at 25 degrees C using BIACORE (brand registered trade) instrument T200 (Cytiva). First, protein L (BioVision) immobilized onto all CM4 sensor chip flow cells using Amine Coupling Kit, type2 (Cytiva). (pH1.4) containing 150 mM NaCl, 0.058 Phosphate buffer 50 mM Tween (trademark) registered) 20 was used as a running buffer, and the antibodies were made to have a binding response of 500 RU or 2000 RU captured on the sensor surface. FcyRs diluted with running buffer (e.g., human or monkey FcyRs) is injected into it and the amount bound to the antibody is measured. The sensor surface is regenerated every cycle, using solution glycine hydrochloride 10 mM, pH 1.5. From the measurement results obtained, the number of FcyR bindings divided by the number of bindings each antibody captured (binding / capture) calculated using the T200 BIACORE evaluation software (registered trademark), version 2.0 (Cytiva). This means that because the amount of FcyR binding depends on the amount of antibody captured, the correction value is calculated by dividing the number of bindings FcyR with the amount of each antibody captured and compared between antibodies. In the antibodies of the present invention, the amount of FcyR binding divided by the number of bindings of each antibody that captured (Binding / capture) shows 1.0, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, O,l, 0.09, 0.08, 0.01, 0.06, 0.05, 0.04, 0.03, 0.02, or 0.01 or less, preferably indicating 0.05, 0.04, 0.03, or 0.02 or less, or especially preferred shows 0.01 or less, or cannot be calculated with reliable because there is no binding activity or activity very low binding activity. Furthermore, the binding activity the relative Fcy receptor of the antibody of the invention, which has mutant constant region that includes at least one acid change amino acids that decrease the binding activity of Fcy receptors, compared to antibodies that have a constant (parent) region which does not include amino acid changes, can be shown by relative values ​​(relative binding to human FcyRs) that calculated by dividing the Binding / catch value obtained with antibodies of the present invention having a mutant constant region which includes at least one amino acid change that decreases Fcy receptor binding activity with values Binding / capture obtained with antibodies that have constant (parent) region that does not include amino acid changes (e.g., Herceptin). The relative value is 0.06 or less, 0.05 or less, 0.04 or less, 0.03 or less, 0.02 or less, 0.01 or less, or 0.00 or less, or preferred 0.00 or less, or cannot be calculated reliably because no binding activity or binding activity very low. ALPHA screening is done using ALPHA technology which using two beads, a donor bead and an acceptor bead, based on the following principle. The luminescence signal is detected only when molecules bound to the donor beads interact in a biological with molecules bound to acceptor beads, and the two beads are close to each other. Laser-excited photosensitizer within the donor bead convert ambient oxygen into singlet oxygen state excited. Singlet oxygen is scattered around the beads donor, and when it reaches the adjacent acceptor bead, chemiluminescence reactions are induced inside the beads, and light finally emitted. When the molecules bound to the beads donors do not interact with molecules bound to the beads. acceptor beads, chemiluminescence reaction does not occur because the singlet oxygen produced by the donor beads does not reach the acceptor beads. For example, when an antibody contains the Fc region of the antibody as the FcRn binding domain, antibodies that have the Fc region wild type and antibodies having mutant Fc regions were produced by adding amino acid mutations to alter binding on Fcy receptors. created, the biotinylated antibody binds to donor beads, and Fcy receptors tagged with glutathione S transferase (GST) bound to acceptor beads. In the presence of antibodies that have mutant Fc regions, the antibodies which has a wild-type Fc region interacts with the Fcy receptor and produces a signal of 520-620 nm. When the antibody has mutant Fc region is not tagged, the antibody competes with antibodies that have a wild-type Fc region to interact with the Fcy receptor. The relative binding affinity can be determined by measuring the decrease in fluorescence observed as a result from competition. Biotinylation of antibodies using Sulfo-NHS-biotin and the like are well known. As a method of giving Fcy receptor tag with GST, Fcy receptor and GST expression method in vector carrier cells that can express the fusion gene produced by combining polynucleotides that encode Fcy receptor in frame with the polynucleotide encoding GST, and purifying it using a glutathione column can be adopted precisely. The obtained signals are analyzed precisely, for example, by fitting it into a one-party competition model. Sites that use non-linear regression analysis with software such as GRAPHPAD PRISM (GraphPad, San Diego). One of the substances (ligands) that is observed for interactions immobilized onto a thin gold film on the sensor chip, and with shining light from the back side of the sensor chip so that the reflection total occurs at the interface between the gold thin film and glass., some with reduced reflection intensity are formed in reflected light portion (SPR signal). Other substances (analytes) observed for interactions made to flow over the surface sensor chip, and when the ligand binds to the analyte, the mass immobilized ligand molecules increase and the refractive index of the solvent on the surface of the sensor chip changes. The position of the SPR signal shifts as a result of this change in the refractive index (conversely, the position signal returns if this binding is released). Biacore System shows the magnitude of the above shift, or more specifically mass time variable, by plotting the change in mass on the surface of the sensor chip on the vertical axis as data measurement (sensorgram). Kinetic parameters such as rate constant association (ka) and dissociation rate constant (kd) are determined from the curves on the sensorgram, and affinity (KD) is determined from the constant ratio In the BIACORE method, the method for measuring inhibition Also suitable for use. Example of a method for measuring inhibition described in Proc. Natl. Acad. Sci USA (2006) 103 (11): 4005- 4010. Here, "decreased Fcy receptor binding activity" or "decreased Fcy receptor binding activity" means that, for example, based on the analytical methods described above, Fcy receptor binding activity of an antibody have a constant region of the control antibody (e.g., the parent antibody, that the original antibody before the change in the present invention) compared with the Fcy receptor binding activity of the antibody after changes to the present invention wherein one or more amino acid mutations (e.g., addition, insertion, deletion, or substitution) inserted into the constant region of the antibody of the original antibody (parent), and antibody binding activity after changes The present invention shows 508 or less, preferably 458 or less, 408 or less, 358 or less, 308 or less, 208 or less, 158 or less, 108 or less, 98 or less, 8$ or less, 18 or less, 68 or less, or preferred 5$&8 or less, 4$ or less, 38 or less, 2$ or less, 18 or less, or 0$ compared to binding activity parent antibodies. For control antibodies (parent antibodies), antibodies before changes that have, for example, domains that include the Fc region from monoclonal antibodies IgGl, 1gG2, 1I1gG3, or 1IgG4 can used appropriately. Furthermore, when the antibodies that containing mutants of the Fc region of a particular antibody isotype used as a test substance, the mutational effects possessed by the mutant on the Fcy receptor binding activity was tested using as a control antibody that has the Fc region of the antibody of a particular isotype. In this way, antibodies containing Fc region mutants whose binding activity towards Fcy receptors proven to decrease in production accordingly. Examples of such mutants include mutants with deletions 231A-238S (International Patent Application No. WO 2009 / 011941), or mutant C226S, C229S, P238S, (C220S) (J. Rheumatol (2007) 34, 11), C226S, C229S (Hum. Antibodies. Hybridomas (1990) 1(1), 47-54), C226S, C229S, E233P, L234V, or L235A (Blood (2007) 109, 1185-1192), where Amino acids are designated by EU numbering. That is, suitable examples include antibodies that has an Fc region where one of the amino acids is at position 220, 226, 229, 231, 232, 233, 234, 235, 236, 231, 238, 239, 240, 264, 265, 266, 261, 269, 2170, 295, 296, 291, 298, 299, 300, 325, 321, 328, 329, 330, 331, and 332 are designated according to EU numbering. has been replaced in the amino acids that make up the Fc region of the antibody of certain isotypes. Positions 235 and 236 are particularly favored. The isotypes of antibodies from which the Fc region is derived are not very limited, and the Fc region derived from the IgGl monoclonal antibody, 14962, IgG3, or IgG4 can be used appropriately, and the Fc region is derived from naturally occurring human IGgI antibodies suitable for use. For example, antibodies that have an Fc region that covers Any substitution specified below is based on EU numbering of the amino acids that make up the Fc region IggGl antibodies (where the number indicates the position of the residue amino acids specified according to EU numbering, amino acid code one letter located before the number indicates the acid residue amino acid before substitution, and the one-letter amino acid code that placed after the number indicates the amino acid residue after substitution): (a) L234F, L235E, P331S (b) C226S, C229S, P238S (c) C226S, C229S (d) C226S, C229S5, E233P, L234v, L235Aj or the Fc region that does not have the amino acid sequence from position 231 to 238 of the amino acids that make up the Fc region IgGI antibodies can be used appropriately. In addition, antibodies that have an Fc region that includes The substitutions specified below are based on EU numbering. from among the amino acids that form the Fc region of antibody 1gG2 (where the number indicates the position of the amino acid residue) defined according to EU numbering, a single-letter amino acid code that placed before the number indicates the amino acid residue before it. Substitution, and the single letter amino acid code placed after numbers indicate amino acid residues after substitution): (e) H2680, V309L, A330S, P3315S (£) vV234A (9g) G237A (h) V234A, G231A (1) A235E, G237A (J7) V234A, A235E, G2317A can be used as intended. In addition, antibodies that have an Fc region that includes The substitutions specified below are based on EU numbering. from among the amino acids that form the Fc region of antibody 1gG3 (where the number indicates the position of the amino acid residue) defined according to EU numbering, a single-letter amino acid code that placed before the number indicates the amino acid residue before it. Substitution, and the single letter amino acid code placed after numbers indicate amino acid residues after substitution): (k) F241A (Ll) D265A (m) V264A can be used as intended. In addition, antibodies that have an Fc region that includes The substitutions specified below are based on EU numbering. from among the amino acids that form the Fc region of antibody 1gG4 (where the number indicates the position of the amino acid residue) defined according to EU numbering, a single-letter amino acid code that placed before the number indicates the amino acid residue before it. Substitution, and the single letter amino acid code placed after numbers indicate amino acid residues after substitution): (n) L235A, G237A, E318A (Oo) L235E (p) F234A, L235A can be used as intended. Other preferred examples include antibodies that has an Fc region where any of the amino acids at that position 233, 234, 235, 236, 231, 321, 330, and 331 are determined according to EU numbering in the amino acids that naturally form the Fc region. The human IGGI antibodies that occur are replaced with amino acids with appropriate EU numbering in IgG2 or 1gG4 as appropriate. Other preferred suitable examples include antibodies which has an Fc region where one or more amino acids at positions 235 and 236 as determined according to the EU numbering in amino acids that constitute the Fc region of human IgGl antibodies which occur naturally are replaced by other amino acids. The types of amino acids present after substitution are not very limited, and antibodies that have an Fc region where one or two of the amino acids at positions 235 and 236 are substituted with arginine more preferable. In certain embodiments, the present invention contemplates antibody variants that have some but not all of the functions effectors, which makes it a desirable candidate for applications where the in vivo half-life of the antibody is important but the function certain effectors (such as complement and ADCC) are not necessary or damaging. Determination of cytotoxicity in vitro and / or in vivo can conducted to confirm reduction / depletion of CDC activity and / or ADCC. For example, determination of Fc receptor (FCcR) binding can be done to ensure that the antibodies do not have Fc binding ADCC activity gamma R (hence the possibility of not having ), but still maintains the binding ability FcRn. Primary cells to mediate ADCC, cells express NK, only n Fc gamma RIII, while monocytes express Fc gamma RI, Fc gamma RII and Fc gamma RIII. FCcR expression in cells hematopoietic are summarized in Table 3 on page 464 of Ravetch and Kinet, Ann Uu. Pastor ImmunoLl. 9:457-492 (1991). Example of in test in vitro to assess the ADCC activity of the molecule The subject of interest is described in United States Patent No. 5,500,362 (see, for example Hellstrom, I. and colleagues Proc. Sci. USA 83:7059- 7063 (1986)) and Helilstrom, Proc. Nat'1 Acad. Sci. USA 82:1499-1502 (1985): 5,821,337 Bruggemann, M. and friends, J. Alternatively, the test method (see, for example, cytotoxicity determination (trademark Inc. Mountain registered) for flow cytometry View, CA: and CytoTox 96 Exp. Med. 166:1351-1361 Nat'1 Acad. I and my friends, (Look (1987)). non-radioactive can be used Non-radioactive cytotoxicity assay (Promega, Madison, WI). non-radioactive ACTI (Cell Technology, (registered trademark) Cell Useful effectors for the assay include mononuclear cells peripheral blood alternatively, or in addition, (PBMC) and cells Natural Killer (NK). of interest can be assessed in vivo, for example, animals like that is expressed in Clynes and As ADCC activity of the molecule on the model friends Proc.Nat'1 Acad.Sci.USA 95:652-656 (1998). Determination of Clg binding can also be done to ensure that antibodies cannot binds Clg and therefore lacks CDC activity.See, for example, the Clg and C3c binding ELISA in the Patent Application International No. WO 2006 / 029879 and WO 2005 / 100402. To assess complement activation, CDC determination can be performed (see, for example, Gazzano-Santor (1996) :Cragg, o and friends, MS and friends, J. Immunol. Methods Blood 101:1045-1052 (2003) : 202:163 And Cragg, MS and MJ Glennie, Blood 103:2738-2743 (2004)). Binding FcRn and in vivo clearance / half-life determination can also be performed. using methods known in the art (see, for example, Petkova, SB and colleagues, Intl. Immunol. 18(12):1759-1769 (2006)) In one embodiment, the antibodies of this application are antibodies where the constant region of the antibody includes the constant region H chain which includes the amino acid sequence consisting of SEO ID NO: 45 and the constant region of the L chain which includes the amino acid sequence which consists of SEO ID NO: 23. In one embodiment, the antibodies of this application are antibodies containing heavy chains (H chains) and light chains (chain L) selected from the group consisting of 1) to 6) below: 1) H chain and L chain which include the amino acid sequences that each consisting of SEO ID NO: 66 and 6 / 1: 2) H chain and L chain which include the amino acid sequences that each consisting of SEO ID NO: 68 and 69: 3) H chain and L chain which include the amino acid sequences each consisting of SEO ID NO: 70 and 71: 4) H chain and L chain which include the amino acid sequences that each consisting of SEO ID NO: 72 and 73j 5) H chain and L chain which include amino acid sequences that each consisting of SEO ID NO: 74 and 75: and 6) H chain and L chain which include amino acid sequences that each consisting of SEO ID NO: 76 and 77. (a7) Other embodiments (Antibody Variant) In certain embodiments, amino acid sequence variants of the antibodies provided herein are intended. For example, can desired to increase binding affinity and / or properties other biological properties of antibodies. Amino acid sequence variants of antibodies can be made by introducing appropriate modifications to in the nucleotide sequence that encodes the antibody, or with peptide synthesis. Such modifications include, for example, deletions from, and / or insertion into and / or substitution of residues in amino acid sequence of antibodies. Combinations of deletions, insertions, and Any substitutions can be made to arrive at the final construction, provided that the final construction has the desired characteristics, for example antigen binding. a1-1) Substitution, Insertion, and Deletion Variants In certain embodiments, an antibody variant having one or more amino acid substitutions are provided. The site that desired for substitution mutagenesis include HVR and FR. Conservative substitutions are shown in Table A under the heading "preferred substitution." More substantial changes given in Table A under the heading "example substitutions", and as further explained below refers to amino acid side chain classes. Amino acid substitutions can incorporated into the desired antibody and the product can be screened for desired activities, such as binding retained / improved antigens, decreased immunogenicity, or an increase in ADCC or CDC. (Table A) Substitution Residue More Examples of Substitution Original liked Ala (A) Val: Leu: Ile Val Arg (R) Lys: Gln: Asn Lys Asn (N) Gln: His: Asp, Lys: Arg Gln Asp (D) Glu: Asn Glu Cys (C) Ser: Ala Ser Gin (O) Asn: Glu Asn Glu (E) Asp: Gln Asp Gly (G) Ala Ala His (H) Asn: Gln,: Lys: Arg Arg Ile (I) Leu, Val: Met, Ala: Phe, Norleusin | Leu Leu (L) Norleusina, Ile, Val, Met, Ala, Phe| Ile Lys (K) Arg: Gln,: Asn Arg Met (M) Leu: Phe: Ile Leu Phe (F) Trp: Leu: Val: Ile,: Ala: Tyr Tyr Pro (P) No No Synthetic (S) Thr Thr Thr (T) Val: Create Create Trp (W) Tyr:, Phe Tyr Tyr (Y) Trp: Phe: Thr: Ser Phe Val (V) Ile: Leu: Met: Phe, Ala, Norleucine |Leu Amino acids can be grouped by the nature of the side chains common ones: (1) hydrophobic: Norleucine, methionine (Met), alanine (Ala), valine (Val), leucine (Leu), isoleucine (Ile): (2) hydrophilic neutral: cysteine ​​(Cys), serine (Ser), threonine (Thr), asparagine (Asn), Glutamine (Gln): (3) acid: aspartic acid (Asp), glutamic acid (Glu): (4) base: histidine (His), lysine (Lys), arginine (Arg): (5) residues that affect chain orientation: glycine (Gly), proline (Pro): (6) aromatic: tryptophan (Trp), tyrosine (Tyr), phenylalanine (Phe). Non-conservative substitution would require an exchange members of one of these classes with another class. One type of substitution variant involves the substitution one or more residues of the hypervariable region of the parent antibody (e.g. humanized or humanized antibodies). In general, The resulting variants were selected for further research. having modifications (e.g., improvements) in biological properties certain (e.g., increased affinity, decreased immunogenicity) relative to the parent antibody and / or to the essentially maintains certain biological properties of the antibody parent. An exemplary substitution variant is the antibody affinity maturation, which can be easily generated, for example, using phage display-based affinity maturation techniques as described here. In short, one or more mutated HVR residues and antibody variants are indicated on phages and screened for specific biological activities (e.g. affinity binding). Changes (e.g. substitutions) can be made to the HVR, for example to increase antibody affinity. These changes can be performed in HVR "hotspots", namely the residues encoded by codons that undergo mutation at high frequency during somatic maturation process (see, e.g., Chowdhury, Methods Mol. Biol. 20171:179-196 (2008)), and / or residues that contact antigen, with the resulting VH or VL variants tested for affinity binding. Maturation of affinity by building and selecting back from secondary libraries has been explained, for example in Hoogenboom et al. Methods in Molecular Biology 178:1- 37 (O'Brien and friends, ed., Human Press, Totowa, NJ, (2001).) In some manifestations of affinity maturation, diversity inserted into the variable gene selected for maturation by one of various methods (e.g., error-prone PCR, chain shuffling, or gene-directed mutagenesis oligonucleotides). A secondary library is then created. The library are then screened to identify variants. any antibody with the desired affinity. Another method for introducing diversity involves a student-led approach HVR, where several HVR residues (e.g., 4-6 residues on one time) are randomized. HVR residues involved in antigen binding can be specifically identified, for example, using alanine scanning mutagenesis or modeling. CDR-H3 and CDR-L3 especially frequently targeted. In certain embodiments, substitutions, insertions, or deletions may occur in one or more HVRs during the change does not essentially reduce the ability of antibodies to bind antigen. For example, conservative changes (e.g., substitutions conservative as provided here) which is not on essentially reducing the binding affinity can be done in HVR. Such changes may, for example, be outside the residuals come into contact with the antigen in the HVR. In certain embodiments of the VH and VL variant sequences provided above, respectively HVR is unchanged, or contains no more than one, two or three amino acid substitutions. A useful method for identifying residues or the region of an antibody that may be targeted for mutagenesis is called "alanine scanning mutagenesis" as described by Cunningham and Wells (1989) Science, 244:1081-1085. In the method this, the target residue or group of residues (e.g., a charged residue such as Arg, Asp, His, Lys, and Glu) are identified and replaced with neutral or negatively charged amino acids (e.g. alanine or polyalanine) to determine whether the antibody interacts with antigen is affected. Further substitutions can be introduced in amino acid locations that exhibit functional sensitivity to the initial substitution. As an alternative, or as In addition, the crystal structure of the antigen-antibody complex can be analyzed to identify the points of contact between the antibody and antigen. These contact residues and neighboring residues can targeted or eliminated as candidates for substitution. Variants can be screened to determine whether they contain the trait. which are desired. Amino acid sequence insertions include amino fusions and / or carboxyl terminals that range in length from one residue to polypeptides containing one hundred or more residues, and intrasequence insertion of single or multiple amino acid residues. Examples of terminal insertions include antibodies with methionyl residues. N-terminal. Other insertion variants of the antibody molecule include fusion enzymes (e.g. for ADEPT) or polypeptides that increasing the plasma half-life of antibodies to the N- or C- terminal from antibodies. a1-2) Glycosylation Variants In certain embodiments, antibodies are provided herein changed to increase or decrease the extent of antibodies glycosylated. Addition or deletion of glycosylation sites to antibodies can be easily done by changing the amino acid sequence such that one or more glycosylation sites are created or removed. If the antibody covers the Fc region, the attached carbohydrate in it can be changed. The original antibodies produced by the cells mammals typically include bi-branched oligosaccharides that generally attached by an N-link to Asn297 of the CH2 domain in Fc area. See, for example, Wright and friends TIBTECH 15:26- 32 (1997). Oligosaccharides can include various carbohydrates, for example mannose, N-acetyl glucosamine (GICNAcC), galactose, and glycerol Sialate, as well as fucose attached to GIcCNAc in the “stem” of the structure Bianteneral oligosaccharides. In some embodiments, the modification oligosaccharides in the antibodies of the present invention can be carried out to create antibody variants with specific properties that are more Good. In one embodiment, an antibody variant is provided with a carbohydrate structure that does not have attached fucose (directly or indirectly) in the Fc area. For example, the amount of fucose in the antibody can be from 1 to 805, from 18 to 658, from 5$ to 658 or from 208 to 405. The amount of fucose is determined by calculating the average amount of fucose in the sugar chain at Asn297, relative to the sum of all the structure of the glycose attached to Asn 297 (e.g. the structure complex, hybrid, and high mannose) as measured by MALDI-TOF mass spectrometry, as described in International Patent Application No. WO 2008 / 077546, for example. Asn297 refers to an asparagine residue located in the vicinity of position 297 in the Fc region (EU numbering for Fc region residues): however, Asn297 can also be located approximately t / - 3 amino acids upstream or downstream from position 297, namely between positions 294 and 300, because small sequence variations in antibodies. These fucosylation variants may have improved ADCC function. See, for example, Publication United States Patent Application No. US 2003 / 0157108 (Presta, L.): United States Patent Application No. US 2004 / 0093621 (Kyowa Hakko Kogyo Co., Ltd). Examples of publications related to variants "defucosylated" or "fucose-deficient" antibodies include: United States Patent Application No. US 2003 / 0157108: Application International Patent No. WO 2000 / 61739: WO 2001 / 29246: Application United States Patent No. US 2003 / 0115614: US 2002 / 0164328: US 2004 / 00936217 US 2004 / 0132140: US 2004 / 0110704: US 2004 / 0110282j US 2004 / 0109865j International Patent Application No. WO 2003 / 085119: WO 2003 / 084570: Wo 2005 / 03558€6: Wo 2005 / 035778: WO2005 / 053742: WO2002 / 031140: Okazaki et al. J.Mol. Biol. 336:1239-1249 (2004): Yamane-Ohnuki et al. Biotech. Bioeng. 87: 614 (2004). Examples of cell lines capable of producing defucosylated antibodies cover Lec13-deficient CHO cells fucosylated proteins (Ripka et al. Arch. Biochem. Biophys. 219:533-545 (1986): United States Patent Application No. US 2003 / 0157108 Al, Presta, L : and International Patent Application No. WO 2004 / 056312 Al, Adams et al., especially on Example 11), and knockout cell lines, such as alpha-1l,6- fucosyltransferase, FUT8, knockout CHO cells (see, for example, Yamane-Ohnuki and colleagues. Biotech.Bioeng.87: 614 (2004) :Kanda, O1 Y. et al., Biotechnol.Bioeng., 94(4):680-688 (2006): and International Patent Application No. WO2003 / 085107). Antibody variants are further prepared with oligosaccharides which is split in half, for example, where the biatener oligosaccharides attached to the Fc region of the antibody is cleaved by GIcNAc. The antibody variant may have reduced fucosylation and / or enhance ADCC function. Examples of such antibody variants described, for example in WO 2003 / 011878 (Jean-Mairet et al.) friends): United States Patent No. 6,602,684 (Umana et al.) friends): and United States Patent No. US 2005 / 0123546 (Umana and friends). Antibody variants with at least one residue galactose in the oligosaccharide attached to the Fc region also provided. The antibody variant may have increased CDC function. These antibody variants are described, for example, in International Patent Application No. WO 1997 / 30087 (Patel and friends- friend): WO 1998 / 58964 (Raju, S.): and WO 1999 / 221764 (Raju, S.). a1-3) Cysteine ​​engineered antibody variants In certain embodiments, it may be desirable to make cysteine-engineered antibodies, for example, “thioMAbs,” which one or more antibody residues are substituted with residues Cysteine. In certain embodiments, the substituted residue occurs at an accessible site of the antibody. By substituting these residues with cysteine, the reactive thiol group is thus positioned in a place accessible to antibodies and can used to conjugate antibodies to other moieties, such as drug moieties or drug-linking moieties, to make immunoconjugates, as further explained here. In the embodiment In certain cases, one or more of the following residues may be substituted with cysteine: V205 (Kabat numbering) of light chain: A118 (EU numbering) of the heavy chain, and S400 (EU numbering) of Fc region of the heavy chain. Cysteine-engineered antibodies can produced as described, for example, in the American Patent Union No. 1,521,541. a1-4) Antibody Derivatives In certain embodiments, antibodies are provided herein can be further modified to contain moieties nonprotein supplements known in the art and available. Suitable moieties for antibody derivatization include but not limited to water-soluble polymers. Examples unlimited range of water-soluble polymers including, but not limited to, polyethylene glycol (PEG), ethylene glycol / propylene glycol copolymer, carboxymethylcellulose, dextran, polyvinyl alcohol, polyvinyl pyrrolidone, poly-l, 3- dioxolane, poly-1,3,@6-trioxane, ethylene / maleic acid copolymer anhydrides, polyamino acids (either homopolymers or random copolymers), and dextran or poly(n-vinylpyrrolidone) polyethylene glycol, polypropylene glycol homopolymer, polypropylene copolymer oxide / ethylene oxide, polyoxyethylated polyols (e.g. glycerol), polyvinyl alcohol, and mixtures thereof. Polyethylene glycol Propionaldehyde may have advantages in manufacturing because stability in water. Polymers can have different molecular weights. whatever, and can be branched or unbranched. The number of polymers that bind to antibodies can vary, and if more than one bonded polymer, can be the same molecule or different. In general, the amount and / or type of polymer used for derivatization can be determined based on considerations including, but not limited to, certain properties or functions of the antibodies to be repaired, whether the antibody derivatives will be used in therapy under specified conditions, etc. In another embodiment, a conjugate of the antibody and the moiety nonproteins that can be selectively heated by exposure radiation is provided. In one embodiment, the nonprotein moiety are carbon nanotubes (Kam and colleagues, Proc. Natl. Acad. Sci. USA 102: 11600-11605 (2005)). Radiation can be long any wave, and includes, but is not limited to, wavelengths that do not damage normal cells, but which heating the nonprotein moieties to a temperature where the cell proximal to the antibody-nonprotein part will be killed. B. Recombinant Methods and Composition Antibodies can be produced using the following methods and recombinant compositions, for example, as described in Patent United States Patent No. 4,816,567. In one embodiment, provided isolated nucleic acid encoding anti-Cls antibodies explained here. These nucleic acids can encode sequences amino acids that include VL and / or amino acid sequences that includes VH antibodies (e.g. light chains and / or heavy chains) of antibodies). In further embodiments, one or more vectors (e.g., expression vectors) that include nucleic acids is provided. In a further embodiment, a cell is provided host that includes said nucleic acid. In one embodiment the host cell includes (for example, has been transformed with): (1) a vector that includes nucleic acid that encodes An amino acid sequence that includes the VL of an antibody and a amino acid sequences that include the VH of the antibody, or (2) vectors The first includes nucleic acids that encode amino acid sequences. which includes VL antibody and the second vector includes nucleic acid which encodes an amino acid sequence that includes the VH antibody. In one embodiment, the host cell is eukaryotic, for example an ovary cell Chinese hamster (CHO) or lymphoid cells (e.g. YO, NSO, Sp2 / 0 cells). In one embodiment, a method of preparing anti-Cls antibodies provided, wherein the method includes culturing 1nang cells which includes nucleic acids that encode antibodies, such as those provided above, under conditions appropriate for the expression antibodies, and optionally recover antibodies. from host cells (or host cell culture medium). For recombinant production of anti-Cls antibodies, acid nucleic acids that encode antibodies, for example, as described in above, isolated and inserted into one or more vectors for further cloning and / or expression in host cells. Acid These nucleic acids can be easily isolated and sequenced. using conventional procedures (for example, by using oligonucleotide tracers capable of specifically binding to genes which encodes the heavy and light chains of antibodies). Suitable host cells for cloning or vector expression that encode antibodies include prokaryotic or eukaryotic cells described here. For example, antibodies can be produced in bacteria, especially when glycosylation and Fc effector function are not required. For the expression of antibody and polypeptide fragments in bacteria, see, for example, United States Patent No. 5,648,237, 5,189,199, and 5,840,523. (See also Charlton, Methods in Molecular Biology, Vol. 248 (BKC Lo, ed., Humana Press, Totowa, NJ, 2003), pp. 245-254, describes the expression of antibody fragments in E. coli.) After expression, antibodies can be isolated from bacterial cell paste in a soluble and purifiable fraction Furthermore. Besides prokaryotes, eukaryotic microbes such as fungi filamentous or yeast is a suitable cloning or expression host for vectors encoding antibodies, including fungi and strains yeast whose glycosylation pathway has been "humanized", which produce antibody production with some or all of the same pattern fully human glycosylation. See Gerngross, Nat. Biotech. 22:1409-1414 (2004), and Li and colleagues, Nat. Biotech. 24:210- 215 (2006). Suitable host cells for glycosylated antibody expression also comes from multicellular organisms (invertebrates and vertebrates). Examples of invertebrate cells include plant and insect cells. Many strain baculovira along with 1 has been identified insect cells, Spodoptera frugiperda. Look 6,420 PLANT especially that can be used for cell transfection Plant cell cultures can also be used as hosts. , for example, United States Patent No. 5,959,177, 6, ,548, 7,125,978, IBODIES (registered trademark) in transgenic plants). And 6,417,429 040,498, (explaining technology to produce antibodies Vertebrate cells can also be used as hosts. For example, mammalian cell lines adapted to grow in suspension can useful. Another example of a line useful mammalian host cells is a monkey kidney line transformed by SV40 (COos- 1): human embryonic kidney line digel 36:59 (TM4 cells as described, Reprod. African green monkey (HELA) : human lung cells mouse mammary glands (MMT 060562): for example, 38314 ask, for example (1977)): baby hamster kidney cells 4-68 (1982): 231243-251 his, in Graham and friends, dog kidney cells MRC cell 5: (1980): (VERO-76): (MDCK ) : (W138): for example, (BAK): (293 or 293 cells as J. Gen Virol. mouse Sertoli cells in Mather, Biol. monkey kidney cells (CV1): Kidney cells human liver cells TRI Cell, in Mather et al., and FS4 cells. cervical carcinoma cells Buffalo rat liver cells man (BRL 3A): (Hep G2): tumor as explained, Annals NY Ac Ad. Sci. Mammalian host cell lines Other useful ones include Chinese hamster ovary (CHO) cells, including DHFR - CHO cells 11142 16 (1980)): and myeloma cell lines such as YO, (Urlaub and friends, Proc. Natl. Acad. Sci. USA NSO and Sp2 / 0. For a review of specific mammalian host cell lines suitable for antibody production, Molecular Biology, Nol. NJ), pp. 255-268 (2003). Look, 218 for example, (BKC Lo, Yaza ed., Ki and Wu, Methods in Humana Press, Totowa, Antibodies with pH-dependent characteristics can obtained by using screening methods and / or methods mutagenesis for example, as described in the Patent Application International No. WO 2009 / 125825. Screening methods may include any process in which antibodies possess characteristics pH-dependent binding was identified in the population specific antibodies for a particular antigen. In this embodiment In certain cases, screening methods may include measuring one or more binding parameters (e.g., KD or kd) of each antibodies in the initial population of antibodies at both acidic and alkaline pH. neutral. Antibody binding parameters can be measured using, for example, surface plasmon resonance, or analytical methods others that allow for quantitative or qualitative assessment from the binding characteristics of antibodies to certain antigens. In certain embodiments, the screening method may include identify antibodies that bind to antigens with acid KD / neutral KD ratio of 2 or greater. Alternatively, Screening methods may include identifying antibodies that binds to antigens with an acidic kd / neutral kd ratio of 2 or more. In another embodiment, the mutagenesis method may include incorporating deletions, substitutions, or additions of amino acids within heavy and / or light chains of antibodies to enhance pH-dependent binding of antibodies to antigens. In certain embodiments, mutagenesis may be performed in one or more variable domains of an antibody, for example, in one or more HVRs (e.g., CDRs). For example, mutagenesis can involves substituting amino acids in one or more HVRs (e.g. CDR) of antibodies with other amino acids. In In certain embodiments, mutagenesis may include substituting one or more amino acids in at least one HVR (e.g., CDR) of antibodies with histidine. In certain embodiments, "enhanced pH-dependent binding" means that the version mutations of the antibody showed a higher acidic KD / neutral KD ratio large, or a greater acid kd / neutral kd ratio, than the original “parent” (i.e., less pH dependent) version of the antibody before mutagenesis. In certain embodiments, the antibody version the mutated ones have an acid KD / neutral KD ratio of 2 or greater. Alternatively, a mutated version of the antibody has a ratio acid kd / neutral kd of 2 or more. Polyclonal antibodies are preferably raised in animals with multiple subcutaneous (sc) or intraperitoneal (ip) injections of relevant antigens and adjuvants. Can be useful for conjugate relevant antigens with immunogenic proteins in the species to be immunized, for example, limpet hemocyanin keyhole, serum albumin, bovine thyroglobulin, or inhibitor soybean trypsin using bifunctional or derivatized substances, for example, maleimidobenzoyl sulfosuccinimide ester (conjugated via cysteine ​​residues), N-hydroxysuccinimide (via residues lysine), glutaraldehyde, succinic anhydride, SOCl», or RIN-C-NR, where R and RI are different alkyl groups. Animals (usually mammals, not humans) are immunized against antigens, immunogenic conjugates, or derivatives thereof by combining, for example, 100 micro g or 5 micro g of protein or conjugate (for rabbits or mice, respectively) with 3 volumes of adjuvant complete Freund and inject the solution intradermally in several places. One month later, the animals were given booster with 1 / 5 to 1 / 10 the original amount of peptide or conjugate in Freund's complete adjuvant with subcutaneous injection in several place. Seven to 14 days later the animal's blood is removed and the serum is checked for antibody titers. The animal is pushed until plateau titer. Preferably, animals are given a booster with conjugates of the same antigen, but conjugated to a protein different and / or through different cross-linking reagents. Conjugates can also be prepared in recombinant cell culture as protein fusion. Also, aggregates such as alum are suitable for use in enhance immune response. Monoclonal antibodies are obtained from a population of antibodies that are essentially homogeneous, that is, individual antibodies that cover identical populations except for naturally occurring mutations and / or post-translational modifications (e.g., isomerization, amidation) which allows it to be present in small amounts. Thus, “monoclonal” modifiers exhibit a unique character. antibodies are not a mixture of discrete antibodies. For example, monoclonal antibodies can be made by using the hybridoma method first described by Kohler and colleagues, Nature 256(5517):495-497 (1975). In hybridoma method, mice or other suitable host animals, such as hamsters, immunized as described above for obtain lymphocytes that produce or are capable of producing antibodies that will specifically bind to the protein used for immunization. Alternatively, lymphocytes can immunized in vitro Immunization substances will generally include antigenic proteins or fusion variants. Generally both peripheral blood lymphocytes (PBL) are used If human-derived cells are desired, or spleen cells or lymph node cells are used if the mammalian source is nonhuman desired. The lymphocytes are then combined with the cell line that immortalized using a suitable fusing agent, such as polyethylene glycol, to form hybridoma cells (Goding, Monoclonal Antibodies: Principles and Practice, Academic Press (1986), pp. 59-103). Immortalized cell lines are usually mammalian cells. transformed, especially myeloma cells derived from rodents, cattle, and humans. Typically, the myeloma cell line mice or rats are used. Hybridoma cells are made then seeded and grown in a suitable culture medium which preferably contains one or more substances that inhibit growth or survival of parental myeloma cells that are not fused. For example, if the parental myeloma cells do not have the enzyme hypoxanthine guanine phosphoribosyl transferase (HGPRT or HPRT), Culture media for hybridomas typically include hypoxanthine, aminopterin, and thymidine (HAT media), which are substances that prevent the growth of HGPRT-deficient cells The preferred immortalized myeloma cells are which fuse efficiently, supporting the production of high levels of antibodies stable high by selected antibody-producing cells, and sensitive to media such as HAT media. Among them, the more preferred are murine myeloma lines, such as those derived from tumors MOPC-21 and MPC-11 mice available from the Salk Institute Cell Distribution Center, San Diego, California USA, and SP-2 cells (and derivatives, for example, X63-Ag8-653) are available from American Type Culture Collection, Manassas, Virginia USA. Myeloma cell lines Human and mouse-human heteromyeloma have also been described for the production of human monoclonal antibodies (Kozbor et al. J. Immunol. 133(6):3001-3005 (1984): Brodeur and friends, Monoclonal Antibody Production Techniques and Applications, Marcel Dekker, Inc., New York, p. 51-63 (1987)). The culture medium in which hybridoma cells grow is determined for production of monoclonal antibodies directed against antigens. Preferably, the binding specificity of the monoclonal antibody is produced by hybridoma cells is determined by immunoprecipitation or by in vitro binding determination, such as determination radioimmunoassay (RIA) or enzyme-linked immunosorbent assay (ELISA). These techniques and determinations are well known in this field. For example, Binding affinity can be determined by Scatchard analysis from Munson, Anal. Biochem.. 107(1):220-239 (1980). Once the hybridoma cells are identified which produce 100 antibodies with specificity, affinity, and / or activity that If desired, clones can be subcloned by restricting the procedure dilution and grown by standard methods (Goding, supra). Suitable culture media for this purpose include, for example, media D-MEM or RPMI-1640. In addition, hybridoma cells can be grown in vivo as tumors in mammals. Monoclonal antibodies secreted by subclones individually appropriately separated from culture media, ascitic fluid, or serum with conventional immunoglobulin purification procedures such as, for example, protein A-Sepharose, hydroxyapatite chromatography, gel electrophoresis, dialysis, or affinity chromatography. III. Determination The anti-Cl1s antibody provided here can identified, screened, or characterized for properties physical / chemical and / or biological activity with various established in this field. A. Determination of binding and other determinations In one aspect, the antibodies of the present invention are tested for activity binding of the antigen, for example by a known method such as ELISA, Western blot, and so on. In another aspect, the determination of competition can be used to identify antibodies that compete for binding to Cl with the anti-Cl1 antibody described here, or identify antibodies that bind to the same epitope with the anti-Cl1 antibody described here. In embodiment certain, when the competing antibodies are present in excessive, blocking (e.g., reducing) antibody binding references to C1 are at least 108, 158, 208, 258, 308, 358, 408, 4558, 508, 558, 608, 658, 708, 158 or more. In certain embodiments, The competing antibodies bind to the same epitope. 1O1 (e.g., linear or conformational epitopes) that are bound by anti-Cls antibodies described here. Examples of methods that detailed to map the epitopes that antibodies bind to provided in Morris (1996) "Epitope Mapping Protocols," in Methods in Molecular Biology vol. 66 (Humana Press, Totowa, NJ). In certain embodiments, the determination of such competition may carried out at neutral pH conditions. In some embodiments, competition determination is the determination of tandem competition using, for example, the Octet system (registered trademark). In the example of competition determination, C1 is immobilized incubated in a solution containing the first labeled antibody that binds to C1 (e.g., the one described in here) and a second unlabeled antibody tested for its ability to compete with the first antibody for binding to Cl. A second antibody may be present in the hybridoma supernatant. As control, immobilized C1 was incubated in a solution containing includes the first labeled antibody but not the unlabeled antibody second label. After incubation under conditions that allow for the binding of the first antibody to Cl, the excess antibody is unbound is removed, and the number of labels associated with Cl immobilized is measured. If the number of labels associated with Immobilized C1 was reduced substantially in the test samples. relative to the control sample, then it shows that the second antibody competes with the first antibody for binds to Cl. See Harlow and Lane (1988) Antibodies: A Laboratory Manual chapter 14 (Cold Spring Harbor Laboratory, Cold Spring Harbor, NY). In another aspect, antibodies that bind to epitopes that the same as the anti-Cls antibody provided here or the compete for binding to Cls with anti-Cls antibodies provided herein can be identified using the designation sandwich. The sandwich assay involves the use of two antibodies, 102 each capable of binding to an immunogenic region, or epitope, that different from the protein to be detected. In the sandwich assay, the analyte test sample is bound by the first immobilized antibody on a solid support, and after that the second antibody binds with the analyte, thus forming a three-part complex that does not soluble. See David & Greene, United States Patent No. 4,376,110. The second antibody can be labeled with a different moiety detected (direct sandwich determination) or measurable using anti-immunoglobulin antibodies labeled with detectable moieties (indirect sandwich assay). For example, one type of sandwich assay is the ELISA assay, In this case, the moiety that can be detected is an enzyme. Antibody which simultaneously binds to Cls with anti-antibodies The C1ls provided here can be specified as an antibody binds to a different epitope than the anti-Cls antibody. By Therefore, antibodies that do not simultaneously bind to C1ls with the anti-Cls antibody provided here can defined as antibodies that bind to the same epitope with anti-Cls antibodies or compete for binding to Cls with anti-Cls antibodies. B. Determination of activities In one aspect, assignment is provided for identify anti-C1 antibodies that have biological activity. Biological activities may include blocking the activation of pathways classical and the formation of breakdown products resulting from activation of these pathways, C2a, C2b, C3a, C3b, Cda, C4b, Cb5a and C5b. Antibodies that have biological activity such as in vivo and / or in vitro is also provided. In certain embodiments, antibodies of the present invention are tested for such biological activity. In some embodiments, antibodies of the present invention can be evaluated for their ability to 103 inhibits complement-mediated hemolysis of red blood cells sheep's red blood cells (RBC) that have been sensitized by antibodies directed against sheep RBC antigens, namely using the RBC test. In some embodiments, the antibodies of the present invention may evaluated its ability to inhibit hemolysis mediated by complement from chicken red blood cells (cRBC) which have been sensitized by antibodies directed against cRBC antigens. By using human serum as a source of complement proteins, the activity of the antibody of the invention can be determined by measuring the amount of hemoglobin released by spectrophotometric method. Determination of red blood cells can be done using known methods such as the method disclosed in J. Vis. Exp. 2010: (37): 1923. This article explains how to do determination of 508 Hemolytic Complement (CH50) as a lysis determination red blood cells. In short, this assay measures the activation of The classical complement pathway, and detects reduction, absence, or inactivity of any path component. This determination assesses activity of complement components in serum to lyse blood cells red. When the antibody is incubated with the test serum, the band activated and causes hemolysis. If one or more classical pathway components decrease, CH50 value decreases. Determination of CH50 not exactly the same as the setting used in the Example above. here which is more measuring the inhibition of cell lysis by complementary components: however, the basic concepts and arrangements on essentially the same as the present invention. In an embodiment, the determination of the cell red blood is carried out as follows. Human serum is pre- incubation with the desired antibody (e.g., for 3 hours at a temperature of 37 degrees Celsius (degrees C)). The serum is then added to sheep red blood cells sensitized with the same volume and incubated (for example, for one hour at temperature of 37 degrees C) to allow lysis of red blood cells. The reaction then stopped. The mixture was centrifuged to form a cell pellet. 104 which is not lysed, and the supernatant is withdrawn, and the absorbance (OD) at 415 nm was used to analyze hemoglobin release. To calculate the percentage inhibition ($) of red blood cell lysis, 0$ inhibition is defined as a condition where there is no antibody (buffer only) added, and inhibition of 1008 defined as the condition where EDTA is added to final concentration of 5mM (see, for example, Example 7). When antibodies indicate the percentage of inhibition ($) of cell lysis red blood, this means that the antibodies have activity human serum complement neutralizers, for example activity for inhibits the interaction between the Clg and C1r2s2 complexes. Thus, RBC determination can be used for evaluate the complement neutralizing activity of human serum from a antibodies, to assess the activity of inhibiting the interaction between Clg and C1r2s2 complexes. In an embodiment, the present invention provides isolated antibodies that inhibit the interaction between the Clg complex and C1r2s2, where the antibodies have neutralizing activity for human serum complement of at least 708 in red blood cell determination. C. Assessment of immunogenic potential The immunogenic potential of antibodies was evaluated by using as an indicator of the proportion of CD4 T cells: which secrete IL-2 before active proliferation is shown as as described in International Patent Application No. WO2018 / 124005 (Kubo C. and friends). Specifically, PBMC CD8- CD251w (peripheral blood mononuclear cells) were prepared from human PBMCs, and cells were cultured for 67 hours in the presence of antibodies. IV. Immunoconjugate The present invention also provides immunoconjugates comprising anti-Cls antibodies which are here conjugated to one or more cytotoxic substances, such as chemotherapy drugs or substances, inhibitors 105 growth, toxins (e.g., protein toxins, active toxins) enzymatically from bacteria, fungi, plants, or animals. origin, or fragments thereof), or radioactive isotopes. In one embodiment, the immunoconjugate is a conjugate antibody-drug (ADC) where the antibody is conjugated to one or more drugs, including but not limited to maitansinoids (see United States Patents Nos. 5,208,020, 5,416,064 and Patent European No. EP 0 425 235 Bl): auristatin like drug group monomethylauristatin DE and DF (MMAFK and MMAF) (see US Patent States No. 5,635,483 and 5,780,588, and 7,198,298): dolastatin: calicheamicin or its derivatives (see United States Patent No. 5,712,374, 5,114,586, 5,739,116, 5,161,285, 5,170,701, 5,170,710, 5,773,001, and 5,871,296: Hinman and colleagues, Cancer Res. 53: 3336-3342 (1993), and Lode and colleagues, Cancer Res.58:2925- 2928 (1998)): anthracyclines such as daunomycin or doxorubicin (see Kratz and colleagues, Current Med. Chem. 13:4717-523 (2006): Jeffrey and colleagues, Bioorganic & Med. Chem. Letters 16:358-362 (2006): Torgov et al., Bioconj.Chem.16:717- 121 (2005):Nagy et al., Proc.Natl.Acad.Sci.USA 917:829- 834 (2000):Dubowchik et al., Bioorg. &« Med. Chem Letters 12:1529-1532 (2002), King and colleagues, J. Med Chem 45:4336- 14343 (2002), and United States Patent No. 6,630,579): methotrexate: vindesine: / taxanes such as docetaxel, paclitaxel, larotaxel, tesetaxel, and ortaxel:,: trichothecenes: and CC1065. In another embodiment, the immunoconjugate includes an antibody as described here which is conjugated to the toxin which enzymatically active or fragments thereof, including but not limited to limited to the diphtheria A chain, the active fragment of diphtheria toxin non-binding, exotoxin A chain (from Pseudomonas aeruginosa), ricin A chain, abrin A chain, modekin A chain, alpha-sarcin, Aleurites fordii protein, dianthin protein, Phytolacca protein americana (PAPI, PAPII, and PAP-S), Momordica charantia inhibitor, 106 curcin, crotin, saponaria officinalis inhibitor, gelonin, mitogellin, restrictosin, phenomisin, enomycin, and trichotecan. In another embodiment, the immunoconjugate includes an antibody as explained here which are conjugated to the atoms radioactive to form radioconjugates. Various isotopes radioactive materials available for the production of radioconjugates. For example includes 21At, 131T, 1251, 90y, 186Re, 188Re, 153m, 212BRi, 32p, 212ph and radioactive isotope of Lu. When the radioconjugate is used for detection, the radioconjugate may include radioactive atoms to scintigraphy studies, for example Tc-99m or 128 I, or spin labeling for nuclear magnetic resonance (NMR) imaging (also known as magnetic resonance imaging, MRI), such as 10din-123 again, 10din-131, indium-lll, fluorine-19, carbon-13, nitrogen-15, oxygen-17, gadolinium, manganese or iron. Conjugates of antibodies and cytotoxic substances can be made using various bifunctional protein coupling agents such as N-succinimidyl-3-(2-pyridyldithio)propionate (SPDP), succinimidyl- 4-(N-maleimidomethyl)cyclohexane-l-carboxylate (SMCC), iminothiolane (IT), a bifunctional derivative of imidoester (such as dimethyl adipimidate HC1), active ester (such as disuccinimidylsuberate), aldehydes (such as glutaraldehyde), bis-azido compounds (such as bis(p-azidobenzoyl)hexanediamine), bis-diazonium derivatives (such as bis-(p-diazoniumbenzoyl)- ethylenediamine), diisocyanates (such as toluene 2,6-diisocyanate), and bis-active fluorine compounds (such as 1,5-difluoro-2, / - dinitrobenzene). For example, the immunotoxin ricin can be made as as described in Vitetta and colleagues, Science 238:1098 (1987). 1-isothiocyanatobenzyl-3-methyldiethylene acid Carbon-14 labeled triaminepentaacetate (MX-DTPA) is an example of a substance chelator for conjugation of radionuclides to antibodies. Look International Patent Application No. WO94 / 11026. The linker may is a "breakable linker" that facilitates the release of 107 cytotoxic drugs inside the cell. For example, acid-labile linkers, peptidase-sensitive linkers, photolabile linkers, dimethyl linkers, or linkers containing disulfides (Chari and friends, Cancer Res. 52:127-131 (1992): United States Patent No. 5,208,020) may used. Immunoconjugates or ADCs here are expressly meant, but not limited to such conjugates made with cross-linking reagents include, but are not limited to, BMPS, EMCS, GMBS, HBVS, LC-SMCC, MBS, MPBH, SBAP, SIA, SIAB, SMCC, SMPB, SMPH, Sulfo-EMCS, sulfo-GMBS, sulfo-KMUS, Ssulfo-MBS, sulfo-SIAB, Sulfo-SMCC, and Sulfo-SMPB, and SVSB (succinimidyl- (4- vinylsulfone)benzoate) which is commercially available (e.g., from Pierce Biotechnology, Inc., Rockford, IL., USA). V. Methods and Compositions for Diagnostics and Detection In certain embodiments, any of the anti- The C1ls provided here are useful for detecting the presence of Cls in biological samples. The term "detect" as used here includes quantitative or qualitative detection. In In certain embodiments, biological samples include cells or tissues, such as serum, whole blood, plasma, biopsy samples, tissue samples, cell suspension, saliva, sputum, oral fluid, cerebrospinal fluid, Amniotic fluid, ascitic fluid, milk, colostrum, glandular secretions Milk, lymph, urine, sweat, lacrimal fluid, saliva stomach, synovial fluid, peritoneal fluid, lens fluid of the eye or mucus. In one embodiment, an anti-Cls antibody is provided for use in diagnostic or detection methods. In this aspect Next, a method is provided to detect the presence of C1 in biological samples. In certain embodiments, the method involves contacting biological samples with anti-Cls antibodies as described here under conditions that allow 108 for binding of anti-Cls antibodies to Cls, and detecting whether complex formed between antibodies anti-Cl1s and Cls. Method These methods can be in vitro or in vivo methods. In one embodiment, anti-Cls antibodies are used to select subjects who eligible for therapy with anti-Cls antibodies, for example where Cls is a biological marker for patient selection. Examples of disorders that can be diagnosed using antibodies of the invention include, age-related macular degeneration, amyotrophic lateral, anaphylaxis, arthritis (eg rheumatoid arthritis), atypical hemolytic uremic syndrome, but dementia disease not limited to, Alzheimer's disease, multiple sclerosis argyrophilic beads, asthma, atherosclerosis, autoimmune syndrome Barraguer-Simons, Behcet's disease, British type amyloid angiopathy, bullous pemphigoid, Buerger's disease, Clg nephropathy, cancer, syndrome catastrophic antiphospholipid syndrome, cerebral amyloid angiopathy, disease cold agglutinins, corticobasal degeneration, Creutzfeldt's disease Jakob, Crohn's disease, cryoglobulinemic vasculitis, pugilistica dementia, dementia with Lewy Bodies (DLB), tangle diffuse neurofibrillary with calcification, Discoid lupus erythematosus, Down syndrome, focal segmental glomerulosclerosis, mental disorders formal, frontotemporal dementia (FTD), frontotemporal dementia with parkinsonism linked to chromosome 17, lobar degeneration frontotemporal, Gerstmann-Straussler-Scheinker disease, syndrome Gulllain-Barre, Hallervorden-Spatz disease, uremic, hereditary angioedema, hypophosphatastasis, idiopathic, complex disease immune, hemolytic syndrome pneumonia syndrome inclusion body myositis, infectious diseases (for example, diseases caused by bacteria) (e.g., Neisseria meningitidis (e.g., immunodeficiency virus) or Streptococcus) virus man (HIV)), or substances other infectious diseases), inflammatory diseases, ischemia / reperfusion injury, mild cognitive impairment, immunothrombocytopenic purpura (ITP), molybdenum cofactor deficiency (MoCD) type A, glomerulonephritis 109 membranoproliferative (MPGCN) I, glomerulonephritis membranoproliferative (MPGN) II (dense deposit disease), nephritis membranes, multi-infarct dementia, lupus (eg, lupus systemic lupus erythematosus (SLE)), glomerulonephritis, Kawasaki disease, multifocal motor neuropathy, multiple sclerosis, systemic atrophy multiple myasthenia gravis, myocardial infarction, myotonic dystrophy, optic neuromyelitis, Niemann-Pick disease type C, neuronal disease non-Guamanian motor with neurofibrillary tangles, a disease Parkinson's, Parkinson's disease with dementia, hemoglobinuria paroxysmal nocturnal, Pemphigus vulgaris, Pick's disease, postencephalitic parkinsonism, polymyositis, amyloid angiopathy cerebral prion protein, progressive subcortical gliosis, paralysis Progressive supraintestinal ulcer, psoriasis, sepsis, Shigella coli toxin (STEC)- HuS, spinal muscular atrophy, stroke, sclerosing panencephalitis Subacute, Dementia only tangles, transplant rejection, vasculitis (eg, ANCA-associated vasculitis), granulomatosis Wegner, sickle cell disease, cryoglobulinemia, cryoglobulinemia mixed, essential mixed cryoglobulinemia, cryoglobulinemia mixed type II, mixed type III cryoglobulinemia, nephritis, drug-induced thrombocytopenia, lupus nephritis, pemphigoid bullous, Epidermolysis bullosa acquired, hemolytic transfusion reaction delayed, hypocomplementemic urticarial vasculitis syndrome, pseudophakic bullous keratopathy, and platelet refractory. In certain embodiments, the anti-C1l antibody is labeled provided. Labels include, but are not limited to, labels or molecules that are directly detected (such as fluorescent labels, chromophoric, electron dense, chemiluminescent, and radioactive), and moieties, such as enzymes or ligands, which are detected directly. indirectly, for example, through enzymatic reactions or interactions molecular. Examples of labels include, but are not limited to, radioisotopes ?P, 14C, 12051, 3H, and BIT, fluorophores such as chelates rare earth or fluorescein and its derivatives, rhodamine and 110 its derivatives, dansyl, umbeliferon, luceriferase, for example, firefly luciferase and bacterial luciferase (American Patent Union No. 4,737,456), luciferin, 2,3-dihydrophthalazinedione, horseradish peroxidase (HRP), alkaline phosphatase, beta- galactosidase, glucoamylase, lysozyme, saccharide oxidase, for example, glucose oxidase, galactose oxidase, and glucose-6-phosphate dehydrogenase, which is combined with an enzyme that uses hydrogen peroxide to oxidize dye precursors such as HRP, lactoperoxidase, or microperoxidase, oxidase heterocyclics such as uricase and xanthine oxidase, biotin / avidin, spin labels, labeled bacteriophages, stable free radicals, and similar. VI. Pharmaceutical Formulation Pharmaceutical formulation of anti-Cls antibody as described here is made by mixing the antibodies which has the desired level of purity with one or more pharmaceutically acceptable carriers (Remington's Pharmaceutical Sciences 16th ed., Osol, A. Ed. (1980)), in the form of lyophilized formulations or aqueous solutions. Pharmaceutically acceptable carriers are generally non-toxic. for the recipient at the dose and concentration used, and including, but not limited to: buffers such as phosphate, citrate, and other organic acids: antioxidants including ascorbic acid and methionine preservatives (such as octadecyldimethylbenzyl ammonium chloride: hexamethonium chloride: benzalkonium chloride: benzethonium chlorides: phenol, butyl or benzyl alcohol: alkyl parabens such as methyl or propyl paraben: catechol,: resorcinol,: cyclohexanol: 3- pentanol, and m-cresol): low molecular weight polypeptides (less than about 10 residues): proteins, such as serum albumin, gelatin, or immunoglobulin: a hydrophilic polymer such as polyvinylpyrrolidone: amino acids such as glycine, glutamine, asparagine, 111 histidine, arginine, or lysine / monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrin,: ingredients chelators such as EDTA: sugars such as sucrose, mannitol, trehalose or sorbitol, salt-forming counterions such as sodium: complex metals (e.g. Zn-protein complexes): and / or nonionic surfactants such as polyethylene glycol (PEG). Examples of possible carriers pharmaceutically accepted here further including dispersion agents interstitial drugs such as neutral-active glycoprotein hyaluronidase soluble (sHASEGP), for example, hyaluronidase glycoprotein PH-20 which are soluble in humans, such as rHuPH20 (HYLENEX (brand name) registered trademark), Baxter International, Inc.). Example sHASEGP and methods for using certain, including rHuPH20, described in United States Patent Publication No. 2005 / 0260186 and 2006 / 0104968. In one aspect, sHASEGP is combined with one or more additional glycosaminoglycanases such as chondroitinase. Examples of lyophilized antibody formulations are described in United States Patent No. 6,267,958. Aqueous antibody formulation including those described in United States Patent No. 6,171,586 and WO2006 / 044908, the final formulation includes histidine buffer- acetate. The formulation here may also contain more than one ingredient. active required for the specific indication being treated, preferably those with complementary activities that do not interfere with each other adversely affect. For example, it may be desired to provide further details of the formulation used for combination therapy, the appropriate active ingredients are contained in combination in an amount effective for the intended purpose. The active ingredients can be trapped in the microcapsules created, for example by coacervation techniques or by inter-polymerization face, for example hydroxymethylcellulose microcapsules or microcapsules gelatin and poly(methylmethacrylate) microcapsules, respectively, 112 in colloidal drug delivery systems (e.g. liposomes, albumin). microspheres, microemulsions, nanoparticles and nanocapsules) or in macroemulsion. The technique is described in Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980). Sustained release creation can be made. An example of this is according to the slow release preparation including semipermeable matrix of solid hydrophobic polymers containing antibodies, which the matrix is ​​in the form of an object, for example a film or microcapsule. The formulation to be used for in vivo administration is generally sterile. Sterility can be easily achieved, for example by filtration through a sterile filtration membrane. VII. Therapeutic Method and Composition Any of the anti-Cls antibodies provided here can be used in therapeutic methods. In one aspect, anti-Cls antibodies are for use as drugs are provided. In further aspects, antibodies are provided anti-Cls for use in treating diseases or disorders complement-mediated. In certain embodiments, provided anti-Cls antibodies for use in treatment methods. In In certain embodiments, the invention provides anti-Cls antibodies for use in methods to treat individuals who have complement-mediated diseases or disorders that include provide the individual with an effective amount of anti-antibodies. The Cls. In one such embodiment, the method further includes providing individuals with an effective amount of at least one additional therapeutic agent. "Individual" according to one the above embodiment is preferred to be human. In a further embodiment, the present invention provides anti-Cls antibodies for use in treating diseases or complement-mediated disorders. In further embodiments, anti-Cls antibodies can be used to increase Cls clearance 113 from plasma. In further embodiments, anti-Cls antibodies may be used to increase the clearance of Cl1r2s2 from plasma. In further embodiment, increase plasma. complement classic a anti-C1ls antibodies can be used in tkan klerens Cl1lr2s2 from plasma but not Clg from In some cases, n classic: in some cases, is C1ls. In certain embodiments, antibodies inhibit components of the pathway complement pathway components the invention provides anti-Cls antibodies for use in methods for treating disease certain manifestations, or disturbance mediated complement. In the invention provides anti-Cls antibodies for use in the method of increasing Cls clearance from plasma. In certain manifestations, the invention provides anti-Cls antibodies for use in the method of increasing Cl1r2s2 clearance from plasma. In certain embodiments, for use in clearance enhancement methods plasma but not Clg from plasma. invention method a number of The invention provides anti-Cls antibodies C1r2s2 from In certain embodiments, provides anti-Cls antibodies for internal use inhibition of complement pathway components case, path component classic: in the classical complement is Cls “Individual” according to one of the above manifestations is preferred by humans. In one aspect, the present disclosure provides a method for modulation inhibit complement activation, C4b2a. In some embodiments, method own complement activation. for activation modulation disease or disorder complement to the indicator mediated In some embodiments of the method for example to reduce production This disclosure provides vidu that complement, method that involves administering anti-C1ls antibodies to individuals of this disclosure or the pharmaceutical composition of this disclosure, Where this disclosure. In some pharmaceutical composition contains antibodies embodiment, method anti-C1ls from the inhibit complement activation. In some embodiments, the individual the are mammals. In some embodiment, individual 114 is human. Giving can be done through any channel that known to persons skilled in the art, including those disclosed herein. In some embodiments, the granting of is done intravenously or subcutaneously. In some embodiment, administration is intrathecal. Complement-mediated diseases or disorders are a disorder characterized by abnormal amounts of complement C1 or abnormal levels of complement C1 proteolytic activity in cells, tissue, or individual fluids. In some cases, the disease or disorder that complement-mediated is characterized by the presence of cells, tissues, or fluid with an increased amount of C1 (higher than normal) or increased levels of complement C1 activity. For example, in some cases, the disease or disorder is mediated complement is characterized by the presence of brain tissue and / or fluid cerebrospinal fluid with increased numbers and / or activity increased from Cl. The amount of C1 was "higher than normal" in in cells, tissues, or fluids indicates that the amount of C1 in in cells, tissues, or fluids higher than control levels normal, for example, higher than the normal control level for individuals or populations of individuals of the same age group. "Higher than normal" levels of C1 activity in cells, Tissue, or fluid indicates that proteolytic breakdown is occurring. influenced by C1 in cells, tissues, or higher fluids from normal, the control level, for example, is higher than normal, level of control for an individual or population of individuals from same age group. In some cases, people who have complement-mediated diseases or disorders show one or more additional symptoms of a disease or disorder the. In other cases, the disease or disorder is mediated complement is characterized by the presence of cells, tissue, or fluids 115 with a lower than normal C1 count or level lower complement C1 activity. For example, in some complement-mediated cases, diseases or disorders characterized by the presence of brain tissue and / or fluid cerebrospinal with lower numbers and / or activity which is lower than Cl. The amount of C1 which is "lower than "normal" in cells, tissues, or fluids indicates that the amount of C1 in cells, tissues, or fluids is lower than normal, levels control, for example, is lower than normal control levels for individuals or populations of individuals of the same age group. “Lower than normal” levels of C1 activity in cells, Tissue, or fluid indicates that proteolytic breakdown is occurring. affected by C1 in cells, tissues, or lower fluids from normal, the control level, for example, is lower than normal., level of control for an individual or population of individuals from same age group. In some cases, people who have complement-mediated diseases or disorders show one or more additional symptoms of a disease or disorder the. Complement-mediated diseases or disorders are disease or disorder where the number of in such a way as to cause individual. In some embodiments, complement-mediated selected from or complement C1 activity disease or disorder in disease or disorder that a group consisting of autoimmune diseases, cancer, hematological diseases, infectious diseases, inflammatory disease, ischemia-reperfusion injury, disease neurodegenerative, neurodegenerative disorders, eye diseases, kidney disease, transplant rejection, vascular disease, and vasculitis disease. In some embodiments, the disease or complement-mediated disorders are autoimmune diseases. In some embodiments, the disease or disorder that complement-mediated is cancer. In some embodiments, 116 complement-mediated diseases or disorders are diseases infectious. In some manifestations, the disease or disorder that Complement-mediated is an inflammatory disease. In some complement-mediated manifestations, diseases or disorders is a hematological disease. In some manifestations, the disease or complement-mediated disorders are ischemic injury- reperfusion. In some embodiments, the disease or disorder that complement-mediated eye disease. In some complement-mediated manifestations, diseases or disorders is a kidney disease. In some manifestations, the disease or complement-mediated disorders are rejection transplantation. In some embodiments, disease or disorder complement-mediated is transplant rejection which antibody-mediated. In some embodiments, the disease or complement-mediated disorders are vascular diseases. In some embodiments, the disease or disorder that complement-mediated vasculitis is a disorder. In some complement-mediated manifestations, diseases or disorders is a neurodegenerative disease or disorder. In some manifestation, complement-mediated disease is a disease neurodegenerative. In some embodiments, the disorder complement-mediated neurodegenerative disorders. In some manifestation, disease or disorder that is mediated complement is tauopathy. Examples of complement-mediated diseases or disorders includes, but is not limited to, macular degeneration related age, Alzheimer's disease, amyotrophic lateral sclerosis, anaphylaxis, argyrophilic manic dementia, arthritis (eg, rheumatoid arthritis), asthma, atherosclerosis, atypical hemolytic uremic syndrome, autoimmune disease, Barraguer-Simons syndrome, Behcet's disease, British type amyloid angiopathy, bullous pemphigoid, Buerger's disease, Clg nephropathy, cancer, antiphospholipid syndrome 117 catastrophic, cerebral amyloid angiopathy, cold agglutinin disease, degeneration corticobasal, Creutzfeldt-Jakob disease, Disease Crohn's, cryoglobulinemia vasculitis, dementia pugilistica, dementia with Lewy Bodies (DLB), diffuse neurofibrillary tangles with calcification, Discoid lupus erythematosus, focal segmental glomerulosclerosis, disorder frontotemporal dementia (FTD), dementia chromosome-related parkinsonism frontotemporal, Guillain-Barre, uremic, hereditary angioedema, idiopathic, Hallervorden-Spatz disease, hypophosphatases, Down syndrome, formal thinking, frontotemporal with 17, lobar degeneration immune complex disease, myositis infectious diseases (for example, tuberculosis) Gerstmann-Straussler-Scheinker disease, syndrome hemolytic syndrome pneumonia syndrome inclusion body, caused by bacteria (for example, Neisseria meningitidis or viruses (for example, human immunodeficiency virus Streptococcus) (HIV)), or substances other infectious diseases), inflammatory diseases, ischemia / reperfusion injury, mild cognitive impairment, immunothrombocytopenic purpura (ITP), molybdenum cofactor deficiency (MoCD) type A, Membranoproliferative (MPGN) I, glomerulonephritis glomerulonephritis membranoproliferative (MPGN) II (dense deposit disease), nephritis membranous, multi-infarct dementia, lupus (e.g., lupus systemic lupus erythematosus (SLE)), glomerulonephritis, Kawasaki disease, multifocal motor neuropathy, multiple, myasthenia gravis, myocardial infarction, multiple sclerosis, system atrophy myotonic dystrophy, optic neuromyelitis, Niemann-Pick disease type C, neuronal disease non-Guamanian motor with neurofibrillary tangles, a disease Parkinson, nocturnal postencephalitis parkinsonism, polymyositis, cerebral prion protein, suprainti (STEC) -HuS, Parkinson's disease with dementia, paroxysmal, Pemphigus vulgaris, progressive, psoriasis, sepsis, spinal muscular atrophy, Shiga- stroke, hemoglobinuria Pick's disease, amyloid aglopathy progressive subcortical gliosis, paralysis FE coli toxin panencephalitis 118 subacute sclerosis, dementia only tangles, transplant rejection, vasculitis (eg, ANCA-associated vasculitis), granulomatosis Wegner, sickle cell disease, cryoglobulinemia, cryoglobulinemia mixed, essential mixed cryoglobulinemia, cryoglobulinemia mixed type II, mixed type III cryoglobulinemia, nephritis, drug-induced thrombocytopenia, lupus nephritis, pemphigoid bullous, Epidermolysis bullosa acquired, hemolytic transfusion reaction delayed, hypocomplementemic urticarial vasculitis syndrome, pseudophatic bullous keratopathy, and platelet refractory. Alzheimer's disease and some forms of dementia Frontotemporal (Pick's disease, sporadic Frontotemporal dementia, and Frontotemporal dementia with Parkinsonism associated with chromosome 17) is the most common form of tauopathy. In accordance with this invention relates to any method as described above, where tauopathies are Alzheimer's disease, Pick's disease, Sporadic Frontotemporal Dementia and Frontotemporal Dementia with Parkinsonism linked to chromosome 17. Other tauopathies including, but not limited to, progressive supraspinatus palsy (PSP), corticobasal degeneration (CBD) and sclerosing panencephalitis Subacute. Neurodegenerative tauopathies include Alzheimer's disease, amyotrophic lateral sclerosis / parkinsonism-dementia complex, arrhythmias, amyloid angiopathy, English type, cerebral amyloid angiopathy, corticobasal degeneration, disease Creutzteldt-Jakob disease, dementia pugilistica, diffuse neurofibrillary tangles with calcification, Down syndrome, frontotemporal dementia, frontotemporal dementia with parkinsonism associated with chromosome 17, frontotemporal lobar degeneration, Gerstmann's disease- Straussler-Scheinker, Hallervorden-Spatz disease, body myositis inclusion, multiple system atrophy, myotonic dystrophy, disease Niemann-Pick type C, a non-Guamanian motor neuron disease with neurofibrillary tangles, Pick's disease, parkinsonism 119 postencephalitic, cerebral amyloid angiopathy prion protein, progressive subcortical gliosis, progressive supranuclear palsy, subacute sclerosing panencephalitis, tangled dementia, dementia multi-infarction, ischemic stroke, chronic traumatic encephalopathy (CTE), traumatic brain injury (TBI), and stroke. This disclosure also provides methods for treating synucleinopathies, such as Parkinson's disease (PD): dementia with Lewy Bodies (DLB): multiple system atrophy(MSA): and so on. For example, PD with dementia (PDD) can be treated with methods from this disclosure. In some embodiments, the disease or disorder that complement-mediated diseases include Alzheimer's disease. In some complement-mediated manifestations, diseases or disorders includes Parkinson's disease. In some embodiments, the disease or complement-mediated disorders include rejection transplantation. In some embodiments, disease or disorder complement-mediated is transplant rejection which antibody-mediated. In some embodiments, anti-Cls antibodies of This disclosure prevents or delays the onset of at least one symptoms of complement-mediated diseases or disorders in individuals. In some embodiments, anti-Cls antibodies from This disclosure reduces or eliminates at least one symptoms of complement-mediated diseases or disorders in individual. Examples of symptoms include, but are not limited to, symptoms associated with autoimmune diseases, cancer, disease hematology, infectious diseases, inflammatory diseases, injuries ischemia-reperfusion, neurodegenerative diseases, disorders neurodegenerative, kidney disease, transplant rejection, eye disease, blood vessel disease or vasculitis disorders. These symptoms can be neurological symptoms, for example disorders cognitive function, memory impairment, loss of motor function, and 120 etc. These symptoms can also be in the form of protein activity Cls in a person's cells, tissues, or fluids. The symptoms also can be the level of complement activation in cells, tissues, or fluids from individuals. In some embodiments, providing anti-Cls antibodies from This disclosure to individuals modulates complement activation in individual cells, tissues, or fluids. In some embodiments, providing the anti-Cls antibodies of the present disclosure to individuals inhibits complement activation in cells, tissues, or individual fluids. For example, in some embodiments, the anti-Cls antibodies of this disclosure, when administered in one or more doses as monotherapy or in therapy combination for individuals who have a disease or disorder that complement-mediated, inhibits complement activation in individuals with at least about 108, at least about 158, at least around 208, at least around 258, at least around 308, at least around 408, at least around 508, at least about 608, at least about 708, at least about 808, at least around 908, or more than 908, compared to with complement activation in individuals prior to treatment with anti-Cls antibodies. In some embodiments, anti-Cls antibodies of This disclosure reduces the deposition of C3 on red blood cells: for example, in some embodiments, anti-Cls antibodies from This disclosure reduces the deposition of C3b, 1C3b, and so on, on red blood cells. In some embodiments, anti- The Cls of this disclosure inhibit the lysis of red blood cells which complement-mediated. In some embodiments, anti-Cls antibodies of This disclosure reduces the deposition of C3 on platelets, for example, in some embodiments, anti-Cls antibodies from This disclosure reduces the deposition of C3b, 1C3b, and so on, 121 on platelets. In some embodiments, providing anti-Cls antibodies from This disclosure produces selected results from the group which consists of: (a) reduction of complement activation; (b) increased cognitive function: (c) reduced neuronal loss: (d) reduction of phospho-Tau levels in neurons (e) reduction glial cell activation: (£) reduction of lymphocyte infiltration: (g) reduction of macrophage infiltration: (h) reduction of deposition antibodies, (1) reduction in glial cell loss: (J) reduction Oligodendrocyte loss:j (k) reduction in cell infiltration dendritic: (1) reduction of neutrophil infiltration:, (m) reduction red blood cell lysis: (n) reduction of phagocytosis of red blood cells, (o) reduction of platelet phagocytosis; (p) reduction of lysis platelets: (g) increased survival of transplanted grafts, (r) macrophage-mediated phagocytosis reduction: (Ss) improved vision: (t) improved motor control: (u) increased thrombus formation: (v) increased blood clotting: (w) increased kidney function; (x) reduced complement activation antibody-mediated: (y) reduction of complement activation autoantibody-mediated:, (z) increased anemia: (aa) reduction of demyelination: (ab) reduction of eosinophilia, (ac) reduction of C3 deposition in red blood cells (e.g., reduction of precipitation of C3b, 1C3b, etc., in red blood cells red): and (ad) reduction of C3 deposition in platelets (e.g., reduction of precipitation of C3b, 1C3b, and so on, in platelets): and (ae) reduction in the production of anaphylactic toxins, (a£) autoantibody-mediated reduction of blister formation: (ag) reduction of autoantibody-induced pruritus: (ah) autoantibody-induced erythematosus reduction: (ai) autoantibody-mediated reduction of skin erosion, (aj) reduction of red blood cell damage due to transfusion reactions, (ak) reduction of red blood cell lysis due to alloantibodies: (al) 122 reduction of hemolysis due to transfusion reactions, (am) reduction allo-antibody-mediated platelet lysis: (an) reduction platelet lysis due to transfusion reaction, (ao) reduced activation mast cells: (ap) reduction of histamine release mast cells: (ag) reduction of vascular permeability, (ar) reduction of edema, (as) reduction of complement deposition on the graft endothelium transplantation, (at) reducing the formation of anaphylatoxins in endothelial transplantation: (au) reduction of separation dermal-epidermal junction: (av) reduction of formation anaphylatoxins at the dermal-epidermal junction: (aw) reduction alloantibody-mediated complement activation in endothelial graft transplantation: (ax) reduction of loss antibody-mediated neuromuscular junction: (ay) reduction of complement activation at the neuromuscular junction,: (az) reduction of anaphylatoxin formation at the junction neuromuscular:j (ba) reduction of complement deposition in neuromuscular junction:, (bb) reduction of paralysis: (bc) reduction of numbness, (bd) increased bladder control, (be) increased bowel control; (bf) reduced mortality related to autoantibodies:, and (bg) reduction of morbidity associated with autoantibodies. In some embodiments, anti-Cls antibodies of this disclosure, when given in one or more doses as monotherapy or in combination therapy for individuals who have a complement-mediated disease or disorder, influential in achieving a reduction of at least about 10 &, at least about 158, at least about 205, at least about 258, at least around 308, at least around 408, at least around 508, at least around 608, at least around 708, at least about 808, at least about 908, or more than 908, from one or more of the following results: (a) complement activation (b) decreased cognitive function, (c) loss of neurons: (d) levels 123 phospho-Tau in neurons: (e) glial cell activation:, (£) infiltration lymphocytes: (g) macrophage infiltration: (h) antibody deposition, (i) loss of glial cells: (jJ) loss of oligodendrocytes, (k) infiltration dendritic cells,: (1) neutrophil infiltration,: (m) red blood cell lysis: (n) phagocytosis of red blood cells: (o) phagocytosis of platelets: (p) platelet lysis: (g) transplant rejection, (x) macrophage-mediated phagocytosis: (Ss) loss vision: (t) antibody-mediated complement activation: (Uu) autoantibody-mediated complement activation:j (v) demyelination: / (w) eosinophilia, compared with the level or degree of outcome in individuals before treatment with antibodies anti-Cls. In some embodiments, anti-Cls antibodies of this disclosure, when given in one or more doses as monotherapy or in combination therapy for individuals who have a complement-mediated disease or disorder, influential in achieving an increase of at least around 10 &, at least about 158, at least about 205, at least about 258, at least around 308, at least around 408, at least around 508, at least around 608, at least around 708, at least about 808, at least about 908, or more than 908, from one or more of the following outcomes: a) cognitive function, b) transplant survival, c) vision, d) motor control, e) thrombus formation: £) clotting: g) kidney function: and h) hematocrit (number of red blood cells), compared to the level or the degree of outcome in individuals before treatment with anti-Cls antibodies. In some embodiments, providing anti-Cls antibodies from This disclosure to individuals reduces complement activation. in individuals. For example, in some embodiments, antibodies anti-Cls of this disclosure, when administered in a single dose or more as monotherapy or in combination therapy for 124 individuals who have a disease or disorder that is mediated complement, reducing complement activation in individuals by at least about 108, at least about 158, at least about 208, at least around 258, at least around 308, at least around 408, at least around 508, at least around 608, at least about 708, at least about 8058, at least about 908, or more than 908, compared to complement activation in individuals prior to treatment with anti-Cls antibodies. In some embodiments, providing anti-Cls antibodies from This disclosure improves cognitive function in individuals. For example, in some embodiments, anti-Cls antibodies from this disclosure, when given in one or more doses as monotherapy or in combination therapy for individuals who have a complement-mediated disease or disorder, improve cognitive function in individuals with at least around 108, at least around 158, at least around 208, at least about 258, at least about 3085, at least about 408, at least around 508, at least around 608, at least around 708, at least around 808, at least around 908, or more than 908, compared to the individual's cognitive function before treatment with anti-Cls antibodies. In some embodiments, providing anti-Cls antibodies from This disclosure reduces the rate of cognitive decline in individual. For example, in some embodiments, anti-Cls antibodies of this disclosure, when administered in one or more doses as monotherapy or in combination therapy for individuals who have a complement-mediated disease or disorder, reduce the rate of cognitive decline in individuals by at least around 108, at least around 158, at least around 208, at least about 258, at least about 3085, at least about 408, at least around 508, at least around 60$, at least around 708, at least around 808, at least around 908, or 125 more than 908, compared to the level of functional decline cognitive impairment in individuals prior to treatment with anti- Class. In some embodiments, providing anti-Cls antibodies from This disclosure to individuals reduces the loss of neurons in the individual. For example, in some embodiments, the anti-Cls antibodies of this disclosure, when administered in one or more doses as monotherapy or in therapy combination for individuals who have a disease or disorder that complement-mediated, reduces neuronal loss in individuals at least about 108, at least about 158, at least around 208, at least around 258, at least around 308, at least about 408, at least about 508, at least about 608, at least around 708, at least around 808, at least around 908, or more than 908, compared to the loss neurons in individuals before treatment with anti-Cls antibodies. In some embodiments, providing anti-Cls antibodies from This disclosure to individuals reduces the levels of phospho-Tau in individual. For example, in some embodiments, anti-Cls antibodies of this disclosure, when administered in one or more doses as monotherapy or in combination therapy for individuals who have a complement-mediated disease or disorder, reduce phospho-Tau in these individuals by at least around 108, at least around 158, at least around 208, at least about 258, at least about 3085, at least about 408, at least around 508, at least around 608, at least around 708, at least around 808, at least around 908, or more than 908, compared to the phospho-Tau levels in individuals before treatment with anti-Cls antibodies. In some embodiments, providing anti-Cls antibodies from This disclosure to individuals reduces glial cell activation in individuals. For example, in some embodiments, anti- 126 C1ls of this disclosure, when administered in a single dose or more as monotherapy or in combination therapy for individuals who have a disease or disorder that is mediated complement, reduces glial activation in individuals by at least about 108, at least about 158, at least about 208, at least around 258, at least around 308, at least around 408, at least around 508, at least around 608, at least about 708, at least about 8058, at least about 908, or more than 908, compared to glial cell activation in individuals prior to treatment with anti-Cls antibodies. In In some embodiments, glial cells are astrocytes or microglia. In some embodiments, providing anti-Cls antibodies from This disclosure to individuals reduces lymphocyte infiltration in individuals. For example, in some embodiments, antibodies anti-Cls of this disclosure, when administered in a single dose or more as monotherapy or in combination therapy for individuals who have a disease or disorder that is mediated complement, reduces lymphocyte infiltration in individuals by at least about 108, at least about 158, at least about 208, at least around 258, at least around 308, at least around 408, at least around 508, at least around 608, at least about 708, at least about 8058, at least about 908, or more than 908, compared with lymphocyte infiltration in individuals prior to treatment with anti-Cls antibodies. In some embodiments, providing anti-Cls antibodies from This disclosure to individuals reduces macrophage infiltration in individuals. For example, in some embodiments, anti- C1ls of this disclosure, when administered in a single dose or more as monotherapy or in combination therapy for individuals who have a disease or disorder that is mediated complement, reduces macrophage infiltration in individuals by at least about 108, at least about 158, at least about 127 208, at least around 258, at least around 308, at least around 408, at least around 508, at least around 608, at least about 708, at least about 8058, at least about 908, or more than 908, compared to macrophage infiltration in individuals prior to treatment with anti-Cls antibodies. In some embodiments, providing anti-Cls antibodies from This disclosure to individuals reduces antibody deposition in individuals. For example, in some embodiments, antibodies anti-Cls of this disclosure, when administered in a single dose or more as monotherapy or in combination therapy for individuals who have a disease or disorder that is mediated complement, reducing antibody deposition in individuals by at least about 108, at least about 158, at least about 208, at least around 258, at least around 308, at least around 408, at least around 508, at least around 608, at least about 708, at least about 8058, at least about 908, or more than 908, compared to antibody precipitation in individuals prior to treatment with anti-Cls antibodies. In some embodiments, providing anti-Cls antibodies from This disclosure to individuals reduces the production of anaphylatoxins. (e.g., C3a, C4a, Cb5a) in individuals. For example, in some embodiments, the anti-Cls antibodies of the present disclosure, when given in one or more doses as monotherapy or in combination therapy for individuals who have the disease or complement-mediated disorders, reducing production anaphylatoxin in individuals is at least about 105, at least about 158, at least about 205, at least about 258, at least around 308, at least around 408, at least around 508, at least around 608, at least around 708, at least about 808, at least about 908, or more than 908, compared to the level of anaphylatoxin production in individuals prior to treatment with anti-Cls antibodies. 128 In some embodiments, the present disclosure provides use of the anti-Cls antibodies of the present disclosure or the compositions pharmaceuticals containing the anti-Cls antibodies of this disclosure and pharmaceutically acceptable excipients for treating individuals who have a disease or disorder that is mediated complement. In some embodiments, this disclosure provides for the use of the anti-Cls antibody of this disclosure to treat individuals who have diseases or disorders that complement-mediated. In some embodiments, the disclosure This provides for the use of pharmaceutical compositions containing antibodies anti-Cls of this disclosure and acceptable excipients pharmaceutically to treat individuals who have diseases or complement-mediated disorders. In some embodiments, the present disclosure provides the use of the anti-Cls antibodies of this disclosure in the manufacture of drugs for the treatment of individuals who have a disease or complement-mediated disorders. In some embodiments, the present disclosure provides use of the anti-Cls antibodies of the present disclosure or the compositions pharmaceuticals containing the anti-Cls antibodies of this disclosure and pharmaceutically acceptable excipients to inhibit complement activation. In some embodiments, this disclosure provides for the use of the anti-Cls antibody of this disclosure or pharmaceutical compositions containing anti-Cls antibodies from this disclosure and pharmaceutically acceptable excipients to inhibit complement activation in individuals who have complement mediation. disease or disorder. In some embodiment, the present disclosure provides for the use of anti- Cls of this disclosure to inhibit complement activation in individuals who have a disease or disorder that is mediated complement. In some embodiments, the present disclosure provides use of pharmaceutical compositions containing anti-Cls antibodies from 129 this disclosure and pharmaceutically acceptable excipients to inhibit complement activation in individuals who have complement-mediated diseases or disorders. In some embodiments, the present disclosure provides the use of the anti-Cls antibodies of this disclosure in the manufacture of drugs for modulating complement activation. In some embodiments, drugs inhibit complement activation. In some embodiments, drugs inhibit complement activation in individuals who have complement-mediated diseases or disorders. In some embodiments, the present disclosure provides anti-Cls antibodies of the present disclosure or pharmaceutical compositions containing the anti-Cls antibodies of this disclosure and excipients pharmaceutically acceptable for use in therapy medical. In some embodiments, the present disclosure provides anti-Cls antibodies of the present disclosure for use in medical therapy. In some embodiments, this disclosure provides a pharmaceutical composition containing anti-Cls antibodies from this disclosure and pharmaceutically acceptable excipients for use in medical therapy. In some embodiments, the present disclosure provides anti-Cls antibodies of the present disclosure or pharmaceutical compositions containing the anti-Cls antibodies of this disclosure and excipients that are pharmaceutically acceptable for treating individuals who have a complement-mediated disease or disorder. In In some embodiments, the present disclosure provides anti- The purpose of this disclosure is to treat individuals who have complement-mediated diseases or disorders. In some embodiments, the present disclosure provides pharmaceutical compositions containing the anti-Cls antibodies of this disclosure and excipients that are pharmaceutically acceptable for treating individuals who have a complement-mediated disease or disorder. In some embodiments, the present disclosure provides 130 anti-Cls antibodies of the present disclosure or pharmaceutical compositions containing the anti-Cls antibodies of this disclosure and excipients pharmaceutically acceptable for modulation of activation complement. In some embodiments, the present disclosure provides anti-Cls antibodies of this disclosure for modulation of activation complement. In some embodiments, the present disclosure provides pharmaceutical composition containing anti-Cls antibodies of the disclosure this and pharmaceutically acceptable excipients for modulation complement activation. In some embodiments, anti-Cls antibodies inhibit complement activation. In a further aspect, the invention provides for the use of anti-Cls antibodies in the production or manufacture of drugs. In one embodiment, medicine is for the treatment of disease or disorder complement-mediated. In a further embodiment, the drug used in methods to treat diseases or disorders that complement-mediated which includes providing to individuals who have a complement-mediated disease or disorder The effective amount of the drug. In one such embodiment, The method further includes providing individuals with The effective amount of at least one additional therapeutic agent, for example as explained below. In the embodiment Next, drugs are used to increase clearance (or remove) C1 from plasma. In a further embodiment, the drug used to increase the clearance (or elimination) of C1lr2s2 from plasma. In further embodiments, the drug is used to increase the clearance (or removal) of Clr2s2 from plasma but not Clg from plasma. In a further embodiment, the drug used to inhibit components of the classical complement pathway: in In some cases, the components of the classical complement pathway are Cls. In a further embodiment, a drug for use in method of treating individuals who have a disease or complement-mediated disorders that include providing 131 to the individual the effective amount of the drug. "Individual" according to one of the above manifestations can be human. In a further aspect, the invention provides a method for treat complement-mediated diseases or disorders. In one embodiment, the method includes providing to an individual who have a complement-mediated disease or disorder that is the effective amount of anti-Cls antibodies. In one such embodiment, the method further comprises providing to individual effective amount of at least one therapeutic substance additional, as explained below. “Individual” according to one the above manifestation can be human. In a further aspect, the invention provides a method for increases the clearance (or removal) of C1 from plasma in individual. In a further aspect, the invention provides a method to increase the clearance (or removal) of C1r2s2 from plasma on individuals. In a further aspect, the invention provides methods to increase the clearance (or elimination) of C1r2s2 from plasma but not Clg from plasma in individuals. In some In this case, the invention provides a method for inhibiting components of the pathway. classical complement in individuals. : in some cases, the components The classical complement pathway is Cls. In one embodiment, "individual" is human. In a further aspect, the invention provides a formulation pharmaceuticals containing any of the anti-Cls antibodies provided here, for example, for use in any of the the above therapeutic method. In one embodiment, the formulation pharmaceuticals containing any of the anti-Cls antibodies that provided herein and a pharmaceutically acceptable carrier. In another embodiment, the pharmaceutical formulation contains any of of the anti-Cls antibodies provided here and at least one additional therapeutic agent, for example as described below This. 132 The antibodies of the present invention may be used alone or in combination with combination with other substances in therapy. For example, antibodies from This invention may be provided together with at least one substance additional therapeutics. The combination therapy above includes administration of combination (where two or more therapeutic substances are included in the same or separate formulations), and separate administration, in In this case, administration of the antibodies of the invention may occur before, simultaneously with, and / or after, the administration of the substance additional therapy. In one embodiment, administration of antibodies anti-Cls and administration of additional therapeutic agents occurs within a short time. about a month, or in about one, two or three months weeks, or in about one, two, three, four, five, or six days., each other. The antibodies of the invention can also used in combination with radiation therapy. The antibodies of the present invention (and additional therapeutic agents) others) may be provided in an appropriate manner, including parenteral, intrapulmonary, and intranasal, and, if desired For local treatment, intralesional administration. Parenteral infusion includes intramuscular, intravenous, intraarterial administration, intraperitoneal, or subcutaneous. The dose can be via the following routes: appropriately, for example by injection, such as intravenous injection or Subcutaneous, partly depending on whether the administration is short or chronic. Various dosing schedules include but are not limited to limited to single or multiple administration at various points time, bolus administration, and pulse infusion are meant here. The antibodies of the present invention will be formulated, dosed, and administered in a manner consistent with established medical practice. good. Factors to consider in this context include disturbances certain treated mammals, certain conditions treated clinical characteristics of each patient, cause of disorder, location substance delivery, administration method, administration scheduling, and 133 other factors known to medical practitioners. Antibodies do not necessary, but optionally formulated with one or more substances currently used to prevent or treat the disorder. The effective amount of the other substance depending on the amount of antibodies present in the formulation, the type disorders or medications, and other factors discussed above. It is generally used in the same doses and by the same route. administration as described here, or approximately 1 to 9958 of the doses described herein, or in any dose and by whatever route is empirically / clinically determined sexual. For the prevention or treatment of disease, the dose of antibodies appropriate invention (when used alone or in combination) with one or more additional therapeutic agents) will depends on the type of disease to be treated, the type of antibody, severity and course of the disease, whether antibodies given for preventive or therapeutic purposes, therapy previously, the patient's clinical history and response to antibodies, and the discretion of the treating physician. Appropriate antibodies are administered to patients at one time or during a series of treatments. Depending on the type and severity of the disease, about 1 micro g / kg to 15 mg / kg (e.g. 0.1 mg / kg-10 mg / kg) of antibodies may be a candidate for the initial dose to be given to patients, for example, by one or more separate gifts, or by continuous infusion. A typical daily dose can range from about 1 microg / kg to 100 mg / kg or more, depending on the factors mentioned above. For repeated administration during several days or more, depending on the condition, treatment will generally be maintained until the disease symptoms are suppressed. desired to occur. One example of an antibody dose would range from about 0.05 mg / kg to about 10 mg / kg. So, one or more doses of approximately 0.5 mg / kg, 2.0 mg / kg, 4.0 mg / kg or 10 mg / kg (or 134 combination) can be given to patients. This dose can be given intermittently, for example every week or every three weeks (for example, the patient receives about two to about twenty, or for example about six doses of antibodies). Dose higher initial loading, followed by one or more doses lower doses may be given. However, other dosage regimens might be useful. The progress of this therapy is easy to monitor with techniques and conventional tests. It is understood that one of the formulations or methods The above therapeutic measures can be carried out using immunoconjugates of the invention as a substitute for or in addition to anti-Cls antibodies. VIII. Manufacturing Articles In other aspects of the present invention, articles are provided manufacturing containing materials that are useful for treatment, prevention and / or diagnosis of disorders that described above. The manufactured article includes the container and label on or in the packaging insert associated with the container. The container that Suitable items include, for example, bottles, vials, syringes, pouches IV solutions, and so on. Containers can be made from various materials. materials such as glass or plastic. The container contains the composition by itself or combined with other compositions effective for treating, preventing and / or diagnosing conditions and may have a sterile access hole (e.g. the container may be intravenous solution bag or vial that has a stopper that can be penetrated with a hypodermic syringe). At least one material active in the composition is the antibody of the present invention. The label or the package insert indicates that the composition is used to treat selected conditions. In addition, manufacturing articles may include (a) a first container with the composition contained therein, wherein the composition contains antibodies of the invention, 135 and (b) a second container with the composition contained therein, wherein the composition contains further cytotoxic substances or substances other therapeutics. Manufactured articles in embodiments of the invention This may further include a packaging insert indicating that the composition can be used to treat certain conditions. As an alternative, or in addition to, manufactured articles may further include a second (or third) container that includes pharmaceutically acceptable buffer, such as water bacteriostatic agent for injection (BWFI), phosphate buffered salt, solution Ringer's and dextrose solution. Further ingredients may include other desirable from a commercial and user perspective, including buffers, diluents, filters, needles, and other syringes. It is understood that one of the articles of manufacture in above may include immunoconjugates of the invention as a substitute or in addition to anti-Cls antibodies. (Example | The following are examples of methods and compositions of the invention. It is understood that various other embodiments may be practiced, keeping in mind the general overview given above. Although the prior art has been described in detail through illustrations and examples for the purpose of clarity of understanding, descriptions and examples should not be construed as limiting scope of the invention. Disclosure of all patents and literature scientific papers cited herein are expressly incorporated into overall through reference. (Example 1) Preparation of recombinant C1r2s2 1.1. Expression and purification of human C1lr2s2 tetramer (hC1r2s2) The sequences used for expression and purification are Human C1 (NCBI Reference Sequence: NP 958850.1) (SEO ID NO: 1) and 136 Human C1lr (NCBI Reference Sequence: NP 001724.3). Human C1lr sequence includes mutations R4630 and S654A (SEO ID NO: 2). For expression recombinant human C1r2s2 tetramer, human C1 and human Clr transiently co-expressed using the HEK293 cell line (Exp1293 (registered trademark)) (Thermo Fisher, Carlsbad, CA, USA) or FreeStyle (registered trademark) 293- F cell line (Thermo Fisher, Carlsbad, CA, USA). The culture supernatant expressing recombinant human C1r2s2 diluted 3-fold with Millig water (registered trademark), Cacl» (Wako) added to it to make a final concentration of 2 mM, pH adjusted with IN NaOH to pH8, this is applied to the Column anion exchange chromatography 0 Sepharose HP (GE healthcare) equilibrated with 50 mM Tris-HCl, 2 mM Call», pH 8.0, and eluted with a NaCl gradient. The eluted fraction containing tetramer Recombinant human C1lr2s2 was collected, concentrated, and then subjected to Superdex gel filtration column (registered trademark) 200 (GE healthcare) balanced with 1x TBS (Wako), 2 mM buffer Call». Fraction containing recombinant human Cl1lr2s2 tetramer then collected, concentrated if necessary, and stored at a temperature of -80”C. 1.2. Expression and purification of the sinomolgus C1r2s2 tetramer (cyC1r2s2) The sequences used for expression and purification are C1ls sinomolgus (SEO ID NO: 3) and Clr sinomolgus. Clr sequence sinomolgus includes mutations R4630 and S6E54A (SEO ID NO: 4). For expression of recombinant sinomolgus C1r2s2 tetramer, sinomolgus Cls and Sinomolgus Clr is transiently co-expressed using HEK293 cell line (Expi293 (registered trademark)) (Thermo Fisher, Carlsbad, CA, USA). Culture supernatant expressing C1r2s2 Recombinant sinomolgus diluted 3-fold with Millid water (registered trademark), Call» (Wako) was added to it to make a final concentration of 2 mM, the pH was adjusted to IN 137 NaOH to pH8, this is applied to the exchange chromatography column anion 0 Sepharose HP (GE healthcare) equilibrated with 50 mM Tris-HCl, 2 mM Call», pH 8.0, and eluted with a NaCl gradient. Fraction eluted containing recombinant human Cl1r2s2 tetramer collected, concentrated, and then subjected to a gel filtration column. Superdex (registered trademark) 200 (GE healthcare) balanced with 1x TBS (Wako), 2 mM Bupar Call» . The fraction that containing recombinant C1r2s2 sSinomolgus tetramer then collected and stored at -80”C. (Example 2) Production of recombinant Fc gamma receptors 2.1. Production of synomolgus Fc gamma receptors (cyFcyRs) Gene of the extracellular domain of the synomolgus Fc gamma receptor constructed using methods known to the person who experts in this field and cloned the cDNA of each Fc gamma receptor from the synomolgus monkey. Amino acid sequence of The extracellular domain of the Fc gamma receptor is shown in the Table The sequence is as follows: (gamma receptor Fc sinomolgus Ia (IcyFcyRIa) is shown in SEO ID NO: 5, Fc gamma receptor sinomolgus Ilal (cyFcyRIlal) is indicated in SEO ID NO: 6, receptor gamma Fc sinomolgus Ila2 (cyFcyRIla2) is shown in SEO ID NO: 7, synomolgus Fc gamma receptor Ila3 (cyFcyRIla3) is shown in SEO ID NO: 8, Fc gamma receptor sinomolgus IIb (cyFcyRIIb)| is shown in SEO ID NO: 9, sinomolgus IIla (R) gamma Fc receptor (IcyFcyRIIlIa(R))| shown in SEO ID NO: 10, Fc gamma receptor sinomolgus IllIla (S) (cyFcyRIIlIa(S)) is shown in SEO ID NO : 11). Next, the genetic sequence encoding the His tag is attached at the 3' terminal of each gene. Each gene that obtained is inserted into an expression vector designed for expression in mammalian cells by methods known to humans who are experts in this field. The expression vector is entered into 138 FreeStyle293 cells (Invitrogen) derived from kidney cells human embryonic to express the target protein. After culture, the culture supernatant obtained in principle screened and purified with the following 4 steps. As the initial step, cation exchange chromatography was carried out using SP Sefarose FF. As a second step, chromatography was performed affinity to the His tag (HisTrap HP). As a third step, gel filtration column chromatography (Superdex200) was performed. As The fourth step, sterile screening is carried out. Protein absorbance purified at 280 nm was measured using spectrophotometer, and the concentration of purified protein determined using the calculated absorption coefficient with the PACE method (Protein Science 4:2411-2423 (1995)). 2.2. Construction of human Fc gamma receptors (hFcyRs) Genetic sequence of the extracellular domain of the Fc gamma receptor human is derived from the human Fc gamma receptor Ia (Reference Sequence NCBI: NM 000566.3), human Fc gamma receptor Ila (Reference Sequence NCBI: NM 001136219.1), human Fc gamma receptor IIb (Sequence NCBI Reference: NM 004001.3), human Fc gamma receptor Illa (Sequence NCBI Reference: NM 001127593.1), and human Fc gamma receptor IIIb (NCBI Reference Sequence: NM 000570.3). Polymorphic sites were designed with reference to the following documents (regarding receptors human gamma Fc Ila: Warmerdam, PAM and friends, 1990, J. Exp. Med. 1172:19-257 on the human Fc gamma receptor IIla: Wu, J and friends, 1997, J. Clin. Invest. 100(5):1059-1070: regarding human Fc gamma receptor IlIIb: Ory, PA and colleagues, 1989, JJ. Clin. Invest. 84:1688-1691) Amino acid sequence of the extracellular domain of the gamma receptor The Fc used for expression and purification is shown in The sequence list is as follows: (human Fc gamma receptor Ia (IhFcyRIa)| shown in SEO ID NO: 12, Fc gamma receptor 139 human Ila 16 / R (hFcyRIla 167 / R) is shown in SEO ID NO: 13, human Fc gamma receptor Ila 16 / H (hFcyIIla 167H| is shown in SEO ID NO: 14, human Fc gamma receptor IIb (hFcyRIIbJ) is shown in SEO ID NO: 15, human Fc gamma receptor TIIla 1 / 6F IhFcyRIIlIla 176F)| indicated in SEO ID NO: 16, Fc gamma receptor human Illa 176v (hFcyRIlla 176V) is shown in SEO ID NO: 17, human Fc gamma receptor IlIIb NA1I (hFcyRIlIIb NA1)| shown in SEO ID NO: 18, human Fc gamma receptor IlIb NA2 (IhFcyRIlIIb NA2) shown in SEO ID NO: 19). Next, the His tag is attached at the C terminus and each of the obtained genes was inserted into in expression vectors designed for expression in cells mammals by methods known to people skilled in This field. The expression vector is entered into the FreeStyle293 cell (Invitrogen) derived from human embryonic kidney cells for express the target protein. After culturing, the supernatant the cultures obtained are, in principle, screened and purified with the following 4 steps, or with 3 steps not included initial anion exchange chromatography step. As a first step, anion exchange chromatography was performed using 0 Sepharose Fast Flow (GE Healthcare). As a second step, affinity chromatography against the His tag using HisTrap HP (GE Healthcare). As a third step, column chromatography was performed gel filtration using HiLoad 26 / 600 Superdex 200 pg (GE Healthcare). As the fourth step, sterile screening is carried out. The absorbance of the purified protein at 280 nm was measured by using a spectrophotometer, and the protein concentration purified is determined by using the absorption coefficient which calculated by the PACE method (Protein Science 4:2411-2423 (1995)). (Example 3) Preparation of anti-Cl1s antibodies 3.1. Manufacturing of IPNOO9VHDVK3-SG1118 140 Polynucleotides from the variable regions of the heavy and light chains of anti-Cls antibodies, IPNOO9VH2 (SEO ID NO: 20) and IPNOO9VK3 (SEO ID NO: 21) (as described in the Patent Application International No. WO2019 / 098212), synthesized. Variable area These heavy and light chains are cloned into an expression vector each containing the constant region of the heavy chain SG1148 (SEO ID NO: 22) and the constant region of the SKI light chain (SEO ID NO: 23). Anti-C1 antibody IPNOO9VH2VK3-SG1148 is expressed while using Expi293 F cells (registered trademark) (Life technologies), according to the manufacturer's instructions. Antibodies recombinant purified with protein A (GE Healthcare) and eluted in D-PBS, Tris-buffered saline (TBS), or His buffer (20 mM Histidine, 150 mM NaCl, pH 6.0). Size exclusion chromatography next step is to remove heavy components high molecular weight and / or low molecular weight, if necessary 3.2. Preparation of anti-Cls antibodies with pH dependence optimized, isoelectric point, and binding ability to Fc gamma receptor, and the production of various anti-Cls antibodies To create a boosting anti-C1 sweeping antibody clearance of C1 from plasma and to achieve long-term neutralization length of C1 in the blood, 3 antibodies are made where the constant region SG1077R heavy chain with enhanced binding to FcyR (FC replacement for sinomolgus corresponding to TT9IR for humans) have been linked to each of the 3 Fabs (COS06317pHv2, C0S0637pHv3, and COS063 / pHv8 (Patent Application Japan No.: 2019-189148)) (see Table 1 for the sequence). This antibody is used to perform pharmacokinetic (PK) tests. in monkeys, however, the PK profiles for all antibodies were lower than common therapeutic antibodies, and complement activity is not can be pressed for a long time (Examples 4 and 10). COS0637pHv2- SG1017R with the lowest PK, and COS0637pHv3-SG1077R and 141 COS0637pHv8-SG1077R with slightly superior PK in comparison. COS0637pHv3-SG1077R and COS0637pHv8-SG1077R have a point lower theoretical isoelectric point (pI) compared to COS0637pHv2-SG1077R (8.176 (COS0637pHv3-SG1077R), 8.16 (COS0637pHv8-SG1017R), and 9. 21 (C0S0637pHv2-SG1077R), respectively respectively). Next, the Fab binding abilities were compared. Compared with COS0637pHv2, COS0637pHv3 and COS0637pHv8 has a stronger pH dependence (Patent Application Japan No.: 2019-189148: KD(pH5.8) / KD(pH7.4)-—141(CO0S0637pHv2), 218(COS0637pHv3), 117(COS0637 pHv8)). Thus, the inventor hypothesized that the PK of anti-Cls antibodies could be enhanced further with further increase in pH dependence and reduction of pI, and tests were performed on this hypothesis. Next, to test the effect on PK and FcyR binding, PK studies in monkeys was performed (Example 4) for COS0637pHv2-SG1077R and for COS0637pHv2-FcgSil (Tables 9 and 10), which was prepared with silencing all sinomolgus FcyR binding in CO0S0637pHv2- SG1077R. As a result, it was revealed that the PK of anti-Cls antibodies COS0637pHv2-SG1077R can be upgraded by silencing binding to FcyR. Based on the above results, it was carried out pharmacokinetic enhancement by optimizing Fab and Fc. List of antibodies and their sequence ID numbers used for monkey PK research is shown in Table 1. Next, antibody sequences COS063 / pHv8-TT9IR and COS0637pHv3-TT9IR which used as a control in determining binding as well shown in Table 1. (Table 1) Names of antibodies used in monkey PK assays and antibodies used as controls in the determination of binding, and the corresponding SEO ID NO SEO ID NO: VH VL CH CL Antibody name 142 COS0637pHv2-SG1077R 41 416 42 23 COS0637pHv2-FcgSil 41 16 43 23 COS0637pHv3-SG1077R 40 64 42 23 COS0637pHv8-SG1077R 24 63 42 23 COS0637pHv8-TT9IR 24 63 44 23 COS0637pHv3-TT9IR 40 64 44 23 For antibody optimization aimed at increasing pharmacokinetics and treatment effects, COS0637pHv8-TT9IR Fab which confirmed to have a high pH dependence (Example 5) is used as a template for looking for amino acid changes in the Fab increasing pH dependence, and to look for changes in acidity amino acids on Fc that decrease p1I and decrease binding to FCyR. First, to increase the pH dependence, amino acids COS0637pHv8 was modified to produce antibodies that shown in Table 2 has a greater pH dependence. good (correction of pH dependence is shown in Example 5). (Table 2) Names of antibodies with increasing pH dependence and SEO ID NO corresponding N SEO ID NO: and , , Rant Rant V IV Cc Cc HVR THVR TNHVR THVR | HVR | HVR Antibody | | a1 H a1 LHLHL —H1 |-H2 1 -H3 I-—L1 | -12 | -L3 COSOE3TPEV | 5g 79 2 (2 A2 los loe lam Teo le 12 15-TT91R is the same (3 COSOE3TPHV | g9 81 3 (21412 135 38 130 Who 157 I58 16-TT91R is the 13 COS063TpHV 2s to 12 82 83 25 hours 127 Who 157 (sg 17-TT91R to Is la (3 COS063TpHV 21a to 12 84 85 25 l2e 125 las las (50 21-TT9IR a57 the I3 COS063TpHV 215 to 12 7 2 1 152 4 In emngan 166 8 sb, Is las Iso (si Is2 (s3 (5 COSOE3TPHV | ag 89 3 (21412 133 I3a 135 Ise 157 Is 25-TT9IR 2 Is the I3 143 Furthermore, these antibodies, were all shown to have “displacement function / activity” or “displacement function / activity Clg”, which promotes the release of Clg from the Clgrs complex with binding of Clg and C1r2s2 complex (Clgrs complex) (Example 6) Next, the constant region of the heavy chain whose pI has been was downregulated and its binding to FcCyR was suppressed (G1A3FcgSiltLowpI) was created (Examples 7 and 8). Changes G137E, H2680, K2140, R3550, and 04195 (all according to the EU numbering system) which inserted into the native IgGl sequence lowers the pI. The L235R and L235R changes G236R inserted into the native IGgGI1 sequence suppresses binding to FCyR. Molecules whose pH dependence has been increased, pI has decreased, and the binding ability to FcyR has been pressed is produced by combining these Fab sequences and heavy chain constant region sequences (Table 3). Furthermore, this anti-Cls Fab sequence with better pH dependence can be combined with, for example, Fcs for sweep antibodies with enhanced FcyR binding such as TT9IR and SG1077R, to demonstrate higher sweeping capabilities and longer neutralizing ability of complement activity compared to antibodies with low pH dependence. (Table 3) Names of antibodies produced by combining Fab with increasing pH dependence and Fc with decreasing pl and suppressed FcyR binding, and the corresponding SEO ID NO SEO ID NO: Antibody Name | Chain Ranta1 H , VH VL CH CL COS0637pHv15- | 66 67 24 59 45 23 G1A3FcgSi1il-#-LowpI COS0637pHv16- | 68 69 36 55 45 23 G1A3FcgSi1il-#-LowpI 144 COS0637pHv17- | 10 11 24 55 45 23 G1A3FcgSi1il-#-LowpI COS0637pHv21- 12 13 24 41 45 23 G1A3FcgSi1il-#-LowpI COS0637pHv23- | 14 15 28 51 45 23 G1A3FcgSi1il-#-LowpI COS0637pHv25- 16 17 32 55 45 23 G1A3FcgSi1il-#-LowpI COS0637pHv8- - - 24 63 45 23 G1A3FcgSi1il-#-LowpI For each antibody sequence, the gene encoding it the variable region of the heavy chain (VH) is synthesized and incorporated with modified constant regions of human IgGl heavy chains (CH) (SG1l, SEO ID NO: 65), modified human IggGl CH, for example, SG1077R (SEO ID NO: 42), FcgSil (SEO ID NO: 43), TT9IR (SEO ID NO: 44), G1A3FcgSiltLowpI (SEO ID NO: 45), and SG1148 (SEO ID NO: 22). Gene encoding the variable region of the light chain (VL) synthesized and combined with the constant region of the light chain human (CL) (SKI, SEO ID NO: 23). This combined sequence was cloned into in the expression vector by a method known to the person who expert in this field. Mixed expression vectors for heavy and light chains co-inserted into HEK293 cells for antibody expression, and each antibody was purified from the culture supernatant. collected using Protein A or Protein G according to the method known to people who are experts in this field. Gel filtration then carried out as needed. (Example 4) In vivo studies for anti-Cls antibodies In vivo studies using synomolgus monkeys Concentration of endogenous antibodies and C1 in plasma after 145 administration of anti-C1 antibodies was evaluated by in vivo studies using 3-5 year old sinomolgus monkeys born in Cambodia (SNBL, Ltd.). Anti-Cls antibody was administered at a dose of 10 mg / kg using a disposable syringe and needle into the vein cephalic forearm. Administration is carried out at a rate of 0.5 mL / kg / min or 2 mL / min. In connection with COS0637pHv2-SG1077R, blood was taken before administration, 5 minutes after administration, 2 hours after administration, 8 hours after administration, 1 day after administration, 2 days after administration, 4 days after administration, / days after administration, 14 days after administration, 21 days after administration, 28 days after administration, 42 days after administration, and 56 days after administration. For other antibodies, Blood was collected further 10 days after administration. Blood collected from the femoral vein using a syringe filled with with heparin sodium. The blood is immediately cooled with ice, and then centrifuged (4”C, 1700 xg, 5 minutes or 10 minutes) for collect plasma. Deep cryogenically preserved plasma Oh deep freezer (acceptable range: -70 C or not enough). The anti-Cls antibodies given are 4 antibodies: COS0637pHv2-SG1077R, COS0637pHv3-SG1077R, COS0637pHv8-SG1077R, and COS0637pHv2-FcgSil. Measurement of antibody concentration in plasma using the method electrochemiluminescence (ECL). Concentration of COS0637pHv2-SG1077R and COS0637pHv2-FcgSil in Sinomolgus monkey plasma was measured by the ECL method. 1gG Fc antibody Anti-human mouse (SouthernBiotech, 9040-01) was dispensed into in a 96-well MULTI-ARRAY plate (Meso Scale Discovery) and left at room temperature for 1 hour for immobilization. For standard curve and sinomolgus monkey plasma samples, 100 dilution times or more is done. The standard curve is made at 0.410, 1.02, 2.56, 6.40, 16.0, 40.0, and 100 ug / mL as concentrations 146 in sinomolgus monkey plasma. After washing the plate where immobilized anti-human IgG Fc antibodies, diluted samples added to the plate, and it was stirred at room temperature for 1 hour. After the plate was washed, biotinylated anti-human IgG antibodies (Bethyl Laboratory, A80-319A) was added and stirred at room temperature. room for 1 hour. After the plate was washed, SULFO-TAG was added Streptavidin (Meso Scale Discovery) and stirred at room temperature for 1 hour. After the plate is washed, Read Buffer T (x2) (Meso Scale Discovery) is immediately added to the plate and the signal is detected. using the SECTOR Imager 2400 (Meso Scale Discovery). Concentration each antibody is calculated using software SOFTmax PRO (Molecular Devices) analysis based on curve signals standard. Changes in antibody concentration in plasma that obtained by current measurements is shown in Figure 1-1. Measurement of antibody concentration in plasma by chromatography high performance liquid-electron spray ionization-mass spectrometry tandem (LC / ESI-MS / MS) Concentration of COS0637pHv3-SG1077R and C0S0637pHv8-SG1077R in the plasma of sinomolgus monkeys was measured by LC / ESI-MS / MS. The curve standards are made at 0.781, 1.56, 3.13, 6.25, 12.5, 25.0, and 50 ug / mL as the plasma concentration of sinomolgus monkeys. Two microliters standard curve and plasma samples were added to 50 uL beads magnetic where antibodies specifically bind COS0637pHv3-8G1077R or COS0637pHv8-SG1077R immobilized (Magnosphere MS300 / Low Carboxyl, JSR), and shaken at 25 ”C for 1.5 hours. The magnetic beads in the sample were washed 3 times. with 0.2 mL PBS containing 0.058 Tween 20, then washed with 0.2 mL PBS. Magnetic beads were suspended in 24 jL 50 mmol / L ammonium bicarbonate containing 7.5 mol / L urea, 8 mmol / L dithiothreitol and 0.1 yug / mL lysozyme (chicken egg white), then shaken at a temperature of 56”C for 45 minutes. . Next, 2 147 UL 500 mmol / L iodoacetamide was added, and this was shaken at room temperature. 37”C for 30 minutes while blocking the light. Next, 160 uL of 50 mmol / L ammonium bicarbonate containing 0.5 yug / mL trypsin modified sequencing quality (Promega) added. The sample was shaken at 37”C for 16 hours, then the reaction stopped by adding 5 juL of trifluoroacetic acid 108. Five Ten microliters of the digested enzyme sample was used for analysis with LC / ESI-MS / MS. Xevo TO-S triple instrument guadrupole (Waters) connected to UPLC class I (Waters) used for LC / ESI-MS / MS analysis. Antibody specific peptides anti-C1 NOVSLTC (Carbamidomethyl)LVK detected by monitoring selected reactions (SRM). The SRM transitions are as follows: ion parent anti-C1ls antibody (Mt2H)J2 (m / z 581.3), daughter ion y' ion (m / z 820.4). The internal calibration standard curve was prepared by regression. linear weighted 1 / x?2 using concentration and peak area. Antibody concentrations in the plasma of sinomolgus monkeys were calculated. using Masslynx Ver.4.1 (Waters) analysis software. Changes in antibody concentration in plasma obtained by current measurements are shown in Figure 1-1. Measurement of endogenous C1s concentration in plasma with high performance liquid chromatography-electron spray ionization- tandem mass spectrometry (LC / ESI-MS / MS) The concentration of C1 in the plasma of sinomolgus monkeys was measured by LC / ESI-MS / MS. Standard curves were generated at 0.477, 0.954, 1.91, 3.82, 1.63, 15.3, and 30.5 yug / mL as the sinomolgus Cls concentrations in plasma, by diluting C1r2s2 sinomolgus with mouse plasma. Sinomolgus monkey plasma samples were diluted 5-fold. using mouse plasma. Two microliters of standard curve and sample plasma was mixed with 26 uL of a 50 mmol / L ammonium chloride solution. bicarbonate (7.5 mol / L urea / 100 mmol / L dithiothreitol / 10 ng / mL lysozyme (chicken egg white) / 100 mg / mL human C1s -— 20 / 2 / 2 / 2), 148 then shaken at 56”"cC for 45 minutes. C1 human used as an internal standard. Furthermore, 2 UL 500 mmol / L iodoacetamide was added, and shaken at 37”C for 30 minutes while blocking light. Next, 160 uL of 50 mmol / L ammonium bicarbonate containing 0.5 uyug / mL trypsin modified sequencing quality (Promega) added. Samples shaken at 37°C for 16 hours, then the reaction was stopped by adding 5 uL of trifluoroacetic acid 108. Fifty microliters of digested enzyme sample were used for analysis. with LC / ESI-MS / MS. Xevo TO-S triple quadrupole instrument (Waters) connected to the UPLC class I (Waters) is used for LC / ESI-MS / MS analysis. Cls sinomolgus specific peptide LLEVPEAR detected by selected reaction monitoring (SRM). SRM transition is as follows: the parent ion of the anti-Cls antibody (Mt2H) 2 (m / z 463.8), daughter ion y$ ion (m / z 700.4). Calibration standard curve internal is made with weighted linear regression 1 / x? using concentration and peak area. Cls concentration in monkey plasma Sinomolgus was calculated using Masslynx analysis software. Ver.4.1 (Waters). Changes in Cls concentration in plasma obtained by current measurements are shown in Figure 1-2. pH-dependent effects and FcyR-silenced antibodies on anti-C1ls antibody concentration and complement inhibitor activity in synomolgus monkeys Three anti-Cls antibodies (C0OS0637pHv2-, COS0637pHv3-, and COS0637pHv8-SG1077R) has Fcs with changes that increased binding to monkey FcyRIlIa and FcyRIIb reduced Cls concentration in plasma is 18.98 to 26.48 maximum 2 days after administration compared to before administration (Figure 1-2). However, these antibodies disappear more quickly compared to conventional therapeutic Ig6G antibodies (Figure 1-1), and along with the decrease in antibody concentration in plasma 149 After 14 days post-administration, the total Cl concentration was observed. increased again. However, on COS0637pHv3- and COS0637pHv8-SG1077R with better pH dependence on binding antigen, an increase in PK antibodies was observed compared to COS0637pHv2-SG1077R. This indicates that the activity complement inhibition achieved by administration of COS0637pHv3- and COS0637pHv8-SG1077R lasted for 14 days and 21 days post administration, while that achieved by administration COS0637pHv2-SG1077R lasts up to 7 days after administration. And thus, long-term antigen neutralization and complement inhibition by COS0637 / pHv3- and COS0637pHv8-SGL0OT7R shown (Figure 4). Meanwhile, anti-Cls antibodies that have Fcs with changes that reduce binding to monkey FcCyRs, COS0637pHv2-FcgSil, showed good PK compared with antibodies with changes to increase binding to FcyRIla and FcyRIIb of monkeys (Figure 1-1). Inhibitory activity complement achieved by administration of COS0637pHv2-FcgSil lasts up to 14 days after administration (Figure 4). Concentration total C1 achieved by administering CO0S0637pHv2-FcgSil was only decreased to a maximum of 75.58 compared to before administration (Figure 1-2): however, due to the increase in PK, compared to COS0637pHv2-SG1077R, long-term antigen neutralization and complement inhibitory activity was demonstrated. (Example 5) Determination of binding under different pH conditions using Biacore (registered trademark) The binding properties of each sample at pH7.4 and pH€6.0 determined at 37 "C using BIACORE (trademark registered) T200 instrument (Cytiva). First, the anti-C1lr2s2 antibody human IPNOO9SVH2Vk3-SG1148 (IPNOO9) immobilized onto all cells 150 CM5 sensor chip flow using Amine Coupling Kit, type2 (Cytiva). 20 mM ACES, 150 mM NaCl, 1.2 mM CaCl», 1 mg / mL BSA (not contains 1gG), 1 mg / mL CMD, 0.058 Tween (registered trademark) 20, 0.005 $w / v NaN3, pH7.4 or pH6.0 buffer was used as running buffer. Next, recombinant human C1r2s2 tetramer (hC1r2s2) and recombinant sinomolgus Cl1r2s2 tetramer (cyC1r2s2), designed to have a binding response of 100 Resonance Units (RU), captured on the sensor surface by IPNOO9. Antibody solution added to it at a rate of 30 uL / min for 120 seconds, the running buffer is then added at a rate of 30 IL / min for 180 seconds, and the dissociation constant (Kp) of each each antibody for hClr2s2 and cyClr2s2 was calculated. For to calculate the Kp value at pH 7.4, the antibody solution was diluted with running buffer pH / .4 to make 0, 0.8, 1.6, 3.1, 6.3, 13 nM injected, and to calculate the xp value at pH6.0, the solution antibodies were made with running buffer pH6.0 to make 0, 6.3, 12.5, 25, 50, 100 nM were injected. The sensor surface was regenerated. each cycle, using 3 M MgCl» (homemade). The Kp value calculated using BIACORE evaluation software (brand registered trademark) T200 version 2.0 (Cytiva). Binding strength at each pH condition compared by dividing the Kr value by pH6.0 with a Kp value at pH7.4. (Table 4) (Table 4) Binding activity of human C1r2s2 antibody in acidic conditions and neutral conditions hC1r2s2 KD 1 / 5 K H6.0 Antibody Name (mol / L) b (p » / pH6.0 pH7.4 Kp (pHT,4) 2, 49E-— COS0637pHv8-TT9IR 1.25E-08 10 50.2 3, 88E- COS0637pHv3-TT9IR 1.03E-08 19 26.5 3.99E- COS0637pHv15-G1A3FcgSiltLowp1I | 3.18E-07 / 10 191.0 151 1.81E- COS0637pHv1e-G1A3FcgSiltLowpI | 2.92E-08 10 161.3 2, 30E- COS0637pHv17 / -G1A3FcgSiltLowp1I | 3.29E-08 10 143.0 2, 60E- COS0637pHv21-G1A3FcgSiltLowp1I | 3.13E-08 10 120.4 | 2.49E- COS0637pHv23-G1A3FcgSil-#LowpI | 2.14E-08 10 110.0 1,98E- COS06317pHv25-G1A3FcgSiltLowp1I |2.13E-08 10 107.6 | 2, 12E- COS06317pHv8-G1A3FcgSil-LowpI 1.93E-08 10 11.0 The KD values ​​against human Cl1lr2s2 at pH6.0 and pH7.4 were calculated using Biacore, and the ratio of the KD value at pH 6.0 to the value KD at pH7.4 is shown (Table 5) Binding activity of sinomolgus Clr2s2 antibody in acidic conditions and neutral conditions cyC1r2s2 KD L / LK Antibody Name (mo1 / L) » (pH6.0) / pH6.0 pH7.4 Kp (pH7.4) ,45E- COS0637pHv8-TT9IR 2.33E-08" ? 61.5 5.02E- COS0637pHv3-TT9IR 2.20E-08 10 43.8 4, 928 - COS0637pHv15-G1A3FcgSil-#LowpI (1.11E-07 10 225.6 1.96E- COS0637pHv1e-G1A3FcgSiltLowp1I |9.12E-08 10 165.3 2, 52E- COS0637pHv17-G1A3FcgSil-#LowpI | 1.06E-07 10 420.6 3, 46E- COS0637pHv21-G1IA3FcgSil-LowpI | 6.29E-08 10 181.8 3, 34E- COS0637pHv23-G1IA3FcgSiltLowpI |4.63E-08 10 138, 6 | 2.43E- COS06317pHv25-G1A3FcgSiltLowpI | 6.71E-08 10 216.1 3.65E- COS0637pHv8-G1A3FcgSil-LowpiI 3.03E-08 10 83.0 152 The KD values ​​for monkey Cl1r2s2 at pH6.0 and pH / .4 were calculated. using Biacore, and the ratio of KD values ​​at pH 6.0 is shown against the KD value at pH 7.4. (Example 61 Evaluation of anti-Cls antibodies for Cl1g transport function The antibody transfer function is shown at a temperature of 37”C with the C1r2s2 capture method using BIACORE (trademark registered) T200 instrument (Cytiva). Anti-human C1lr2s2 antibody IPNOO9VH2Vk3-SG1148 was immobilized onto the CM5 sensor chip using Amine Coupling Kit, type2 (Cytiva). Antibody, Cl1r2s2 tetramer recombinant human (hC1r2s2), and native human Clg (CompTech, hClg) was prepared with running buffer pH 1.4 (20 mM ACES, 150 mM Nacl, 1.2 mM CaC12, 1 mg / mL, BSA (does not contain Ig6), 1 mg / mL CMD, 0.058 Tween (registered trademark) 20, 0.005 $8b / v NaN3 pH7.4). First, hC1lr2s2 is captured on the sensor surface by IPNOO9VH2Vk3-SG1148. As a catch amount, 200 units resonance (RU) is directed. Next, hClg diluted with running buffer to make 100 nM injected, and immediately After that, the antibody solution was diluted with running buffer up to 500 nM was injected at 10 nL / min for 1500 seconds. The sensor surface is regenerated every cycle, using 3 M MgCl» (homemade). The results are shown in Fig. 2-1 up to 2-14. Sensorgrams were obtained using the device BIACORE evaluation software (registered trademark) T200, version 2.0 (Cytiva). The solid line shows the sensorgram obtained when hClg is injected into hClr2s2 and then buffer is injected (C1r2s2tC19), and reflects the formation of the Clgrs complex on the surface of the sensor chip (below referred to as sensorgram 1). The dotted line shows the obtained sensorgram. when hClg is injected into hClr2s2 and then antibodies injected (C1r2s24tClgtAb), and reflects the effect of the antibody on 153 Clgrs complex on the surface of the sensor chip (hereinafter referred to as as sensorgram 2). The dotted line shows the sensorgram which is obtained when hClg is not injected into hC1r2s2 and only injected antibody (C1r2s2-#Ab), and depicts antibody binding to hC1r2s2 only on the surface of the sensor chip (below referred to as sensorgram 3 ). Fig. 2-1 to 2-14 shows sensorgrams 1 to 3. For comparison In this sensorgram, the Cl1r2s2 binding response is normalized as 100 RU. Anti-C1 antibodies bind to Clgrs, and thus, from the time point after the addition of Clg, the sensorgram response increases when antibodies are added. In relation to antibodies C1ls which does not have the Clg shift function, from the point in time after the addition of Clg, the sensorgram response increased when antibodies were added, and the response units were almost unchanged at when the addition of antibodies is stopped (Citation: Patent Application International No. WO 2019198807, Image. 2A, C0S0583). In relation to antibodies that have a transfer function Clg, from the time point after the addition of Clg, the sensorgram response increased when antibodies were added: however, the response units in When stopping the addition of antibodies is lower than the unit response when only Bupar is added after Clg addition, or the degree of decrease in response units at the time of termination increase in antibodies over time immediately after the start of increase. the increase in antibodies is greater than the rate of decrease when only buffer is added. With respect to sensorgram 3 in Figures 2-1 to 2-14, each Ab is considered to bind C1lr2s2? stably without the presence of Clg. In sensorgram 1, Clg is stably bound to C1r2s2 in the absence of Ab. In addition, in most antibodies, response units at the time of cessation of antibody addition in sensorgram 2 is lower than in sensorgram 1, and at 154 some antibodies, the level of response unit decline at the time cessation of addition compared to immediately after. addition antibodies in sensorgram 2 are greater than the degree of reduction sensorgram 1. The results above show that all antibodies that modified to separate Clg from the Clgrs complex. (Example 7) Evaluation of anti-Cls antibodies for isoelectric point (pI) 4.1. Measurement of the isoelectric point of anti-C1s antibody (pl) using capillary isoelectric focusing (cIEP) Maurice (Protein simple) is used with capillary cartridges. to perform cIEF. The anolyte and catholyte used are 0.08 M phosphate containing 0.1 S&w / v methylcellulose (MC) and 0.1 M sodium hydroxide each containing 0.1 $w / v MC. All samples analyzed contained 0.2 mg / mL of antibodies. function, MC 0.358 w / v, IDA (iminodiacetic acid) 6.0 mM, arginine 10 mM, pI marker 0.5 $Sb / v 5.85 and marker pI 0.5 $#b / v 9.99, and 2 Svol pharmalyte 8-10.5 and 2 Svol pharmalyte 5-8. All samples vortexed and centrifuged briefly before being placed in automatic sampling compartment. The sample is centered on 1.5 kV condition for 1 minute followed by 3.0 kV each time each for 7 minutes. Automatic sampling compartment stored at a temperature of 10”C. The measurement was repeated 2 times for each each sample, and the pI value is obtained by calculating the average n — 2 measurements. The calculated pI values ​​are shown in Table 6. (Table 6) Measurement of pI of each anti-Cls antibody have Fcs with decreased pI and suppressed binding to FcCyRs Antibody Name pI (Average of n2 measurements) COS0637pHv8-TT9IR 9.0 COS0637pHv8-G1A3FcgSil#tLowpI 1,1 155 COS0637pHv15-G1A3FcgSil-LowpI 1.5 COS0637pHv16-G1A3FcgSil-LowpI 1.8 COS0637pHv17-G1A3FcgSil-LowpI 1.8 COS0637pHv21-G1A3FcgSil-LowpI 1.6 COS0637pHv23-G1A3FcgSil-LowpI 1.6 COS0637pHv25-G1A3FcgSil-LowpI 1.8 The PI of each antibody was measured using Maurice (Simple proteins) are shown. The pI value is the average of the values obtained by two measurements. (Example 8) Confirmation of binding to FcyR The binding properties of each sample to FcyR on pH7.4 was determined at 25 “C using BIACORE (trademark registered) T200 instrument (Cytiva). First, protein L (BioVision) immobilized onto all CM4 sensor chip flow cells using Amine Coupling Kit, type 2 (Cytiva). Phosphate buffer 50 mM (pH 71.4) contains 150 mM NaCl, 0.058 Tween (registered trademark) 20 used as a running buffer, and antibodies with a response bindings created up to 500 RU or 2000 RU captured on surface sensors. Human and monkey FcyR diluted with running buffer is injected into it and the amount bound with antibodies measured. hFcyRIa and cyFcyRIa were diluted to 8 nM, and the remainder was diluted to 1000 nM. The sensor surface was made repeat each cycle, using 10% glycine hydrochloride solution mM, pH1.5 (self-made). From the measurement results obtained, The number of FcyR bindings divided by the number of bindings of each each antibody captured (Binding / capture) is calculated by using the T200 BIACORE evaluation software (brand registered trademark), version 2.0 (Cytiva) (Table 7 and Table 9). Next, from these results, the Binding / capture value for Other specimens are shown in the tables (Table 8 and Table 10), where 156 Binding / capture values ​​were obtained with Herceptin (Chugai Pharmaceutical Co., Ltd.) (human IgGl / kappa) is designated as 1. 5 (Table 7) Response value per 1 RU of antibody captured against Human FcyR hFc (hFcy IhFcy IhFc IhFcy IhFcy (hFc IhFc YR RR YR R Rs YR YR la Ila |Ila |IIb | IIIa | IIIA | III TII 167 167 17 17 bN IbN HR 6F 6V Al A2 hFcyRs Herseptin 0,210.06 10.05 10,010.04 10.10 (0.0 10.0 (pengik 0 1 1 2 atan / cOS0637pHv 10.0 10.00 10.00 10.0 10.00 10.00 10.0 10.0 catch |8- 0 0 0 0 an) G1A3FcgSil #Lowpl Calculated binding / capture values ​​for human FcyR using Biacore is indicated. (Table 8) Relative binding to human FcyRs hFc (IhFcyR (hFc IhFc IhFcy IhFcy (hFc (hFc YR Ila 1 | YR YR R Rs YR YR Ia 67H Ila IIb |IIIa | IIIA | III III 16 217 217 bN IbN 1R 6F 6V Al A2 NFCYRS T erseptin (HO T1.00 (PO (RO 001.00 (V8 (0 (value 0 0 0 0 0 relatively from COS0637pHv fan | 8- 1 0.01 lo,o To,ol- N o,1 |o,o tan / G1A3FcgSil | 0 1 g 0.05 |0.02 » 7 catch | #Lowpl an) From the calculated Binding / capture values ​​for human FcyR using Biacore, the relative binding of the antibody was moderate 157 developed against Herceptin is calculated. (Table 9) Response value per 1 RU of antibody captured against FcyRs sinomolgus CyFc CyFc cyFc |cyFrc IcyFrc IcyFrc | cyFc RRRRR YR YR YYYYY Illa IIla Ta ITJal |IIa2 |IIa3 |IIb (R) (S) Herseptin 0.22 10.02 10.02 10.01 10.03 10.12 0.13 COS0637pHv8 FcyR N 0.00 (0.00 10.00 10.00 10.00 10.00 0.00 CY CAS G1A3FcgSil- (tie LowplI tan / COS0637pHv2 catch n) - 0.02 (0.05 10.05 10.03 10.08 10.01 0.01 SG1077R COS0637pHv2 | Pr 0.00 (0.00 10.00 10.00 10.00 10.00 0.00 —-FcgSil Calculated binding / capture values ​​for monkey FcyR using Biacore is indicated. (Table 10) Relative binding to sinomolgus FcyRs CyFc CyFc cyFc |(cyFc |cyFrc 1cyFc | cyFrc ng Y ng Y RRRRR YYYYY IIIla( |IIIlal Ta IJal |Ila2 |Ila3 |(IIb R) S) Herseptin 1.00 11.00 11.00 (1.00 11.00 11.00 1.00 cyFcyRs |cC0S0637pHv8 Mark - - - - - (Value | 0.00 -0.01 | -0.01 relative |G1A3FcgSil- 0.01 10.04 (0.09 10.01 from LowpiI binder | COS0637pHv2 tan / — 0.07 12.16 12.55 14.47 12.14 10.07 0.08 catch | SG1077R an COS0637pHv2 — — | | Pr 0.00 10.00 0.00 | -0.0O1 / -0.01 -FcgSil 0.02 10.06 From the Binding / capture values ​​for monkey FcyR that is counted 158 using Biacore, the relative binding of the antibodies being developed against Herceptin is calculated. (Example 9) In vivo studies using synomolgus monkeys The research was conducted using a method similar to Example 4. The anti-Cls antibodies given are 2 antibodies, COS0637pHv16-G1A3FcgSil-LowpI and COS0637pHv21-G1IA3FcgSil-LowpI. Measurement of antibody concentration in plasma by chromatography high performance liquid-electron spray ionization-mass spectrometry tandem (LC / ESI-MS / MS) Concentration of COS0637pHv16-G1A3FcgSil-LowpI and COS0637pHv21- G1A3FcgSilt-LowpI1I in the plasma of sinomolgus monkeys was measured by LC / ESI-MS / MS. Standard curves were generated at 0.781, 1.56, 3.13, 6.25, 12.5, 25.0, and 50 ug / mL as monkey plasma concentrations sinomolgus. Two microliters of standard curve and plasma sample added to 50 juL of magnetic beads where the antibodies are specifically binds COS0637pHv16-G1A3FcgSiltLowpI or COS0637pHv21-G1A3FcgSiltLowpiI immobilized (Magnosphere MS$S300 / Low Carboxyl, JSR), and after centrifugation it was shaken at a temperature of 25 “C for 1.5 hours. The magnetic beads on the sample were washed 3 times with 0.2 mL PBS containing 0.058 Tween 20, then washed with 0.2 mL PBS. Magnetic beads suspended in 24 uL of 50 mmol / L ammonium bicarbonate contains 7.5 mol / L urea, 8.3 mmol / L dithiothreitol and 0.083 ug / mL, lysozyme (chicken egg white), and shaken at 56°C for 45 minutes. minutes. Next, 2 uL of 500 mmol / L iodoacetamide was added, and This was shaken at 37”C for 30 minutes while blocking light. Next, 160 uL of 50 mmol / L ammonium bicarbonate was added. contains 0.5 yug / mL sequencing quality modified trypsin (Promega) was added. The samples were shaken at 37”C overnight, 159 and then the reaction was stopped by adding 5 uL of acid trifluoroacetate 108. Fifty microliters of the enzyme sample were digested used for analysis by LC / ESI-MS / MS. Instrument Xevo TO-S triple guadrupole (Waters) connected to UPLC class I (waters) was used for LC / ESI-MS / MS analysis. Peptides specific anti-Cl1ls antibodies GPSVFPLAPSSR were detected by monitoring selected reactions (SRM). The SRM transitions are as follows: ion parent anti-Cls antibody (Mt2HJ 2? (m / z 607.8), daughter ion y ' ion (m / z 121.4). The internal calibration standard curve was made by regression linear weighted 1 / x? using concentration and peak area. Antibody concentrations in the plasma of sinomolgus monkeys were calculated. using Masslynx Ver.4.2 (Waters) analysis software. Changes in antibody concentration in plasma obtained by current measurements are shown in Figure 3-1. Measurement of endogenous C1s concentration in plasma with high performance liquid chromatography-electron spray ionization- tandem mass spectrometry (LC / ESI-MS / MS) The concentration of C1 in the plasma of sinomolgus monkeys was measured by LC / ESI-MS / MS. Standard curves were generated at 0.477, 0.954, 1.91, 3.82, 1.63, 15.3, and 30.5 ug / mL as Cls concentrations in plasma sinomolgus monkeys, by diluting sinomolgus Cl1r2s2 with Mouse plasma. Sinomolgus monkey plasma samples were diluted 5 times fold using mouse plasma. Two microliters of standard curve and plasma samples were mixed with 26 uUL of a 50 mmol / L mixed solution ammonium bicarbonate (71.5 mol / L urea / 100 mmol / L dithiothreitol / 10 hg / mL lysozyme (chicken egg white) / 300 mg / mL human C1s2r2 - 20 / 2 / 2 / 2), then shaken at 56"C for 45 minutes. CI1 human was used as an internal standard. Next, 2 pL of 500 mmol / L iodoacetamide was added, and it was shaken at 37°C. for 30 minutes while blocking the light. Next, 160 pL of 50 mmol / L ammonium bicarbonate containing 0.5 ug / mL trypsin 160 modified sequencing quality (Promega) added. The sample was shaken at 37”C for 16 hours, then the reaction stopped by adding 5 juL of trifluoroacetic acid 108. Five Ten microliters of the digested enzyme sample was used for analysis with LC / ESI-MS / MS. Xevo TO-S triple instrument guadrupole (Waters) connected to UPLC class I (Waters) used for LC / ESI-MS / MS analysis. Cls specific peptides sinomolgus LLEVPEAR is detected by monitoring selected reactions (SRM). The SRM transition is as follows: the parent ion of the antibody anti-C1ls (Mt2H)| 2 (m / z 463.8), child ion y Zion (m / z 700.4). Curve internal ca...

Claims

1. Isolated antibodies that cover the antigen-binding region and constant antibody region, where the antibody promotes the dissociation of Clg from the Clgrs complex and / or inhibits the binding of Clg to C1r2s2, and where the antigen binding region includes the HVR-HIl combination, HVR-H2, HVR-H3, HVR-Ll, HVR-L2, and HVR-L3 were selected from the group consisting of 1) to 6) below: 1) HVR-H1I, HVR-H2, HVR-H3, HVR-LI1, HVR-L2, and HVR-L3 which includes amino acid sequence consisting of SEO ID NO: 25, 26, 21, 60, 61, and 62, respectively: 2) HVR-H1, HVR-H2, HVR-H3, HVR-LI, HVR-L2, and HVR-L3 which include amino acid sequence consisting of SEO ID NO: 37, 38, 39, 56, 57, and 58, respectively: 3) HVR-H1, HVR-H2, HVR-H3, HVR-LI1, HVR-L2, and HVR-L3 which includes amino acid sequence consisting of SEO ID NO: 25, 26, 21, 56, 57, and 58, respectively: 4) HVR-H1l, HVR-H2, HVR-H3, HVR- Ll, HVR-L2, and HVR-L3 includes the amino acid sequence consisting of SEO ID NO: 25, 26, 21, 48, 49, and 50, respectively: 5) HVR-H1, HVR-H2, HVR-H3, HVR-LI1, HVR-L2, and HVR-L3 which includes amino acid sequence consisting of SEO ID NO: 29, 30, 31, 52, 53, and 54, respectively: and 6) HVR-H1, HVR-H2, HVR-H3, HVR-LI1, HVR-L2, and HVR-L3 which includes amino acid sequence consisting of SEO ID NO: 33, 34, 35, 56, 57, and 58, respectively.

2. The antibody of claim 1, wherein the antibody covers a region heavy chain variable (VH) and light chain variable (VL) regions selected from the group consisting of 1) to 6) below: 216 1) VH and VL which include amino acid sequences consisting of SEO ID NO: 24 and 59, respectively: 2) NH and VL which include amino acid sequences consisting of SEO ID NO: 36 and 55, respectively: 3) VH and VL which include amino acid sequences consisting of SEO ID NO: 24 and 55, respectively: 4) VH and VL which include amino acid sequences consisting of SEO ID NO: 24 and 47, respectively: 5) VH and VL which include amino acid sequences consisting of SEO ID NO: 28 and 51, respectively: and 6) VH and VL which include amino acid sequences consisting of SEO ID NO: 32 and 55, respectively.

3. The antibody of claim 1 or 2, wherein the ratio of the KD values ​​in acidic pH range to KD value in the neutral pH range, the ratio Acid KD / neutral KD, is 107 or more.

4. Antibodies of any one of claims 1 to 3, wherein antigen binding region can specifically bind to CUBI1-EGF-CUB? domain of human C1.

5. Antibodies of any one of claims 1 to 4, wherein antibodies have a mutant constant region that covers at least one amino acid change that decreases binding activity Fcy receptor.

6. The antibody of claim 5, wherein the mutant constant region comprises amino acid change in at least one of positions 235 and 236 according to EU numbering.

1. Antibodies of any one of claims 1 to 6, wherein antibodies have a mutant constant region that covers at least 241 one amino acid change, and where the amino acid change is lowering the isoelectric point (pIl) of the constant region of the mutant compared to that of the parent constant area.

8. Antibodies of claim / , wherein the mutant constant region includes amino acid changes in at least one of positions 137, 268, 214, 355, and 419 according to EU numbering. 9, Antibodies of any one of claims 1 to 8, wherein pI is 7.8 or less.

10. Antibodies of any one of claims 1 to 8, wherein the constant region includes the constant region of the heavy chain which includes amino acid sequence consisting of SEO ID NO: 45 and the region light chain constants that include amino acid sequences consisting of from SEO ID NO:

23.

11. Antibodies that have binding activity on Cl, where antibodies include combinations of HVR-Hl, HVR-H2, HVR-H3, HVR-Ll, HVR- L2, and HVR-L3 selected from a group consisting of 1) to 6) below: 1) HVR-H1I, HVR-H2, HVR-H3, HVR-LI1, HVR-L2, and HVR-L3 which includes amino acid sequence consisting of SEO ID NO: 25, 26, 21, 60, 61, and 62, respectively: 2) HVR-H1, HVR-H2, HVR-H3, HVR-LI, HVR-L2, and HVR-L3 which include amino acid sequence consisting of SEO ID NO: 37, 38, 39, 56, 57, and 58, respectively: 3) HVR-H1, HVR-H2, HVR-H3, HVR-LI1, HVR-L2, and HVR-L3 which includes amino acid sequence consisting of SEO ID NO: 25, 26, 21, 56, 57, and 58, respectively: 4) HVR-H1l, HVR-H2, HVR-H3, HVR- Ll, HVR-L2, and HVR-L3 includes the amino acid sequence consisting of SEO ID NO: 25, 26, 218 21, 48, 49, and 50, respectively: 5) HVR-H1, HVR-H2, HVR-H3, HVR-LI1, HVR-L2, and HVR-L3 which includes amino acid sequence consisting of SEO ID NO: 29, 30, 31, 52, 53, and 54, respectively: and 6) HVR-H1, HVR-H2, HVR-H3, HVR-LI1, HVR-L2, and HVR-L3 which includes amino acid sequence consisting of SEO ID NO: 33, 34, 35, 56, 57, and 58, respectively.

12. The antibody of claim 11, wherein the antibody covers a region heavy chain variable (VH) and light chain variable (VL) regions selected from the group consisting of 1) to 6) below: 1) VH and VL which include amino acid sequences consisting of SEO ID NO: 24 and 59, respectively: 2) NH and VL which include amino acid sequences consisting of SEO ID NO: 36 and 55, respectively: 3) VH and VL which include amino acid sequences consisting of SEO ID NO: 24 and 55, respectively: 4) VH and VL which include amino acid sequences consisting of SEO ID NO: 24 and 47, respectively: 5) VH and VL which include amino acid sequences consisting of SEO ID NO: 28 and 51, respectively: and 6) VH and VL which include amino acid sequences consisting of SEO ID NO: 32 and 55, respectively.

13. The antibody of claim 11 or 12, wherein the constant region antibodies encompass the constant region of the H chain which includes the sequence amino acids consisting of SEO ID NO: 45 and constant region L chain which includes the amino acid sequence consisting of SEO ID NO:

23.

14. Antibodies containing heavy chains (H chains) and chains light (L chain) is selected from the group consisting of 1) to 219 6) below: 1) H chain and L chain which include the amino acid sequences that each consisting of SEO ID NO: 66 and 61: 2) H chain and L chain which include the amino acid sequences that each consisting of SEO ID NO: 68 and 69: 3) H chain and L chain which include the amino acid sequences each consisting of SEO ID NO: 70 and 71: 4) H chain and L chain which include the amino acid sequences that each consisting of SEO ID NO: 72 and 73j 5) H chain and L chain which include amino acid sequences that each consisting of SEO ID NO: 74 and 1 / 5: and 6) H chain and L chain which include amino acid sequences that each consisting of SEO ID NO: 76 and 77.