Antibodies and uses thereof

Abstract

Provided herein are antibodies and uses thereof.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 63 / 145,348, filed February 3, 2021, the entire contents of which are incorporated herein by reference.

[0002] The present disclosure relates to the field of biotechnology, and more particularly to antigen-binding molecules such as antibodies. [Background technology]

[0003] Antibody-drug conjugates have been engineered to address a variety of diseases. One particular advantage of this approach is their ability to have cytostatic or cytotoxic effects. Despite many years of development, improvements in antibody-drug conjugates are desirable. Summary of the Invention [Means for solving the problem]

[0004] The present invention is based on the concept that it is possible to generate antibodies that exhibit improved efficacy (e.g., one or more of increased (e.g., detectable increase) toxin release in target mammalian cells, increased (e.g., detectable increase) killing of target mammalian cells, and increased (e.g., detectable increase) endolysosomal delivery).

[0005] Provided herein is an antibody comprising: (a) a heavy chain variable domain and a light chain variable domain, each of which comprises: (i) SEQ ID NO:5 and SEQ ID NO:6, respectively; (ii) SEQ ID NO:7 and SEQ ID NO:8, respectively; (iii) SEQ ID NO:9 and SEQ ID NO:10, respectively; (iv) SEQ ID NO:11 and SEQ ID NO:12, respectively; (v) SEQ ID NO:13 and SEQ ID NO:14, respectively; (vi) SEQ ID NO:15 and SEQ ID NO:16, respectively; (vii) SEQ ID NO:17 and SEQ ID NO:18, respectively; (viii) SEQ ID NO:19 and SEQ ID NO:20, respectively; (ix) SEQ ID NO:21 and SEQ ID NO:22, respectively; (x) SEQ ID NO:23 and SEQ ID NO:24, respectively; (xi) SEQ ID NO:25 and SEQ ID NO:26, respectively; (xii) SEQ ID NO:27 and SEQ ID NO:28, respectively; (xiii) SEQ ID NO:29 and SEQ ID NO:30, respectively; (xiv) SEQ ID NO:31 and SEQ ID NO:32, respectively; (xv) each of which comprises: and (b) a heavy chain variable domain and a light chain variable domain selected from the group consisting of SEQ ID NO: 33 and SEQ ID NO: 34, and (c) a heavy chain CH1-CH2-CH3 sequence of SEQ ID NO: 155 or SEQ ID NO: 189, comprising one or more of: (i) a lysine to cysteine ​​substitution at amino acid position 105 and a deletion of threonine at amino acid positions 106 and 108; (ii) a methionine to tyrosine substitution at amino acid position 135, a serine to threonine substitution at amino acid position 137, and a threonine to glutamic acid substitution at amino acid position 139; (iii) a methionine to leucine substitution at amino acid position 311 and an asparagine to serine substitution at amino acid position 317; and / or a light chain CH1-CH2-CH3 sequence of SEQ ID NO: 157. L Light chain C of SEQ ID NO: 157, which contains a valine to cysteine ​​substitution at amino acid position 98. L The present invention provides an antibody comprising the sequence:

[0006] In some embodiments of any of the antibodies described herein, the heavy chain CH1-CH2-CH3 sequence of SEQ ID NO: 155 or SEQ ID NO: 189 comprises a lysine to cysteine ​​substitution at amino acid position 105 and a deletion of threonines at amino acid positions 106 and 108. In some embodiments of any of the antibodies described herein, the antibody comprises heavy and light chain sequences selected from the group of: (i) SEQ ID NO:35 and SEQ ID NO:41, respectively; (ii) SEQ ID NO:43 and SEQ ID NO:49, respectively; (iii) SEQ ID NO:51 and SEQ ID NO:57, respectively; (iv) SEQ ID NO:59 and SEQ ID NO:65, respectively; (v) SEQ ID NO:67 and SEQ ID NO:73, respectively; (vi) SEQ ID NO:75 and SEQ ID NO:81, respectively; (vii) SEQ ID NO:83 and SEQ ID NO:89, respectively; (viii) SEQ ID NO:91 and SEQ ID NO:97, respectively; (ix) SEQ ID NO:99 and SEQ ID NO:105, respectively; (x) SEQ ID NO:107 and SEQ ID NO:113, respectively; (xi) SEQ ID NO:115 and SEQ ID NO:121, respectively; (xii) SEQ ID NO:123 and SEQ ID NO:129, respectively; (xiii) SEQ ID NO:131 and SEQ ID NO:137, respectively; (xiv) SEQ ID NO:139 and SEQ ID NO:145, respectively; or (xv) SEQ ID NO:147 and SEQ ID NO:153, respectively.

[0007] In some embodiments of any of the antibodies described herein, the heavy chain CH1-CH2-CH3 sequence of SEQ ID NO: 155 or SEQ ID NO: 189 comprises a lysine to cysteine ​​substitution at amino acid position 105, and a deletion of threonines at amino acid positions 106 and 108, as well as a methionine to leucine substitution at amino acid position 311, and an asparagine to serine substitution at amino acid position 317. In some embodiments of any of the antibodies described herein, the antibody comprises heavy and light chain sequences selected from the group of: (i) SEQ ID NO:36 and SEQ ID NO:41, respectively; (ii) SEQ ID NO:44 and SEQ ID NO:49, respectively; (iii) SEQ ID NO:52 and SEQ ID NO:57, respectively; (iv) SEQ ID NO:60 and SEQ ID NO:65, respectively; (v) SEQ ID NO:68 and SEQ ID NO:73, respectively; (vi) SEQ ID NO:76 and SEQ ID NO:81, respectively; (vii) SEQ ID NO:84 and SEQ ID NO:89, respectively; (viii) SEQ ID NO:92 and SEQ ID NO:97, respectively; (ix) SEQ ID NO:100 and SEQ ID NO:105, respectively; (x) SEQ ID NO:108 and SEQ ID NO:113, respectively; (xi) SEQ ID NO:116 and SEQ ID NO:121, respectively; (xii) SEQ ID NO:124 and SEQ ID NO:129, respectively; (xiii) SEQ ID NO:132 and SEQ ID NO:137, respectively; (xiv) SEQ ID NO:140 and SEQ ID NO:145, respectively; or (xv) SEQ ID NO:148 and SEQ ID NO:153, respectively.

[0008] In some embodiments of any of the antibodies described herein, the heavy chain CH1-CH2-CH3 sequence of SEQ ID NO: 155 or SEQ ID NO: 189 comprises a lysine to cysteine ​​substitution at amino acid position 105 and a deletion of threonines at amino acid positions 106 and 108, as well as a methionine to tyrosine substitution at amino acid position 135, a serine to threonine substitution at amino acid position 137, and a threonine to glutamic acid substitution at amino acid position 139. In some embodiments of any of the antibodies described herein, the antibody comprises heavy and light chain sequences selected from the group of: (i) SEQ ID NO:37 and SEQ ID NO:41, respectively; (ii) SEQ ID NO:45 and SEQ ID NO:49, respectively; (iii) SEQ ID NO:53 and SEQ ID NO:57, respectively; (iv) SEQ ID NO:61 and SEQ ID NO:65, respectively; (v) SEQ ID NO:69 and SEQ ID NO:73, respectively; (vi) SEQ ID NO:77 and SEQ ID NO:81, respectively; (vii) SEQ ID NO:85 and SEQ ID NO:89, respectively; (viii) SEQ ID NO:93 and SEQ ID NO:97, respectively; (ix) SEQ ID NO:101 and SEQ ID NO:105, respectively; (x) SEQ ID NO:109 and SEQ ID NO:113, respectively; (xi) SEQ ID NO:117 and SEQ ID NO:121, respectively; (xii) SEQ ID NO:125 and SEQ ID NO:129, respectively; (xiii) SEQ ID NO:133 and SEQ ID NO:137, respectively; (xiv) SEQ ID NO:141 and SEQ ID NO:145, respectively; or (xv) SEQ ID NO:149 and SEQ ID NO:153, respectively.

[0009] In some embodiments of any of the antibodies described herein, the heavy chain CH1-CH2-CH3 sequence of SEQ ID NO: 155 or SEQ ID NO: 189 comprises a lysine to cysteine ​​substitution at amino acid position 105 and a deletion of threonines at amino acid positions 106 and 108, and the light chain C sequence of SEQ ID NO: 157 comprises a cysteine ​​to lysine substitution at amino acid position 105 and a deletion of threonines at amino acid positions 106 and 108. L In some embodiments of any of the antibodies described herein, the antibody comprises a heavy chain sequence and a light chain sequence comprising: (ix) SEQ ID NO:99 and SEQ ID NO:106, respectively; (x) SEQ ID NO:107 and SEQ ID NO:114, respectively; (xi) SEQ ID NO:115 and SEQ ID NO:122, respectively; (xii) SEQ ID NO:123 and SEQ ID NO:130, respectively; (xiii) SEQ ID NO:131 and SEQ ID NO:138, respectively; (xiv) SEQ ID NO:139 and SEQ ID NO:146, respectively; or (xv) SEQ ID NO:147 and SEQ ID NO:154, respectively.

[0010] In some embodiments of any of the antibodies described herein, the heavy chain CH1-CH2-CH3 sequence of SEQ ID NO: 155 or SEQ ID NO: 189 comprises a lysine to cysteine ​​substitution at amino acid position 105, and a deletion of threonines at amino acid positions 106 and 108, as well as a methionine to leucine substitution at amino acid position 311, and an asparagine to serine substitution at amino acid position 317; and the light chain C LThe sequence contains a valine to cysteine ​​substitution at amino acid position 98. In some embodiments of any of the antibodies described herein, the antibody comprises heavy and light chain sequences selected from the group of: (i) SEQ ID NO:36 and SEQ ID NO:42, respectively; (ii) SEQ ID NO:44 and SEQ ID NO:50, respectively; (iii) SEQ ID NO:52 and SEQ ID NO:58, respectively; (iv) SEQ ID NO:60 and SEQ ID NO:66, respectively; (v) SEQ ID NO:68 and SEQ ID NO:74, respectively; (vi) SEQ ID NO:76 and SEQ ID NO:82, respectively; (vii) SEQ ID NO:84 and SEQ ID NO:90, respectively; (viii) SEQ ID NO:92 and SEQ ID NO:98, respectively; (ix) SEQ ID NO:100 and SEQ ID NO:106, respectively; (x) SEQ ID NO:108 and SEQ ID NO:114, respectively; (xi) SEQ ID NO:116 and SEQ ID NO:122, respectively; (xii) SEQ ID NO:124 and SEQ ID NO:130, respectively; (xiii) SEQ ID NO:132 and SEQ ID NO:138, respectively; (xiv) SEQ ID NO:140 and SEQ ID NO:146, respectively; or (xv) SEQ ID NO:148 and SEQ ID NO:154, respectively.

[0011] In some embodiments of any of the antibodies described herein, the heavy chain CH1-CH2-CH3 sequence of SEQ ID NO: 155 or SEQ ID NO: 189 includes a lysine to cysteine ​​substitution at amino acid position 105, and deletion of threonines at amino acid positions 106 and 108, as well as a methionine to tyrosine substitution at amino acid position 135, a serine to threonine substitution at amino acid position 137, and a threonine to glutamic acid substitution at amino acid position 139; and the light chain C LThe sequence contains a valine to cysteine ​​substitution at amino acid position 98. In some embodiments of any of the antibodies described herein, the antibody comprises heavy and light chain sequences selected from the group of: (i) SEQ ID NO:37 and SEQ ID NO:42, respectively; (ii) SEQ ID NO:45 and SEQ ID NO:50, respectively; (iii) SEQ ID NO:53 and SEQ ID NO:58, respectively; (iv) SEQ ID NO:61 and SEQ ID NO:66, respectively; (v) SEQ ID NO:69 and SEQ ID NO:74, respectively; (vi) SEQ ID NO:77 and SEQ ID NO:82, respectively; (vii) SEQ ID NO:85 and SEQ ID NO:90, respectively; (viii) SEQ ID NO:93 and SEQ ID NO:98, respectively; (ix) SEQ ID NO:101 and SEQ ID NO:106, respectively; (x) SEQ ID NO:109 and SEQ ID NO:114, respectively; (xi) SEQ ID NO:117 and SEQ ID NO:122, respectively; (xii) SEQ ID NO:125 and SEQ ID NO:130, respectively; (xiii) SEQ ID NO:133 and SEQ ID NO:138, respectively; (xiv) SEQ ID NO:141 and SEQ ID NO:146, respectively; or (xv) SEQ ID NO:149 and SEQ ID NO:154, respectively.

[0012] In some embodiments of any of the antibodies described herein, the heavy chain CH1-CH2-CH3 sequence of SEQ ID NO: 155 or SEQ ID NO: 189 comprises a lysine to cysteine ​​substitution at amino acid position 105, and deletion of threonines at positions 106 and 108, and an alanine to cysteine ​​substitution at amino acid position 1. In some embodiments of any of the antibodies described herein, the antibody comprises heavy and light chain sequences selected from the group of: (i) SEQ ID NO:38 and SEQ ID NO:41, respectively; (ii) SEQ ID NO:46 and SEQ ID NO:49, respectively; (iii) SEQ ID NO:54 and SEQ ID NO:57, respectively; (iv) SEQ ID NO:62 and SEQ ID NO:65, respectively; (v) SEQ ID NO:70 and SEQ ID NO:73, respectively; (vi) SEQ ID NO:78 and SEQ ID NO:81, respectively; (vii) SEQ ID NO:86 and SEQ ID NO:89, respectively; (viii) SEQ ID NO:94 and SEQ ID NO:97, respectively; (ix) SEQ ID NO:102 and SEQ ID NO:105, respectively; (x) SEQ ID NO:110 and SEQ ID NO:113, respectively; (xi) SEQ ID NO:118 and SEQ ID NO:121, respectively; (xii) SEQ ID NO:126 and SEQ ID NO:129, respectively; (xiii) SEQ ID NO:134 and SEQ ID NO:137, respectively; (xiv) SEQ ID NO:142 and SEQ ID NO:145, respectively; or (xv) SEQ ID NO:150 and SEQ ID NO:153, respectively.

[0013] In some embodiments of any of the antibodies described herein, the heavy chain CH1-CH2-CH3 sequence of SEQ ID NO: 155 or SEQ ID NO: 189 comprises a lysine to cysteine ​​substitution at amino acid position 105 and deletion of threonines at amino acid positions 106 and 108, a methionine to leucine substitution at amino acid position 311 and an asparagine to serine substitution at amino acid position 317, and an alanine to cysteine ​​substitution at amino acid position 1. In some embodiments of any of the antibodies described herein, the antibody comprises heavy and light chain sequences selected from the group of: (i) SEQ ID NO:39 and SEQ ID NO:41, respectively; (ii) SEQ ID NO:47 and SEQ ID NO:49, respectively; (iii) SEQ ID NO:55 and SEQ ID NO:57, respectively; (iv) SEQ ID NO:63 and SEQ ID NO:65, respectively; (v) SEQ ID NO:71 and SEQ ID NO:73, respectively; (vi) SEQ ID NO:79 and SEQ ID NO:81, respectively; (vii) SEQ ID NO:87 and SEQ ID NO:89, respectively; (viii) SEQ ID NO:95 and SEQ ID NO:97, respectively; (ix) SEQ ID NO:103 and SEQ ID NO:105, respectively; (x) SEQ ID NO:111 and SEQ ID NO:113, respectively; (xi) SEQ ID NO:119 and SEQ ID NO:121, respectively; (xii) SEQ ID NO:127 and SEQ ID NO:129, respectively; (xiii) SEQ ID NO:135 and SEQ ID NO:137, respectively; (xiv) SEQ ID NO:143 and SEQ ID NO:145, respectively; or (xv) SEQ ID NO:151 and SEQ ID NO:153, respectively.

[0014] In some embodiments of any of the antibodies described herein, the heavy chain CH1-CH2-CH3 sequence of SEQ ID NO: 155 or SEQ ID NO: 189 includes a lysine to cysteine ​​substitution at amino acid position 105 and a deletion of threonines at amino acid positions 106 and 108, a methionine to tyrosine substitution at amino acid position 135, a serine to threonine substitution at amino acid position 137, and a threonine to glutamic acid substitution at amino acid position 139, and an alanine to cysteine ​​substitution at amino acid position 1. In some embodiments of any of the antibodies described herein, the antibody comprises heavy and light chain sequences selected from the group of: (i) SEQ ID NO:40 and SEQ ID NO:41, respectively; (ii) SEQ ID NO:48 and SEQ ID NO:49, respectively; (iii) SEQ ID NO:56 and SEQ ID NO:57, respectively; (iv) SEQ ID NO:64 and SEQ ID NO:65, respectively; (v) SEQ ID NO:72 and SEQ ID NO:73, respectively; (vi) SEQ ID NO:80 and SEQ ID NO:81, respectively; (vii) SEQ ID NO:88 and SEQ ID NO:89, respectively; (viii) SEQ ID NO:96 and SEQ ID NO:97, respectively; (ix) SEQ ID NO:104 and SEQ ID NO:105, respectively; (x) SEQ ID NO:112 and SEQ ID NO:113, respectively; (xi) SEQ ID NO:120 and SEQ ID NO:121, respectively; (xii) SEQ ID NO:128 and SEQ ID NO:129, respectively; (xiii) SEQ ID NO:136 and SEQ ID NO:137, respectively; (xiv) SEQ ID NO:144 and SEQ ID NO:145, respectively; or (xv) SEQ ID NO:152 and SEQ ID NO:153, respectively.

[0015] In some embodiments of any of the antibodies described herein, the antibody further comprises a cytotoxic agent conjugated to one or more of: (a) a heavy chain CH1-CH2-CH3 of SEQ ID NO: 155 or SEQ ID NO: 189 that comprises one or more of: (i) a cysteine ​​at amino acid position 103, (ii) a cysteine ​​in the lysine-to-cysteine ​​substitution at amino acid position 105, (iii) a cysteine ​​at amino acid position 109, and (iv) a cysteine ​​at amino acid position 112; and / or (b) a cysteine ​​at amino acid position 107 of SEQ ID NO: 157.

[0016] In some embodiments of any of the antibodies described herein, the antibody further comprises a cytotoxic or cytostatic agent conjugated to the cysteine ​​at position 98 of SEQ ID NO:157.

[0017] In some embodiments of any of the antibodies described herein, the antibody further comprises a cytotoxic or cytostatic agent conjugated to cysteine ​​at position 1 of SEQ ID NO:155 or SEQ ID NO:189.

[0018] In some embodiments of any of the antibodies described herein, the cytotoxic or cytostatic agent is a conjugated toxin, radioisotope, drug, or small molecule.

[0019] In some embodiments of any of the antibodies described herein, (a) the dissociation rate of the antibody at a pH of about 4.0 to about 6.5 is faster than the dissociation rate at a pH of about 7.0 to about 8.0, or (b) the dissociation constant (K D ) at pH 7.0 to 8.0 D In some embodiments of any of the antibodies described herein, a composition comprising the antibody results in one or more of increased toxin release in target mammalian cells compared to a composition comprising the same amount of a control antibody, increased killing of target mammalian cells compared to a composition comprising the same amount of the control antibody, and increased endolysosomal delivery in target mammalian cells compared to a composition comprising the same amount of the control antibody.

[0020] In some embodiments of any of the antibodies described herein, a composition comprising the antibody does not significantly reduce the level of MET displayed on the surface of target mammalian cells, or does not result in a detectable reduction in the level of MET displayed on the surface of target mammalian cells, compared to a composition comprising the same amount of a control antibody.

[0021] In some embodiments of any of the antibodies described herein, the antibody is degraded in the target mammalian cell after intracellular uptake of the antibody by the target mammalian cell. In some embodiments of any of the antibodies described herein, the target mammalian cell is a cancer cell. In some embodiments of any of the antibodies described herein, the antibody is cytotoxic or cytostatic to the target mammalian cell. In some embodiments of any of the antibodies described herein, the antibody has an avidity that confers increased selectivity for cancer cells over non-cancerous cells.

[0022] In some embodiments of any of the antibodies described herein, the antibody is cross-reactive with non-human primate MET and human MET, or cross-reactive with non-human primate MET, human MET, and one or both of rat MET and mouse MET. In some embodiments of any of the antibodies described herein, the half-life of the antibody in vivo is increased compared to the half-life of a control antibody in vivo.

[0023] Also provided herein are pharmaceutical compositions comprising an effective amount of any of the antibodies described herein. Also provided herein are kits comprising at least one dose of any of the antibodies described herein or any of the pharmaceutical compositions described herein.

[0024] Also provided herein is a method of treating a cancer characterized by having a population of cancer cells that have MET or an epitope of MET displayed on their surface, comprising administering a therapeutically effective amount of any of the antibodies described herein or any of the pharmaceutical compositions described herein to a subject identified as having a cancer characterized by having a population of cancer cells.

[0025] Also provided herein is a method for reducing tumor volume in a subject, wherein the tumor is characterized by having a population of cancer cells, the cancer cells having MET or an epitope of MET displayed on their surface, comprising administering a therapeutically effective amount of any of the antibodies described herein or any of the pharmaceutical compositions described herein to a subject identified as having a cancer characterized by having a population of cancer cells.

[0026] Also provided herein is a method of inducing cell death of cancer cells in a subject, wherein the cancer cells have MET or an epitope of MET displayed on their surface, comprising administering a therapeutically effective amount of any of the antibodies described herein or any of the pharmaceutical compositions described herein to a subject identified as having a cancer characterized by having a population of cancer cells.

[0027] Also provided herein is a method for reducing the risk of developing metastases or reducing the risk of developing further metastases in a subject having cancer characterized by having a population of cancer cells, the cancer cells having MET or an epitope of MET displayed on their surface, comprising administering a therapeutically effective amount of any of the antibodies described herein or any of the pharmaceutical compositions described herein to a subject identified as having a cancer characterized by having a population of cancer cells.

[0028] Also provided herein is an antibody comprising: (a) a heavy chain variable domain and a light chain variable domain selected from the group consisting of: (i) SEQ ID NO: 159 and SEQ ID NO: 160, respectively; (ii) SEQ ID NO: 161 and SEQ ID NO: 162, respectively; and (iii) SEQ ID NO: 163 and SEQ ID NO: 164, respectively; and (b) a heavy chain CH1-CH2-CH3 sequence of SEQ ID NO: 155 or SEQ ID NO: 189, wherein: (i) a lysine to cysteine ​​substitution at amino acid position 105 and a deletion of the threonine amino acid at amino acid positions 106 and 108. (ii) a methionine to tyrosine substitution at amino acid position 135, a serine to threonine substitution at amino acid position 137, and a threonine to glutamic acid substitution at amino acid position 139; (iii) a methionine to leucine substitution at amino acid position 311 and an asparagine to serine substitution at amino acid position 317; and (iv) an alanine to cysteine ​​substitution at amino acid position 1; and / or a light chain C1-CH2-CH3 sequence of SEQ ID NO: 155 or SEQ ID NO: 189, comprising one or more of the following: (i) a methionine to tyrosine substitution at amino acid position 135, a serine to threonine substitution at amino acid position 137, and a threonine to glutamic acid substitution at amino acid position 139; (ii) a methionine to tyrosine substitution at amino acid position 135, a serine to threonine substitution at amino acid position 137, and a threonine to glutamic acid substitution at amino acid position 139; (iii) a methionine to leucine substitution at amino acid position 311 and an asparagine to serine substitution at amino acid position 317; and (iv) an alanine to cysteine ​​substitution at amino acid position 1; and / or a light chain C1-CH2-CH3 sequence of SEQ ID NO: 157, comprising a valine to cysteine ​​substitution at position 98. L Also provided are antibodies comprising the sequence:

[0029] In some embodiments of any of the antibodies described herein, the heavy chain CH1-CH2-CH3 sequence of SEQ ID NO: 155 or SEQ ID NO: 189 comprises a lysine to cysteine ​​substitution at amino acid position 105 and a deletion of threonines at amino acid positions 106 and 108. In some embodiments of any of the antibodies described herein, the antibody comprises heavy and light chain sequences selected from the group of: (i) SEQ ID NO: 165 and SEQ ID NO: 171, respectively; (ii) SEQ ID NO: 173 and SEQ ID NO: 179, respectively; or (iii) SEQ ID NO: 181 and SEQ ID NO: 187, respectively.

[0030] In some embodiments of any of the antibodies described herein, the heavy chain CH1-CH2-CH3 sequence of SEQ ID NO: 155 or SEQ ID NO: 189 comprises a lysine to cysteine ​​substitution at amino acid position 105 and a deletion of threonines at amino acid positions 106 and 108, a methionine to leucine substitution at amino acid position 311, and an asparagine to serine substitution at amino acid position 317. In some embodiments of any of the antibodies described herein, the antibody comprises heavy and light chain sequences selected from the group of: (i) SEQ ID NO: 166 and SEQ ID NO: 171, respectively; (ii) SEQ ID NO: 174 and SEQ ID NO: 179, respectively; or (iii) SEQ ID NO: 182 and SEQ ID NO: 187, respectively.

[0031] In some embodiments of any of the antibodies described herein, the heavy chain CH1-CH2-CH3 sequence of SEQ ID NO: 155 or SEQ ID NO: 189 comprises a lysine to cysteine ​​substitution at amino acid position 105, and deletion of threonines at amino acid positions 106 and 108, as well as a methionine to tyrosine substitution at amino acid position 135, a serine to threonine substitution at amino acid position 137, and a threonine to glutamic acid substitution at amino acid position 139. In some embodiments of any of the antibodies described herein, the antibody comprises heavy and light chain sequences selected from the group of: (i) SEQ ID NO: 167 and SEQ ID NO: 171, respectively; (ii) SEQ ID NO: 175 and SEQ ID NO: 179, respectively; or (iii) SEQ ID NO: 183 and SEQ ID NO: 187, respectively.

[0032] In some embodiments of any of the antibodies described herein, the heavy chain CH1-CH2-CH3 sequence of SEQ ID NO: 155 or SEQ ID NO: 189 comprises a lysine to cysteine ​​substitution at amino acid position 105 and a deletion of threonines at amino acid positions 106 and 108, and the light chain C sequence of SEQ ID NO: 157 comprises a cysteine ​​to lysine substitution at amino acid position 105 and a deletion of threonines at amino acid positions 106 and 108. LThe sequence comprises a valine to cysteine ​​substitution at amino acid position 98. In some embodiments of any of the antibodies described herein, the antibody comprises heavy and light chain sequences selected from the group of: (i) SEQ ID NO: 165 and SEQ ID NO: 172, respectively; (ii) SEQ ID NO: 173 and SEQ ID NO: 180, respectively; or (iii) SEQ ID NO: 181 and SEQ ID NO: 188, respectively.

[0033] In some embodiments of any of the antibodies described herein, the heavy chain CH1-CH2-CH3 sequence of SEQ ID NO: 155 or SEQ ID NO: 189 includes a lysine to cysteine ​​substitution at amino acid position 105, a deletion of threonines at amino acid positions 106 and 108, a methionine to leucine substitution at amino acid position 311, and an asparagine to serine substitution at amino acid position 317; and the light chain C L The sequence comprises a valine to cysteine ​​substitution at amino acid position 98. In some embodiments of any of the antibodies described herein, the antibody comprises heavy and light chain sequences selected from the group of: (i) SEQ ID NO: 166 and SEQ ID NO: 172, respectively; (ii) SEQ ID NO: 174 and SEQ ID NO: 180, respectively; or (iii) SEQ ID NO: 182 and SEQ ID NO: 188, respectively.

[0034] In some embodiments of any of the antibodies described herein, the heavy chain CH1-CH2-CH3 sequence of SEQ ID NO: 155 or SEQ ID NO: 189 includes a lysine to cysteine ​​substitution at amino acid position 105, and deletion of threonines at amino acid positions 106 and 108, as well as a methionine to tyrosine substitution at amino acid position 135, a serine to threonine substitution at amino acid position 137, and a threonine to glutamic acid substitution at amino acid position 139; and the light chain C LThe sequence comprises a valine to cysteine ​​substitution at amino acid position 98. In some embodiments of any of the antibodies described herein, the antibody comprises heavy and light chain sequences selected from the group of: (i) SEQ ID NO: 167 and SEQ ID NO: 172, respectively; (ii) SEQ ID NO: 175 and SEQ ID NO: 180, respectively; or (iii) SEQ ID NO: 183 and SEQ ID NO: 188, respectively.

[0035] In some embodiments of any of the antibodies described herein, the heavy chain CH1-CH2-CH3 sequence of SEQ ID NO: 155 or SEQ ID NO: 189 comprises a lysine to cysteine ​​substitution at amino acid position 105, and deletions of threonines at amino acid positions 106 and 108, and an alanine to cysteine ​​substitution at amino acid position 1. In some embodiments of any of the antibodies described herein, the antibody comprises heavy and light chain sequences selected from the group of: (i) SEQ ID NO: 168 and SEQ ID NO: 171, respectively; (ii) SEQ ID NO: 176 and SEQ ID NO: 179, respectively; or (iii) SEQ ID NO: 184 and SEQ ID NO: 187, respectively.

[0036] In some embodiments of any of the antibodies described herein, the heavy chain CH1-CH2-CH3 sequence of SEQ ID NO: 155 or SEQ ID NO: 189 comprises a lysine to cysteine ​​substitution at amino acid position 105, and deletion of threonines at amino acid positions 106 and 108, a methionine to leucine substitution at amino acid position 311, and an asparagine to serine substitution at amino acid position 317, and an alanine to cysteine ​​substitution at amino acid position 1. In some embodiments of any of the antibodies described herein, the antibody comprises heavy and light chain sequences selected from the group of: (i) SEQ ID NO: 169 and SEQ ID NO: 171, respectively; (ii) SEQ ID NO: 177 and SEQ ID NO: 179, respectively; or (iii) SEQ ID NO: 185 and SEQ ID NO: 187, respectively.

[0037] In some embodiments of any of the antibodies described herein, the heavy chain CH1-CH2-CH3 sequence of SEQ ID NO: 155 or SEQ ID NO: 189 comprises a lysine to cysteine ​​substitution at amino acid position 105 and deletion of threonines at amino acid positions 106 and 108, a methionine to tyrosine substitution at amino acid position 135, a serine to threonine substitution at amino acid position 137 and a threonine to glutamic acid substitution at amino acid position 139, and an alanine to cysteine ​​substitution at amino acid position 1. In some embodiments of any of the antibodies described herein, the antibody comprises heavy and light chain sequences selected from the group of: (i) SEQ ID NO: 170 and SEQ ID NO: 171, respectively; (ii) SEQ ID NO: 178 and SEQ ID NO: 179, respectively; or (iii) SEQ ID NO: 186 and SEQ ID NO: 187, respectively.

[0038] In some embodiments of any of the antibodies described herein, the antibody further comprises a cytotoxic agent conjugated to one or more of: (a) a heavy chain CH1-CH2-CH3 of SEQ ID NO: 155 or SEQ ID NO: 189 comprising one or more of: (i) a cysteine ​​at amino acid position 103; (ii) a cysteine ​​in the lysine-to-cysteine ​​substitution at amino acid position 105; (iii) a cysteine ​​at amino acid position 109; (iv) a cysteine ​​at amino acid position 112; and / or (b) a cysteine ​​at amino acid position 107 of SEQ ID NO: 157.

[0039] In some embodiments of any of the antibodies described herein, the antibody further comprises a cytotoxic or cytostatic agent conjugated to the cysteine ​​at position 98 of SEQ ID NO: 157. In some embodiments of any of the antibodies described herein, the antibody further comprises a cytotoxic or cytostatic agent conjugated to the cysteine ​​at position 1 of SEQ ID NO: 155 or SEQ ID NO: 189.

[0040] In some embodiments of any of the antibodies described herein, the cytotoxic or cytostatic agent is a conjugated toxin, radioisotope, drug, or small molecule. In some embodiments of any of the antibodies described herein, the antibody is cytotoxic or cytostatic to target mammalian cells. In some embodiments of any of the antibodies described herein, the antibody is degraded in the target mammalian cells after intracellular uptake of the antibody by the target mammalian cells. In some embodiments of any of the antibodies described herein, the target mammalian cells are cancer cells. In some embodiments of any of the antibodies described herein, the antibody has an avidity that results in increased selectivity for cancer cells over non-cancerous cells.

[0041] In some embodiments of any of the antibodies described herein, the antibody is cross-reactive with non-human primate MET and human MET, or cross-reactive with non-human primate MET, human MET, and one or both of rat MET and mouse MET.

[0042] In some embodiments of any of the antibodies described herein, the half-life of the antibody in vivo is increased compared to the half-life of a control antibody in vivo.

[0043] In some embodiments of any of the antibodies described herein, the target mammalian cell is a cancer cell.

[0044] Also provided herein are pharmaceutical compositions comprising an effective amount of any of the antibodies described herein. Also provided herein are kits comprising at least one dose of any of the antibodies described herein or any of the pharmaceutical compositions described herein.

[0045] Also provided herein is a method of treating a cancer characterized by having a population of cancer cells that have MET or an epitope of MET displayed on their surface, comprising administering a therapeutically effective amount of any of the antibodies described herein or any of the pharmaceutical compositions described herein to a subject identified as having a cancer characterized by having a population of cancer cells.

[0046] Also provided herein is a method for reducing tumor volume in a subject, wherein the tumor is characterized by having a population of cancer cells, the cancer cells having MET or an epitope of MET displayed on their surface, comprising administering a therapeutically effective amount of any of the antibodies described herein or any of the pharmaceutical compositions described herein to a subject identified as having a cancer characterized by having a population of cancer cells.

[0047] Also provided herein is a method of inducing cell death of cancer cells in a subject, wherein the cancer cells have MET or an epitope of MET displayed on their surface, comprising administering a therapeutically effective amount of any of the antibodies described herein or any of the pharmaceutical compositions described herein to a subject identified as having a cancer characterized by having a population of cancer cells.

[0048] Also provided herein is a method for reducing the risk of developing metastases or reducing the risk of developing further metastases in a subject having cancer characterized by having a population of cancer cells, the cancer cells having MET or an epitope of MET displayed on their surface, comprising administering a therapeutically effective amount of any of the antibodies described herein or any of the pharmaceutical compositions described herein to a subject identified as having a cancer characterized by having a population of cancer cells.

[0049] An "antigen-binding domain" is one or more protein domains (e.g., formed from amino acids from a single polypeptide or formed from amino acids from two or more polypeptides (e.g., the same or different polypeptides) that can specifically bind to one or more different antigens). In some examples, an antigen-binding domain can bind to an antigen or epitope with specificity and affinity similar to that of a naturally occurring antibody. In some embodiments, an antigen-binding domain may be an antibody or fragment thereof. In some embodiments, an antigen-binding domain may comprise an alternative scaffold. Non-limiting examples of antigen-binding domains are described herein. Further examples of antigen-binding domains are known in the art. In some examples, an antigen-binding domain can bind to a single antigen.

[0050] The term "antibody" is used herein in its broadest sense and includes a specific type of immunoglobulin molecule that contains one or more antigen-binding domains that specifically bind to an antigen or epitope. Antibodies include, for example, intact antibodies (e.g., intact immunoglobulins, such as human IgG (e.g., human IgG1, human IgG2, human IgG3, human IgG4)), antibody fragments, and multispecific antibodies, among others. One example of an antigen-binding domain is the antigen-binding domain formed by a VH-VL dimer. Further examples of antibodies are described herein. Further examples of antibodies are known in the art.

[0051] The phrase "endosomal / lysosomal pathway" refers to the network of endosomes (early endosomes, multivesicular bodies, late endosomes, and lysosomes) in the cytoplasm of mammalian cells, where molecules taken up into the cell via cell-mediated endocytosis processes, such as pinocytosis, micropinocytosis, receptor-mediated endocytosis, and / or phagocytosis, are sorted.

[0052] Once endosomes in the endosomal / lysosomal pathway have been purified or isolated, assays for target proteins (e.g., antibodies described herein) can be performed using methods known in the art (e.g., ELISA, Western blot, immunofluorescence, and immunoprecipitation followed by protein concentration assays) and can be used to determine the concentration or relative levels of target proteins in endosomes. Alternatively, endosomes in the endosomal / lysosomal pathway can be imaged by immunofluorescence microscopy using a detectably labeled antibody (e.g., a fluorescently, dye-, or GFP-labeled antibody, such as CellLight™ Early Endosome-GFP) that specifically binds to a characteristic protein present in endosomes (e.g., EEA1 in early endosomes) and a fluorescently labeled antibody that specifically binds to the protein of interest (e.g., an antibody), and the level of target protein in the endosome can be determined by quantifying the overlap of the fluorescence emissions of the two different antibodies.

[0053] The phrase "endolysosomal delivery" refers to the rate of accumulation over time or the total amount of accumulation at a particular time of an antibody (e.g., any of the antibodies described herein) within the endosomal / lysosomal pathway in a mammalian cell (e.g., any of the exemplary target mammalian cells described herein).

[0054] An exemplary assay for measuring the endolysosomal delivery of any of the antibodies described herein involves labeling the antibody with a fluorescent dye, followed by incubation of the labeled antibody with cells, and measuring cellular fluorescence as an indicator of endolysosomal delivery of the antibody (e.g., as reviewed in Wustner, Traffic 7(6):699-715, 2006). Alternatively, any of the antibodies described herein can be labeled with a pH-sensitive dye that preferentially fluoresces at acidic pH but not at neutral pH, which can then be incubated with cells, and cellular fluorescence can be measured as an indicator of delivery of the antibody to acidic endolysosomal compartments.

[0055] When the term "population" is used before a noun, it means two or more of that particular noun. For example, the phrase "population of cancer cells" means "two or more cancer cells." Non-limiting examples of cancer cells are described herein.

[0056] The phrase "cytostatic to a cell" refers to a direct or indirect reduction in the proliferation (cell division) of the cell (e.g., a cancer cell) in vivo or in vitro. When an agent is cytostatic to a cell, the agent may, for example, directly or indirectly cause cell cycle arrest of the cell (e.g., a cancer cell). In some examples, an agent that is cytostatic to a cell may reduce the number of cells in a population of cells in S phase (compared to the number of cells in the population of cells in S phase before contact with the agent). In some examples, an agent that is cytostatic to a cell may reduce the percentage of cells in S phase by at least 20%, at least 40%, at least 60%, or at least 80% (e.g., compared to the percentage of cells in the population of cells in S phase before contact with the agent).

[0057] The phrase "cytotoxic to a cell" refers to directly or indirectly inducing death (eg, necrosis or apoptosis) of the cell (eg, a mammalian cell, eg, a cancer cell) of interest.

[0058] "Affinity" refers to the strength of the sum total of non-covalent interactions between an antigen-binding site and its binding partner (e.g., antigen or epitope). Unless otherwise indicated, as used herein, "affinity" refers to the intrinsic binding affinity, which reflects a 1:1 interaction between a member of the antigen-binding domain and the antigen or epitope. The affinity of a molecule X for its partner Y is determined by the dissociation equilibrium constant (K D). Affinity can be measured by conventional methods known in the art, including those described herein. Affinity can be determined, for example, using surface plasmon resonance (SPR) technology (e.g., BIACORE®) or biolayer interferometry (e.g., FORTEBIO®). Additional methods for determining the affinity of an antigen-binding domain for its corresponding antigen or epitope are known in the art.

[0059] The term "epitope" refers to a portion of an antigen to which an antigen-binding domain specifically binds through a series of physical interactions between (i) all monomers (e.g., individual amino acid residues, sugar side chains, and post-translationally modified amino acid residues) on the portion of the antigen-binding domain that specifically binds to the antigen and (ii) all monomers (e.g., individual amino acid residues, sugar side chains, and post-translationally modified amino acid residues) on the portion of the antigen that is specifically bound by the antigen-binding domain. An epitope may consist of, for example, surface-accessible amino acid residues, sugar side chains, phosphorylated amino acid residues, methylated amino acid residues, and / or acetylated amino acid residues, and may also have specific three-dimensional structural characteristics, as well as specific charge characteristics. Conformational and nonconformational epitopes are distinguished in that binding to the former, but not the latter, can be lost in the presence of denaturing solvents. In some embodiments, an epitope is defined by a linear amino acid sequence of at least about 3-6 amino acids, or about 10-15 amino acids. In some embodiments, an epitope refers to a portion of a full-length protein or a portion thereof defined by a three-dimensional structure (e.g., protein folding). In some embodiments, an epitope is defined by discontinuous amino acid sequences held together through protein folding. In some embodiments, an epitope is defined by discontinuous amino acid sequences held together by a quaternary structure (e.g., a cleft formed by the interaction of two different polypeptide chains). The amino acid sequence between the residues defining the epitope may not be important to the three-dimensional structure of the epitope. Assays comparing antibody binding to denatured versions of the antigen can be used to determine and screen conformational epitopes so that linear epitopes are generated. An epitope may include amino acid residues directly involved in binding and other amino acid residues not directly involved in binding.

[0060] Methods for identifying the epitope to which an antigen-binding domain specifically binds are known in the art, such as structural-based analysis (e.g., X-ray crystallography, NMR, and / or electron microscopy) (e.g., on the antigen and / or antigen-antigen binding domain complex), and / or mutagenesis-based analysis in which mutants are measured in binding assays with a binding partner (e.g., alanine scanning mutagenesis, glycine scanning mutagenesis, and homology scanning mutagenesis), many of which are known in the art.

[0061] The term "paratope" refers to a portion of an antigen-binding domain that specifically binds to an antigen through a series of physical interactions between (i) all of the monomers (e.g., individual amino acid residues, sugar side chains, post-translationally modified amino acid residues) on the portion of the antigen-binding domain that specifically binds to the antigen and (ii) all of the monomers (e.g., individual amino acid residues, sugar side chains, post-translationally modified amino acid residues) on the portion of the antigen to which the antigen-binding domain specifically binds. A paratope can consist of, for example, surface-accessible amino acid residues and can have specific three-dimensional structural characteristics as well as specific charge characteristics. In some embodiments, a paratope refers to a portion of a full-length antigen-binding domain or a portion thereof that is defined by a three-dimensional structure (e.g., protein folding). In some embodiments, a paratope is defined by discontinuous amino acid sequences held together through protein folding. In some embodiments, an epitope is defined by discontinuous amino acid sequences held together by a quaternary structure (e.g., a cleft formed by the interaction of two different polypeptide chains). The amino acid sequence between the residues that define the paratope may not be important to the three-dimensional structure of the paratope. The paratope can include amino acid residues that are directly involved in binding and other amino acid residues that are not directly involved in binding.

[0062] Methods for identifying the paratope to which an antigen-binding domain specifically binds are known in the art, such as structural-based analyses (e.g., X-ray crystallography, NMR, and / or electron microscopy) (e.g., of the antigen-binding domain and / or antigen-binding domain-antigen complex), and / or mutagenesis-based analyses in which mutants are measured in binding assays with a binding partner (e.g., alanine scanning mutagenesis, glycine scanning mutagenesis, and homology scanning mutagenesis), many of which are known in the art.

[0063] The phrase "present on the surface of a mammalian cell" refers to (1) an antigen that is physically associated with or at least partially incorporated into the plasma membrane of a mammalian cell (e.g., a transmembrane protein, a peripheral membrane protein, a lipid-binding protein (e.g., a GPI anchor), an N-myristolyated protein, or an S-palmitoylated protein), or (2) an antigen that is stably bound to its cognate receptor, which is physically associated with the plasma membrane of a mammalian cell (e.g., a ligand bound to its cognate receptor, which is physically associated with the plasma membrane). Non-limiting methods for determining the presence of an antigen on the surface of a mammalian cell include fluorescence-activated cell sorting (FACS), immunohistochemistry, cell fractionation assays, and Western blot.

[0064] The phrase "control antibody" refers to (i) an antibody that is capable of specifically binding to MET or an epitope of MET displayed on the surface of a mammalian cell (e.g., a target mammalian cell), and (a) the dissociation rate of its first antigen-binding domain at a pH of about 4.0 to about 6.5 (e.g., any subrange of this range described herein) is no more than three-fold (e.g., 2-fold) higher than the dissociation rate at a pH of about 7.0 to about 8.0 (e.g., any subrange of this range described herein). or (b) the dissociation constant (K) of the first antigen-binding domain at a pH of about 4.0 to about 6.5 (e.g., any of the subranges of this range described herein), or (c) the dissociation constant (K) of the first antigen-binding domain at a pH of about 4.0 to about 6.5 (e.g., any of the subranges of this range described herein), or D ) at a pH of about 7.0 to about 8.0 (e.g., any of the subranges of this range described herein). D and / or (ii) telisotuzumab, (iii) emibetuzumab, and / or (iv) P3D12.

[0065] The term "extracellular space" refers to the fluid outside the plasma membrane of a mammalian cell. When the mammalian cell is in vitro, the extracellular space can be liquid culture medium. When the mammalian cell is in vivo, the extracellular space can be, for example, plasma, serum, blood, interstitial fluid, or lymph.

[0066] The term "endolysosomal space" refers to the fluid enclosed by the vesicles and organelles that make up the endosomal / lysosomal pathway in mammalian cells.

[0067] The phrase "reduced level" or "diminished level" can be a reduction or decrease that is a reduction of at least 1% (e.g., at least 2%, at least 4%, at least 6%, at least 8%, at least 10%, at least 12%, at least 14%, at least 16%, at least 18%, at least 20%, at least 22%, at least 24%, at least 26%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%) compared to a reference level or value.

[0068] The term "cytocidal activity" refers to the ability of an agent (e.g., any of the antibodies described herein) to directly or indirectly induce apoptosis and / or necrosis of mammalian cells (e.g., cancer cells), measured as a rate over time or at relevant time points. Methods for determining the cell-killing activity of a cell are known in the art (e.g., trypan blue staining, microscopy, fluorescence-assisted cell sorting, and assays detecting markers of apoptosis (e.g., Annexin V)). In non-limiting examples, cell-killing activity can be measured, for example, by cell killing at a single concentration of the agent, by the agent's IC50 (i.e., the concentration of the agent that achieves half of the maximal cell-killing activity), or by the ratio of the agent's dissociation constant KD in mammalian cells divided by its IC50. In some non-limiting examples, the IC50 and / or KD ratios described herein are compared to those of a control antibody (as defined herein), optionally demonstrating that the antibodies described herein have higher cell-killing activity compared to the control antibody.

[0069] The term "toxin release" refers to the ability of mammalian cells (e.g., non-cancerous mammalian cells or cancer cells) to internalize (e.g., via pinocytosis and / or receptor-mediated endocytosis) any of the antibodies described herein (e.g., any of the antibodies described herein or control antibodies) conjugated to a toxin and subsequently release the toxin conjugated to the antibody, measured as a rate over time or at specific time points. Toxin release can be assessed using a variety of different exemplary assays, such as ELISA, immunofluorescence, cell killing assays, cell cycle arrest assays, DNA damage assays, mass spectrometry, HPLC, and / or isotope-labeled toxins.

[0070] The phrases "target cell" or "target mammalian cell" or "mammalian target cell" refer to mammalian cells having at least one MET present on their surface. In some examples, the mammalian target cell can be a cancer cell. In some embodiments of the target mammalian cell, a total of about 1 to about 10,000,000, about 1 to about 9,000,000, about 1 to about 8,000,000, about 1 to about 7,000,000, about 1 to about 6,000,000, about 1 to about 5,000,000, about 1 to about 4,000,000, about 1 to about 3,000,000, about 1 to about 2,000,000, about 1 to about 1,000,000, about 1 to about 800,000, about 1 to about 600,000, about 1 to about 4 00,000 pieces, about 1 to about 200,000 pieces, about 1 to about 100,000 pieces, about 1 to about 80,000 pieces, about 1 to about 80,000 pieces, about 1 to about 75,000 pieces, about 1 to about 70,000 pieces, about 1 to about 65,000 pieces, about 1 to about 60,000 pieces, about 1 to about 5 5,000 pieces, about 1 to about 50,000 pieces, about 1 to about 45,000 pieces, about 1 to about 40,000 pieces, about 1 to about 35,000 pieces, about 1 to about 30,000 pieces, about 1 to about 25,000 pieces, about 1 to about 20,000 pieces, about 1 to about 15,000 pieces, about 1 to about 10,00 0 pieces, about 1 to about 7,500 pieces, about 1 to about 5,000 pieces, about 1 to about 4,000 pieces, about 1 to about 3,000 pieces, about 1 to about 2,000 pieces, about 1 to about 1,000 pieces, about 1 to about 500 pieces, about 1 to about 100 pieces, about 1 to about 50 pieces, about 1 to about 10 pieces, about 10 to about 10, 000,000 pieces, about 10 to about 9,000,000 pieces, about 10 to about 8,000,000 pieces, about 10 to about 7,000,000 pieces, about 10 to about 6,000,000 pieces, about 10 to about 5,000,000 pieces, about 10 to about 4,000,000 pieces, about 10 to about 3, 000,000 pieces, about 10 to about 2,000,000 pieces, about 10 to about 1,000,000 pieces, about 10 to about 800,000 pieces, about 10 to about 600,000 pieces, about 10 to about 400,000 pieces, about 10 to about 200,000 pieces, about 10 to about 100,000 pieces, Approx. 10 to approx. 80,000 pieces, approx. 10 to approx. 80,000 pieces, approx. 10 to approx. 75,000 pieces, approx. 10 to approx. 70,000 pieces, approx. 10 to approx. 65,000 pieces, approx.000, about 10 to about 40,000, about 10 to about 35,000, about 10 to about 30,000, about 10 to about 25,000, about 10 to about 20,000, about 10 to about 15,000, about 10 to about 10,000, about 10 to about 7,500, about 10 to about 5,000, about 10 to about 4,000, about 10 to about 3,000, about 10 to about 2,000, about 10 to about 1,000, about 10 to about 500, about 10 to about 100, about 10 to about 50, about 50 to about 10,000,000, about 50 to about 9,000,000, about 50 to about 8,000,000, about 50 to about 7,000,000, about 50 to about 6,000,000, about 50 to about 5,000,000, about 50 to about 4,000,000, about 50 to about 3,000,000, about 50 to about 2,000,000, about 50 to about 1,000,000, about 50 to about 800,000, about 50 to about 600,000, about 50 to about 400,000, about 50 to about 200,000, about 50 to about 100,000, about 50 to about 80,000, about 50 to about 80,000, about 50 to about 75,000, about 50 to about 70,000, about 50 to about 65,000, about 50 to about 60,000, about 50 to about 55,000, about 50 to about 50,000, about 50 to about 45,000, about 50 to about 40,000, about 50 to about 35,000, about 50 to about 30,000, about 50 to about 25,000, about 50 to about 20,000, about 50 to about 15,000 , about 50 to about 10,000, about 50 to about 7,500, about 50 to about 5,000, about 50 to about 4,000, about 50 to about 3,000, about 50 to about 2,000, about 50 to about 1,000, about 50 to about 500, about 50 to about 100, about 100 to about 10,000,000, about 100 to about 9,000,000, about 100 to about 8,000,000, about 100 to about 7,000,000, about 100 to about 6,000,000, about 100 to about 5,000,000, about 100 to about 4,000,000, about 100 to about 3,000,000, about 100 to about 2 ,000,000, about 100 to about 1,000,000, about 100 to about 800,000, about 100 to about 600,000, about 100 to about 400,000, about 100 to about 200,000, about 100 to about 100,000, about 100 to about 80,000, about 100 to about 75,000, about 100 to about 70,000, about 100 to about 65,000, about 100 to about 60,000, about 100 to about 55,000, about 100 to about 50,000, about 100 to about 45,000, about 100 to about 40,000, about 100 to about 35,000, about 100 to about 3 0,000, about 100 to about 25,000, about 100 to about 20,000, about 100 to about 15,000, about 100 to about 10,000, about 100 to about 7,500, about 100 to about 5,000, about 100 to about 4,000, about 100 to about 3,000, about 100 to about 2,000 0, about 100 to about 1,000, about 100 to about 500, about 500 to about 10,000,000, about 500 to about 9,000,000, about 500 to about 8,000,000, about 500 to about 7,000,000, about 500 to about 6,000,000, about 500 to about 5,000 ,000, about 500 to about 4,000,000, about 500 to about 3,000,000, about 500 to about 2,000,000, about 500 to about 1,000,000, about 500 to about 800,000, about 500 to about 600,000, about 500 to about 400,000, about 500 to about 200,000, about 500 to about 100,000, about 500 to about 80,000, about 500 to about 75,000, about 500 to about 70,000, about 500 to about 65,000, about 500 to about 60,000, about 500 to about 55,000, about 500 to about 50,000, about 5 00 to about 45,000, about 500 to about 40,000, about 500 to about 35,000, about 500 to about 30,000, about 500 to about 25,000, about 500 to about 20,000, about 500 to about 15,000, about 500 to about 10,000, about 500 to about 7,500, about 5 00 to about 5,000, about 500 to about 4,000, about 500 to about 3,000, about 500 to about 2,000, about 500 to about 1,000, about 1,000 to about 10,000,000, about 1,000 to about 9,000,000, about 1,000 to about 8,000,000, about 1, 000 to about 7,000,000, about 1,000 to about 6,000,000, about 1,000 to about 5,000,000, about 1,000 to about 4,000,000, about 1,000 to about 3,000,000, about 1,000 to about 2,000,000, about 1,000 to about 1,000,000, about 1,000 to about 800,000, about 1,000 to about 600,000, about 1,000 to about 400,000, about 1,000 to about 200,000, about 1,000 to about 100,000, about 1,000 to about 80,000, about 1,000 to about 75,000, about 1 ,000 to about 70,000, about 1,000 to about 65,000, about 1,000 to about 60,000, about 1,000 to about 55,000, about 1,000 to about 50,000, about 1,000 to about 45,000, about 1,000 to about 40,000, about 1,000 to about 35,000 , about 1,000 to about 30,000, about 1,000 to about 25,000, about 1,000 to about 20,000, about 1,000 to about 15,000, about 1,000 to about 10,000, about 1,000 to about 7,500, about 1,000 to about 5,000, about 1,000 to about 4,000 , about 1,000 to about 3,000, about 1,000 to about 2,000, about 2,000 to about 10,000,000, about 2,000 to about 9,000,000, about 2,000 to about 8,000,000, about 2,000 to about 7,000,000, about 2,000 to about 6,000,000 0, about 2,000 to about 5,000,000, about 2,000 to about 4,000,000, about 2,000 to about 3,000,000, about 2,000 to about 2,000,000, about 2,000 to about 1,000,000, about 2,000 to about 800,000, about 2,000 to about 6 00,000, about 2,000 to about 400,000, about 2,000 to about 200,000, about 2,000 to about 100,000, about 2,000 to about 80,000, about 2,000 to about 75,000, about 2,000 to about 70,000, about 2,000 to about 65,000, about 2 ,000 to about 60,000, about 2,000 to about 55,000, about 2,000 to about 50,000, about 2,000 to about 45,000, about 2,000 to about 40,000, about 2,000 to about 35,000, about 2,000 to about 30,000, about 2,000 to about 25,000 , about 2,000 to about 20,000, about 2,000 to about 15,000, about 2,000 to about 10,000, about 2,000 to about 7,500, about 2,000 to about 5,000, about 2,000 to about 4,000, about 2,000 to about 3,000, about 3,000 to about 10,000,000, about 3,000 to about 9,000,000, about 3,000 to about 8,000,000, about 3,000 to about 7,000,000, about 3,000 to about 6,000,000, about 3,000 to about 5,000,000, about 3,000 to about 4,000,000, about 3,000 to about 3,000,000, about 3,000 to about 2,000,000, about 3,000 to about 1,000,000, about 3,000 to about 800,000, about 3,000 to about 600,000, about 3,000 to about 400,000, about 3,000 to about 200,000, about 3,000 ~ about 100,000, about 3,000 to about 80,000, about 3,000 to about 75,000, about 3,000 to about 70,000, about 3,000 to about 65,000, about 3,000 to about 60,000, about 3,000 to about 55,000, about 3,000 to about 50,000, about 3 ,000 to about 45,000, about 3,000 to about 40,000, about 3,000 to about 35,000, about 3,000 to about 30,000, about 3,000 to about 25,000, about 3,000 to about 20,000, about 3,000 to about 15,000, about 3,000 to about 10,000 , about 3,000 to about 7,500, about 3,000 to about 5,000, about 3,000 to about 4,000, about 4,000 to about 10,000,000, about 4,000 to about 9,000,000, about 4,000 to about 8,000,000, about 4,000 to about 7,000,000, about 4 ,000 to about 6,000,000, about 4,000 to about 5,000,000, about 4,000 to about 4,000,000, about 4,000 to about 3,000,000, about 4,000 to about 2,000,000, about 4,000 to about 1,000,000, about 4,000 to about 800,0 00, about 4,000 to about 600,000, about 4,000 to about 400,000, about 4,000 to about 200,000, about 4,000 to 100,000, about 4,000 to about 80,000, about 4,000 to about 75,000, about 4,000 to about 70,000, about 4,000 ~ about 65,000, about 4,000 to about 60,000, about 4,000 to about 55,000, about 4,000 to about 50,000, about 4,000 to about 45,000, about 4,000 to about 40,000, about 4,000 to about 35,000, about 4,000 to about 30,000, about 4,000 to about 25,000, about 4,000 to about 20,000, about 4,000 to about 15,000, about 4,000 to about 10,000, about 4,000 to about 7,500, about 4,000 to about 5,000, about 5,000 to about 10,000,000, about 5,000 to about 9,000,000, about 5,000, to about 8,000,000, about 5,000 to about 7,000,000, about 5,000 to about 6,000,000, about 5,000 to about 5,000,000, about 5,000 to about 4,000,000, about 5,000 to about 3,000,000, about 5,000 to about 2,000,000 0, about 5,000 to about 1,000,000, about 5,000 to about 800,000, about 5,000 to about 600,000, about 5,000 to about 400,000, about 5,000 to about 200,000, about 5,000 to about 100,000, about 5,000 to about 80,000, about 5 ,000 to about 75,000, about 5,000 to about 70,000, about 5,000 to about 65,000, about 5,000 to about 60,000, about 5,000 to about 55,000, about 5,000 to about 50,000, about 5,000 to about 45,000, about 5,000 to about 40,000 , about 5,000 to about 35,000, about 5,000 to about 30,000, about 5,000 to about 25,000, about 5,000 to about 20,000, about 5,000 to about 15,000, about 5,000 to about 10,000, about 5,000 to about 7,500, about 7,500 to about 10,0 00,000, about 7,500 to about 9,000,000, about 7,500 to about 8,000,000, about 7,500 to about 7,000,000, about 7,500 to about 6,000,000, about 7,500 to about 5,000,000, about 7,500 to about 4,000,000, about 7 ,500 to about 3,000,000, about 7,500 to about 2,000,000, about 7,500 to about 1,000,000, about 7,500 to about 800,000, about 7,500 to about 600,000, about 7,500 to about 400,000, about 7,500 to about 200,000, about 7 ,500 to about 100,000, about 7,500 to about 80,000, about 7,500 to about 75,000, about 7,500 to about 70,000, about 7,500 to about 65,000, about 7,500 to about 60,000, about 7,500 to about 55,000, about 7,500 to about 50,000 , about 7,500 to about 45,000, about 7,500 to about 40,000, about 7,500 to about 35,000, about 7,500 to about 30,000, about 7,500 to about 25,000, about 7,500 to about 20,000, about 7,500 to about 15,000, about 7,500 to about 10,000, about 10,000 to about 10,000,000, about 10,000 to about 9,000,000, about 10,000 to about 8,000,000, about 10,000 to about 7,000,000, about 10,000 to about 6,000,000, about 10,000 to about 5,000,000 , about 10,000 to about 4,000,000, about 10,000 to about 3,000,000, about 10,000 to about 2,000,000, about 10,000 to about 1,000,000, about 10,000 to about 800,000, about 10,000 to about 600,000, about 10,000 to about 400,000, about 10,000 to about 200,000, about 10,000 to about 100,000, about 10,000 to about 80,000, about 10,000 to about 75,000, about 10,000 to about 70,000, about 10,000 to about 65,000, about 10,000 to about 6 0,000, about 10,000 to about 55,000, about 10,000 to about 50,000, about 10,000 to about 45,000, about 10,000 to about 40,000, about 10,000 to about 35,000, about 10,000 to about 30,000, about 10,000 to about 25,000 , about 10,000 to about 20,000, about 10,000 to about 15,000, about 15,000 to about 10,000,000, about 15,000 to about 9,000,000, about 15,000 to about 8,000,000, about 15,000 to about 7,000,000, about 15,000 to about 6,000,000, about 15,000 to about 5,000,000, about 15,000 to about 4,000,000, about 15,000 to about 3,000,000, about 15,000 to about 2,000,000, about 15,000 to about 1,000,000, about 15,000 to about 800,000 00, about 15,000 to about 600,000, about 15,000 to about 400,000, about 15,000 to about 200,000, about 15,000 to about 100,000, about 15,000 to about 80,000, about 15,000 to about 75,000, about 15,000 to about 70,000 , about 15,000 to about 65,000, about 15,000 to about 60,000, about 15,000 to about 55,000, about 15,000 to about 50,000, about 15,000 to about 45,000, about 15,000 to about 40,000, about 15,000 to about 35,000, about 15,000 to about 30,000, about 15,000 to about 25,000, about 15,000 to about 20,000, about 20,000 to about 10,000,000, about 20,000 to about 9,000,000, about 20,000 to about 8,000,000, about 20,000 to about 7,000,000 00, about 20,000 to about 6,000,000, about 20,000 to about 5,000,000, about 20,000 to about 4,000,000, about 20,000 to about 3,000,000, about 20,000 to about 2,000,000, about 20,000 to about 1,000,000, about 20,000 to about 800,000, about 20,000 to about 600,000, about 20,000 to about 400,000, about 20,000 to about 200,000, about 20,000 to about 100,000, about 20,000 to about 80,000, about 20,000 to about 75,000, about 2 0,000 to about 70,000, about 20,000 to about 65,000, about 210,000 to about 60,000, about 20,000 to about 55,000, about 20,000 to about 50,000, about 20,000 to about 45,000, about 20,000 to about 40,000, about 20,000 to about 35,000, about 20,000 to about 30,000, about 20,000 to about 25,000, about 25,000 to 10,000,000, about 25,000 to about 9,000,000, about 25,000 to about 8,000,000, about 25,000 to about 7,000,000, About 25,000 to about 6,000,000, about 25,000 to about 5,000,000, about 25,000 to about 4,000,000, about 25,000 to about 3,000,000, about 25,000 to about 2,000,000, about 25,000 to about 1,000,000, about 25,000 to about 1,000,000, about 25,000 to about 2,000,000 00 to about 800,000, about 25,000 to about 600,000, about 25,000 to about 400,000, about 25,000 to about 200,000, about 25,000 to about 100,000, about 25,000 to about 80,000, about 25,000 to about 75,000, about 25,000 0 to about 70,000, about 25,000 to about 65,000, about 25,000 to about 60,000, about 25,000 to about 55,000, about 25,000 to about 50,000, about 25,000 to about 45,000, about 25,000 to about 40,000, about 25,000 to about 35,000, about 25,000 to about 30,000, about 30,000 to about 10,000,000, about 30,000 to about 9,000,000, about 30,000 to about 8,000,000, about 30,000 to about 7,000,000, about 30,000 to about 6,000,000, about 30,000 to about 5,000,000, about 30,000 to about 4,000,000, about 30,000 to about 3,000,000, about 30,000 to about 2,000,000, about 30,000 to about 1,000,000, about 30,000 to about 800,000, about 30,000 to About 600,000, about 30,000 to about 400,000, about 30,000 to about 200,000, about 30,000 to about 100,000, about 30,000 to about 80,000, about 30,000 to about 75,000, about 30,000 to about 70,000, about 30,000 to about 6 5,000, about 30,000 to about 60,000, about 30,000 to about 55,000, about 30,000 to about 50,000, about 30,000 to about 45,000, about 30,000 to about 40,000, about 30,000 to about 35,000, about 35,000 to about 10,000, 000, about 35,000 to about 9,000,000, about 35,000 to about 8,000,000, about 35,000 to about 7,000,000, about 35,000 to about 6,000,000, about 35,000 to about 5,000,000, about 35,000 to about 4,000,000, About 35,000 to about 3,000,000, about 35,000 to about 2,000,000, about 35,000 to about 1,000,000, about 35,000 to about 800,000, about 35,000 to about 600,000, about 35,000 to about 400,000, about 35,000 to about 20 0,000, about 35,000 to about 100,000, about 35,000 to about 80,000, about 35,000 to about 75,000, about 35,000 to about 70,000, about 35,000 to about 65,000, about 35,000 to about 60,000, about 35,000 to about 55,000 , about 35,000 to about 50,000, about 35,000 to about 45,000, about 35,000 to about 40,000, about 40,000 to about 10,000,000, about 40,000 to about 9,000,000, about 40,000 to about 8,000,000, about 40,000 to about 7,000,000, about 40,000 to about 6,000,000, about 40,000 to about 5,000,000, about 40,000 to about 4,000,000, about 40,000 to about 3,000,000, about 40,000 to about 2,000,000, about 40,000 to about 1,000, 000, about 40,000 to about 800,000, about 40,000 to about 600,000, about 40,000 to about 400,000, about 40,000 to about 200,000, about 40,000 to about 100,000, about 40,000 to about 80,000, about 40,000 to about 75,000 00, about 40,000 to about 70,000, about 40,000 to about 65,000, about 40,000 to about 60,000, about 40,000 to about 55,000, about 40,000 to about 50,000, about 40,000 to about 45,000, about 45,000 to 10,000,000 , about 45,000 to about 9,000,000, about 45,000 to about 8,000,000, about 45,000 to about 7,000,000, about 45,000 to about 6,000,000, about 45,000 to about 5,000,000, about 45,000 to about 4,000,000, about 45 ,000 to about 3,000,000, about 45,000 to about 2,000,000, about 45,000 to about 1,000,000, about 45,000 to about 800,000, about 45,000 to about 600,000, about 45,000 to about 400,000, about 45,000 to about 200, 000, about 45,000 to about 100,000, about 45,000 to about 80,000, about 45,000 to about 75,000, about 45,000 to about 70,000, about 45,000 to about 65,000, about 45,000 to about 60,000, about 45,000 to about 55,000, About 45,000 to about 50,000, about 50,000 to about 10,000,000, about 50,000 to about 9,000,000, about 50,000 to about 8,000,000, about 50,000 to about 7,000,000, about 50,000 to about 6,000,000, about 50,000 0 to about 5,000,000, about 50,000 to about 4,000,000, about 50,000 to about 3,000,000, about 50,000 to about 2,000,000, about 50,000 to about 1,000,000, about 50,000 to about 800,000, about 50,000 to about 600,000, about 50,000 to about 400,000, about 50,000 to about 200,000, about 50,000 to about 100,000, about 50,000 to about 80,000, about 50,000 to about 75,000, about 50,000 to about 70,000, about 50,000 to about 65,000, about 50,000, 00 to about 60,000, about 50,000 to about 55,000, about 55,000 to about 10,000,000, about 55,000 to about 9,000,000, about 55,000 to about 8,000,000, about 55,000 to about 7,000,000, about 55,000 to about 6,000 ,000, about 55,000 to about 5,000,000, about 55,000 to about 4,000,000, about 55,000 to about 3,000,000, about 55,000 to about 2,000,000, about 55,000 to about 1,000,000, about 55,000 to about 800,000, About 55,000 to about 600,000, about 55,000 to about 400,000, about 55,000 to about 200,000, about 55,000 to about 100,000, about 55,000 to about 80,000, about 55,000 to about 75,000, about 55,000 to about 70,000, about 55,000 to about 65,000, about 55,000 to about 60,000, about 60,000 to about 10,000,000, about 60,000 to about 9,000,000, about 60,000 to about 8,000,000, about 60,000 to about 7,000,000, about 60,000 to about 6, 000,000, about 60,000 to about 5,000,000, about 60,000 to about 4,000,000, about 60,000 to about 3,000,000, about 60,000 to about 2,000,000, about 60,000 to about 1,000,000, about 60,000 to about 800,000 0, about 60,000 to about 600,000, about 60,000 to about 400,000, about 60,000 to about 200,000, about 60,000 to about 100,000, about 60,000 to about 80,000, about 60,000 to about 75,000, about 60,000 to about 70,000 , about 60,000 to about 65,000, about 65,000 to 10,000,000, about 65,000 to about 9,000,000, about 65,000 to about 8,000,000, about 65,000 to about 7,000,000, about 65,000 to about 6,000,000, about 65,000 0 to about 5,000,000, about 65,000 to about 4,000,000, about 65,000 to about 3,000,000, about 65,000 to about 2,000,000, about 65,000 to about 1,000,000, about 65,000 to about 800,000, about 65,000 to about 600,000, about 65,000 to about 400,000, about 65,000 to about 200,000, about 65,000 to about 100,000, about 65,000 to about 80,000, about 65,000 to about 75,000, about 65,000 to about 70,000, about 70,000 to about 10,000 0,000, about 70,000 to about 9,000,000, about 70,000 to about 8,000,000, about 70,000 to about 7,000,000, about 70,000 to about 6,000,000, about 70,000 to about 5,000,000, about 70,000 to about 4,000,000 0, about 70,000 to about 3,000,000, about 70,000 to about 2,000,000, about 70,000 to about 1,000,000, about 70,000 to about 800,000, about 70,000 to about 600,000, about 70,000 to about 400,000, about 70,000 to about 200,000, about 70,000 to about 100,000, about 70,000 to about 90,000, about 70,000 to about 80,000, about 80,000 to about 10,000,000, about 80,000 to about 9,000,000, about 80,000 to about 8,000,000, About 80,000 to about 7,000,000, about 80,000 to about 6,000,000, about 80,000 to about 5,000,000, about 80,000 to about 4,000,000, about 80,000 to about 3,000,000, about 80,000 to about 2,000,000, about 80, 000 to about 1,000,000, about 80,000 to about 800,000, about 80,000 to about 600,000, about 80,000 to about 400,000, about 80,000 to about 200,000, about 80,000 to about 100,000, about 80,000 to about 90,000, about 90,000 to about 10,000,000, about 90,000 to about 9,000,000, about 90,000 to about 8,000,000, about 90,000 to about 7,000,000, about 90,000 to about 6,000,000, about 90,000 to about 5,000,000, about 90, 000 to about 4,000,000, about 90,000 to about 3,000,000, about 90,000 to about 2,000,000, about 90,000 to about 1,000,000, about 90,000 to about 800,000, about 90,000 to about 600,000, about 90,000 to about 400,000, about 90,000 to about 200,000, about 90,000 to about 100,000, about 100,000 to about 10,000,000, about 100,000 to about 9,000,000, about 100,000 to about 8,000,000, about 100,000 to about 7,000,000 , about 100,000 to about 6,000,000, about 100,000 to about 5,000,000, about 100,000 to about 4,000,000, about 100,000 to about 3,000,000, about 100,000 to about 2,000,000, about 100,000 to about 1,000,000 0, about 100,000 to about 800,000, about 100,000 to about 600,000, about 100,000 to about 400,000, about 100,000 to about 200,000, about 200,000 to about 10,000,000, about 200,000 to about 9,000,000, about 20 0,000 to about 8,000,000, about 200,000 to about 7,000,000, about 200,000 to about 6,000,000, about 200,000 to about 5,000,000, about 200,000 to about 4,000,000, about 200,000 to about 3,000,000, about 2 00,000 to about 2,000,000, about 200,000 to about 1,000,000, about 200,000 to about 800,000, about 200,000 to about 600,000, about 200,000 to about 400,000, about 400,000 to about 10,000,000, about 400, 000 to about 9,000,000, about 400,000 to about 8,000,000, about 400,000 to about 7,000,000, about 400,000 to about 6,000,000, about 400,000 to about 5,000,000, about 400,000 to about 4,000,000, about 400 ,000 to about 3,000,000, about 400,000 to about 2,000,000, about 400,000 to about 1,000,000, about 400,000 to about 800,000, about 400,000 to about 600,000, about 600,000 to about 10,000,000, about 600,000 00 to about 9,000,000, about 600,000 to about 8,000,000, about 600,000 to about 7,000,000, about 600,000 to about 6,000,000, about 600,000 to about 5,000,000, about 600,000 to about 4,000,000, about 600,000 to about 3,000,000, about 600,000 to about 2,000,000, about 600,000 to about 1,000,000, about 600,000 to about 800,000, about 800,000 to about 10,000,000, about 800,000 to about 9,000,000, about 800, 000 to about 8,000,000, about 800,000 to about 7,000,000, about 800,000 to about 6,000,000, about 800,000 to about 5,000,000, about 800,000 to about 4,000,000, about 800,000 to about 3,000,000, about 800 ,000 to about 2,000,000, about 800,000 to about 1,000,000, about 1,000,000 to about 10,000,000, about 1,000,000 to about 9,000,000, about 1,000,000 to about 8,000,000, about 1,000,000 to about 7,000 ,000, about 1,000,000 to about 6,000,000, about 1,000,000 to about 5,000,000, about 1,000,000 to about 4,000,000, about 1,000,000 to about 3,000,000, about 1,000,000 to about 2,000,000, about 2,0 00,000 to about 10,000,000, about 2,000,000 to about 9,000,000, about 2,000,000 to about 8,000,000, about 2,000,000 to about 7,000,000, about 2,000,000 to about 6,000,000, about 2,000,000 to about 5 ,000,000, approximately 2,000,000 to approximately 4,000,000, approximately 2,000,000 to approximately 3,000,000, approximately 3,000,000 to approximately 10,000,000, approximately 3,000,000 to approximately 9,000,000, approximately 3,000,000 to approximately 8,000,000 , about 3,000,000 to about 7,000,000, about 3,000,000 to about 6,000,000, about 3,000,000 to about 5,000,000, about 3,000,000 to about 4,000,000, about 4,000,000 to about 10,000,000, about 4,000,000 00 to about 9,000,000, about 4,000,000 to about 8,000,000, about 4,000,000 to about 7,000,000, about 4,000,000 to about 6,000,000, about 4,000,000 to about 5,000,000, about 5,000,000 to about 10,000,000 pieces, about 5,000,000 to about 9,000,000 pieces, about 5,000,000 to about 8,000,000 pieces, about 5,000,000 to about 7,000,000 pieces, about 5,000,000 to about 6,000,000 pieces, about 6,000,000 to about 10,000,000 pieces, about 6,000,000 to about 9,000,000 pieces, about 6,000,000 to about 8,000,000 pieces, about 6,00 The METs may be 0,000 to about 7,000,000, about 7,000,000 to about 10,000,000, about 7,000,000 to about 9,000,000, about 7,000,000 to about 8,000,000, about 8,000,000 to about 10,000,000, about 8,000,000 to about 9,000,000, or about 9,000,000 to about 10,000,000.

[0071] The phrase "antigen density" refers to the number of METs present on the surface of a target mammalian cell, or the average number of METs on the surface of a population of target mammalian cells of a particular type, which can be measured, for example, using a Quantibright bead kit or radiolabeling (e.g., BD Biosciences PE Phycoerythrin Fluorescence Quantitation Kit, Catalog No. 340495).

[0072] The phrase "amino acid substituted with histidine" refers to the substitution of a non-histidine amino acid residue in a reference polypeptide sequence with histidine. Non-limiting methods for substituting an amino acid residue in a reference polypeptide with histidine are described herein. Additional methods for substituting an amino acid residue in a reference polypeptide with histidine are known in the art.

[0073] The phrase "amino acid substituted with alanine" refers to the substitution of an amino acid residue that is a histidine in a reference polypeptide sequence with alanine. Non-limiting methods for substituting alanine for histidine in a reference polypeptide are described herein. Additional methods for substituting alanine for histidine in a reference polypeptide are known in the art.

[0074] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs. Methods and materials for use in the present invention are described herein; however, other suitable methods and materials known in the art may also be used. These materials, methods, and examples are illustrative only and are not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

[0075] Other features and advantages of the invention will become apparent from the following detailed description and drawings, and from the claims. [Brief explanation of the drawings]

[0076] [Figure 1A] Figures 1A-C show the cellular uptake and endolysosomal delivery of histidine-scanning and alanine-scanning variants of emibetuzumab and P3D12 in Detroit 562 cells. Histidine-scanning and alanine-scanning variants of the heavy chain combinations MYT4826 (emibetuzumab) and MYT4325 (P3D12) were assayed for cellular uptake in Detroit 562 cells at the indicated time points and final ABPC concentrations using Incucyte Human FabFluor-pH Red antibody labeling reagent. The fold increase in cellular uptake and endolysosomal delivery is indicated by the numbers above each variant. All variants contain TH and YTE substitution forms. [Figure 1B] Same as above. [Figure 1C] Same as above. [Figure 2]Figure 2 shows the binding of histidine-scanning and alanine-scanning mutants of telisotuzumab to MET by biolayer interferometry. MYT4953, a heavy chain combination of histidine-scanning and alanine-scanning mutants, was captured on an anti-human Fc biosensor and allowed to bind to MET at pH 7.4. Dissociation was at pH 7.4 (black trace) or pH 5.4 (gray trace). All mutants contain TH and YTE substitution forms. [Figure 3A] Figures 3a-3c show the binding of histidine-scanning and alanine-scanning mutants of P3D12 to MET by biolayer interferometry. Histidine-scanning and alanine-scanning mutants of the heavy chain combinations MYT4312, MYT4313, and MYT4325 were captured on an anti-human Fc biosensor and allowed to bind to MET at low or high pH, ​​as indicated in the figure. All mutants contain TH and YTE substitution forms. [Figure 3B] Same as above. [Figure 3C] Same as above. [Figure 4A] Figures 4A-4D show the binding of histidine and alanine scanning mutants of P3D12 and emibetuzumab to MET by biolayer interferometry. Paired heavy and light chain histidine and alanine scanning mutants, MYT5344, MYT5351, MYT5367, and MYT4826, combined with light chain histidine and alanine scanning mutants or light chain combinations with heavy chain histidine and alanine scanning mutants or heavy chain combinations, were captured on an anti-human Fc biosensor and allowed to bind to MET at pH 7.4. Dissociation was performed at pH 7.4 (black trace) or pH 5.4 (gray trace). All mutants contain TH and YTE substitution forms. [Figure 4B] Same as above. [Figure 4C] Same as above. [Figure 4D] Same as above. [Figure 5-1] FIG. 5 is a table listing the various antibodies tested with their variable heavy and light chain sequences. [Figure 5-2] Same as above. [Figure 5-3] Same as above. [Figure 6] Figure 6 shows the cellular uptake and endolysosomal delivery of histidine-scanning and alanine-scanning variants of MYT mutants in Detroit 562 cells. The following heavy chain combinations of histidine-scanning and alanine-scanning variants were assayed for cellular uptake in Detroit 562 cells at the indicated time points and final antibody concentrations using Incucyte Human FabFluor-pH Red antibody labeling reagent. The fold increase in cellular uptake and endolysosomal delivery is indicated by the numbers next to each variant. All variants contain TH and YTE substitution forms.

[0077] [Figure 7A] 7A to 7G show the binding of histidine-scanning mutants and alanine-scanning mutants to MET by biolayer interferometry. [Figure 7B] Same as above. [Figure 7C] Same as above. [Figure 7D] Same as above. [Figure 7E] Same as above. [Figure 7F] Same as above. [Figure 7G] Same as above. DETAILED DESCRIPTION OF THE INVENTION

[0078] Paired heavy and light chain histidine and alanine scanning mutants, MYT4940, MYT4942, MYT4888, MYT4827, MYT4837, MYT4849, and MYT5309, in which light chain histidine and alanine scanning mutants or light chain combination histidine and alanine scanning mutants were combined with heavy chain histidine and alanine scanning mutants or heavy chain combination histidine and alanine scanning mutants, were captured on an anti-human Fc biosensor and bound to MET at pH 7.4. The black trace represents pH 7.4, the red trace represents association at 7.4 followed by dissociation at pH 6.4, and the orange trace represents pH 6.4. All mutants contain TH and YTE substitution formats.

[0079] Provided herein are antibodies capable of specifically binding to MET or an epitope of MET displayed on the surface of a target mammalian cell, wherein the antibodies (a) have a faster dissociation rate at a pH of about 4.0 to about 6.5 than at a pH of about 7.0 to about 8.0, and / or (b) have a dissociation constant (K) at a pH of about 4.0 to about 6.5 that is greater than the dissociation rate at a pH of about 7.0 to about 8.0. D ) at pH 7.0 to 8.0 D In some embodiments of these antibodies, the antibody is degraded in the target mammalian cell after intracellular uptake of the antibody by the target mammalian cell. Some embodiments of any of the antibodies described herein may further include a conjugated toxin, radioisotope, drug, or small molecule (e.g., a fluorophore or dye).

[0080] Also provided are antibodies capable of specifically binding to MET or an epitope of MET displayed on the surface of a target mammalian cell, and conjugated toxins, radioisotopes, drugs, or small molecules, which (a) have a faster dissociation rate at a pH of about 4.0 to about 6.5 than at a pH of about 7.0 to about 8.0, and / or a dissociation constant (K) at a pH of about 4.0 to about 6.5 that is greater than or equal to 100% of the dissociation rate at a pH of about 4.0 to about 6.5. D ) at pH 7.0 to 8.0 Dand (b) a composition comprising the antibody results in one or more (e.g., two or three) of: increased (e.g., a detectable increase) in toxin release in target mammalian cells compared to a composition comprising the same amount of control antibody; increased (e.g., a detectable increase) in killing of target mammalian cells compared to a composition comprising the same amount of control antibody; and increased (e.g., a detectable increase) in endolysosomal delivery in target mammalian cells compared to a composition comprising the same amount of control antibody.

[0081] In some embodiments of any of the antibodies described herein, the antibody comprises a heavy chain variable domain and a light chain variable domain of telisotuzumab, and / or a heavy chain CH1-CH2-CH3 domain and / or a C L In some embodiments of any of the antibodies described herein, the antibody comprises a heavy chain variable domain and a light chain variable domain of emibetuzumab, and a heavy chain CH1-CH2-CH3 domain and / or a C domain of emibetuzumab. L In some embodiments of any of the antibodies described herein, the antibody comprises one or more amino acid substitutions within the heavy chain variable domain and light chain variable domain of P3D12 anti-cMET, and the heavy chain CH1-CH2-CH3 domain and / or C domain of P3D12-cMet. L It contains one or more amino acid substitutions within the domain.

[0082] In some embodiments of any of the antibodies described herein, the antibody comprises (a) a heavy chain variable domain and a light chain variable domain, each of which comprises: (i) SEQ ID NO:5 and SEQ ID NO:6, respectively; (ii) SEQ ID NO:7 and SEQ ID NO:8, respectively; (iii) SEQ ID NO:9 and SEQ ID NO:10, respectively; (iv) SEQ ID NO:11 and SEQ ID NO:12, respectively; (v) SEQ ID NO:13 and SEQ ID NO:14, respectively; (vi) SEQ ID NO:15 and SEQ ID NO:16, respectively; (vii) SEQ ID NO:17 and SEQ ID NO:18, respectively; (viii) SEQ ID NO:19 and SEQ ID NO:20, respectively; (ix) SEQ ID NO:21 and SEQ ID NO:22, respectively; (x) SEQ ID NO:23 and SEQ ID NO:24, respectively; (xi) SEQ ID NO:25 and SEQ ID NO:26, respectively; (xii) SEQ ID NO:27 and SEQ ID NO:28, respectively; (xiii) SEQ ID NO:29 and SEQ ID NO:30, respectively; (xiv) SEQ ID NO:31 and SEQ ID NO:31, respectively; 2, (xv) a heavy chain variable domain and a light chain variable domain selected from the group consisting of SEQ ID NO: 33 and SEQ ID NO: 34, respectively; and (b) a heavy chain CH1-CH2-CH3 sequence of SEQ ID NO: 155 or SEQ ID NO: 189, comprising one or more of: (i) a lysine to cysteine ​​substitution at amino acid position 105 and deletion of threonine at amino acid positions 106 and 108; (ii) a methionine to tyrosine substitution at amino acid position 135, a serine to threonine substitution at amino acid position 137, and a threonine to glutamic acid substitution at amino acid position 139; (iii) a methionine to leucine substitution at amino acid position 311 and an asparagine to serine substitution at amino acid position 317; and / or a light chain C1 sequence of SEQ ID NO: 157. L Light chain C of SEQ ID NO: 157, which contains a valine to cysteine ​​substitution at amino acid position 98 L Arrays, including

[0083] In some embodiments of any of the antibodies described herein, the heavy chain CH1-CH2-CH3 sequence of SEQ ID NO: 155 or SEQ ID NO: 189 includes a lysine to cysteine ​​substitution at amino acid position 105 and a deletion of threonines at amino acid positions 106 and 108. In some embodiments of any of the antibodies described herein, the heavy and light chain sequences are (i) SEQ ID NO:35 and SEQ ID NO:41, respectively; (ii) SEQ ID NO:43 and SEQ ID NO:49, respectively; (iii) SEQ ID NO:51 and SEQ ID NO:57, respectively; (iv) SEQ ID NO:59 and SEQ ID NO:65, respectively; (v) SEQ ID NO:67 and SEQ ID NO:73, respectively; (vi) SEQ ID NO:75 and SEQ ID NO:81, respectively; (vii) SEQ ID NO:83 and SEQ ID NO:89, respectively; (viii) SEQ ID NO:91 and SEQ ID NO:97, respectively; (ix) SEQ ID NO:99 and SEQ ID NO:105, respectively; (x) SEQ ID NO:107 and SEQ ID NO:113, respectively; (xi) SEQ ID NO:115 and SEQ ID NO:121, respectively; (xii) SEQ ID NO:123 and SEQ ID NO:129, respectively; (xiii) SEQ ID NO:131 and SEQ ID NO:137, respectively; (xiv) SEQ ID NO:139 and SEQ ID NO:145, respectively; or (xv) SEQ ID NO:147 and SEQ ID NO:153, respectively.

[0084] In some examples of any of the antibodies described herein, the heavy chain CH1-CH2-CH3 sequence of SEQ ID NO: 155 or SEQ ID NO: 189 includes a lysine to cysteine ​​substitution at amino acid position 105, and a deletion of threonines at amino acid positions 106 and 108, as well as a methionine to leucine substitution at amino acid position 311, and an asparagine to serine substitution at amino acid position 317. In some embodiments of any of the antibodies described herein, the heavy and light chain sequences are (i) SEQ ID NO:36 and SEQ ID NO:41, respectively; (ii) SEQ ID NO:44 and SEQ ID NO:49, respectively; (iii) SEQ ID NO:52 and SEQ ID NO:57, respectively; (iv) SEQ ID NO:60 and SEQ ID NO:65, respectively; (v) SEQ ID NO:68 and SEQ ID NO:73, respectively; (vi) SEQ ID NO:76 and SEQ ID NO:81, respectively; (vii) SEQ ID NO:84 and SEQ ID NO:89, respectively; (viii) SEQ ID NO:92 and SEQ ID NO:97, respectively; (ix) SEQ ID NO:100 and SEQ ID NO:105, respectively; (x) SEQ ID NO:108 and SEQ ID NO:113, respectively; (xi) SEQ ID NO:116 and SEQ ID NO:121, respectively; (xii) SEQ ID NO:124 and SEQ ID NO:129, respectively; (xiii) SEQ ID NO:132 and SEQ ID NO:137, respectively; (xiv) SEQ ID NO:140 and SEQ ID NO:145, respectively; or (xv) SEQ ID NO:148 and SEQ ID NO:153, respectively.

[0085] In some embodiments of any of the antibodies described herein, the heavy chain CH1-CH2-CH3 sequence of SEQ ID NO: 155 or SEQ ID NO: 189 includes a lysine to cysteine ​​substitution at amino acid position 105 and a deletion of threonines at amino acid positions 106 and 108, as well as a methionine to tyrosine substitution at amino acid position 135, a serine to threonine substitution at amino acid position 137, and a threonine to glutamic acid substitution at amino acid position 139. In some embodiments of any of the antibodies described herein, the heavy and light chain sequences are (i) SEQ ID NO:37 and SEQ ID NO:41, respectively; (ii) SEQ ID NO:45 and SEQ ID NO:49, respectively; (iii) SEQ ID NO:53 and SEQ ID NO:57, respectively; (iv) SEQ ID NO:61 and SEQ ID NO:65, respectively; (v) SEQ ID NO:69 and SEQ ID NO:73, respectively; (vi) SEQ ID NO:77 and SEQ ID NO:81, respectively; (vii) SEQ ID NO:85 and SEQ ID NO:89, respectively; (viii) SEQ ID NO:93 and SEQ ID NO:97, respectively; (ix) SEQ ID NO:101 and SEQ ID NO:105, respectively; (x) SEQ ID NO:109 and SEQ ID NO:113, respectively; (xi) SEQ ID NO:117 and SEQ ID NO:121, respectively; (xii) SEQ ID NO:125 and SEQ ID NO:129, respectively; (xiii) SEQ ID NO:133 and SEQ ID NO:137, respectively; (xiv) SEQ ID NO:141 and SEQ ID NO:145, respectively; or (xv) SEQ ID NO:149 and SEQ ID NO:153, respectively.

[0086] In some embodiments of any of the antibodies described herein, the heavy chain CH1-CH2-CH3 sequence of SEQ ID NO: 155 or SEQ ID NO: 189 includes a lysine to cysteine ​​substitution at amino acid position 105 and a deletion of threonines at amino acid positions 106 and 108, and the light chain C sequence of SEQ ID NO: 157 includes a cysteine ​​to lysine substitution at amino acid position 105 and a deletion of threonines at amino acid positions 106 and 108. LThe sequence comprises a valine to cysteine ​​substitution at amino acid position 98. In some embodiments of any of the antibodies described herein, the heavy and light chain sequences are (i) SEQ ID NO:35 and SEQ ID NO:42, respectively, (ii) SEQ ID NO:43 and SEQ ID NO:50, respectively, (iii) SEQ ID NO:51 and SEQ ID NO:58, respectively, (iv) SEQ ID NO:59 and SEQ ID NO:66, respectively, (v) SEQ ID NO:67 and SEQ ID NO:74, respectively, (vi) SEQ ID NO:75 and SEQ ID NO:82, respectively, (vii) SEQ ID NO:83 and SEQ ID NO:90, respectively, (viii) SEQ ID NO:91 and SEQ ID NO:98, respectively, (ix) SEQ ID NO:99 and SEQ ID NO:106, respectively, (x) SEQ ID NO:107 and SEQ ID NO:114, respectively, (xi) SEQ ID NO:115 and SEQ ID NO:122, respectively, (xii) SEQ ID NO:123 and SEQ ID NO:130, respectively, (xiii) SEQ ID NO:131 and SEQ ID NO:138, respectively, (xiv) SEQ ID NO:139 and SEQ ID NO:146, respectively, or (xv) SEQ ID NO:147 and SEQ ID NO:154, respectively.

[0087] In some embodiments of any of the antibodies described herein, the heavy chain CH1-CH2-CH3 sequence of SEQ ID NO: 155 or SEQ ID NO: 189 includes a lysine to cysteine ​​substitution at amino acid position 105, and a deletion of threonines at amino acid positions 106 and 108, as well as a methionine to leucine substitution at amino acid position 311, and an asparagine to serine substitution at amino acid position 317; and the light chain C sequence of SEQ ID NO: 157 includes a lysine to cysteine ​​substitution at amino acid position 105, and a deletion of threonines at amino acid positions 106 and 108, as well as a methionine to leucine substitution at amino acid position 311, and an asparagine to serine substitution at amino acid position 317. LThe sequence comprises a valine to cysteine ​​substitution at amino acid position 98. In some embodiments of any of the antibodies described herein, the heavy and light chain sequences are (i) SEQ ID NO:36 and SEQ ID NO:42, respectively, (ii) SEQ ID NO:44 and SEQ ID NO:50, respectively, (iii) SEQ ID NO:52 and SEQ ID NO:58, respectively, (iv) SEQ ID NO:60 and SEQ ID NO:66, respectively, (v) SEQ ID NO:68 and SEQ ID NO:74, respectively, (vi) SEQ ID NO:76 and SEQ ID NO:82, respectively, (vii) SEQ ID NO:84 and SEQ ID NO:90, respectively, (viii) SEQ ID NO:92 and SEQ ID NO:98, respectively, (ix) SEQ ID NO:100 and SEQ ID NO:106, respectively, (x) SEQ ID NO:108 and SEQ ID NO:114, respectively, (xi) SEQ ID NO:116 and SEQ ID NO:122, respectively, (xii) SEQ ID NO:124 and SEQ ID NO:130, respectively, (xiii) SEQ ID NO:132 and SEQ ID NO:138, respectively, (xiv) SEQ ID NO:140 and SEQ ID NO:146, respectively, or (xv) SEQ ID NO:148 and SEQ ID NO:154, respectively.

[0088] In some embodiments of any of the antibodies described herein, the heavy chain CH1-CH2-CH3 sequence of SEQ ID NO: 155 or SEQ ID NO: 189 includes a lysine to cysteine ​​substitution at amino acid position 105 and a deletion of threonines at amino acid positions 106 and 108, as well as a methionine to tyrosine substitution at amino acid position 135, a serine to threonine substitution at amino acid position 137, and a threonine to glutamic acid substitution at amino acid position 139; and the light chain C LThe sequence comprises a valine to cysteine ​​substitution at amino acid position 98. In some embodiments of any of the antibodies described herein, the heavy and light chain sequences are (i) SEQ ID NO:37 and SEQ ID NO:42, respectively, (ii) SEQ ID NO:45 and SEQ ID NO:50, respectively, (iii) SEQ ID NO:53 and SEQ ID NO:58, respectively, (iv) SEQ ID NO:61 and SEQ ID NO:66, respectively, (v) SEQ ID NO:69 and SEQ ID NO:74, respectively, (vi) SEQ ID NO:77 and SEQ ID NO:82, respectively, (vii) SEQ ID NO:85 and SEQ ID NO:90, respectively, (viii) SEQ ID NO:93 and SEQ ID NO:98, respectively, (ix) SEQ ID NO:101 and SEQ ID NO:106, respectively, (x) SEQ ID NO:109 and SEQ ID NO:114, (xi) SEQ ID NO:117 and SEQ ID NO:122, respectively, (xii) SEQ ID NO:125 and SEQ ID NO:130, respectively, (xiii) SEQ ID NO:133 and SEQ ID NO:138, respectively, (xiv) SEQ ID NO:141 and SEQ ID NO:146, respectively, or (xv) SEQ ID NO:149 and SEQ ID NO:154, respectively.

[0089] In some embodiments of any of the antibodies described herein, the heavy chain CH1-CH2-CH3 sequence of SEQ ID NO: 155 or SEQ ID NO: 189 includes a lysine to cysteine ​​substitution at amino acid position 105, and deletion of threonines at amino acid positions 106 and 108, and an alanine to cysteine ​​substitution at amino acid position 1. In some embodiments of any of the antibodies described herein, the heavy and light chain sequences are (i) SEQ ID NO:38 and SEQ ID NO:41, respectively; (ii) SEQ ID NO:46 and SEQ ID NO:49, respectively; (iii) SEQ ID NO:54 and SEQ ID NO:57, respectively; (iv) SEQ ID NO:62 and SEQ ID NO:65, respectively; (v) SEQ ID NO:70 and SEQ ID NO:73, respectively; (vi) SEQ ID NO:78 and SEQ ID NO:81, respectively; (vii) SEQ ID NO:86 and SEQ ID NO:89, respectively; (viii) SEQ ID NO:94 and SEQ ID NO:97, respectively; (ix) SEQ ID NO:102 and SEQ ID NO:105, respectively; (x) SEQ ID NO:110 and SEQ ID NO:113, respectively; (xi) SEQ ID NO:118 and SEQ ID NO:121, respectively; (xii) SEQ ID NO:126 and SEQ ID NO:129, respectively; (xiii) SEQ ID NO:134 and SEQ ID NO:137, respectively; (xiv) SEQ ID NO:142 and SEQ ID NO:145, respectively; or (xv) SEQ ID NO:150 and SEQ ID NO:153, respectively.

[0090] In some embodiments of any of the antibodies described herein, the heavy chain CH1-CH2-CH3 sequence of SEQ ID NO: 155 or SEQ ID NO: 189 includes a lysine to cysteine ​​substitution at amino acid position 105 and deletion of threonines at amino acid positions 106 and 108, a methionine to leucine substitution at amino acid position 311 and an asparagine to serine substitution at amino acid position 317, and an alanine to cysteine ​​substitution at amino acid position 1. In some embodiments of any of the antibodies described herein, the heavy and light chain sequences are (i) SEQ ID NO:39 and SEQ ID NO:41, respectively; (ii) SEQ ID NO:47 and SEQ ID NO:49, respectively; (iii) SEQ ID NO:55 and SEQ ID NO:57, respectively; (iv) SEQ ID NO:63 and SEQ ID NO:65, respectively; (v) SEQ ID NO:71 and SEQ ID NO:73, respectively; (vi) SEQ ID NO:79 and SEQ ID NO:81, respectively; (vii) SEQ ID NO:87 and SEQ ID NO:89, respectively; (viii) SEQ ID NO:95 and SEQ ID NO:97, respectively; (ix) SEQ ID NO:103 and SEQ ID NO:105, respectively; (x) SEQ ID NO:111 and SEQ ID NO:113, respectively; (xi) SEQ ID NO:119 and SEQ ID NO:121, respectively; (xii) SEQ ID NO:127 and SEQ ID NO:129, respectively; (xiii) SEQ ID NO:135 and SEQ ID NO:137, respectively; (xiv) SEQ ID NO:143 and SEQ ID NO:145, respectively; or (xv) SEQ ID NO:151 and SEQ ID NO:153, respectively.

[0091] In some embodiments of any of the antibodies described herein, the heavy chain CH1-CH2-CH3 sequence of SEQ ID NO: 155 or SEQ ID NO: 189 includes a lysine to cysteine ​​substitution at amino acid position 105 and deletion of threonines at amino acid positions 106 and 108, a methionine to tyrosine substitution at amino acid position 135, a serine to threonine substitution at amino acid position 137, and a threonine to glutamic acid substitution at amino acid position 139, and an alanine to cysteine ​​substitution at amino acid position 1. In some embodiments of any of the antibodies described herein, the heavy and light chain sequences are (i) SEQ ID NO:40 and SEQ ID NO:41, respectively; (ii) SEQ ID NO:48 and SEQ ID NO:49, respectively; (iii) SEQ ID NO:56 and SEQ ID NO:57, respectively; (iv) SEQ ID NO:64 and SEQ ID NO:65, respectively; (v) SEQ ID NO:72 and SEQ ID NO:73, respectively; (vi) SEQ ID NO:80 and SEQ ID NO:81, respectively; (vii) SEQ ID NO:88 and SEQ ID NO:89, respectively; (viii) SEQ ID NO:96 and SEQ ID NO:97, respectively; (ix) SEQ ID NO:104 and SEQ ID NO:105, respectively; (x) SEQ ID NO:112 and SEQ ID NO:113, respectively; (xi) SEQ ID NO:120 and SEQ ID NO:121, respectively; (xii) SEQ ID NO:128 and SEQ ID NO:129, respectively; (xiii) SEQ ID NO:136 and SEQ ID NO:137, respectively; (xiv) SEQ ID NO:144 and SEQ ID NO:145, respectively; or (xv) SEQ ID NO:152 and SEQ ID NO:153, respectively.

[0092] In some embodiments, (a) the dissociation rate of the antibody at about pH 4.0 to about 6.5 is no faster than the dissociation rate at about pH 7.0 to about 8.0; or (b) the dissociation constant (K D ) at pH 7.0 to 8.0 D is greater than.

[0093] In such examples, the antibody comprises: (a) heavy and light chain variable domains selected from the group consisting of: (i) SEQ ID NO: 159 and SEQ ID NO: 160, respectively; (ii) SEQ ID NO: 161 and SEQ ID NO: 162, respectively; and (iii) SEQ ID NO: 163 and SEQ ID NO: 164, respectively; (b) a heavy chain CH1-CH2-CH3 sequence of SEQ ID NO: 155 or SEQ ID NO: 189, comprising: (i) a lysine to cysteine ​​substitution at amino acid position 105 and deletion of threonine amino acids at amino acid positions 106 and 108; (ii) an amino acid substitution of cysteine ​​at amino acid position 109 and deletion of threonine amino acids at amino acid positions 109 and 110; a heavy chain CH1-CH2-CH3 sequence of SEQ ID NO: 155 or SEQ ID NO: 189, comprising one or more of: (i) a methionine to tyrosine substitution at amino acid position 135, a serine to threonine substitution at amino acid position 137, and a threonine to glutamic acid substitution at amino acid position 139; (ii) a methionine to leucine substitution at amino acid position 311 and an asparagine to serine substitution at amino acid position 317; and (iii) an alanine to cysteine ​​substitution at amino acid position 1; and / or a light chain C1-CH2-CH3 sequence of SEQ ID NO: 157, comprising a valine to cysteine ​​substitution at position 98. L Arrays, including

[0094] In such examples, the heavy chain CH1-CH2-CH3 sequence of SEQ ID NO: 155 or SEQ ID NO: 189 comprises a lysine to cysteine ​​substitution at amino acid position 105 and a deletion of threonines at amino acid positions 106 and 108 of SEQ ID NO: 155 or SEQ ID NO: 189. In some examples, the heavy and light chain sequences are (i) SEQ ID NO: 165 and SEQ ID NO: 171, respectively, (ii) SEQ ID NO: 173 and SEQ ID NO: 179, respectively, or (iii) SEQ ID NO: 181 and SEQ ID NO: 187, respectively.

[0095] In some examples, the heavy chain CH1-CH2-CH3 sequence of SEQ ID NO:155 or SEQ ID NO:189 comprises a lysine to cysteine ​​substitution at amino acid position 105, and deletion of threonines at amino acid positions 106 and 108, as well as a methionine to leucine substitution at amino acid position 311 and an asparagine to serine substitution at amino acid position 317. In some examples, the heavy and light chain sequences are (i) SEQ ID NO:166 and SEQ ID NO:171, respectively, (ii) SEQ ID NO:174 and SEQ ID NO:179, respectively, or (iii) SEQ ID NO:182 and SEQ ID NO:187, respectively.

[0096] In some examples, the heavy chain CH1-CH2-CH3 sequence of SEQ ID NO: 155 or SEQ ID NO: 189 contains a lysine to cysteine ​​substitution at amino acid position 105 and deletions of threonines at amino acid positions 106 and 108, and the light chain C sequence of SEQ ID NO: 157 contains a cysteine ​​to lysine substitution at amino acid position 105 and deletions of threonines at amino acid positions 106 and 108. L The sequence comprises a valine to cysteine ​​substitution at amino acid position 98. In some examples, the heavy and light chain sequences are (i) SEQ ID NO: 165 and SEQ ID NO: 172, respectively, (ii) SEQ ID NO: 173 and SEQ ID NO: 180, respectively, or (iii) SEQ ID NO: 181 and SEQ ID NO: 188, respectively.

[0097] In some examples, the heavy chain CH1-CH2-CH3 sequence of SEQ ID NO: 155 or SEQ ID NO: 189 comprises a lysine to cysteine ​​substitution at amino acid position 105, a deletion of threonines at amino acid positions 106 and 108, a methionine to leucine substitution at amino acid position 311, and an asparagine to serine substitution at amino acid position 317; and the light chain C L The sequence comprises a valine to cysteine ​​substitution at amino acid position 98. In some examples, the heavy and light chain sequences are (i) SEQ ID NO: 166 and SEQ ID NO: 172, respectively, (ii) SEQ ID NO: 174 and SEQ ID NO: 180, respectively, or (iii) SEQ ID NO: 182 and SEQ ID NO: 188, respectively.

[0098] In some examples, the heavy chain CH1-CH2-CH3 sequence of SEQ ID NO: 155 or SEQ ID NO: 189 comprises a lysine to cysteine ​​substitution at amino acid position 105, and deletion of threonines at amino acid positions 106 and 108, as well as a methionine to tyrosine substitution at amino acid position 135, a serine to threonine substitution at amino acid position 137, and a threonine to glutamic acid substitution at amino acid position 139; and the light chain C sequence of SEQ ID NO: 157. L The sequence comprises a valine to cysteine ​​substitution at amino acid position 98. In some examples, the heavy and light chain sequences are (i) SEQ ID NO: 167 and SEQ ID NO: 172, respectively, (ii) SEQ ID NO: 175 and SEQ ID NO: 180, respectively, or (iii) SEQ ID NO: 183 and SEQ ID NO: 188, respectively.

[0099] In some examples, the heavy chain CH1-CH2-CH3 sequence of SEQ ID NO:155 or SEQ ID NO:189 contains a lysine to cysteine ​​substitution at amino acid position 105, and deletions of threonines at amino acid positions 106 and 108, and an alanine to cysteine ​​substitution at amino acid position 1. In such examples, the heavy and light chain sequences are (i) SEQ ID NO:168 and SEQ ID NO:171, respectively, (ii) SEQ ID NO:176 and SEQ ID NO:179, respectively, or (iii) SEQ ID NO:184 and SEQ ID NO:187, respectively.

[0100] In some examples, the heavy chain CH1-CH2-CH3 sequence of SEQ ID NO:155 or SEQ ID NO:189 comprises a lysine to cysteine ​​substitution at amino acid position 105 and deletion of threonines at amino acid positions 106 and 108, a methionine to leucine substitution at amino acid position 311 and an asparagine to serine substitution at amino acid position 317, and an alanine to cysteine ​​substitution at amino acid position 1. In some examples, the heavy and light chain sequences are (i) SEQ ID NO:169 and SEQ ID NO:171, respectively, (ii) SEQ ID NO:177 and SEQ ID NO:179, respectively, or (iii) SEQ ID NO:185 and SEQ ID NO:187, respectively.

[0101] In some examples, the heavy chain CH1-CH2-CH3 sequence of SEQ ID NO:155 or SEQ ID NO:189 comprises a lysine to cysteine ​​substitution at amino acid position 105 and deletion of threonines at amino acid positions 106 and 108, a methionine to tyrosine substitution at amino acid position 135, a serine to threonine substitution at amino acid position 137 and a threonine to glutamic acid substitution at amino acid position 139, and an alanine to cysteine ​​substitution at amino acid position 1. In some examples, the heavy chain and light chain sequences are (i) SEQ ID NO:170 and SEQ ID NO:171, respectively, (ii) SEQ ID NO:178 and SEQ ID NO:179, respectively, or (iii) SEQ ID NO:186 and SEQ ID NO:187, respectively.

[0102] Also provided herein are pharmaceutical compositions comprising any of the antibodies described herein. Also provided herein are methods of treating a subject in need thereof, comprising administering to the subject a therapeutically effective amount of any of the antibodies described herein.

[0103] In some embodiments of any of the antibodies described herein, a composition comprising the antibody (e.g., any of the antibodies described herein) may exhibit an increase (e.g., a detectable increase) (e.g., at least a 1% increase, at least a 2% increase, at least a 5% increase, at least a 10% increase, at least a 15% increase, at least a 20% increase, at least a 25% increase, at least a 30% increase, at least a 35% increase, at least a 40% increase, at least a 45% increase, at least a 50% increase, at least a 55% increase, at least a 60% increase, at least a 65% increase, at least a 70% increase, at least a 75% increase, at least a 80% increase, at least a 85% increase, at least a 90% increase, at least a 95% increase, at least a 100% increase, at least a 120% increase, at least a 140 ... % increase, at least a 160% increase, at least a 180% increase, at least a 200% increase, at least a 250% increase, at least a 300% increase, at least a 350% increase, at least a 400% increase, at least a 450% increase, at least a 500% increase, at least a 1,000% increase, at least a 2,000% increase, at least a 3,000% increase, at least a 4,000% increase, at least a 5,000% increase, at least a 6,000% increase, at least a 7,000% increase , at least an 8,000% increase, at least a 9,000% increase, or at least a 10,000% increase, or about a 1% increase to about a 10,000% increase, about a 1% increase to about a 9,000% increase, about a 1% increase to about a 8,000% increase, about a 1% increase to about a 7,000% increase, about a 1% increase to about a 6,000% increase, about a 1% increase to about a 5,000% increase, about a 1% increase to about a 4,000% increase, about a 1% increase to about a 3,000% increase, about a 1% increase to about a 2,000% increase, about a 1% increase to about a 1,000% increase, approximately 1% increase to approximately 500% increase, approximately 1% increase to approximately 450% increase, approximately 1% increase to approximately 400% increase, approximately 1% increase to approximately 350% increase, approximately 1% increase to approximately 300% increase, approximately 1% increase to approximately 250% increase, approximately 1% increase to approximately 200% increase, approximately 1% increase to approximately 180% increase, approximately 1% increase to approximately 160% increase, approximately 1% increase to approximately 140% increase, approximately 1% increase to approximately 120% increase, approximately 1% increase to approximately 100% increase, approximately 1% increase to approximately 95% increase, approximately 1% increase to approximately 90% increase, approximately 1% increase to approximately 85% increase, approximately 1% increase to approximately 80% increase, approximately 1% increase to approximately 75% increase, approximately 1% increase to approximately 70% increase, approximately 1% increase to approximately 65% ​​increase, approximately 1% increase to approximately 60% increase, approximately 1% increase to approximately 55% increase, approximately 1% increase to approximately 50% increase, approximately 1% increase to approximately 45% increase, approximately 1% increase to approximately 40% increase, approximately 1% increase to approximately 35% increase, approximately 1% increase to approximately 25% increase, approximately 1% increase to approximately 20% increase, approximately 1% increase to approximately 15% increase, approximately 1% increase to approximately 10% increase, approximately 1% increase to approximately 5% increase, approximately 2% increase to approximately 10,000% increase, approximately 2% increase to approximately 9,000% increase, approximately 2% increase to approximately 8,000% increase, approximately 2% increase to approximately 7,000% increase, approximately 2% increase to approximately 6,000% increase, approximately 2% increase to approximately 5,000% increase, approximately 2% increase to approximately 4,000% increase, approximately 2% increase to approximately 3,000% increase, approximately 2% increase to approximately 2,000% increase, approximately 2% increase to approximately 1,000% increase, approximately 2% increase to approximately 500% increase, approximately 2% increase to approximately 450% increase, approximately 2% increase to approximately 400% increase, approximately 2% increase to approximately 350% increase, approximately 2% increase to approximately 300% increase, approximately 2% increase to approximately 250% increase, approximately 2% increase to approximately 200% increase, approximately 2% increase to approximately 180% increase, approximately 2% increase to approximately 160% increase, approximately 2% increase to approximately 140% increase, approximately 2% increase to approximately 120% increase, approximately 2% increase to approximately 100% increase, approximately 2% increase to approximately 95% increase, approximately 2% increase to approximately 90% increase, approximately 2% increase to approximately 85% increase, approximately 2% increase to approximately 80% increase, approximately 2% increase to approximately 75% increase, approximately 2% increase to approximately 70% increase, approximately 2% increase to approximately 65% ​​increase, approximately 2% increase to approximately 60% increase, approximately 2% increase to approximately 55% increase, approximately 2% increase to approximately 50% increase, approximately 2% increase to approximately 45% increase, approximately 2% increase to approximately 40% increase, approximately 2% increase to approximately 35% increase, approximately 2% increase to approximately 25% increase, approximately 2% increase to approximately 20% increase, approximately 2% increase to approximately 15% increase, approximately 2% increase to approximately 10% increase, approximately 2% increase to approximately 5% increase, approximately 5% increase to approximately 10,000% increase, approximately 5% increase to approximately 9,000% increase, approximately 5% increase to approximately 8,000% increase, approximately 5% increase to approximately 7,000% increase, approximately 5% increase to approximately 6,000% increase, approximately 5% increase to approximately 5,000% increase, approximately 5% increase to approximately 4,000% increase, approximately 5% increase to approximately 3,000% increase, approximately 5% increase to approximately 2,000% increase, approximately 5% increase to approximately 1,000% increase, approximately 5% increase to approximately 500% increase, approximately 5% increase to approximately 450% increase, approximately 5% increase to approximately 400% increase, approximately 5% increase to approximately 350% increase, approximately 5% increase to approximately 300% increase, approximately 5% increase to approximately 250% increase, approximately 5% increase to approximately 200% increase, approximately 5% increase to approximately 180% increase, approximately 5% increase to approximately 160% increase, approximately 5% increase to approximately 140% increase, approximately 5% increase to approximately 120% increase, approximately 5% increase to approximately 100% increase, approximately 5% increase to approximately 95% increase, approximately 5% increase to approximately 90% increase, approximately 5% increase to approximately 85% increase, approximately 5% increase to approximately 80% increase, approximately 5% increase to approximately 75% increase, approximately 5% increase to approximately 70% increase, approximately 5% increase to approximately 65% ​​increase, approximately 5% increase to approximately 60% increase , approximately 5% increase to approximately 55% increase, approximately 5% increase to approximately 50% increase, approximately 5% increase to approximately 45% increase, approximately 5% increase to approximately 40% increase, approximately 5% increase to approximately 35% increase, approximately 5% increase to approximately 25% increase, approximately 5% increase to approximately 20% increase, approximately 5% increase to approximately 15% increase, approximately 5% increase to approximately 10% increase, approximately 10% increase to approximately 10,000% increase, approximately 10 % increase to approximately 9,000% increase, approximately 10% increase to approximately 8,000% increase, approximately 10% increase to approximately 7,000% increase, approximately 10% increase to approximately 6,000% increase, approximately 10% increase to approximately 5,000% increase, approximately 10% increase to approximately 4,000% increase, approximately 10% increase to approximately 3,000% increase, approximately 10% increase to approximately 2,000% increase, approximately 10% increase to approximately 1,000% increase, approximately 10% increase to approximately 500% increase, approximately 10% increase to approximately 450% increase, approximately 10% increase to approximately 400% increase, approximately 10% increase to approximately 350% increase, approximately 10% increase to approximately 300% increase, approximately 10% increase to approximately 250% increase, approximately 10% increase to approximately 200% increase, approximately 10% increase to approximately 180% increase, approximately 10% increase to approximately 160% increase, approximately 10% Increase to approximately 140% increase, approximately 10% increase to approximately 120% increase, approximately 10% increase to approximately 100% increase, approximately 10% increase to approximately 95% increase, approximately 10% increase to approximately 90% increase, approximately 10% increase to approximately 85% increase, approximately 10% increase to approximately 80% increase, approximately 10% increase to approximately 75% increase, approximately 10% increase to approximately 70% increase, approximately 10% increase to approximately 65% ​​increase, approximately 10% increase to approximately 60% increase, approximately 10% increase to approximately 55% increase, approximately 10% increase to approximately 50% increase, approximately 10% increase to approximately 45% increase, approximately 10% increase to approximately 40% increase, approximately 10% increase to approximately 35% increase, approximately 10% increase to approximately 30% increase, approximately 10% increase to approximately 25% increase, approximately 10% increase to approximately 20% increase, approximately 10% increase to approximately 15% increase, approximately 15% increase to approximately 10,000% increase, about 15% increase to about 9,000% increase, about 15% increase to about 8,000% increase, about 15% increase to about 7,000% increase, about 15% increase to about 6,000% increase, about 15% increase to about 5,000% increase, about 15% increase to about 4,000% increase, about 15% increase to about 3,000% increase, about 15% increase to about 2,000% increase, about 15% increase to about 1,000% increase, approximately 15% increase to approximately 500% increase, approximately 15% increase to approximately 450% increase, approximately 15% increase to approximately 400% increase, approximately 15% increase to approximately 350% increase, approximately 15% increase to approximately 300% increase, approximately 15% increase to approximately 250% increase, approximately 15% increase to approximately 200% increase, approximately 15% increase to approximately 180% increase, approximately 15% increase to approximately 160% increase, approximately 15% increase to approximately 140% increase, approximately 15% increase to approximately 120% increase, approximately 15% increase to approximately 100% increase, approximately 15% increase to approximately 95% increase, approximately 15% increase to approximately 90% increase, approximately 15% increase to approximately 85% increase, approximately 15% increase to approximately 80% increase, approximately 15% increase to approximately 75% increase, approximately 15% increase to approximately 70% increase, approximately 15% increase to approximately 65% ​​increase, approximately 15% increase to approximately 60% increase, approximately 15% increase to approximately 55% increase, approximately 15% increase to approximately 50% increase, approximately 15% increase to approximately 45% increase, approximately 15% increase to approximately 40% increase, approximately 15% increase to approximately 35% increase, approximately 15% increase to approximately 30% increase, approximately 15% increase to approximately 25% increase, approximately 15% increase to approximately 20% increase, approximately 20% increase to approximately 10,000% increase , approximately 20% increase to approximately 9,000% increase, approximately 20% increase to approximately 8,000% increase, approximately 20% increase to approximately 7,000% increase, approximately 20% increase to approximately 6,000% increase, approximately 20% increase to approximately 5,000% increase, approximately 20% increase to approximately 4,000% increase, approximately 20% increase to approximately 3,000% increase, approximately 20% increase to approximately 2,000% increase, approximately 20% increase to approximately 1,000% increase, approximately 20% increase to approximately 500% increase, approximately 20% increase to approximately 450% increase, approximately 20% increase to approximately 400% increase, approximately 20% increase to approximately 350% increase, approximately 20% increase to approximately 300% increase, approximately 20% increase to approximately 250% increase, approximately 20% increase to approximately 200% increase, approximately 20% increase to approximately 180% increase, approximately 20% increase to approximately 160% increase, approximately 20% increase to approximately 140% increase, approximately 20% increase to approximately 120% increase, approximately 20% increase to approximately 100% increase, approximately 20% increase to approximately 95% increase, approximately 20% increase to approximately 90% increase, Approximately 20% increase to approximately 85% increase, approximately 20% increase to approximately 80% increase, approximately 20% increase to approximately 75% increase, approximately 20% increase to approximately 70% increase, approximately 20% increase to approximately 65% ​​increase, approximately 20% increase to approximately 60% increase, approximately 20% increase to approximately 55% increase, approximately 20% increase to approximately 50% increase, approximately 20% increase to approximately 45% increase, approximately 20% increase to approximately 40% increase, approximately 20% increase to approximately 35% increase, approximately 20% increase to approximately 30% increase, approximately 20% increase to approximately 25% increase, approximately 25% increase to approximately 10,000% increase, approximately 25% increase to approximately 9,000% increase Increased by approximately 25% to approximately 8,000%; increased by approximately 25% to approximately 7,000%; increased by approximately 25% to approximately 6,000%; increased by approximately 25% to approximately 5,000%; increased by approximately 25% to approximately 4,000%; increased by approximately 25% to approximately 3,000%; increased by approximately 25% to approximately 2,000%; increased by approximately 25% to approximately 1,000%; increased by approximately 25% to approximately 500%; increased by approximately 25% to approximately 450%; increased by approximately 25% to approximately 400%; increased by approximately 25% to approximately 350%; increased by approximately 25% to approximately 300%; Increase ~ approximately 250% increase, approximately 25% increase ~ approximately 200% increase, approximately 25% increase ~ approximately 180% increase, approximately 25% increase ~ approximately 160% increase, approximately 25% increase ~ approximately 140% increase, approximately 25% increase ~ approximately 120% increase, approximately 25% increase ~ approximately 100% increase, approximately 25% increase ~ approximately 95% increase, approximately 25% increase ~ approximately 90% increase, approximately 25% increase ~ approximately 85% increase, approximately 25% increase ~ approximately 80% increase, approximately 25% increase ~ approximately 75% increase, approximately 25% increase ~ approximately 70% increase, approximately 25% increase ~ approximately 65% ​​increase, approximately 25% increase ~ approximately 60% increase, approximately 2, 5% increase to approximately 55% increase, approximately 25% increase to approximately 50% increase, approximately 25% increase to approximately 45% increase, approximately 25% increase to approximately 40% increase, approximately 25% increase to approximately 35% increase, approximately 25% increase to approximately 30% increase, approximately 30% increase to approximately 10,000% increase, approximately 30% increase to approximately 9,000% increase, approximately 30% increase to approximately 8,000% increase, approximately 30% increase to approximately 7,000% increase, approximately 30% increase to approximately 6,000% increase, approximately 30% increase to approximately 5,000% increase, approximately 30% increase to approximately 4, 000% increase, approximately 30% increase to approximately 3,000% increase, approximately 30% increase to approximately 2,000% increase, approximately 30% increase to approximately 1,000% increase, approximately 30% increase to approximately 500% increase, approximately 30% increase to approximately 450% increase, approximately 30% increase to approximately 400% increase, approximately 30% increase to approximately 350% increase, approximately 30% increase to approximately 300% increase, approximately 30% increase to approximately 250% increase, approximately 30% increase to approximately 200% increase, approximately 30% increase to approximately 180% increase, approximately 30% increase to approximately 160% increase, approximately 3 0% increase to approximately 140% increase, approximately 30% increase to approximately 120% increase, approximately 30% increase to approximately 100% increase, approximately 30% increase to approximately 95% increase, approximately 30% increase to approximately 90% increase, approximately 30% increase to approximately 85% increase, approximately 30% increase to approximately 80% increase, approximately 30% increase to approximately 75% increase, approximately 30% increase to approximately 70% increase, approximately 30% increase to approximately 65% ​​increase, approximately 30% increase to approximately 60% increase, approximately 30% increase to approximately 55% increase, approximately 30% increase to approximately 50% increase, approximately 30% increase to approximately 45 % increase, approximately 30% increase to approximately 40% increase, approximately 30% increase to approximately 35% increase, approximately 35% increase to approximately 10,000% increase, approximately 35% increase to approximately 9,000% increase, approximately 35% increase to approximately 8,000% increase, approximately 35% increase to approximately 7,000% increase, approximately 35% increase to approximately 6,000% increase, approximately 35% increase to approximately 5,000% increase, approximately 35% increase to approximately 4,000% increase, approximately 35% increase to approximately 3,000% increase, approximately 35% increase to approximately 2,000% increase, approximately 35% increase to approximately 1,000% increase, approximately 35% increase to approximately 500% increase, approximately 35% increase to approximately 450% increase, approximately 35% increase to approximately 400% increase, approximately 35% increase to approximately 350% increase, approximately 35% increase to approximately 300% increase, approximately 35% increase to approximately 250% increase, approximately 35% increase to approximately 200% increase, approximately 35% increase to approximately 180% increase, approximately 35% increase to approximately 160% increase, approximately 35% increase to approximately 140% increase, approximately 35% increase to approximately 120% increase, approximately 35% increase to approximately 100% increase, approximately 35% increase to approximately 95% increase, approximately 35% increase to approximately 90% increase, approximately 3 5% increase to approximately 85% increase, approximately 35% increase to approximately 80% increase, approximately 35% increase to approximately 75% increase, approximately 35% increase to approximately 70% increase, approximately 35% increase to approximately 65% ​​increase, approximately 35% increase to approximately 60% increase, approximately 35% increase to approximately 55% increase, approximately 35% increase to approximately 50% increase, approximately 35% increase to approximately 45% increase, approximately 35% increase to approximately 40% increase, approximately 40% increase to approximately 10,000% increase, approximately 40% increase to approximately 9,000% increase, approximately 40% increase to approximately 8,000% increase, approximately 40% increase to approximately 7,000% increase, approximately 40% increase to approximately 6,0 00% increase, approximately 40% increase to approximately 5,000% increase, approximately 40% increase to approximately 4,000% increase, approximately 40% increase to approximately 3,000% increase, approximately 40% increase to approximately 2,000% increase, approximately 40% increase to approximately 1,000% increase, approximately 40% increase to approximately 500% increase, approximately 40% increase to approximately 450% increase, approximately 40% increase to approximately 400% increase, approximately 40% increase to approximately 350% increase, approximately 40% increase to approximately 300% increase, approximately 40% increase to approximately 250% increase, approximately 40% increase to approximately 200% increase, approximately 40% increase to approximately 180% increase, approximately 40% increase to approximately 160% increase, approximately 40% increase to approximately 140% increase, approximately 40% increase to approximately 120% increase, approximately 40% increase to approximately 100% increase, approximately 40% increase to approximately 95% increase, approximately 40% increase to approximately 90% increase, approximately 40% increase to approximately 85% increase, approximately 40% increase to approximately 80% increase, approximately 40% increase to approximately 75% increase, approximately 40% increase to approximately 70% increase, approximately 40% increase to approximately 65% ​​increase, approximately 40% increase to approximately 60% increase, approximately 40% increase to approximately 55% increase, approximately 40% increase to approximately 50% increase, approximately 40% increase to approximately 45% increase, approximately 45% increase to approximately 10,000% increase, approximately 45% increase to approximately 9,000% increase, approximately 45% increase to approximately 8,000% increase, approximately 45% increase to approximately 7,000% increase, approximately 45% increase to approximately 6,000% increase, approximately 45% increase to approximately 5,000% increase, approximately 45% increase to approximately 4,000% increase, approximately 45% increase to approximately 3,000% increase, approximately 45% increase to approximately 2,000% increase, approximately 45% increase to approximately 1,000% increase, approximately 4 5% increase to approximately 500% increase, approximately 45% increase to approximately 450% increase, approximately 45% increase to approximately 400% increase, approximately 45% increase to approximately 350% increase, approximately 45% increase to approximately 300% increase, approximately 45% increase to approximately 250% increase, approximately 45% increase to approximately 200% increase, approximately 45% increase to approximately 180% increase, approximately 45% increase to approximately 160% increase, approximately 45% increase to approximately 140% increase, approximately 45% increase to approximately 120% increase, about 45% increase to about 100% increase, about 45% increase to about 95% increase, about 45% increase to about 90% increase, about 45% increase to about 85% increase, about 45% increase to about 80% increase, about 45% increase to about 75% increase, about 45% increase to about 70% increase, about 45% increase to about 65% increase, about 45% increase to about 60% increase, about 45% increase to about 55% increase, about 45% increase to about 50% increase, about 50% increase to approximately 10,000% increase, approximately 50% increase to approximately 9,000% increase, approximately 50% increase to approximately 8,000% increase, approximately 50% increase to approximately 7,000% increase, approximately 50% increase to approximately 6,000% increase, approximately 50% increase to approximately 5,000% increase, approximately 50% increase to approximately 4,000% increase, approximately 50% increase to approximately 3,000% increase, approximately 50% increase to approximately 2,000% increase, approximately 50% increase to approximately 1,000% increase, approximately 50% increase to approximately 500% increase, approximately 50% increase to approximately 450% increase, approximately 50% increase to approximately 400% increase, approximately 50% increase to approximately 350% increase, approximately 50% increase to approximately 300% increase, approximately 50% increase to approximately 250% increase, approximately 50% increase to approximately 200% increase, approximately 50% increase to approximately 180% increase, approximately 50% increase to approximately 160% increase, approximately 50% increase to approximately 140% increase, approximately 50% increase to approximately 120% increase, approximately 50% increase to approximately 100% increase, approximately 50% increase to approximately 95% increase, approximately 50% increase to approximately 90% increase, approximately 5 0% increase to approximately 85% increase, approximately 50% increase to approximately 80% increase, approximately 50% increase to approximately 75% increase, approximately 50% increase to approximately 70% increase, approximately 50% increase to approximately 65% ​​increase, approximately 50% increase to approximately 60% increase, approximately 50% increase to approximately 55% increase, approximately 55% increase to approximately 10,000% increase, approximately 55% increase to approximately 9,000% increase, approximately 55% increase to approximately 8,000% increase, approximately 55% increase to approximately 7,000% increase, approximately 55% increase to approximately 6,000% increase, approximately 55% increase to approximately 5,000% increase, approximately 55% increase to approximately 4,000% increase, approximately 55 % increase to approximately 3,000% increase, approximately 55% increase to approximately 2,000% increase, approximately 55% increase to approximately 1,000% increase, approximately 55% increase to approximately 500% increase, approximately 55% increase to approximately 450% increase, approximately 55% increase to approximately 400% increase, approximately 55% increase to approximately 350% increase, approximately 55% increase to approximately 300% increase, approximately 55% increase to approximately 250% increase, approximately 55% increase to approximately 200% increase, approximately 55% increase to approximately 180% increase, approximately 55% increase to approximately 160% increase, approximately 55% increase to approximately 140% increase, approximately 55% increase to approximately 120% increase, approximately 55% Increase ~ approximately 100% increase, approximately 55% increase ~ approximately 95% increase, approximately 55% increase ~ approximately 90% increase, approximately 55% increase ~ approximately 85% increase, approximately 55% increase ~ approximately 80% increase, approximately 55% increase ~ approximately 75% increase, approximately 55% increase ~ approximately 70% increase, approximately 55% increase ~ approximately 65% ​​increase, approximately 55% increase ~ approximately 60% increase, approximately 60% increase ~ approximately 10,000% increase, approximately 60% increase ~ approximately 9,000% increase, approximately 60% increase ~ approximately 8,000% increase, approximately 60% increase ~ approximately 7,000% increase, approximately 60% increase ~ approximately 6,000% increase, approximately 60% increase ~ approximately 5,000% increase, approximately 60% increase to approximately 4,000% increase, approximately 60% increase to approximately 3,000% increase, approximately 60% increase to approximately 2,000% increase, approximately 60% increase to approximately 1,000% increase, approximately 60% increase to approximately 500% increase, approximately 60% increase to approximately 450% increase, approximately 60% increase to approximately 400% increase, approximately 60% increase to approximately 350% increase, approximately 60% increase to approximately 300% increase, approximately 60% increase to approximately 250% increase, approximately 60% increase to approximately 200% increase, approximately 60% increase to approximately 180% increase, approximately 60% increase to approximately 160% increase, approximately 60% increase to approximately 140 % increase, approximately 60% increase to approximately 120% increase, approximately 60% increase to approximately 100% increase, approximately 60% increase to approximately 95% increase, approximately 60% increase to approximately 90% increase, approximately 60% increase to approximately 85% increase, approximately 60% increase to approximately 80% increase, approximately 60% increase to approximately 75% increase, approximately 60% increase to approximately 70% increase, approximately 60% increase to approximately 65% ​​increase, approximately 65% ​​increase to approximately 10,000% increase, approximately 65% ​​increase to approximately 9,000% increase, approximately 65% ​​increase to approximately 8,000% increase, approximately 65% ​​increase to approximately 7,000% increase, approximately 65% ​​increase to approximately 6,000% increase, approximately 65 % increase ~ approximately 5,000% increase, approximately 65% ​​increase ~ approximately 4,000% increase, approximately 65% ​​increase ~ approximately 3,000% increase, approximately 65% ​​increase ~ approximately 2,000% increase, approximately 65% ​​increase ~ approximately 1,000% increase, approximately 65% ​​increase ~ approximately 500% increase, approximately 65% ​​increase ~ approximately 450% increase, approximately 65% ​​increase ~ approximately 400% increase, approximately 65% ​​increase ~ approximately 350% increase, approximately 65% ​​increase ~ approximately 300% increase, approximately 65% ​​increase ~ approximately 250% increase, approximately 65% ​​increase ~ approximately 200% increase, approximately 65% ​​increase ~ approximately 180% increase, approximately 65% ​​increase ~ approximately 160% increase, approximately 65% Increase of about 140% to about 120% increase, Increase of about 65% to about 100% increase, Increase of about 65% to about 95% increase, Increase of about 65% to about 90% increase, Increase of about 65% to about 85% increase, Increase of about 65% to about 80% increase, Increase of about 65% to about 75% increase, Increase of about 65% to about 70% increase, Increase of about 70% to about 10,000% increase, Increase of about 70% to about 9,000% increase, Increase of about 70% to about 8,000% increase, Increase of about 70% to about 7,000% increase, Increase of about 70% to about 6,000% increase, Increase of about 70% to about 5,000% increase, approximately 70% increase to approximately 4,000% increase, approximately 70% increase to approximately 3,000% increase, approximately 70% increase to approximately 2,000% increase, approximately 70% increase to approximately 1,000% increase, approximately 70% increase to approximately 500% increase, approximately 70% increase to approximately 450% increase, approximately 70% increase to approximately 400% increase, approximately 70% increase to approximately 350% increase, approximately 70% increase to approximately 300% increase, approximately 70% increase to approximately 250% increase, approximately 70% increase to approximately 200% increase, approximately 70% increase to approximately 180% increase, approximately 70% increase to approximately 160% increase, approximately 70% increase to approximately 140% increase, approximately 70% increase to approximately 120% increase, approximately 70% increase to approximately 100% increase, approximately 70% increase to approximately 95% increase, approximately 70% increase to approximately 90% increase, approximately 70% increase to approximately 85% increase, approximately 70% increase to approximately 80% increase, approximately 70% increase to approximately 75% increase, approximately 75% increase to approximately 10,000% increase, approximately 75% increase to approximately 9,000% increase, approximately 75% increase to approximately 8,000% increase, approximately 75% increase to approximately 7,000% increase, approximately 75% increase to approximately 6,000% increase, approximately 75% increase to approximately 5,000% increase, approximately 75% increase to approximately 4,000% increase, approximately 75% increase to approximately 3,000% increase, approximately 75% increase to approximately 2,000% increase, approximately 75%, Increase of about 1,000% to about 1,000% increase, increase of about 75% to about 500% increase, increase of about 75% to about 450% increase, increase of about 75% to about 400% increase, increase of about 75% to about 350% increase, increase of about 75% to about 300% increase, increase of about 75% to about 250% increase, increase of about 75% to about 200% increase, increase of about 75% to about 180% increase, increase of about 75% to about 160% increase, increase of about 75% to about 140% increase, increase of about 75% to about 120% increase, increase of about 75% to about 100% increase, increase of about 75% to Approximately 95% increase, approximately 75% increase to approximately 90% increase, approximately 75% increase to approximately 85% increase, approximately 75% increase to approximately 80% increase, approximately 80% increase to approximately 10,000% increase, approximately 80% increase to approximately 9,000% increase, approximately 80% increase to approximately 8,000% increase, approximately 80% increase to approximately 7,000% increase, approximately 80% increase to approximately 6,000% increase, approximately 80% increase to approximately 5,000% increase, approximately 80% increase to approximately 4,000% increase, approximately 80% increase to approximately 3,000% increase, approximately 80% increase to approximately 2,000% increase , approximately 80% increase to approximately 1,000% increase, approximately 80% increase to approximately 500% increase, approximately 80% increase to approximately 450% increase, approximately 80% increase to approximately 400% increase, approximately 80% increase to approximately 350% increase, approximately 80% increase to approximately 300% increase, approximately 80% increase to approximately 250% increase, approximately 80% increase to approximately 200% increase, approximately 80% increase to approximately 180% increase, approximately 80% increase to approximately 160% increase, approximately 80% increase to approximately 140% increase, approximately 80% increase to approximately 120% increase, approximately 80% increase to approximately 100% increase, approximately 80 % increase to approximately 95% increase, approximately 80% increase to approximately 90% increase, approximately 80% increase to approximately 85% increase, approximately 85% increase to approximately 10,000% increase, approximately 85% increase to approximately 9,000% increase, approximately 85% increase to approximately 8,000% increase, approximately 85% increase to approximately 7,000% increase, approximately 85% increase to approximately 6,000% increase, approximately 85% increase to approximately 5,000% increase, approximately 85% increase to approximately 4,000% increase, approximately 85% increase to approximately 3,000% increase, approximately 85% increase to approximately 2,000% increase, approximately 85% increase to approximately 1,000% increase, approximately 85% increase to approximately 500% increase, approximately 85% increase to approximately 450% increase, approximately 85% increase to approximately 400% increase, approximately 85% increase to approximately 350% increase, approximately 85% increase to approximately 300% increase, approximately 85% increase to approximately 250% increase, approximately 85% increase to approximately 200% increase, approximately 85% increase to approximately 180% increase, approximately 85% increase to approximately 160% increase, approximately 85% increase to approximately 140% increase, approximately 85% increase to approximately 120% increase, approximately 85% increase to approximately 100% increase, about 85% increase to about 95% increase, about 85% increase to about 90% increase, about 90% increase to about 10,000% increase, about 90% increase to about 9,000% increase, about 90% increase to about 8,000% increase, about 90% increase to about 7,000% increase, about 90% increase to about 6,000% increase, about 90% increase to about 5,000% increase, about 90% increase to about 4,000% increase, about 90% increase to about 3,000% increase, about 90% increase to about 2,000% increase, about 9 0% increase to approximately 1,000% increase, approximately 90% increase to approximately 500% increase, approximately 90% increase to approximately 450% increase, approximately 90% increase to approximately 400% increase, approximately 90% increase to approximately 350% increase, approximately 90% increase to approximately 300% increase, approximately 90% increase to approximately 250% increase, approximately 90% increase to approximately 200% increase, approximately 90% increase to approximately 180% increase, approximately 90% increase to approximately 160% increase, approximately 90% increase to approximately 140% increase, approximately 90% increase to approximately 120% increase, approximately 90% increase Increased to approximately 100% increase, increased to approximately 90% increase, increased to approximately 95%, increased to approximately 10,000%, increased to approximately 9,000%, increased to approximately 8,000%, increased to approximately 7,000%, increased to approximately 6,000%, increased to approximately 5,000%, increased to approximately 4,000%, increased to approximately 3,000%, increased to approximately 2,000%, increased to approximately 1,000% increase, about 95% increase to about 500% increase, about 95% increase to about 450% increase, about 95% increase to about 400% increase, about 95% increase to about 350% increase, about 95% increase to about 300% increase, about 95% increase to about 250% increase, about 95% increase to about 200% increase, about 95% increase to about 180% increase, about 95% increase to about 160% increase, about 95% increase to about 140% increase, about 95% increase to about 120% increase, about 95% increase to about 100% increase, about 100% increase to about 10,000% increase, about 100% increase to about 9,000% increase, about 100% increase to about 8,000% Increase, approximately 100% increase to approximately 7,000% increase, approximately 100% increase to approximately 6,000% increase, approximately 100% increase to approximately 5,000% increase, approximately 100% increase to approximately 4,000% increase, approximately 100% increase to approximately 3,000% increase, approximately 100% increase to approximately 2,000% increase, approximately 100% increase to approximately 1,000% increase, approximately 100% increase to approximately 500% increase, approximately 100% increase to approximately 450% increase, approximately 100% increase to approximately 400% increase, approximately 100% increase to approximately 350% increase, approximately 100% increase to approximately 300% increase, approximately 100% increase to approximately 250% increase, approximately 100% increase to approximately 200% increase, Approximately 100% increase to approximately 180% increase, approximately 100% increase to approximately 160% increase, approximately 100% increase to approximately 140% increase, approximately 100% increase to approximately 120% increase, approximately 120% increase to approximately 10,000% increase, approximately 120% increase to approximately 9,000% increase, approximately 120% increase to approximately 8,000% increase, approximately 120% increase to approximately 7,000% increase, approximately 120% increase to approximately 6,000% increase, approximately 120% increase to approximately 5,000% increase, approximately 120% increase to approximately 4,000% increase, approximately 120% increase to approximately 3,000% increase, approximately 120% increase to approximately 2,000% increase 0% increase, approximately 120% increase to approximately 1,000% increase, approximately 120% increase to approximately 500% increase, approximately 120% increase to approximately 450% increase, approximately 120% increase to approximately 400% increase, approximately 120% increase to approximately 350% increase, approximately 120% increase to approximately 300% increase, approximately 120% increase to approximately 250% increase, approximately 120% increase to approximately 200% increase, approximately 120% increase to approximately 180% increase, approximately 120% increase to approximately 160% increase, approximately 120% increase to approximately 140% increase, approximately 140% increase to approximately 10,000% increase, approximately 140% increase to approximately 9,000% increase, Approximately 140% increase to approximately 8,000% increase, approximately 140% increase to approximately 7,000% increase, approximately 140% increase to approximately 6,000% increase, approximately 140% increase to approximately 5,000% increase, approximately 140% increase to approximately 4,000% increase, approximately 140% increase to approximately 3,000% increase, approximately 140% increase to approximately 2,000% increase, approximately 140% increase to approximately 1,000% increase, approximately 140% increase to approximately 500% increase, approximately 140% increase to approximately 450% increase, approximately 140% increase to approximately 400% increase, approximately 140% increase to approximately 350% increase, approximately 140% increase to approximately 300% increase, approximately 140% increase to approximately 250% increase, approximately 140% increase to approximately 200% increase, approximately 140% increase to approximately 180% increase, approximately 140% increase to approximately 160% increase, approximately 160% increase to approximately 10,000% increase, approximately 160% increase to approximately 9,000% increase, approximately 160% increase to approximately 8,000% increase, approximately 160% increase to approximately 7,000% increase, approximately 160% increase to approximately 6,000% increase, approximately 160% increase to approximately 5,000% increase, approximately 160% increase to approximately 4,000% increase, approximately 160% increase to approximately 3,000% increase, approximately 160% increase to approximately 2,000% increase, approximately 160% increase to approximately 1,000% increase, approximately 160% increase to approximately 500% increase, approximately 160% increase to approximately 450% increase, approximately 160% increase to approximately 400% increase, approximately 160% increase to approximately 350% increase, approximately 160% increase to approximately 300% increase, approximately 160% increase to approximately 250% increase, approximately 160% increase to approximately 200% increase, approximately 160% increase to approximately 180% increase, approximately 180% increase to approximately 10,000% increase, approximately 180% increase to approximately 9,000% increase, approximately 180% increase to approximately 8,000% increase, approximately 180% increase to approximately 7,000% increase, approximately 180% increase to approximately 6,000% increase, approximately 180% increase to approximately 5,000% increase, approximately 180% increase to approximately 4,000% increase, approximately 180% increase to approximately 3,000% increase, approximately 180% increase to approximately 2,000% increase, approximately 180% increase to approximately 1,000% increase, approximately 180% increase to approximately 500% increase, approximately 180% increase to approximately 450% increase, approximately 180% increase to approximately 400% increase, approximately 180% increase to approximately 350% increase, approximately 180% increase to approximately 300% increase, approximately 180% increase to approximately 250% increase, approximately 180% increase to approximately 200% increase, approximately 200% increase to approximately 10,000% increase, approximately 200% increase to approximately 9,000% increase, approximately 200% increase to approximately 8,000% increase, approximately 200% increase to approximately 7,000% increase, approximately 200% increase to approximately 6,000% increase, approximately 200% increase to approximately 5,000% increase, approximately 200% increase to approximately 4,000% increase, approximately 200% increase to approximately 3,000% increase, approximately 200% increase to approximately 2,000% increase, approximately 200% increase to approximately 1,000% increase, approximately 200% increase to approximately 500% increase, approximately 200% increase to approximately 450% increase, approximately 200% increase to approximately 400% increase, approximately 200% increase to approximately 350% increase, approximately 200% increase to approximately 300% increase, approximately 200% increase to approximately 250% increase, approximately 250% increase to approximately 10,000% increase, approximately 250% increase to approximately 9,000% increase, approximately 250% increase to approximately 8,000% increase, approximately 250% increase to approximately 7,000% increase, approximately 250% increase to approximately 6,000% increase, approximately 250% increase to approximately 5,000% increase, approximately 250% increase to approximately 4,000% increase, approximately 250% increase to approximately 3,000% increase, approximately 250% increase to approximately 2,000% increase, approximately 250% increase to approximately 1,000% increase, approximately 250% increase to approximately 500% increase, approximately 250% increase to approximately 450% increase, approximately 250% increase to approximately 400% increase, approximately 250% increase to approximately 350% increase, approximately 250% increase to approximately 300% increase, approximately 300% increase to approximately 10,000% increase, approximately 300% increase to approximately 9,000% increase, approximately 300% increase to approximately 8,000% increase, approximately 300% increase to approximately 7,000% increase, approximately 300% increase to approximately 6,000% increase, approximately 300% increase to approximately 5,000% increase, approximately 300% increase to approximately 4,000% increase, approximately 300% increase to approximately 3,000% increase, approximately 300% increase to approximately 2,000% increase, approximately 300% increase to approximately 1,000% increase, approximately 300% increase to approximately 500% increase, approximately 300% increase to approximately 450% increase, approximately 300% increase to approximately 400% increase, approximately 300% increase to approximately 350% increase, approximately 350% increase to approximately 10,000% increase, approximately 350% increase to approximately 9,000% increase, approximately 350% increase to approximately 8,000% increase, approximately 350% increase to approximately 7,000% increase, approximately 350% increase to approximately 6,000% increase, approximately 350% increase to approximately 5,000% increase, approximately 350% Increase ~ approximately 4,000% increase, approximately 350% increase ~ approximately 3,000% increase, approximately 350% increase ~ approximately 2,000% increase, approximately 350% increase ~ approximately 1,000% increase, approximately 350% increase ~ approximately 500% increase, approximately 350% increase ~ approximately 450% increase, approximately 350% increase ~ approximately 400% increase, approximately 400% increase ~ approximately 10,000% increase, approximately 400% increase ~ approximately 9,000% increase, approximately 400% increase ~ approximately 8,000% increase, approximately 400% increase ~ approximately 7,000% increase, approximately 400% increase ~ approximately 6,000% increase, approximately 400% increase ~ approximately 5,000% increase, Approximately 400% increase to approximately 4,000% increase, approximately 400% increase to approximately 3,000% increase, approximately 400% increase to approximately 2,000% increase, approximately 400% increase to approximately 1,000% increase, approximately 400% increase to approximately 500% increase, approximately 400% increase to approximately 450% increase, approximately 450% increase to approximately 10,000% increase, approximately 450% increase to approximately 9,000% increase, approximately 450% increase to approximately 8,000% increase, approximately 450% increase to approximately 7,000% increase, approximately 450% increase to approximately 6,000% increase, approximately 450% increase to approximately 5,000% increase, approximately 450% increase to approximately 4,000% increase, approximately 450% increase to approximately 3,000% increase, approximately 450% increase to approximately 2,000% increase, approximately 450% increase to approximately 1,000% increase, approximately 450% increase to approximately 500% increase, approximately 500% increase to approximately 10,000% increase, approximately 500% increase to approximately 9,000% increase, approximately 500% increase to approximately 8,000% increase, approximately 500% increase to approximately 7,000% increase, approximately 500% increase to approximately 6,000% increase, approximately 500% increase to approximately 5,000% increase, approximately 500% increase to approximately 4,000% increase, approximately 500% increase to approximately 3,000% increase, approximately 5 00% increase to approximately 2,000% increase, approximately 500% increase to approximately 1,000% increase, approximately 1,000% increase to approximately 10,000% increase, approximately 1,000% increase to approximately 9,000% increase, approximately 1,000% increase to approximately 8,000% increase, approximately 1,000% increase to approximately 7,000% increase, approximately 1,000% increase to approximately 6,000% increase, approximately 1,000% increase to approximately 5,000% increase, approximately 1,000% increase to approximately 4,000% increase, approximately 1,000% increase to approximately 3,000% increase, approximately 1,000% increase to approximately 2,000% increase, approximately 2,000% increase to approximately 1 0,000% increase, approximately 2,000% increase to approximately 9,000% increase, approximately 2,000% increase to approximately 8,000% increase, approximately 2,000% increase to approximately 7,000% increase, approximately 2,000% increase to approximately 6,000% increase, approximately 2,000% increase to approximately 5,000% increase, approximately 2,000% increase to approximately 4,000% increase, approximately 2,000% increase to approximately 3,000% increase, approximately 3,000% increase to approximately 10,000% increase, approximately 3,000% increase to approximately 9,000% increase, approximately 3,000% increase to approximately 8,000% increase, approximately 3,000% increase to approximately 7,000% increase, approximately 3,000% increase to approximately 6,000% increase, approximately 3,000% increase to approximately 5,000% increase, approximately 3,000% increase to approximately 4,000% increase, approximately 4,000% increase to approximately 10,000% increase, approximately 4,000% increase to approximately 9,000% increase, approximately 4,000% increase to approximately 8,000% increase, approximately 4,000% increase to approximately 7,000% increase, approximately 4,000% increase to approximately 6,000% increase, approximately 4,000% increase to approximately 5,000% increase, approximately 5,000% increase to approximately 10,000% increase, approximately 5,000% increase to approximately 9,000% increase, approximately 5,000% increase to about 8,000% increase, about 5,000% increase to about 7,000% increase, about 5,000% increase to about 6,000% increase, about 6,000% increase to about 10,000% increase, about 6,000% increase to about 9,000% increase, about 6,000% increase to about 8,000% increase, about 6,000% increase to about 7,000% increase, about 7,000% increase to about 10,000% increase, about 7,000% increase to about 9,000% increase, about 7,000% increase to about 8,000% increase, about 8,000% increase to about 10,000% increase, about 8,000% increase to about 9,000% increase, or about 9,000% increase to about 10,000% increase.

[0104] In some embodiments of any of the antibodies described herein, a composition comprising the antibody (e.g., any of the antibodies described herein) exhibits an increase (e.g., a detectable increase) (e.g., at least a 0.1-fold increase, at least a 0.2-fold increase, at least a 0.3-fold increase, at least a 0.4-fold increase, at least a 0.5-fold increase, at least a 0.6-fold increase, at least a 0.7-fold increase, at least a 0.8-fold increase, at least a 0.9-fold increase, at least a 0.10-fold increase, at least a 0.11-fold increase, at least a 0.12-fold increase, at least a 0.13-fold increase, at least a 0.14-fold increase, at least a 0.15-fold increase, at least a 0.16-fold increase, at least a 0.17-fold increase, at least a 0.18-fold increase, at least a 0.19-fold increase, at least a 0.20-fold increase, at least a 0.21-fold increase, at least a 0.22-fold increase, at least a 0.23-fold increase, at least a 0.24-fold increase, at least a 0.25-fold increase, at least a 0.26-fold increase, at least a 0.27-fold increase, at least a 0.28-fold increase, at least a 0.29-fold increase, at least a 0.30-fold increase, at least a 0.31-fold increase, at least a 0.32-fold increase, at least a 0.33-fold increase, at least a 0.34-fold increase, at least a 0.35-fold increase, at least a 0.36-fold increase, at least a 0.37-fold increase, at least a 0.38-fold increase, at least a 0.39-fold increase, at least at least a 0.7 fold increase, at least a 0.8 fold increase, at least a 0.9 fold increase, at least a 1.0 fold increase, at least a 1.2 fold increase, at least a 1.4 fold increase, at least a 1.5 fold increase, at least a 1.6 fold increase, at least a 1.8 fold increase, at least a 2.0 fold increase, at least a 2.2 fold increase, at least a 2.4 fold increase, at least a 2.5 fold increase, at least a 2.6 fold increase, at least a 2.8 fold increase, at least a 3.0 fold increase, at least a 3.5 fold increase, at least a 4.0 fold increase, at least a 4.5 fold increase, at least also a 5.0-fold increase, at least a 5.5-fold increase, at least a 6.0-fold increase, at least a 6.5-fold increase, at least a 7.0-fold increase, at least a 7.5-fold increase, at least an 8.0-fold increase, at least an 8.5-fold increase, at least a 9.0-fold increase, at least a 9.5-fold increase, at least a 10-fold increase, at least a 15-fold increase, at least a 20-fold increase, at least a 25-fold increase, at least a 30-fold increase, at least a 35-fold increase, at least a 40-fold increase, at least a 45-fold increase, at least a 50-fold increase, at least a 55-fold increase, at least a 60-fold increase, at least a 70-fold increase, at least a 80-fold increase, at least a 90-fold increase, at least a 100-fold increase, at least a 100-fold increase, at least a 150-fold increase, at least a 200-fold increase, at least a 250-fold increase, at least a 300-fold increase, at least a 350-fold increase, at least a 400-fold increase, at least a 450-fold increase, at least a 500-fold increase, at least a 550-fold increase, at least a 600-fold increase, at least a 700-fold increase, at least a 800-fold increase, at least a 900-fold increase, at least a 10 ... or at least a 60-fold increase, at least a 65-fold increase, at least a 70-fold increase, at least a 75-fold increase, at least an 80-fold increase, at least an 85-fold increase, at least a 90-fold increase, at least a 95-fold increase, or at least a 100-fold increase, or about a 0.1-fold increase to about a 100-fold increase, about a 0.1-fold increase to about a 90-fold increase, about a 0.1-fold increase to about a 80-fold increase, about a 0.1-fold increase to about a 70-fold increase, about a 0.1-fold increase to about a 60-fold increase, about a 0.1-fold increase to about a 50-fold increase, about a 0.1-fold increase to about a 40-fold increase, about a 0.1-fold increase to about a 3 ...50-fold increase, about a 0.1-fold increase to about a 60-fold increase, about a 0.1-fold increase to about a 50-fold increase, about a 0.1-fold increase to about a 40-fold increase, about a 0.1-fold increase to about a 30-fold increase, about a 0.1-fold increase to about a 50-fold increase, about a 0.1-fold increase to about a 50-fold1x increase to approximately 20x increase, approximately 0.1x increase to approximately 10x increase, approximately 0.1x increase to approximately 9.5x increase, approximately 0.1x increase to approximately 9.0x increase, approximately 0.1x increase to approximately 8.5x increase, approximately 0.1x increase to approximately 8.0x increase, approximately 0.1x increase to approximately 7.5x increase, approximately 0.1x increase to approximately 7.0x increase, approximately 0.1x increase to approximately 6.5x increase, approximately 0.1x increase to approximately 6.0x increase, approximately 0.1x increase to approximately 5.5x increase, approximately 0.1x increase to approximately 5.0x increase, approximately 0.1x increase to approximately 4.5x increase, approximately 0.1x increase to approximately 4.0x increase, approximately 0 0.1x increase to approximately 3.5x increase, approximately 0.1x increase to approximately 3.0x increase, approximately 0.1x increase to approximately 2.8x increase, approximately 0.1x increase to approximately 2.6x increase, approximately 0.1x increase to approximately 2.5x increase, approximately 0.1x increase to approximately 2.4x increase, approximately 0.1x increase to approximately 2.2x increase, approximately 0.1x increase to approximately 2.0x increase, approximately 0.1x increase to approximately 1.8x increase, approximately 0.1x increase to approximately 1.6x increase, approximately 0.1x increase to approximately 1.5x increase, approximately 0.1x increase to approximately 1.4x increase, approximately 0.1x increase to approximately 1.2x increase, approximately 0.1x increase to approximately 1.0x increase , approximately 0.1x increase to approximately 0.9x increase, approximately 0.1x increase to approximately 0.8x increase, approximately 0.1x increase to approximately 0.7x increase, approximately 0.1x increase to approximately 0.6x increase, approximately 0.1x increase to approximately 0.5x increase, approximately 0.1x increase to approximately 0.4x increase, approximately 0.1x increase to approximately 0.3x increase, approximately 0.2x increase to approximately 100x increase, approximately 0.2x increase to approximately 90x increase, approximately 0.2x increase to approximately 80x increase, approximately 0.2x increase to approximately 70x increase, approximately 0.2x increase to approximately 60x increase, approximately 0.2x increase to approximately 50x increase, approximately 0.2x increase to approximately 40x increase, approximately 0 0.2x increase to approximately 30x increase, approximately 0.2x increase to approximately 20x increase, approximately 0.2x increase to approximately 10x increase, approximately 0.2x increase to approximately 9.5x increase, approximately 0.2x increase to approximately 9.0x increase, approximately 0.2x increase to approximately 8.5x increase, approximately 0.2x increase to approximately 8.0x increase, approximately 0.2x increase to approximately 7.5x increase, approximately 0.2x increase to approximately 7.0x increase, approximately 0.2x increase to approximately 6.5x increase, approximately 0.2x increase to approximately 6.0x increase, approximately 0.2x increase to approximately 5.5x increase, approximately 0.2x increase to approximately 5.0x increase, approximately 0.2x increase to approximately 4.5x increase, approximately 0.2x increase to approximately 4.0x increase, approximately 0.2x increase to approximately 3.5x increase, approximately 0.2x increase to approximately 3.0x increase, approximately 0.2x increase to approximately 2.8x increase, approximately 0.2x increase to approximately 2.6x increase, approximately 0.2x increase to approximately 2.5x increase, approximately 0.2x increase to approximately 2.4x increase, approximately 0.2x increase to approximately 2.2x increase, approximately 0.2x increase to approximately 2.0x increase, approximately 0.2x increase to approximately 1.8x increase, approximately 0.2x increase to approximately 1.6x increase, approximately 0.2x increase to approximately 1.5x increase, approximately 0.2x increase to approximately 1.4x increase, approximately 0.2x increase to approximately 1.2x increase, Approximately 0.2x increase to approximately 1.0x increase, approximately 0.2x increase to approximately 0.9x increase, approximately 0.2x increase to approximately 0.8x increase, approximately 0.2x increase to approximately 0.7x increase, approximately 0.2x increase to approximately 0.6x increase, approximately 0.2x increase to approximately 0.5x increase, approximately 0.2x increase to approximately 0.4x increase, approximately 0.3x increase to approximately 100x increase, approximately 0.3x increase to approximately 90x increase, approximately 0.3x increase to approximately 80x increase, approximately 0.3x increase to approximately 70x increase, approximately 0.3x increase to approximately 60x increase, approximately 0.3x increase to approximately 50x increase, approximately 0.3x increase to approximately 40x increase, approximately 0.3 fold increase to approximately 30-fold increase, approximately 0.3-fold increase to approximately 20-fold increase, approximately 0.3-fold increase to approximately 10-fold increase, approximately 0.3-fold increase to approximately 9.5-fold increase, approximately 0.3-fold increase to approximately 9.0-fold increase, approximately 0.3-fold increase to approximately 8.5-fold increase, approximately 0.3-fold increase to approximately 8.0-fold increase, approximately 0.3-fold increase to approximately 7.5-fold increase, approximately 0.3-fold increase to approximately 7.0-fold increase, approximately 0.3-fold increase to approximately 6.5-fold increase, approximately 0.3-fold increase to approximately 6.0-fold increase, approximately 0.3-fold increase to approximately 5.5-fold increase, approximately 0.3-fold increase to approximately 5.0-fold increase, approximately 0.3-fold increase to approximately 4.5-fold increase, approximately 0.3 Increase of about 4.0 times, increase of about 0.3 times to about 3.5 times, increase of about 0.3 times to about 3.0 times, increase of about 0.3 times to about 2.8 times, increase of about 0.3 times to about 2.6 times, increase of about 0.3 times to about 2.5 times, increase of about 0.3 times to about 2.4 times, increase of about 0.3 times to about 2.2 times, increase of about 0.3 times to about 2.0 times, increase of about 0.3 times to about 1.8 times, increase of about 0.3 times to about 1.6 times, increase of about 0.3 times to about 1.5 times, increase of about 0.3 times to about 1.4 times, increase of about 0.3 times to about 1.2 times, increase of about 0.3x increase to approximately 1.0x increase, approximately 0.3x increase to approximately 0.9x increase, approximately 0.3x increase to approximately 0.8x increase, approximately 0.3x increase to approximately 0.7x increase, approximately 0.3x increase to approximately 0.6x increase, approximately 0.3x increase to approximately 0.5x increase, approximately 0.4x increase to approximately 100x increase, approximately 0.4x increase to approximately 90x increase, approximately 0.4x increase to approximately 80x increase, approximately 0.4x increase to approximately 70x increase, approximately 0.4x increase to approximately 60x increase, approximately 0.4x increase to approximately 50x increase, approximately 0.4x increase to approximately 40x increase, approximately 0.4x increase to approximately 30x increase, approximately 0.4x increase Increased to approximately 20 times, increased to approximately 10 times, increased to approximately 9.5 times, increased to approximately 9.0 times, increased to approximately 8.5 times, increased to approximately 8.0 times, increased to approximately 7.5 times, increased to approximately 7.0 times, increased to approximately 6.5 times, increased to approximately 6.0 times, increased to approximately 5.5 times, increased to approximately 5.0 times, increased to approximately 4.5 times, increased to approximately 4.0 times, increased to approximately 0.4 times Increased to approximately 3.5 times, increased by approximately 0.4 times to approximately 3.0 times, increased by approximately 0.4 times to approximately 2.8 times, increased by approximately 0.4 times to approximately 2.6 times, increased by approximately 0.4 times to approximately 2.5 times, increased by approximately 0.4 times to approximately 2.4 times, increased by approximately 0.4 times to approximately 2.2 times, increased by approximately 0.4 times to approximately 2.0 times, increased by approximately 0.4 times to approximately 1.8 times, increased by approximately 0.4 times to approximately 1.6 times, increased by approximately 0.4 times to approximately 1.5 times, increased by approximately 0.4 times to approximately 1.4 times, increased by approximately 0.4 times to approximately 1.2 times, increased by approximately 0.4 times to approximately 1.0 times, increased by approximately 0.4 times Increase of about 0.9 times, increase of about 0.4 times to about 0.8 times, increase of about 0.4 times to about 0.7 times, increase of about 0.4 times to about 0.6 times, increase of about 0.5 times to about 100 times, increase of about 0.5 times to about 90 times, increase of about 0.5 times to about 80 times, increase of about 0.5 times to about 70 times, increase of about 0.5 times to about 60 times, increase of about 0.5 times to about 50 times, increase of about 0.5 times to about 40 times, increase of about 0.5 times to about 30 times, increase of about 0.5 times to about 20 times, increase of about 0.5 times to about 10 times, increase of about 0.5 times to about 9 times.5x increase, approximately 0.5x increase to approximately 9.0x increase, approximately 0.5x increase to approximately 8.5x increase, approximately 0.5x increase to approximately 8.0x increase, approximately 0.5x increase to approximately 7.5x increase, approximately 0.5x increase to approximately 7.0x increase, approximately 0.5x increase to approximately 6.5x increase, approximately 0.5x increase to approximately 6.0x increase, approximately 0.5x increase to approximately 5.5x increase, approximately 0.5x increase to approximately 5.0x increase, approximately 0.5x increase to approximately 4.5x increase, approximately 0.5x increase to approximately 4.0x increase, approximately 0.5x increase to approximately 3.5x increase, approximately 0.5x increase to approximately 3.0x increase, approximately 0.5x increase Increased by approximately 2.8 times, increased by approximately 0.5 times to approximately 2.6 times, increased by approximately 0.5 times to approximately 2.5 times, increased by approximately 0.5 times to approximately 2.4 times, increased by approximately 0.5 times to approximately 2.2 times, increased by approximately 0.5 times to approximately 2.0 times, increased by approximately 0.5 times to approximately 1.8 times, increased by approximately 0.5 times to approximately 1.6 times, increased by approximately 0.5 times to approximately 1.5 times, increased by approximately 0.5 times to approximately 1.4 times, increased by approximately 0.5 times to approximately 1.2 times, increased by approximately 0.5 times to approximately 1.0 times, increased by approximately 0.5 times to approximately 0.9 times, increased by approximately 0.5 times to approximately 0.8 times, increased by approximately 0.5 times Increased to approximately 0.7 times, Increased to approximately 100 times, Increased to approximately 90 times, Increased to approximately 80 times, Increased to approximately 70 times, Increased to approximately 60 times, Increased to approximately 50 times, Increased to approximately 40 times, Increased to approximately 30 times, Increased to approximately 20 times, Increased to approximately 10 times, Increased to approximately 9.5 times, Increased to approximately 9.0 times, Increased to approximately 8.5 times, Increased to approximately 8.0 times Increase of approximately 0.6 times to approximately 7.5 times, increase of approximately 0.6 times to approximately 7.0 times, increase of approximately 0.6 times to approximately 6.5 times, increase of approximately 0.6 times to approximately 6.0 times, increase of approximately 0.6 times to approximately 5.5 times, increase of approximately 0.6 times to approximately 5.0 times, increase of approximately 0.6 times to approximately 4.5 times, increase of approximately 0.6 times to approximately 4.0 times, increase of approximately 0.6 times to approximately 3.5 times, increase of approximately 0.6 times to approximately 3.0 times, increase of approximately 0.6 times to approximately 2.8 times, increase of approximately 0.6 times to approximately 2.6 times, increase of approximately 0.6 times to approximately 2.5 times, increase of approximately 0.6 times to approximately 2.4x increase, approximately 0.6x increase to approximately 2.2x increase, approximately 0.6x increase to approximately 2.0x increase, approximately 0.6x increase to approximately 1.8x increase, approximately 0.6x increase to approximately 1.6x increase, approximately 0.6x increase to approximately 1.5x increase, approximately 0.6x increase to approximately 1.4x increase, approximately 0.6x increase to approximately 1. 0.2x increase, approximately 0.6x increase to approximately 1.0x increase, approximately 0.6x increase to approximately 0.9x increase, approximately 0.6x increase to approximately 0.8x increase, approximately 0.7x increase to approximately 100x increase, approximately 0.7x increase to approximately 90x increase, approximately 0.7x increase to approximately 80x increase, approximately 0.7x increase to approximately 70x increase, approximately 0.7x increase to approximately 60x increase, approximately 0.7x increase to approximately 50x increase, approximately 0.7x increase to approximately 40x increase, approximately 0.7x increase to approximately 30x increase, approximately 0.7x increase to approximately 20x increase, approximately 0.7x increase to approximately 10x increase, approximately 0.7x increase to approximately 9.5x increase, Increased by approximately 0.7 times to approximately 9.0 times, increased by approximately 0.7 times to approximately 8.5 times, increased by approximately 0.7 times to approximately 8.0 times, increased by approximately 0.7 times to approximately 7.5 times, increased by approximately 0.7 times to approximately 7.0 times, increased by approximately 0.7 times to approximately 6.5 times, increased by approximately 0.7 times to approximately 6.0 times, increased by approximately 0.7 times to approximately 5.5 times, increased by approximately 0.7 times to approximately 5.0 times, increased by approximately 0.7 times to approximately 4.5 times, increased by approximately 0.7 times to approximately 4.0 times, increased by approximately 0.7 times to approximately 3.5 times, increased by approximately 0.7 times to approximately 3.0 times, increased by approximately 0.7 times to approximately 2.8 times Increased, approximately 0.7 times increase to approximately 2.6 times increase, approximately 0.7 times increase to approximately 2.5 times increase, approximately 0.7 times increase to approximately 2.4 times increase, approximately 0.7 times increase to approximately 2.2 times increase, approximately 0.7 times increase to approximately 2.0 times increase, approximately 0.7 times increase to approximately 1.8 times increase, approximately 0.7 times increase to approximately 1.6 times increase, approximately 0.7 times increase to approximately 1.5 times increase, approximately 0.7 times increase to approximately 1.4 times increase, approximately 0.7 times increase to approximately 1.2 times increase, approximately 0.7 times increase to approximately 1.0 times increase, approximately 0.7 times increase to approximately 0.9 times increase, approximately 0.8 times increase to approximately 100 times increase, approximately 0.8 times increase to approximately 90 times increase Increase, approximately 0.8x increase to approximately 80x increase, approximately 0.8x increase to approximately 70x increase, approximately 0.8x increase to approximately 60x increase, approximately 0.8x increase to approximately 50x increase, approximately 0.8x increase to approximately 40x increase, approximately 0.8x increase to approximately 30x increase, approximately 0.8x increase to approximately 20x increase, approximately 0.8x increase to approximately 10x increase, approximately 0.8x increase to approximately 9.5x increase, approximately 0.8x increase to approximately 9.0x increase, approximately 0.8x increase to approximately 8.5x increase, approximately 0.8x increase to approximately 8.0x increase, approximately 0.8x increase to approximately 7.5x increase, approximately 0.8x increase to approximately 7.0x increase, approximately 0.8x increase to approximately 6.5x increase, approximately 0.8x increase to approximately 6.0x increase, approximately 0.8x increase to approximately 5.5x increase, approximately 0.8x increase to approximately 5.0x increase, approximately 0.8x increase to approximately 4.5x increase, approximately 0.8x increase to approximately 4.0x increase, approximately 0.8x increase to approximately 3.5x increase, approximately 0.8x increase to approximately 3.0x increase, approximately 0.8x increase to approximately 2.8x increase, approximately 0.8x increase to approximately 2.6x increase, approximately 0.8x increase to approximately 2.5x increase, approximately 0.8x increase to approximately 2.4x increase, approximately 0.8x increase to approximately 2.2x increase, approximately 0.8x increase to approximately 2.0x increase, Approximately 0.8x increase to approximately 1.8x increase, approximately 0.8x increase to approximately 1.6x increase, approximately 0.8x increase to approximately 1.5x increase, approximately 0.8x increase to approximately 1.4x increase, approximately 0.8x increase to approximately 1.2x increase, approximately 0.8x increase to approximately 1.0x increase, approximately 1.0x increase to approximately 100x increase, approximately 1.0x increase to approximately 90x increase, approximately 1.0x increase to approximately 80x increase, approximately 1.0x increase to approximately 70x increase, approximately 1.0x increase to approximately 60x increase, approximately 1.0x increase to approximately 50x increase, approximately 1.0x increase to approximately 40x increase, approximately 1.0x increase to approximately 30x increase, approximately 1.0x Increase of about 20 times, increase of about 1.0 times, increase of about 10 times, increase of about 1.0 times, increase of about 9.5 times, increase of about 1.0 times, increase of about 9.0 times, increase of about 1.0 times, increase of about 8.5 times, increase of about 1.0 times, increase of about 8.0 times, increase of about 1.0 times, increase of about 7.5 times, increase of about 1.0 times, increase of about 7.0 times, increase of about 1.0 times, increase of about 6.5 times, increase of about 1.0 times, increase of about 6.0 times, increase of about 1.0 times, increase of about 5.5 times, increase of about 1.0 times, increase of about 5.0 times, increase of about 1.0 times, increase of about 4.5 times, increase of about 1.0 times, increase of about 4.0 times, increase of about 1.0 times Increase of about 3.5 times, increase of about 1.0 times to about 3.0 times, increase of about 1.0 times to about 2.8 times, increase of about 1.0 times to about 2.6 times, increase of about 1.0 times to about 2.5 times, increase of about 1.0 times to about 2.4 times, increase of about 1.0 times to about 2.2 times, increase of about 1.0 times to about 2.0 times, increase of about 1.0 times to about 1.8 times, increase of about 1.0 times to about 1.6 times, increase of about 1.0 times to about 1.5 times, increase of about 1.0 times to about 1.4 times, increase of about 1.0 times to about 1.2 times, increase of about 1.2 times to about 100 times, increase of about 1.2x increase to approximately 90x increase, approximately 1.2x increase to approximately 80x increase, approximately 1.2x increase to approximately 70x increase, approximately 1.2x increase to approximately 60x increase, approximately 1.2x increase to approximately 50x increase, approximately 1.2x increase to approximately 40x increase, approximately 1.2x increase to approximately 30x increase, approximately 1.2x increase to approximately 20x increase, approximately. 1.2x increase to approximately 10x increase, approximately 1.2x increase to approximately 9.5x increase, approximately 1.2x increase to approximately 9.0x increase, approximately 1.2x increase to approximately 8.5x increase, approximately 1.2x increase to approximately 8.0x increase, approximately 1.2x increase to approximately 7.5x increase, approximately 1.2x increase to approximately 7.0x increase, approximately 1.2x increase to approximately 6.5x increase, approximately 1.2x increase to approximately 6.0x increase, approximately 1.2x increase to approximately 5.5x increase, approximately 1.2x increase to approximately 5.0x increase, approximately 1.2x increase to approximately 4.5x increase, approximately 1.2x increase to approximately 4.0x increase, approximately 1.2x increase to approximately 3.5x increase, Approximately 1.2x increase to approximately 3.0x increase, approximately 1.2x increase to approximately 2.8x increase, approximately 1.2x increase to approximately 2.6x increase, approximately 1.2x increase to approximately 2.5x increase, approximately 1.2x increase to approximately 2.4x increase, approximately 1.2x increase to approximately 2.2x increase, approximately 1.2x increase to approximately 2.0x increase, approximately 1.2x increase to approximately 1.8x increase, approximately 1.2x increase to approximately 1.6x increase, approximately 1.2x increase to approximately 1.5x increase, approximately 1.2x increase to approximately 1.4x increase, approximately 1.4x increase to approximately 100x increase, approximately 1.4x increase to approximately 90x increase, approximately 1.4x increase to approximately 80x increase, Approximately 1.4x increase to approximately 70x increase, approximately 1.4x increase to approximately 60x increase, approximately 1.4x increase to approximately 50x increase, approximately 1.4x increase to approximately 40x increase, approximately 1.4x increase to approximately 30x increase, approximately 1.4x increase to approximately 20x increase, approximately 1.4x increase to approximately 10x increase, approximately 1.4x increase to approximately 9.5x increase, approximately 1.4x increase to approximately 9.0x increase, approximately 1.4x increase to approximately 8.5x increase, approximately 1.4x increase to approximately 8.0x increase, approximately 1.4x increase to approximately 7.5x increase, approximately 1.4x increase to approximately 7.0x increase, approximately 1.4x increase to approximately 6.5x increase, approximately 1.4x Increase of about 6.0 times, increase of about 1.4 times to about 5.5 times, increase of about 1.4 times to about 5.0 times, increase of about 1.4 times to about 4.5 times, increase of about 1.4 times to about 4.0 times, increase of about 1.4 times to about 3.5 times, increase of about 1.4 times to about 3.0 times, increase of about 1.4 times to about 2.8 times, increase of about 1.4 times to about 2.6 times, increase of about 1.4 times to about 2.5 times, increase of about 1.4 times to about 2.4 times, increase of about 1.4 times to about 2.2 times, increase of about 1.4 times to about 2.0 times, increase of about 1.4 times to about 1.8 times, increase of about 1.4x increase ~ approx. 1.6x increase, approx. 1.6x increase ~ approx. 10x increase, approx. 1.6x increase ~ approx. 100x increase, approx. 1.6x increase ~ approx. 90x increase, approx. 1.6x increase ~ approx. 80x increase, approx. 1.6x increase ~ approx. 70x increase, approx. 1.6x increase ~ approx. 60x increase, approx. 1.6x increase ~ approx. 50x increase, approx. 1.6x increase ~ approx. 40x increase, approx. 1.6x increase ~ approx. 30x increase, approx. 1.6x increase ~ approx. 20x increase, approx. 1.6x increase ~ approx. 9.5x increase, approx. 1.6x increase ~ approx. 9.0x increase, approx. 1.6x increase ~ approx. 8.5x increase, approx. 1.6x increase ~ Approximately 8.0x increase, approximately 1.6x increase to approximately 7.5x increase, approximately 1.6x increase to approximately 7.0x increase, approximately 1.6x increase to approximately 6.5x increase, approximately 1.6x increase to approximately 6.0x increase, approximately 1.6x increase to approximately 5.5x increase, approximately 1.6x increase to approximately 5.0x increase, approximately 1.6x increase to approximately 4.5x increase, approximately 1.6x increase to approximately 4.0x increase, approximately 1.6x increase to approximately 3.5x increase, approximately 1.6x increase to approximately 3.0x increase, approximately 1.6x increase to approximately 2.8x increase, approximately 1.6x increase to approximately 2.6x increase, approximately 1.6x increase to approximately 2.5x increase, approximately 1.6x increase Increased to approximately 2.4 times, increased to approximately 2.2 times, increased to approximately 2.0 times, increased to approximately 1.6 times, increased to approximately 1.8 times, increased to approximately 100 times, increased to approximately 90 times, increased to approximately 80 times, increased to approximately 70 times, increased to approximately 60 times, increased to approximately 50 times, increased to approximately 40 times, increased to approximately 30 times, increased to approximately 20 times, increased to approximately 10 times, increased to approximately 9.5 times Increase of approximately 1.8 times to approximately 9.0 times, increase of approximately 1.8 times to approximately 8.5 times, increase of approximately 1.8 times to approximately 8.0 times, increase of approximately 1.8 times to approximately 7.5 times, increase of approximately 1.8 times to approximately 7.0 times, increase of approximately 1.8 times to approximately 6.5 times, increase of approximately 1.8 times to approximately 6.0 times, increase of approximately 1.8 times to approximately 5.5 times, increase of approximately 1.8 times to approximately 5.0 times, increase of approximately 1.8 times to approximately 4.5 times, increase of approximately 1.8 times to approximately 4.0 times, increase of approximately 1.8 times to approximately 3.5 times, increase of approximately 1.8 times to approximately 3.0 times, increase of approximately 1.8 times to approximately 2.8-fold increase, approximately 1.8-fold increase to approximately 2.6-fold increase, approximately 1.8-fold increase to approximately 2.5-fold increase, approximately 1.8-fold increase to approximately 2.4-fold increase, approximately 1.8-fold increase to approximately 2.2-fold increase, approximately 1.8-fold increase to approximately 2.0-fold increase, approximately 2.0-fold increase to approximately 100-fold increase, approximately 2.0-fold increase to approximately 90-fold increase, approximately 2.0-fold increase to approximately 80-fold increase, approximately 2.0-fold increase to approximately 70-fold increase, approximately 2.0-fold increase to approximately 60-fold increase, approximately 2.0-fold increase to approximately 50-fold increase, approximately 2.0-fold increase to approximately 40-fold increase, approximately 2.0-fold increase to approximately 30-fold increase, approximately 2.0-fold increase to approximately 20-fold increase , approximately 2.0x increase to approximately 10x increase, approximately 2.0x increase to approximately 9.5x increase, approximately 2.0x increase to approximately 9.0x increase, approximately 2.0x increase to approximately 8.5x increase, approximately 2.0x increase to approximately 8.0x increase, approximately 2.0x increase to approximately 7.5x increase, approximately 2.0x increase to approximately 7.0x increase, approximately 2.0x increase to approximately 6.5x increase, approximately 2.0x increase to approximately 6.0x increase, approximately 2.0x increase to approximately 5.5x increase, approximately 2.0x increase to approximately 5.0x increase, approximately 2.0x increase to approximately 4.5x increase, approximately 2.0x increase to approximately 4.0x increase, approximately 2.0x increase to approximately 3.5x increase Increased, approximately 2.0-fold increase to approximately 3.0-fold increase, approximately 2.0-fold increase to approximately 2.8-fold increase, approximately 2.0-fold increase to approximately 2.6-fold increase, approximately 2.0-fold increase to approximately 2.5-fold increase, approximately 2.0-fold increase to approximately 2.4-fold increase, approximately 2.0-fold increase to approximately 2.2-fold increase, approximately 2.2-fold increase to approximately 100-fold increase, approximately 2.2-fold increase to approximately 90-fold increase, approximately 2.2-fold increase to approximately 80-fold increase, approximately 2.2-fold increase to approximately 70-fold increase, approximately 2.2-fold increase to approximately 60-fold increase, approximately 2.2-fold increase to approximately 50-fold increase, approximately 2.2-fold increase to approximately 40-fold increase, approximately 2.2-fold increase to approximately 30-fold increase, approximately 2. 2x increase to approximately 20x increase, approximately 2.2x increase to approximately 10x increase, approximately 2.2x increase to approximately 9.5x increase, approximately 2.2x increase to approximately 9.0x increase, approximately 2.2x increase to approximately 8.5x increase, approximately 2.2x increase to approximately 8.0x increase, approximately 2.2x increase to approximately 7.5x increase, approximately 2.2x increase to approximately 7.0x increase, approximately 2.2x increase to approximately 6.5x increase, approximately 2.2x increase to approximately 6.0x increase, approximately 2.2x increase to approximately 5.5x increase, approximately 2.2x increase to approximately 5.0x increase, approximately 2.2x increase to approximately 4.5x increase, approximately 2.2x increase to approximately 4.0x increase, approximately 2.2x increase to approximately 3.5x increase, approximately 2.2x increase to approximately 3.0x increase, approximately 2.2x increase to approximately 2.8x increase, approximately 2.2x increase to approximately 2.6x increase, approximately 2.2x increase to approximately 2.5x increase, approximately 2.2x increase to approximately 2.4x increase, approximately 2.4x increase to approximately 100x increase, approximately 2.4x increase to approximately 90x increase, approximately 2.4x increase to approximately 80x increase, approximately 2.4x increase to approximately 70x increase, approximately 2.4x increase to approximately 60x increase, approximately 2.4x increase to approximately 50x increase, approximately 2.4x increase to approximately 40x increase, approximately 2.4x increase to approximately 30x increase, approximately 2.4x increase Increased to approximately 20 times, increased to approximately 10 times, increased to approximately 9.5 times, increased to approximately 9.0 times, increased to approximately 8.5 times, increased to approximately 8.0 times, increased to approximately 7.5 times, increased to approximately 7.0 times, increased to approximately 6.5 times, increased to approximately 6.0 times, increased to approximately 5.5 times, increased to approximately 5.0 times, increased to approximately 4.5 times, increased to approximately 4.0 times, increased to approximately 2.4 times Increased to approximately 3.5 times, increased to approximately 3.0 times, increased to approximately 2.4 times, increased to approximately 2.8 times, increased to approximately 2.4 times, increased to approximately 2.6 times, increased to approximately 100 times, increased to approximately 90 times, increased to approximately 80 times, increased to approximately 70 times, increased to approximately 60 times, increased to approximately 50 times, increased to approximately 40 times, increased to approximately 30 times, increased to approximately 20 times, increased to approximately 10 times, increased to approximately 9.5 times Increase of approximately 2.6 times to approximately 9.0 times, increase of approximately 2.6 times to approximately 8.5 times, increase of approximately 2.6 times to approximately 8.0 times, increase of approximately 2.6 times to approximately 7.5 times, increase of approximately 2.6 times to approximately 7.0 times, increase of approximately 2.6 times to approximately 6.5 times, increase of approximately 2.6 times to approximately 6.0 times, increase of approximately 2.6 times to approximately 5.5 times, increase of approximately 2.6 times to approximately 5.0 times, increase of approximately 2.6 times to approximately 4.5 times, increase of approximately 2.6 times to approximately 4.0 times, increase of approximately 2.6 times to approximately 3.5 times, increase of approximately 2.6 times to approximately 3.0 times, increase of approximately 2.6 times to approximately 2.8-fold increase, approximately 2.8-fold increase to approximately 100-fold increase, approximately 2.8-fold increase to approximately 90-fold increase, approximately 2.8-fold increase to approximately 80-fold increase, approximately 2.8-fold increase to approximately 70-fold increase, approximately 2.8-fold increase to approximately 60-fold increase, approximately 2.8-fold increase to approximately 50-fold increase, approximately 2.8-fold increase to approximately 40-fold increase, approximately 2.8-fold increase to approximately 30-fold increase, approximately 2.8-fold increase to approximately 20-fold increase, approximately 2.8-fold increase to approximately 10-fold increase, approximately 2.8-fold increase to approximately 9.5-fold increase, approximately 2.8-fold increase to approximately 9.0-fold increase, approximately 2.8-fold increase to approximately 8.5-fold increase, approximately 2.8-fold increase to approximately 8.0-fold increase Increased, approximately 2.8-fold increase to approximately 7.5-fold increase, approximately 2.8-fold increase to approximately 7.0-fold increase, approximately 2.8-fold increase to approximately 6.5-fold increase, approximately 2.8-fold increase to approximately 6.0-fold increase, approximately 2.8-fold increase to approximately 5.5-fold increase, approximately 2.8-fold increase to approximately 5.0-fold increase, approximately 2.8-fold increase to approximately 4.5-fold increase, approximately 2.8-fold increase to approximately 4.0-fold increase, approximately 2.8-fold increase to approximately 3.5-fold increase, approximately 2.8-fold increase to approximately 3.0-fold increase, approximately 3.0-fold increase to approximately 100-fold increase, approximately 3.0-fold increase to approximately 90-fold increase, approximately 3.0-fold increase to approximately 80-fold increase, approximately 3.0-fold increase to approximately 70-fold increase increase, approximately 3.0x increase to approximately 60x increase, approximately 3.0x increase to approximately 50x increase, approximately 3.0x increase to approximately 40x increase, approximately 3.0x increase to approximately 30x increase, approximately 3.0x increase to approximately 20x increase, approximately 3.0x increase to approximately 10x increase, approximately 3.0x increase to approximately 9.5x increase, approximately 3.0x increase to approximately 9.0x increase, approximately 3.0x increase to approximately 8.5x increase, approximately 3.0x increase to approximately 8.0x increase, approximately 3.0x increase to approximately 7.5x increase, approximately 3.0x increase to approximately 7.0x increase, approximately 3.0x increase to approximately 6.5x increase, approximately 3.0x increase to approximately 6.0x increase , approximately 3.0x increase to approximately 5.5x increase, approximately 3.0x increase to approximately 5.0x increase, approximately 3.0x increase to approximately 4.5x increase, approximately 3.0x increase to approximately 4.0x increase, approximately 3.0x increase to approximately 3.5x increase, approximately 3.5x increase to approximately 100x increase, approximately 3.5x increase to approximately 90x increase, approximately 3.5x increase to approximately 80x increase, approximately 3.5x increase to approximately 70x increase, approximately 3.5x increase to approximately 60x increase, approximately 3.5x increase to approximately 50x increase, approximately 3.5x increase to approximately 40x increase, approximately 3.5x increase to approximately 30x increase, approximately 3.5x increase to approximately 20x increase, approximately 3.5x increase to approximately 10x increase, approximately 3.5x increase to approximately 9.5x increase, approximately 3.5x increase to approximately 9.0x increase, approximately 3.5x increase to approximately 8.5x increase, approximately 3.5x increase to approximately 8.0x increase, approximately 3.5x increase to approximately 7.5x increase, approximately 3.5x increase to approximately 7.0x increase, approximately 3.5x increase to approximately 6. 0.5x increase, approximately 3.5x increase to approximately 6.0x increase, approximately 3.5x increase to approximately 5.5x increase, approximately 3.5x increase to approximately 5.0x increase, approximately 3.5x increase to approximately 4.5x increase, approximately 3.5x increase to approximately 4.0x increase, approximately 4.0x increase to approximately 100x increase, approximately 4.0x increase to approximately 90x increase, approximately 4.0x increase to approximately 80x increase, approximately 4.0x increase to approximately 70x increase, approximately 4.0x increase to approximately 60x increase, approximately 4.0x increase to approximately 50x increase, approximately 4.0x increase to approximately 40x increase, approximately 4.0x increase to approximately 30x increase, approximately 4.0x increase to approximately 20x increase , approximately 4.0x increase to approximately 10x increase, approximately 4.0x increase to approximately 9.5x increase, approximately 4.0x increase to approximately 9.0x increase, approximately 4.0x increase to approximately 8.5x increase, approximately 4.0x increase to approximately 8.0x increase, approximately 4.0x increase to approximately 7.5x increase, approximately 4.0x increase to approximately 7.0x increase, approximately 4.0x increase to approximately 6.5x increase, approximately 4.0x increase to approximately 6.0x increase, approximately 4.0x increase to approximately 5.5x increase, approximately 4.0x increase to approximately 5.0x increase, approximately 4.0x increase to approximately 4.5x increase, approximately 4.5x increase to approximately 100x increase, approximately 4.5x increase to approximately 90x increase , approximately 4.5x increase to approximately 80x increase, approximately 4.5x increase to approximately 70x increase, approximately 4.5x increase to approximately 60x increase, approximately 4.5x increase to approximately 50x increase, approximately 4.5x increase to approximately 40x increase, approximately 4.5x increase to approximately 30x increase, approximately 4.5x increase to approximately 20x increase, approximately 4.5x increase to approximately 10x increase, approximately 4.5x increase to approximately 9.5x increase, approximately 4.5x increase to approximately 9.0x increase, approximately 4.5x increase to approximately 8.5x increase, approximately 4.5x increase to approximately 8.0x increase, approximately 4.5x increase to approximately 7.5x increase, approximately 4.5x increase to approximately 7.0x increase, approximately 4.5x Increase to approximately 6.5x increase, approximately 4.5x increase to approximately 6.0x increase, approximately 4.5x increase to approximately 5.5x increase, approximately 4.5x increase to approximately 5.0x increase, approximately 5.0x increase to approximately 100x increase, approximately 5.0x increase to approximately 90x increase, approximately 5.0x increase to approximately 80x increase, approximately 5.0x increase to approximately 70x increase, approximately 5.0x increase to approximately 60x increase, approximately 5.0x increase to approximately 50x increase, approximately 5.0x increase to approximately 40x increase, approximately 5.0x increase to approximately 30x increase, approximately 5.0x increase to approximately 20x increase, approximately 5.0x increase to approximately 10x increase, approximately 5.0x increase to approximately 9.5x increase, approximately 5.0x increase to approximately 9.0x increase, approximately 5.0x increase to approximately 8.5x increase, approximately 5.0x increase to approximately 8.0x increase, approximately 5.0x increase to approximately 7.5x increase, approximately 5.0x increase to approximately 7.0x increase, approximately 5.0x increase to approximately 6.5x increase, approximately 5.0x increase to approximately 6.0x increase, approximately 5.0x increase to approximately 5.5x increase, approximately 5.5x increase to approximately 100x increase, approximately 5.5x increase to approximately 90x increase, approximately 5.5x increase to approximately 80x increase, approximately 5.5x increase to approximately 70x increase, approximately 5.5x increase to approximately 60x increase, approximately 5.5x increase to approximately 50x increase, about 5.5x increase to about 40x increase, about 5.5x increase to about 30x increase, about 5.5x increase to about 20x increase, about 5.5x increase to about 10x increase, about 5.5x increase to about 9.5x increase, about 5.5x increase to about 9.0x increase, about 5.5x increase to about 8.5x increase, about 5.5x increase to about 8.0x increase, about 5.5x increase to about 7.5x increase, about 5.5x increase to about 7.0x increase, about 5.5x increase to about 6.5x increase, about 5.5x increase to about 6.0x increase, about 6.0x increase to about 100x increase, about 6.0x increase to about 90x increase , approximately 6.0x increase to approximately 80x increase, approximately 6.0x increase to approximately 70x increase, approximately 6.0x increase to approximately 60x increase, approximately 6.0x increase to approximately 50x increase, approximately 6.0x increase to approximately 40x increase, approximately 6.0x increase to approximately 30x increase, approximately 6.0x increase to approximately 20x increase, approximately 6.0x increase to approximately 10x increase, approximately 6.0x increase to approximately 9.5x increase, approximately 6.0x increase to approximately 9.0x increase, approximately 6.0x increase to approximately 8.5x increase, approximately 6.0x increase to approximately 8.0x increase, approximately 6.0x increase to approximately 7.5x increase, approximately 6.0x increase to approximately 7.0x increase, approximately 6.0x Increase ~ approximately 6.5x increase, approximately 6.5x increase ~ approximately 100x increase, approximately 6.5x increase ~ approximately 90x increase, approximately 6.5x increase ~ approximately 80x increase, approximately 6.5x increase ~ approximately 70x increase, approximately 6.5x increase ~ approximately 60x increase, approximately 6.5x increase ~ approximately 50x increase, approximately 6.5x increase ~ approximately 40x increase, approximately 6.5x increase ~ approximately 30x increase, approximately 6.5x increase ~ approximately 20x increase, approximately 6.5x increase ~ approximately 10x increase, approximately 6.5x increase ~ approximately 9.5x increase, approximately 6.5x increase ~ approximately 9.0x increase, approximately 6.5x increase ~ approximately 8.5x increase, approximately 6.5x increase ~ approximately 8.0-fold increase, approximately 6.5-fold increase to approximately 7.5-fold increase, approximately 6.5-fold increase to approximately 7.0-fold increase, approximately 7.0-fold increase to approximately 100-fold increase, approximately 7.0-fold increase to approximately 90-fold increase, approximately 7.0-fold increase to approximately 80-fold increase, approximately 7.0-fold increase to approximately 70-fold increase, approximately 7.0-fold increase to approximately 60-fold increase, approximately 7.0-fold increase to approximately 50-fold increase, approximately 7.0-fold increase to approximately 40-fold increase, approximately 7.0-fold increase to approximately 30-fold increase, approximately 7.0-fold increase to approximately 20-fold increase, approximately 7.0-fold increase to approximately 10-fold increase, approximately 7.0-fold increase to approximately 9.5-fold increase, approximately 7.0-fold increase to approximately 9.0-fold increase, Approximately 7.0x increase to approximately 8.5x increase, approximately 7.0x increase to approximately 8.0x increase, approximately 7.0x increase to approximately 7.5x increase, approximately 7.5x increase to approximately 100x increase, approximately 7.5x increase to approximately 90x increase, approximately 7.5x increase to approximately 80x increase, approximately 7.5x increase to approximately 70x increase, approximately 7.5x increase to approximately 60x increase, approximately 7.5x increase to approximately 50x increase, approximately 7.5x increase to approximately 40x increase, approximately 7.5x increase to approximately 30x increase, approximately 7.5x increase to approximately 20x increase, approximately 7.5x increase to approximately 10x increase, approximately 7.5x increase to approximately 9.5x increase, approximately 7.5x increase Increased to approximately 9.0 times, increased by approximately 7.5 times to approximately 8.5 times, increased by approximately 7.5 times to approximately 8.0 times, increased by approximately 8.0 times to approximately 100 times, increased by approximately 8.0 times to approximately 90 times, increased by approximately 8.0 times to approximately 80 times, increased by approximately 8.0 times to approximately 70 times, increased by approximately 8.0 times to approximately 60 times, increased by approximately 8.0 times to approximately 50 times, increased by approximately 8.0 times to approximately 40 times, increased by approximately 8.0 times to approximately 30 times, increased by approximately 8.0 times to approximately 20 times, increased by approximately 8.0 times to approximately 10 times, increased by approximately 8.0 times to approximately 9.5 times, increased by approximately 8.0 times to approximately 9.0 times Increase of approximately 8.0 times to approximately 8.5 times, increase of approximately 8.5 times to approximately 100 times, increase of approximately 8.5 times to approximately 90 times, increase of approximately 8.5 times to approximately 80 times, increase of approximately 8.5 times to approximately 70 times, increase of approximately 8.5 times to approximately 60 times, increase of approximately 8.5 times to approximately 50 times, increase of approximately 8.5 times to approximately 40 times, increase of approximately 8.5 times to approximately 30 times, increase of approximately 8.5 times to approximately 20 times, increase of approximately 8.5 times to approximately 10 times, increase of approximately 8.5 times to approximately 9.5 times, increase of approximately 8.5 times to approximately 9.0 times, increase of approximately 9.0 times to approximately 100 times, increase of approximately 9 times.0-fold increase to approximately 90-fold increase, approximately 9.0-fold increase to approximately 80-fold increase, approximately 9.0-fold increase to approximately 70-fold increase, approximately 9.0-fold increase to approximately 60-fold increase, approximately 9.0-fold increase to approximately 50-fold increase, approximately 9.0-fold increase to approximately 40-fold increase, approximately 9.0-fold increase to approximately 30-fold increase, approximately 9.0-fold increase to approximately 20-fold increase, approximately 9.0-fold increase to approximately 10-fold increase, approximately 9.0-fold increase to approximately 9. 5-fold increase, approximately 9.5-fold increase to approximately 100-fold increase, approximately 9.5-fold increase to approximately 90-fold increase, approximately 9.5-fold increase to approximately 80-fold increase, approximately 9.5-fold increase to approximately 70-fold increase, approximately 9.5-fold increase to approximately 60-fold increase, approximately 9.5-fold increase to approximately 50-fold increase, approximately 9.5-fold increase to approximately 40-fold increase, approximately 9.5-fold increase to approximately 30-fold increase, approximately 9.5-fold increase to approximately 20-fold increase, approximately 9.5x increase to approximately 10x increase, approximately 10x increase to approximately 100x increase, approximately 10x increase to approximately 90x increase, approximately 10x increase to approximately 80x increase, approximately 10x increase to approximately 70x increase, approximately 10x increase to approximately 60x increase, approximately 10x increase to approximately 50x increase, approximately 10x increase to approximately 40x increase, approximately 10x increase to approximately 30x increase, approximately 10x increase to approximately 20x increase, approximately 20x increase to approximately 100x increase, approximately 20x increase to approximately 90x increase, about 20-fold increase to about 80-fold increase, about 20-fold increase to about 70-fold increase, about 20-fold increase to about 60-fold increase, about 20-fold increase to about 50-fold increase, about 20-fold increase to about 40-fold increase, about 20-fold increase to about 30-fold increase, about 30-fold increase to about 100-fold increase, about 30-fold increase to about 90-fold increase, about 30-fold increase to about 80-fold increase, about 30-fold increase to about 70-fold increase, about 30-fold increase to about 60-fold increase, about 30-fold increase to Approximately 50-fold increase, approximately 30-fold increase to approximately 40-fold increase, approximately 40-fold increase to approximately 100-fold increase, approximately 40-fold increase to approximately 90-fold increase, approximately 40-fold increase to approximately 80-fold increase, approximately 40-fold increase to approximately 70-fold increase, approximately 40-fold increase to approximately 60-fold increase, approximately 40-fold increase to approximately 50-fold increase, approximately 50-fold increase to approximately 100-fold increase, approximately 50-fold increase to approximately 90-fold increase, approximately 50-fold increase to approximately 80-fold increase, approximately 50-fold increase to approximately 70-fold increase, approximately 5 The increase may result in a 0-fold increase to about 60-fold increase, about 60-fold increase to about 100-fold increase, about 60-fold increase to about 90-fold increase, about 60-fold increase to about 80-fold increase, about 60-fold increase to about 70-fold increase, about 70-fold increase to about 100-fold increase, about 70-fold increase to about 90-fold increase, about 70-fold increase to about 80-fold increase, about 80-fold increase to about 100-fold increase, about 80-fold increase to about 90-fold increase, or about 90-fold increase to about 100-fold increase).

[0105] In some embodiments of any of the antibodies described herein, a composition comprising the antibody (e.g., any of the antibodies described herein) may exhibit an increase (e.g., a detectable increase) (e.g., at least a 1% increase, at least a 2% increase, at least a 5% increase, at least a 10% increase, at least a 15% increase, at least a 20% increase, at least a 25% increase, at least a 30% increase, at least a 35% increase, at least a 40% increase, at least a 45% increase, at least a 50% increase, at least a 55% increase, at least a 60% increase, at least a 65% increase, at least a 70% increase, at least a 75% increase, at least a 80% increase, at least a 85% increase, at least a 10 ... The method may result in at least a 90% increase, at least a 95% increase, at least a 100% increase, at least a 120% increase, at least a 140% increase, at least a 160% increase, at least a 180% increase, at least a 200% increase, at least a 250% increase, at least a 300% increase, at least a 350% increase, at least a 400% increase, at least a 450% increase, at least a 500% increase, at least a 1,000% increase, at least a 2,000% increase, at least a 3,000% increase, at least a 4,000% increase, at least a 5,000% increase, at least a 6,000% increase, at least a 7,000% increase, at least a 8,000% increase, at least a 9,000% increase, or at least a 10,000% increase, or from about a 1% increase to about a 10,000% increase (or, for example, any of the sub-ranges of this range described herein)).

[0106] In some embodiments of any of the antibodies described herein, a composition comprising the antibody (e.g., any of the antibodies described herein) may exhibit an increase (e.g., a detectable increase) (e.g., at least a 0.1-fold increase, at least a 0.2-fold increase, at least a 0.3-fold increase, at least a 0.4-fold increase, at least a 0.5-fold increase, at least a 0.6-fold increase, at least a 0.7-fold increase, at least a 0.8-fold increase, at least a 0.9-fold increase, at least a 1.0-fold increase, at least a 1.2-fold increase, at least a 1.4-fold increase, at least a 1.5-fold increase, at least a 1.6-fold increase, at least a 1.8-fold increase, at least a 2.0-fold increase, at least a 2.2-fold increase, at least a 2.4-fold increase, at least a 2.5-fold increase, at least a 2.6-fold increase, at least a 2.8-fold increase, at least a 3.0-fold increase, at least a 4.0-fold increase, at least a 5.0-fold increase, at least a 6.0-fold increase, at least a 7.0-fold increase, at least a 8.0-fold increase, at least a 9.0-fold increase, at least a 10 ... The increase may result in at least a 3.5-fold increase, at least a 4.0-fold increase, at least a 4.5-fold increase, at least a 5.0-fold increase, at least a 5.5-fold increase, at least a 6.0-fold increase, at least a 6.5-fold increase, at least a 7.0-fold increase, at least a 7.5-fold increase, at least a 8.0-fold increase, at least a 8.5-fold increase, at least a 9.0-fold increase, at least a 9.5-fold increase, at least a 10-fold increase, at least a 15-fold increase, at least a 20-fold increase, at least a 25-fold increase, at least a 30-fold increase, at least a 35-fold increase, at least a 40-fold increase, at least a 40-fold increase, at least a 45-fold increase, at least a 50-fold increase, at least a 55-fold increase, at least a 60-fold increase, at least a 65-fold increase, at least a 70-fold increase, at least a 80-fold increase, at least a 85-fold increase, at least a 90-fold increase, at least a 95-fold increase, or at least a 100-fold increase, or from about a 0.1-fold increase to about a 100-fold increase (or any of the sub-ranges of this range described herein)).

[0107] In some embodiments of any of the antibodies described herein, a composition comprising any of the antibodies described herein (e.g., upon contact with a target mammalian cell that displays MET on its surface) exhibits an IC200 of a composition comprising an equal amount of a control antibody (e.g., any of the control antibodies described herein). 50 compared to (e.g., when contacted with the same target mammalian cells), IC 50 results in a reduction (with respect to killing of target mammalian cells) (e.g., at least a 1% reduction, at least a 5% reduction, at least a 10% reduction, at least a 15% reduction, at least a 20% reduction, at least a 25% reduction, at least a 30% reduction, at least a 35% reduction, at least a 40% reduction, at least a 45% reduction, at least a 50% reduction, at least a 55% reduction, at least a 60% reduction, at least a 65% reduction, at least a 70% reduction, at least a 75% reduction, at least an 80% reduction, at least an 85% reduction, at least a 90% reduction, at least a 95% reduction, or at least a 99% reduction, from about a 1% reduction to about a 99% reduction, or any of the sub-ranges within this range described herein).

[0108] In some embodiments of any of the antibodies described herein, a composition comprising any of the antibodies described herein (e.g., upon contact with a target mammalian cell that displays MET on its surface) may reduce the K in the target mammalian cell that displays MET on its surface at neutral pH (about pH 7.0 to about 8.0), e.g., compared to a control antibody (e.g., any of the exemplary control antibodies described herein). D IC at neutral pH on the same target cells 50to about a 0.1-fold increase, at least a 0.2-fold increase, at least a 0.4-fold increase, at least a 0.6-fold increase, at least a 0.8-fold increase, at least a 1-fold increase, at least a 2-fold increase, at least a 5-fold increase, at least a 10-fold increase, at least a 15-fold increase, at least a 20-fold increase, at least a 25-fold increase, at least a 30-fold increase, at least a 35-fold increase, at least a 40-fold increase, at least a 45-fold increase, at least a 50-fold increase, at least a 55-fold increase, at least a 60-fold increase, at least a 65-fold increase, at least a 70-fold increase, at least a 75-fold increase, at least an 80-fold increase, at least an 85-fold increase, at least a 90-fold increase, at least a 95-fold increase, or at least a 100-fold increase, or between about a 0.1-fold increase and about a 500-fold increase (or any of the sub-ranges within this range described herein).

[0109] In some embodiments of any of the antibodies described herein, a composition comprising the antibody (e.g., any of the antibodies described herein) exhibits an increase (e.g., a detectable increase) (e.g., at least a 1% increase, at least a 2% increase, at least a 5% increase, at least a 10% increase, at least a 15% increase, at least a 20% increase, at least a 25% increase, at least a 30% increase, at least a 35% increase, at least a 40% increase, at least a 45% increase, at least a 50% increase, at least a 55% increase, at least a 60% increase, at least a 65% increase, at least a 70% increase, at least a 75% increase, at least a 80% increase, at least a 85% increase) in endolysosomal delivery in a target mammalian cell (e.g., any of the exemplary target mammalian cells described herein) compared to a composition comprising an equal amount of a control antibody (e.g., any of the exemplary control antibodies described herein). an increase of at least 90%; an increase of at least 95%; an increase of at least 100%; an increase of at least 120%; an increase of at least 140%; an increase of at least 160%; an increase of at least 180%; an increase of at least 200%; an increase of at least 250%; an increase of at least 300%; an increase of at least 350%; an increase of at least 400%; an increase of at least 450%; an increase of at least 500%; an increase of at least 1,000%; an increase of at least 2,000%; an increase of at least 3,000%; an increase of at least 4,000%; an increase of at least 5,000%; an increase of at least 6,000%; an increase of at least 7,000%; an increase of at least 8,000%; an increase of at least 9,000%; or an increase of at least 10,000%, or an increase of between about 1% and about 10,000% (or, for example, any of the sub-ranges of this range described herein).

[0110] In some examples, a composition comprising any of the antibodies described herein (e.g., any of the antibodies described herein) exhibits an increase (e.g., a detectable increase) (e.g., at least a 0.1-fold increase, at least a 0.2-fold increase, at least a 0.3-fold increase, at least a 0.4-fold increase, at least a 0.5-fold increase, at least a 0.6-fold increase, at least a 0.7-fold increase, at least a 0.8-fold increase, at least a 0.9-fold increase, at least a 1.0-fold increase, at least a 1.2-fold increase, at least a 1.4-fold increase, at least a 1.5-fold increase, at least a 1.6-fold increase, at least a 1.8-fold increase, at least a 2.0-fold increase, at least a 2.2-fold increase, at least a 2.4-fold increase, at least a 2.5-fold increase, at least a 2.6-fold increase, at least a 2.8-fold increase, at least a 3.0-fold increase, at least a 4.0-fold increase, at least a 5.0-fold increase, at least a 6.0-fold increase, at least a 7.0-fold increase, at least a 8.0-fold increase, at least a 9.0-fold increase, at least a 10 ... fold increase, at least a 3.5-fold increase, at least a 4.0-fold increase, at least a 4.5-fold increase, at least a 5.0-fold increase, at least a 5.5-fold increase, at least a 6.0-fold increase, at least a 6.5-fold increase, at least a 7.0-fold increase, at least a 7.5-fold increase, at least an 8.0-fold increase, at least an 8.5-fold increase, at least a 9.0-fold increase, at least a 9.5-fold increase, at least a 10-fold increase, at least a 15-fold increase, at least a 20-fold increase, at least a 25-fold increase, at least a 30-fold increase, at least a 35-fold increase, at least a 40-fold increase, at least a 45-fold increase, at least a 50-fold increase, at least a 55-fold increase, at least a 60-fold increase, at least a 65-fold increase, at least a 70-fold increase, at least a 75-fold increase, at least an 80-fold increase, at least an 85-fold increase, at least a 90-fold increase, at least a 95-fold increase, or at least a 100-fold increase, or from about a 0.1-fold increase to about a 100-fold increase (or any of the sub-ranges of this range described herein)).

[0111] In some embodiments of any of the antibodies described herein, the target mammalian cells do not express FcRn receptors or express them at lower (e.g., detectably lower) levels (e.g., at least 1%, at least 2%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99%) compared to control cells that express FcRn receptors (e.g., HUVEC-ThermoFisher #C0035C). In some embodiments of any of the antibodies described herein, the target mammalian cells are cancer cells. In some embodiments of any of the antibodies described herein, the antibody is cytotoxic or cytostatic to target mammalian cells.

[0112] In some embodiments of any of the antibodies described herein, a composition comprising any of the antibodies described herein (e.g., when administered to a subject) causes a less significant decrease (e.g., a 1% decrease to about a 99% decrease, or any subrange of this range described herein) in the level of MET displayed on the surface of target cells compared to a composition comprising the same amount of a control antibody (e.g., any of the control antibodies described herein). In some embodiments of any of the antibodies described herein, the composition does not cause a detectable decrease in the level of MET displayed on the surface of target mammalian cells.

[0113] In some embodiments of any of the antibodies described herein, the antibody is cross-reactive with non-human primate MET and human MET. In some embodiments of any of the antibodies described herein, the antibody is cross-reactive with non-human primate MET, human MET, and one or both of rat MET and mouse MET. In some embodiments of any of the antibodies described herein, the antibody is cross-reactive with non-human primate MET, human MET, rat MET, and mouse MET. In some embodiments of any of the antibodies described herein, the antibody is cross-reactive with mouse MET and rat MET. In some embodiments of any of the antibodies described herein, the antigen-binding domain binds to an epitope of MET present on the surface of cells from Old World monkeys.

[0114] Some examples of any of the antibodies described herein may further comprise a second antigen binding domain (e.g., any of the exemplary antigen binding domains described herein).

[0115] Non-limiting aspects of these methods are described below and may be used in any combination without limitation. Further aspects of these methods are known in the art.

[0116] MET or epitopes of MET The MET proto-oncogene, receptor tyrosine kinase (MET), is a tumor antigen known in the art and a target of therapeutic antibodies in oncology (Wang J et al (2017) ABBV-399, a c-Met Antibody-Drug Conjugate that Targets Both MET-Amplified and c-Met-Overexpressing Tumors, Irrespective of MET Pathway Dependence, Clin Cancer Res, 23:992-1000). The sequence of mature human MET can be found in SEQ ID NO: 1. The sequence of cDNA encoding mature human MET can be found in SEQ ID NO: 2. The sequence of the extracellular domain of MET can be found in SEQ ID NO: 3. The sequence of cDNA encoding the extracellular domain of MET can be found in SEQ ID NO: 4.

[0117] Exemplary Properties of Antibodies In some embodiments of any of the antibodies described herein, the antibody may be lyophilized at a pH of about 4.0 to about 6.5 (e.g., about 4.0 to about 6.4, about 4.0 to about 6.3, about 4.0 to about 6.2, about 4.0 to about 6.1, about 4.0 to about 6.0, about 4.0 to about 5.9, about 4.0 to about 5.8, about 4.0 to about 5.7, about 4.0 to about 5.6, about 4.0 to about 5.5, about 4.0 to about 5.4, about 4.0 to about 5.3, about 4.0 to about 5.2, about 4.0 to about 5.1, about 4.0 to about 5.0, about 4.0 to about 4.9, about 4.0 to about 4.8, about 4.0 to about 4.7, about 4.0 to about 4.6, about 4.0 to about 4.5, about 4.0 to about 5.6, about 4.0 to about 5.7, about 4.0 to about 5.8, about 4.0 to about 5.9, about 4.0 to about 5.8, about 4.0 to about 5.7, about 4.0 to about 5.6, about 4.0 to about 5.5, about 4.0 to about 5.4, about 4.0 to about 5.3, about 4.0 to about 5.2, about 4.0 to about 5.1, about 4.0 to about 5.0, about 4.0 to about 4.9, about 4.0 to about 4.8, about 4.0 to about 4.7, about 4.0 to about 4.6, about 4.0 to about 4.5, about 4.0 to about 5.6, about 4 About 4.4, about 4.0 to about 4.3, about 4.0 to about 4.2, about 4.0 to about 4.1, about 4.1 to about 6.5, about 4.1 to about 6.4, about 4.1 to about 6.3, about 4.1 to about 6.2, about 4.1 to about 6.1, about 4.1 to about 6.0, about 4.1 to about 5.9, about 4.1 to about 5.8, about 4.1 to about 5.7 , about 4.1 to about 5.6, about 4.1 to about 5.5, about 4.1 to about 5.4, about 4.1 to about 5.3, about 4.1 to about 5.2, about 4.1 to about 5.1, about 4.1 to about 5.0, about 4.1 to about 4.9, about 4.1 to about 4.8, about 4.1 to about 4.7, about 4.1 to about 4.6, about 4.1 to about 4.5, about 4. 1 to about 4.4, about 4.1 to about 4.3, about 4.1 to about 4.2, about 4.2 to about 6.5, about 4.2 to about 6.4, about 4.2 to about 6.3, about 4.2 to about 6.2, about 4.2 to about 6.1, about 4.2 to about 6.0, about 4.2 to about 5.9, about 4.2 to about 5.8, about 4.2 to about 5.7, about 4.2 to about 5 .6, about 4.2 to about 5.5, about 4.2 to about 5.4, about 4.2 to about 5.3, about 4.2 to about 5.2, about 4.2 to about 5.1, about 4.2 to about 5.0, about 4.2 to about 4.9, about 4.2 to about 4.8, about 4.2 to about 4.7, about 4.2 to about 4.6, about 4.2 to about 4.5, about 4.2 to about 4.4, about 4.2 to about 4.3, about 4.3 to about 6.5, about 4.3 to about 6.4, about 4.3 to about 6.3, about 4.3 to about 6.2, about 4.3 to about 6.1, about 4.3 to about 6.0, about 4.3 to about 5.9, about 4.3 to about 5.8, about 4.3 to about 5.7, about 4.3 to about 5.6, about 4.3 to about 5.5, about 4.3 to about 5.4, about 4.3 to about 5.3, about 4.3 to about 5.2, about 4.3 to about 5.1, about 4.3 to about 5.0, about 4.3 to about 4.9, about 4.3 to about 4.8, about 4.3 to about 4.7, about 4.3 to about 4.6, about 4.3 to about 4.5, about 4.3 to about 4.4, about 4.4 to about 6.5, about 4.4 to about 6.4,About 4.4 to about 6.3, about 4.4 to about 6.2, about 4.4 to about 6.1, about 4.4 to about 6.0, about 4.4 to about 5.9, about 4.4 to about 5.8, about 4.4 to about 5.7, about 4.4 to about 5.6, about 4.4 to about 5.5, about 4.4 to about 5.4, about 4.4 to about 5.3, about 4.4 to about 5.2, about 4.4 to about 5.1, about 4.4 to about 5.0, about 4.4 to about 4.9, about 4.4 to about 4.8, about 4.4 to about 4.7, about 4.4 to about 4.6, about 4.4 to about 4.5, about 4.5 to about 6.5, about 4.5 to about 6.4, about 4.5 to about 6.3, about 4.5 to about 6.2, about 4.5 to about 6.1, about 4.5 to about 6.0, About 4.5 to about 5.9, about 4.5 to about 5.8, about 4.5 to about 5.7, about 4.5 to about 5.6, about 4.5 to about 5.5, about 4.5 to about 5.4, about 4.5 to about 5.3, about 4.5 to about 5.2, about 4.5 to about 5.1, about 4.5 to about 5.0, about 4.5 to about 4.9, about 4.5 to about 4.8, about 4.5 to about 4.7, about 4.5 to about 4.6, about 4.6 to about 6.5, about 4.6 to about 6.4, about 4.6 to about 6.3, about 4.6 to about 6.2, about 4.6 to about 6.1, about 4.6 to about 6.0, about 4.6 to about 5.9, about 4.6 to about 5.8, about 4.6 to about 5.7, about 4.6 to about 5.6, about 4.6 to about 5.5, About 4.6 to about 5.4, about 4.6 to about 5.3, about 4.6 to about 5.2, about 4.6 to about 5.1, about 4.6 to about 5.0, about 4.6 to about 4.9, about 4.6 to about 4.8, about 4.6 to about 4.7, about 4.7 to about 6.5, about 4.7 to about 6.4, about 4.7 to about 6.3, about 4.7 to about 6.2, about 4.7 to about 6.1, about 4.7 to about 6.0, about 4.7 to about 5.9, about 4.7 to about 5.8, about 4.7 to about 5.7, about 4.7 to about 5.6, about 4.7 to about 5.5, about 4.7 to about 5.4, about 4.7 to about 5.3, about 4.7 to about 5.2, about 4.7 to about 5.1, about 4.7 to about 5.0, about 4.7 to about 4.9, About 4.7 to about 4.8, about 4.8 to about 6.5, about 4.8 to about 6.4, about 4.8 to about 6.3, about 4.8 to about 6.2, about 4.8 to about 6.1, about 4.8 to about 6.0, about 4.8 to about 5.9, about 4.8 to about 5.8, about 4.8 to about 5.7, about 4.8 to about 5.6, about 4.8 to about 5.5, about 4.8 to about 5.4, about 4.8 to about 5.3, about 4.8 to about 5.2, about 4.8 to about 5.1, about 4.8 to about 5.0, about 4.8 to about 4.9, about 4.9 to about 6.5, about 4.9 to about 6.4, about 4.9 to about 6.3, about 4.9 to about 6.2, about 4.9 to about 6.1, about 4.9 to about 6.0, about 4.9 to about 5.9,About 4.9 to about 5.8, about 4.9 to about 5.7, about 4.9 to about 5.6, about 4.9 to about 5.5, about 4.9 to about 5.4, about 4.9 to about 5.3, about 4.9 to about 5.2, about 4.9 to about 5.1, about 4.9 to about 5.0, about 5.0 to about 6.5, about 5.0 to about 6.4, about 5.0 to about 6.3, about 5.0 to about 6.2, about 5.0 to about 6.1, about 5.0 to about 6.0, about 5.0 to about 5.9, about 5.0 to about 5.8, about 5.0 to about 5.7, about 5.0 to about 5.6, about 5.0 to about 5.5, about 5.0 to about 5.4, about 5.0 to about 5.3, about 5.0 to about 5.2, about 5.0 to about 5.1, about 5.1 to about 6.5, about 5.1 to about 6.4, about 5.1 to about 6.3, about 5.1 to about 6.2, about 5.1 to about 6.1, about 5.1 to about 6.0, about 5.1 to about 5.9, about 5.1 to about 5.8, about 5.1 to about 5.7, about 5.1 to about 5.6, about 5.1 to about 5.5, about 5.1 to about 5.4, about 5.1 to about 5.3, about 5.1 to about 5.2, about 5.2 to about 6.5, about 5.2 to about 6.4, about 5.2 to about 6.3, about 5.2 to about 6.2, about 5.2 to about 6.1, about 5.2 to about 6.0, about 5.2 to about 5.9, about 5.2 to about 5.8, about 5.2 to about 5.7, about 5.2 to about 5.6, about 5.2 to about 5.5, about 5.2 to about 5.4, About 5.2 to about 5.3, about 5.3 to about 6.5, about 5.3 to about 6.4, about 5.3 to about 6.3, about 5.3 to about 6.2, about 5.3 to about 6.1, about 5.3 to about 6.0, about 5.3 to about 5.9, about 5.3 to about 5.8, about 5.3 to about 5.7, about 5.3 to about 5.6, about 5.3 to about 5.5, about 5.3 to about 5.4, about 5.4 to about 6.5, about 5.4 to about 6.4, about 5.4 to about 6.3, about 5.4 to about 6.2, about 5.4 to about 6.1, about 5.4 to about 6.0, about 5.4 to about 5.9, about 5.4 to about 5.8, about 5.4 to about 5.7, about 5.4 to about 5.6, about 5.4 to about 5.5, about 5.5 to about 6.5, About 5.5 to about 6.4, about 5.5 to about 6.3, about 5.5 to about 6.2, about 5.5 to about 6.1, about 5.5 to about 6.0, about 5.5 to about 5.9, about 5.5 to about 5.8, about 5.5 to about 5.7, about 5.5 to about 5.6, about 5.6 to about 6.5, about 5.6 to about 6.4, about 5.6 to about 6.3, about 5.6 to about 6.2, about 5.6 to about 6.1, about 5.6 to about 6.0, about 5.6 to about 5.9, about 5.6 to about 5.8, about 5.6 to about 5.7, about 5.7 to about 6.5, about 5.7 to about 6.4, about 5.7 to about 6.3, about 5.7 to about 6.2, about 5.7 to about 6.1, about 5.7 to about 6.0, about 5.7 to about 5.9,About 5.7 to about 5.8, about 5.8 to about 6.5, about 5.8 to about 6.4, about 5.8 to about 6.3, about 5.8 to about 6.2, about 5.8 to about 6.1, about 5.8 to about 6.0, about 5.8 to about 5.9, about 5.9 to about 6.5, about 5.9 to about 6.4, about 5.9 to about 6.3, about 5.9 to about 6.2, about 5.9 to about 6.1, about 5.9 to about 6.0, about 6.0 to about 6.5, about 6.0 to about 6.4, about 6.0 to about 6.3, about 6.0 to about 6.2, about 6.0 to about 6.1, about 6.1 to about 6.5, about 6.1 to about 6.4, about 6.1 to about 6.3, about 6.1 to about 6.2, about 6.2 to about 6.5, about 6.2 to about 6. 7.0 to about 7.4, about 6.2 to about 6.3, about 6.3 to about 6.5, about 6.3 to about 6.4, or about 6.4 to about 6.5) and the dissociation rate at pH about 7.0 to about 8.0 (e.g., about 7.0 to about 7.9, about 7.0 to about 7.8, about 7.0 to about 7.7, about 7.0 to about 7.6, about 7.0 to about 7.5, about 7.0 to about 7.4, about 7.0 to about 7.3, about 7.0 to about 7.2, about 7.0 to about 7.1, about 7.1 to about 8.0, about 7.1 to about 7.9, about 7.1 to about 7.8, about 7.1 to about 7.7, about 7.1 to about 7.6, about 7.1 to about 7.5, about 7.1 to about 7.4, about 7.1 to about 7.3, about 7.1 to about 7.2) , about 7.2 to about 8.0, about 7.2 to about 7.9, about 7.2 to about 7.8, about 7.2 to about 7.7, about 7.2 to about 7.6, about 7.2 to about 7.5, about 7.2 to about 7.4, about 7.2 to about 7.3, about 7.3 to about 8.0, about 7.3 to about 7.9, about 7.3 to about 7.8, about 7.3 to about 7.7, about 7. 3 to about 7.6, about 7.3 to about 7.5, about 7.3 to about 7.4, about 7.4 to about 8.0, about 7.4 to about 7.9, about 7.4 to about 7.8, about 7.4 to about 7.7, about 7.4 to about 7.6, about 7.4 to about 7.5, about 7.5 to about 8.0, about 7.5 to about 7.9, about 7.5 to about 7.8, about 7.5 to about 7 7.7, about 7.5 to about 7.6, about 7.6 to about 8.0, about 7.6 to about 7.9, about 7.6 to about 7.8, about 7.6 to about 7.7, about 7.7 to about 8.0, about 7.7 to about 7.9, about 7.7 to about 7.8, about 7.8 to about 8.0, about 7.7 to about 7.9, about 7.7 to about 7.8, about 7.8 to about 8.0, about 7.8 to about 7.9, or about 7.9 to about 8.0).at least 55% faster, at least 60% faster, at least 65% faster, at least 70% faster, at least 75% faster, at least 80% faster, at least 85% faster, at least 90% faster, at least 95% faster, at least 100% faster, at least 120% faster, at least 140% faster, at least 160% faster, at least 180% faster, at least 200% faster, at least 220% faster, at least 240% faster, at least 260% faster, at least 280% faster, at least 300% faster, at least 320% faster, at least 340% faster, at least 360% faster, at least 380% faster, at least 400% faster, at least 420% faster, at least 440% faster, at least 460% faster, at least 480% faster, at least 500% faster, at least 1,000% faster, at least 2,000% faster, at least 3,000% faster, at least 4,000% faster, at least 5,000% faster, at least 6,000% faster, at least 7,000% faster, at least 8,000% faster, at least 9,000% faster, or at least 10,000% faster, or about 5% faster to about 10,000% faster, about 5% faster to about 9,000% faster, about 5% faster to about 8,000% faster, about 5% faster to about 7,000% faster, about 5% faster to about 6,000% faster, about 5% faster to about 5,000% faster, about 5% faster to about 4,000% faster, about 5% faster to about 3,000% faster, about 5% faster to about 2,000% faster, about 5% faster to about 1,000% faster, about 5% faster to about 500% faster, about 5% faster to about 480% faster, about 5% faster to about 460% faster, about 5% faster to about 440% faster, about 5% faster to about 420% faster, about 5% faster to about 400% faster, about 5% faster to about 380% faster, about 5% faster to about 360% faster, about 5% faster to about 340% faster, about 5% faster to about 320% faster, about 5% faster to about 300% faster, about 5% faster to about 280% faster, about 5% faster to about 260% faster, about 5% faster to about 240% faster, about 5% faster to about 220% faster, about 5% faster to about 200% faster, about 5% faster to about 180% faster, about 5% faster to about 160% faster, about 5% faster to about 140% faster, about 5% faster to about 120% faster, about 5% faster to about 100% faster, about 5% faster to about 95% faster, about 5% faster to about 90% faster, about 5% faster to about 85% faster,Approximately 5% faster to approximately 80% faster, approximately 5% faster to approximately 75% faster, approximately 5% faster to approximately 70% faster, approximately 5% faster to approximately 65% ​​faster, approximately 5% faster to approximately 60% faster, approximately 5% faster to approximately 55% faster, approximately 5% faster to approximately 50% faster, approximately 5% faster to approximately 45% faster, approximately 5% faster to approximately 40% faster, approximately 5% faster to approximately 35% faster, approximately 5% faster to approximately 30% faster, , about 5% faster to about 25% faster, about 5% faster to about 20% faster, about 5% faster to about 15% faster, about 5% faster to about 10% faster, about 10% faster to about 10,000% faster, about 10% faster to about 9,000% faster, about 10% faster to about 8,000% faster, about 10% faster to about 7,000% faster, about 10% faster to about 6,000% faster, about 10% faster to about 5,000% faster, about 10% faster to about 4,000% faster, about 10% faster to about 3,000% faster, about 10% faster to about 2,000% faster, about 10% faster to about 1,000% faster, about 10% faster to about 500 % faster, 10% faster to 480% faster, 10% faster to 460% faster, 10% faster to 440% faster, 10% faster to 420% faster, 10% faster to 400% faster, 10% faster to 380% faster, 10% faster to 360% faster, 10% faster to 340% faster, 10% faster to 320% faster, 10% faster to 300% faster, 10% faster to 280% faster, 10% faster to 260% faster, 10% faster to 240% faster, 10% faster to 220% faster, 10% faster to 200% faster, 10% faster ~180% faster, ~10% faster~160% faster, ~10% faster~140% faster, ~10% faster~120% faster, ~10% faster~100% faster, ~10% faster~95% faster, ~10% faster~90% faster, ~10% faster~85% faster, ~10% faster~80% faster, ~10% faster~75% faster, ~10% faster~70% faster, ~10% faster~65% faster, ~10% faster~60% faster, ~10% faster~55% faster, ~10% faster~50% faster, ~10% faster~45% faster, ~10% faster~40% faster , about 10% faster to about 35% faster, about 10% faster to about 30% faster, about 10% faster to about 25% faster, about 10% faster to about 20% faster, about 10% faster to about 15% faster, about 15% faster to about 10,000% faster, about 15% faster to about 9,000% faster, about 15% faster to about 8,000% faster, about 15% faster to about 7,000% faster, about 15% faster to about 6,000% faster, about 15% faster to about 5,000% faster, about 15% faster to about 4,000% faster, about 15% faster to about 3,000% faster, about 15% faster to about 2,000% faster, about 15% faster to about 1,000% faster, approx. 15% faster to approx. 500% faster, approx. 15% faster to approx. 480% faster, approx. 15% faster to approx. 460% faster, approx. 15% faster to approx. 440% faster, approx. 15% faster to approx. 420% faster, approx. 15% faster to approx. 400% faster, approx. 15% faster to approx. 380% faster, approx. 15% faster to approx. 360% faster, approx. 15% faster to approx. 340% faster, approx. 15% faster to approx. 320% faster, approx. 15% faster to approx. 300% faster, approx. 15% faster ~280% faster, ~15% faster ~260% faster, ~15% faster ~240% faster, ~15% faster ~220% faster, ~15% faster ~200% faster, ~15% faster ~180% faster, ~15% faster ~160% faster, ~15% faster ~140% faster, ~15% faster ~120% faster, ~15% faster ~100% faster, ~15% faster ~95% faster, ~15% faster ~90% faster, ~15% faster ~ about 85% faster, about 15% faster ~ about 80% faster, about 15% faster ~ about 75% faster, about 15% faster ~ about 70% faster, about 15% faster ~ about 65% faster, about 15% faster ~ about 60% faster, about 15% faster ~ about 55% faster, about 15% faster ~ about 50% faster, about 15% faster ~ about 45% faster, about 15% faster ~ about 40% faster, about 15% faster ~ about 35% faster, about 15% faster ~ about 30% faster, about 15% faster ~ about 25% faster, Approximately 15% faster to approximately 20% faster, approximately 20% faster to approximately 10,000% faster, approximately 20% faster to approximately 9,000% faster, approximately 20% faster to approximately 8,000% faster, approximately 20% faster to approximately 7,000% faster, approximately 20% faster to approximately 6,000% faster, approximately 20% faster to approximately 5,000% faster, approximately 20% faster to approximately 4,000% faster, approximately 20% faster to approximately 3,000% faster, approximately 20% faster to approximately 2,000% faster, approximately 20% faster to approximately 1,000% faster, approx. 20% faster to approx. 500% faster, approx. 20% faster to approx. 480% faster, approx. 20% faster to approx. 460% faster, approx. 20% faster to approx. 440% faster, approx. 20% faster to approx. 420% faster, approx. 20% faster to approx. 400% faster, approx. 20% faster to approx. 380% faster, approx. 20% faster to approx. 360% faster, approx. 20% faster to approx. 340% faster, approx. 20% faster to approx. 320% faster, approx. 20% faster to approx. 300% faster, approx. 2 0% faster to 280% faster, 20% faster to 260% faster, 20% faster to 240% faster, 20% faster to 220% faster, 20% faster to 200% faster, 20% faster to 180% faster, 20% faster to 160% faster, 20% faster to 140% faster, 20% faster to 120% faster, 20% faster to 100% faster, 20% faster to 95% faster, 20% faster to 90% faster , about 20% faster to about 85% faster, about 20% faster to about 80% faster, about 20% faster to about 75% faster, about 20% faster to about 70% faster, about 20% faster to about 65% faster, about 20% faster to about 60% faster, about 20% faster to about 55% faster, about 20% faster to about 50% faster, about 20% faster to about 45% faster, about 20% faster to about 40% faster, about 20% faster to about 35% faster, about 20% faster to about 30% faster, about 20% faster ~ about 25% faster, ~ about 25% faster ~ about 10,000% faster, ~ about 25% faster ~ about 9,000% faster, ~ about 25% faster ~ about 8,000% faster, ~ about 25% faster ~ about 7,000% faster, ~ about 25% faster ~ about 6,000% faster, ~ about 25% faster ~ about 5,000% faster, ~ about 25% faster ~ about 4,000% faster, ~ about 25% faster ~ about 3,000% faster, ~ about 25% faster ~ about 2,000% faster, ~ about 25% faster ~ about 1,000% faster, 25% faster to 500% faster, 25% faster to 480% faster, 25% faster to 460% faster, 25% faster to 440% faster, 25% faster to 420% faster, 25% faster to 400% faster, 25% faster to 380% faster, 25% faster to 360% faster, 25% faster to 340% faster, 25% faster to 320% faster, 25% faster to 300% faster 25% faster to 280% faster, 25% faster to 260% faster, 25% faster to 240% faster, 25% faster to 220% faster, 25% faster to 200% faster, 25% faster to 180% faster, 25% faster to 160% faster, 25% faster to 140% faster, 25% faster to 120% faster, 25% faster to 100% faster, 25% faster to 95% faster, 25% faster ~90% faster, ~25% faster~~85% faster, ~25% faster~~80% faster, ~25% faster~~75% faster, ~25% faster~~70% faster, ~25% faster~~65% faster, ~25% faster~~60% faster, ~25% faster~~55% faster, ~25% faster~~50% faster, ~25% faster~~45% faster, ~25% faster~~40% faster, ~25% faster~~35% faster, ~25% faster~ Approximately 30% faster, approximately 30% faster to approximately 10,000% faster, approximately 30% faster to approximately 9,000% faster, approximately 30% faster to approximately 8,000% faster, approximately 30% faster to approximately 7,000% faster, approximately 30% faster to approximately 6,000% faster, approximately 30% faster to approximately 5,000% faster, approximately 30% faster to approximately 4,000% faster, approximately 30% faster to approximately 3,000% faster, approximately 30% faster to approximately 2,000% faster, approximately 30% faster to approximately 1,000% faster, approx. 30% faster to approx. 500% faster, approx. 30% faster to approx. 480% faster, approx. 30% faster to approx. 460% faster, approx. 30% faster to approx. 440% faster, approx. 30% faster to approx. 420% faster, approx. 30% faster to approx. 400% faster, approx. 30% faster to approx. 380% faster, approx. 30% faster to approx. 360% faster, approx. 30% faster to approx. 340% faster, approx. 30% faster to approx. 320% faster, approx. 30% faster to approx. 30 0% faster, 30% faster to 280% faster, 30% faster to 260% faster, 30% faster to 240% faster, 30% faster to 220% faster, 30% faster to 200% faster, 30% faster to 180% faster, 30% faster to 160% faster, 30% faster to 140% faster, 30% faster to 120% faster, 30% faster to 100% faster, 30% faster to 95% faster , about 30% faster to about 90% faster, about 30% faster to about 85% faster, about 30% faster to about 80% faster, about 30% faster to about 75% faster, about 30% faster to about 70% faster, about 30% faster to about 65% faster, about 30% faster to about 60% faster, about 30% faster to about 55% faster, about 30% faster to about 50% faster, about 30% faster to about 45% faster, about 30% faster to about 40% faster, about 30% faster to about 35% Fast, approx. 35% faster to approx. 10,000% faster, approx. 35% faster to approx. 9,000% faster, approx. 35% faster to approx. 8,000% faster, approx. 35% faster to approx. 7,000% faster, approx. 35% faster to approx. 6,000% faster, approx. 35% faster to approx. 5,000% faster, approx. 35% faster to approx. 4,000% faster, approx. 35% faster to approx. 3,000% faster, approx. 35% faster to approx. 2,000% faster, approx. 35% faster to approx. 1,000% faster, approx. 35% faster to approx. 500% faster, approx. 35% faster to approx. 480% faster, approx. 35% faster to approx. 460% faster, approx. 35% faster to approx. 440% faster, approx. 35% faster to approx. 420% faster, approx. 35% faster to approx. 400% faster, approx. 35% faster to approx. 380% faster, approx. 35% faster to approx. 360% faster, approx. 35% faster to approx. 340% faster, approx. 35% faster to approx. 320% faster, approx. 35% faster ~approx. 300% faster, ~approx. 35% faster~approx. 280% faster, ~approx. 35% faster~approx. 260% faster, ~approx. 35% faster~approx. 240% faster, ~approx. 35% faster~approx. 220% faster, ~approx. 35% faster~approx. 200% faster, ~approx. 35% faster~approx. 180% faster, ~approx. 35% faster~approx. 160% faster, ~approx. 35% faster~approx. 140% faster, ~approx. 35% faster~approx. 120% faster, ~approx. 35% faster~approx. 100% faster, ~approx. 35% faster ~ about 95% faster, about 35% faster ~ about 90% faster, about 35% faster ~ about 85% faster, about 35% faster ~ about 80% faster, about 35% faster ~ about 75% faster, about 35% faster ~ about 70% faster, about 35% faster ~ about 65% faster, about 35% faster ~ about 60% faster, about 35% faster ~ about 55% faster, about 35% faster ~ about 50% faster, about 35% faster ~ about 45% faster, about 35% faster ~ about 40% faster, Approximately 40% faster to approximately 10,000% faster, approximately 40% faster to approximately 9,000% faster, approximately 40% faster to approximately 8,000% faster, approximately 40% faster to approximately 7,000% faster, approximately 40% faster to approximately 6,000% faster, approximately 40% faster to approximately 5,000% faster, approximately 40% faster to approximately 4,000% faster, approximately 40% faster to approximately 3,000% faster, approximately 40% faster to approximately 2,000% faster, approximately 40% faster to approximately 1,000% faster, approx. 40% faster to approx. 500% faster, approx. 40% faster to approx. 480% faster, approx. 40% faster to approx. 460% faster, approx. 40% faster to approx. 440% faster, approx. 40% faster to approx. 420% faster, approx. 40% faster to approx. 400% faster, approx. 40% faster to approx. 380% faster, approx. 40% faster to approx. 360% faster, approx. 40% faster to approx. 340% faster, approx. 40% faster to approx. 320% faster, approx. 40% faster to approx. 300% faster, approx. 40% faster to approx. 280% faster, approx. 40% faster ~260% faster, ~40% faster ~240% faster, ~40% faster ~220% faster, ~40% faster ~200% faster, ~40% faster ~180% faster, ~40% faster ~160% faster, ~40% faster ~140% faster, ~40% faster ~120% faster, ~40% faster ~100% faster, ~40% faster ~95% faster, ~40% faster ~90% faster, ~40% faster ~85% faster, ~40% faster ~80% faster, ~40% faster ~75% faster, ~40% faster~~70% faster, ~40% faster~~65% faster, ~40% faster~~60% faster, ~40% faster~~55% faster, ~40% faster~~50% faster, ~40% faster~~45% faster, ~45% faster~~10,000% faster, ~45% faster~~9,000% faster, ~45% faster~~8,000% faster, ~45% faster~~7,000% faster, ~45% faster~~6,000% faster, ~45% faster~~5,000% Fast, 45% faster to 4,000% faster, 45% faster to 3,000% faster, 45% faster to 2,000% faster, 45% faster to 1,000% faster, 45% faster to 500% faster, 45% faster to 480% faster, 45% faster to 460% faster, 45% faster to 440% faster, 45% faster to 420% faster, 45% faster to 400% faster, 45% faster to 380% faster, 45% faster to 360% faster, approx. 45% faster to 340% faster, 45% faster to 320% faster, 45% faster to 300% faster, 45% faster to 280% faster, 45% faster to 260% faster, 45% faster to 240% faster, 45% faster to 220% faster, 45% faster to 200% faster, 45% faster to 180% faster, 45% faster to 160% faster, 45% faster to 140% faster, 45% faster to 120% faster, 45% faster to 100% faster, 45% faster to 95% faster, 45% faster to 90% faster, 45% faster to 85% faster, 45% faster to 80% Fast, 45% faster to 75% faster, 45% faster to 70% faster, 45% faster to 65% faster, 45% faster to 60% faster, 45% faster to 55% faster, 45% faster to 50% faster, 50% faster to 10,000% faster, 50% faster to 9,000% faster, 50% faster to 8,000% faster, 50% faster to 7,000% faster, 50% faster to 6,000% faster, 50% faster to 5,000% faster, 50% faster to 4,000% faster, 50% faster to 3,000% faster, 50% faster to 2,000% faster, 50% faster Approximately 1,000% faster, approximately 50% faster to approximately 500% faster, approximately 50% faster to approximately 480% faster, approximately 50% faster to approximately 460% faster, approximately 50% faster to approximately 440% faster, approximately 50% faster to approximately 420% faster, approximately 50% faster to approximately 400% faster, approximately 50% faster to approximately 380% faster, approximately 50% faster to approximately 360% faster, approximately 50% faster to approximately 340% faster, approximately 50% faster to approximately 320% faster, approximately 50% faster to approximately 300% faster, approximately 50% faster to approximately 280% faster, approximately 50% faster to approximately 260% faster, approximately 50% faster to approximately 240% faster, approximately 50% faster to approximately 220% faster, approximately 50% faster to approximately 200% faster , about 50% faster to about 180% faster, about 50% faster to about 160% faster, about 50% faster to about 140% faster, about 50% faster to about 120% faster, about 50% faster to about 100% faster, about 50% faster to about 95% faster, about 50% faster to about 90% faster, about 50% faster to about 85% faster, about 50% faster to about 80% faster, about 50% faster to about 75% faster, about 50% faster to about 70% faster, about 50% faster to about 65% faster, about 50% faster to about 60% faster, about 50% faster to about 55% faster, about 55% faster to about 10,000% faster, about 55% faster to about 9,000% faster, about 55% faster to about 8,000% faster, 55% faster to 7,000% faster, 55% faster to 6,000% faster, 55% faster to 5,000% faster, 55% faster to 4,000% faster, 55% faster to 3,000% faster, 55% faster to 2,000% faster, 55% faster to 1,000% faster, 55% faster to 500% faster, 55% faster to 480% faster, 55% faster to 460% faster, 55% faster to approx. 440% faster, 55% faster to 420% faster, 55% faster to 400% faster, 55% faster to 380% faster, 55% faster to 360% faster, 55% faster to 340% faster, 55% faster to 320% faster, 55% faster to 300% faster, 55% faster to 280% faster, 55% faster to 260% faster, 55% faster to 240% faster, 55% faster to 220% faster, 55% faster Approximately 200% faster, approximately 55% faster to approximately 180% faster, approximately 55% faster to approximately 160% faster, approximately 55% faster to approximately 140% faster, approximately 55% faster to approximately 120% faster, approximately 55% faster to approximately 100% faster, approximately 55% faster to approximately 95% faster, approximately 55% faster to approximately 90% faster, approximately 55% faster to approximately 85% faster, approximately 55% faster to approximately 80% faster, approximately 55% faster to approximately 75% faster, approximately 55% faster to approximately 70% faster, approximately 55% faster to approximately 65% ​​faster , about 55% faster to about 60% faster, about 60% faster to about 10,000% faster, about 60% faster to about 9,000% faster, about 60% faster to about 8,000% faster, about 60% faster to about 7,000% faster, about 60% faster to about 6,000% faster, about 60% faster to about 5,000% faster, about 60% faster to about 4,000% faster, about 60% faster to about 3,000% faster, about 60% faster to about 2,000% faster, about 60% faster to about 1,000% faster, approx. 60% faster to approx. 500% faster, approx. 60% faster to approx. 480% faster, approx. 60% faster to approx. 460% faster, approx. 60% faster to approx. 440% faster, approx. 60% faster to approx. 420% faster, approx. 60% faster to approx. 400% faster, approx. 60% faster to approx. 380% faster, approx. 60% faster to approx. 360% faster, approx. 60% faster to approx. 340% faster, approx. 60% faster to approx. 320% faster, approx. 60% faster to approx. 300% faster, approx. 60% faster to approx. 280% faster, approx. 60% faster to approx. 260% faster, approx. 60% faster to approx. 240% faster, approx. 60% faster to approx. 220% faster, approx. 60% faster to approx. 200% faster, approx. 60 % faster to about 180% faster, about 60% faster to about 160% faster, about 60% faster to about 140% faster, about 60% faster to about 120% faster, about 60% faster to about 100% faster, about 60% faster to about 95% faster, about 60% faster to about 90% faster, about 60% faster to about 85% faster, about 60% faster to about 80% faster, about 60% faster to about 75% faster, about 60% faster to about 70% faster, about 60% faster to about 65% faster, about 65% faster to about 10,000% faster, about 65% faster to about 9,000% faster, about 65% faster to about 8,000% faster, about 65% faster to about 7,000% faster, about 65% faster to about 6,0 00% faster, approx. 65% faster to approx. 5,000% faster, approx. 65% faster to approx. 4,000% faster, approx. 65% faster to approx. 3,000% faster, approx. 65% faster to approx. 2,000% faster, approx. 65% faster to approx. 1,000% faster, approx. 65% faster to approx. 500% faster, approx. 65% faster to approx. 480% faster, approx. 65% faster to approx. 460% faster, approx. 65% faster to approx. 440% faster, approx. 65% faster to approx. 420% faster, approx. 65% faster to approx. 400% faster, approx. 65% faster to approx. 380% faster, approx. 65% faster to approx. 360% faster, approx. 65% faster to approx. 340% faster, approx. 65% faster to approx. 320% faster, approx. 65% faster to approx. 3 00% fast, 65% fast to 280% fast, 65% fast to 260% fast, 65% fast to 240% fast, 65% fast to 220% fast, 65% fast to 200% fast, 65% fast to 180% fast, 65% fast to 160% fast, 65% fast to 140% fast, 65% fast to 120% fast, 65% fast to 100% fast, 65% fast to 95% fast, 65% fast to 90% fast, 65% fast to 85% fast, 65% fast to 80% fast, 65% fast to 75% fast, 65% fast to 70% fast, 70% fast to 10,000% faster, approx. 70% faster to approx. 9,000% faster, approx. 70% faster to approx. 8,000% faster, approx. 70% faster to approx. 7,000% faster, approx. 70% faster to approx. 6,000% faster, approx. 70% faster to approx. 5,000% faster, approx. 70% faster to approx. 4,000% faster, approx. 70% faster to approx. 3,000% faster, approx. 70% faster to approx. 2,000% faster, approx. 70% faster to approx. 1,000% faster, approx. 70% faster to approx. 500% faster, approx. 7 0% faster to approx. 480% faster, approx. 70% faster to approx. 460% faster, approx. 70% faster to approx. 440% faster, approx. 70% faster to approx. 420% faster, approx. 70% faster to approx. 400% faster, approx. 70% faster to approx. 380% faster, approx. 70% faster to approx. 360% faster, approx. 70% faster to approx. 340% faster, approx. 70% faster to approx. 320% faster, approx. 70% faster to approx. 300% faster, approx. 70% faster to approx. 280% faster, approx. 70% faster to approx. 260% faster , about 70% faster to about 240% faster, about 70% faster to about 220% faster, about 70% faster to about 200% faster, about 70% faster to about 180% faster, about 70% faster to about 160% faster, about 70% faster to about 140% faster, about 70% faster to about 120% faster, about 70% faster to about 100% faster, about 70% faster to about 95% faster, about 70% faster to about 90% faster, about 70% faster to about 85% faster, about 70% faster to about 80% faster, Approximately 70% faster to approximately 75% faster, approximately 75% faster to approximately 10,000% faster, approximately 75% faster to approximately 9,000% faster, approximately 75% faster to approximately 8,000% faster, approximately 75% faster to approximately 7,000% faster, approximately 75% faster to approximately 6,000% faster, approximately 75% faster to approximately 5,000% faster, approximately 75% faster to approximately 4,000% faster, approximately 75% faster to approximately 3,000% faster, approximately 75% faster to approximately 2,000% faster, approximately 75% faster to approximately 1,000% faster, approx. 75% faster to approx. 500% faster, approx. 75% faster to approx. 480% faster, approx. 75% faster to approx. 460% faster, approx. 75% faster to approx. 440% faster, approx. 75% faster to approx. 420% faster, approx. 75% faster to approx. 400% faster, approx. 75% faster to approx. 380% faster, approx. 75% faster to approx. 360% faster, approx. 75% faster to approx. 340% faster, approx. 75% faster to approx. 320% faster, approx. 75% faster to approx. 300% faster, approx. 75% faster to approx. 280% faster, approx. 75% faster to approx. 260% faster, approx. 75% faster to approx. 240% faster, 75% faster to 220% faster, 75% faster to 200% faster, 75% faster to 180% faster, 75% faster to 160% faster, 75% faster to 140% faster, 75% faster to 120% faster, 75% faster to 100% faster, 75% faster to 95% faster, 75% faster to 90% faster, 75% faster to 85% faster, 75% faster to 80% faster, 80% faster to 10,000% faster, 80% faster to 9,000% faster, 80% faster Approximately 8,000% faster, approximately 80% faster to approximately 7,000% faster, approximately 80% faster to approximately 6,000% faster, approximately 80% faster to approximately 5,000% faster, approximately 80% faster to approximately 4,000% faster, approximately 80% faster to approximately 3,000% faster, approximately 80% faster to approximately 2,000% faster, approximately 80% faster to approximately 1,000% faster, approximately 80% faster to approximately 500% faster, approximately 80% faster to approximately 480% faster, approximately 80 % faster to approx. 460% faster, approx. 80% faster to approx. 440% faster, approx. 80% faster to approx. 420% faster, approx. 80% faster to approx. 400% faster, approx. 80% faster to approx. 380% faster, approx. 80% faster to approx. 360% faster, approx. 80% faster to approx. 340% faster, approx. 80% faster to approx. 320% faster, approx. 80% faster to approx. 300% faster, approx. 80% faster to approx. 280% faster, approx. 80% faster to approx. 260% faster, approx. 80% faster to about 240% faster, about 80% faster to about 220% faster, about 80% faster to about 200% faster, about 80% faster to about 180% faster, about 80% faster to about 160% faster, about 80% faster to about 140% faster, about 80% faster to about 120% faster, about 80% faster to about 100% faster, about 80% faster to about 95% faster, about 80% faster to about 90% faster, about 80% faster to about 85% faster, about 85% faster to about 10,000% faster, about 85% faster to about 9,000% faster, about 85% faster to about 8,000% faster, about 85% faster to about 7,000% faster, about 85% faster to about 6,000% faster, about 85% faster to about 5,000% faster, about 85% faster to about 4,000% faster, about 85% faster to about 3,000% faster, about 85% faster to about 2,000% faster, about 85% faster to about 1,000% faster, 85% faster to 500% faster, 85% faster to 480% faster, 85% faster to 460% faster, 85% faster to 440% faster, 85% faster to 420% faster, 85% faster to 400% faster, 85% faster to 380% faster, 85% faster to 360% faster, 85% faster to 340% faster, 85% faster to 320% faster, 85% faster to 300% faster, 85% faster to 280% faster, 85% faster to 260% faster, 85% faster to 240% faster, 85% faster to 220% faster, 85% faster to 2 ...220% faster, 85% faster to 200% faster, 85% faster to 380% faster, 85% faster to 360% faster, 85% faster to 340% faster, 85% faster to 320% faster, 85% faster to 300% faster, 85% faster to 280% faster, 85% faster to 260% faster, 85% faster to 240 5% faster to 180% faster, 85% faster to 160% faster, 85% faster to 140% faster, 85% faster to 120% faster, 85% faster to 100% faster, 85% faster to 95% faster, 85% faster to 90% faster, 90% faster to 10,000% faster, 90% faster to 9,000% faster, 90% faster to 8,000% faster, 90% faster to 7,000% faster, 90% faster to 6,000% faster, 90% faster to 5,000% faster, 90% faster to 4,000% faster, 90% faster to 3,000% faster, 90% faster to 2,0 00% faster, approx. 90% faster to approx. 1,000% faster, approx. 90% faster to approx. 500% faster, approx. 90% faster to approx. 480% faster, approx. 90% faster to approx. 460% faster, approx. 90% faster to approx. 440% faster, approx. 90% faster to approx. 420% faster, approx. 90% faster to approx. 400% faster, approx. 90% faster to approx. 380% faster, approx. 90% faster to approx. 360% faster, approx. 90% faster to approx. 340% faster, approx. 90% faster to approx. 320% faster, approx. 90% faster to approx. 300% faster, approx. 90% faster to approx. 280% faster, approx. 90% faster to approx. 260% faster, approx. 90% faster to approx. 240% faster, approx. 90% faster to approx. 220% faster, approx. 90% faster to about 200% faster, about 90% faster to about 180% faster, about 90% faster to about 160% faster, about 90% faster to about 140% faster, about 90% faster to about 120% faster, about 90% faster to about 100% faster, about 90% faster to about 95% faster, about 95% faster to about 10,000% faster, about 95% faster to about 9,000% faster, about 95% faster to about 8,000% faster, about 95% faster to about 7,000% faster, about 95% faster to about 6,000% faster, about 95% faster to about 5,000% faster, about 95% faster to about 4,000% faster, about 95% faster to about 3,000% faster, about 95% faster to about 2,000% faster, approx. 95% faster to approx. 1,000% faster, approx. 95% faster to approx. 500% faster, approx. 95% faster to approx. 480% faster, approx. 95% faster to approx. 460% faster, approx. 95% faster to approx. 440% faster, approx. 95% faster to approx. 420% faster, approx. 95% faster to approx. 400% faster, approx. 95% faster to approx. 380% faster, approx. 95% faster to approx. 360% faster, approx. 95% faster to approx. 340% faster, approx. 95% faster to approx. 320% faster, approx. 95% faster to approx. 300% faster, approx. 95% faster to approx. 280% faster, approx. 95% faster to approx. 260% faster, approx. 95% faster to approx. 240% faster, approx. 95% faster to approx. 220% faster, Approximately 95% faster to approximately 200% faster, approximately 95% faster to approximately 180% faster, approximately 95% faster to approximately 160% faster, approximately 95% faster to approximately 140% faster, approximately 95% faster to approximately 120% faster, approximately 95% faster to approximately 100% faster, approximately 100% faster to approximately 10,000% faster, approximately 100% faster to approximately 9,000% faster, approximately 100% faster to approximately 8,000% faster, approximately 100% faster to approximately 7,000% faster, approximately 100% faster to approximately 6,000% faster, approximately 100% faster to approximately 5,000% faster, approximately 100% faster to approximately 4,000% faster, approximately 100% faster to approximately 3,000% faster, approximately 100% faster to approximately 2,000 % faster, approx. 100% faster to approx. 1,000% faster, approx. 100% faster to approx. 500% faster, approx. 100% faster to approx. 480% faster, approx. 100% faster to approx. 460% faster, approx. 100% faster to approx. 440% faster, approx. 100% faster to approx. 420% faster, approx. 100% faster to approx. 400% faster, approx. 100% faster to approx. 380% faster, approx. 100% faster to approx. 360% faster, approx. 100% faster to approx. 340% faster, approx. 100% faster to approx. 320% faster, approx. 100% faster to approx. 300% faster, approx. 100% faster to approx. 280% faster, approx. 100% faster to approx. 260% faster, approx. 100% faster to approx. 240% faster, approx. 10 0% faster to approx. 220% faster, approx. 100% faster to approx. 200% faster, approx. 100% faster to approx. 180% faster, approx. 100% faster to approx. 160% faster, approx. 100% faster to approx. 140% faster, approx. 100% faster to approx. 120% faster, approx. 120% faster to approx. 10,000% faster, approx. 120% faster to approx. 9,000% faster, approx. 120% faster to approx. 8,000% faster, approx. 120% faster to approx. 7,000% faster, approx. 120% faster to approx. 6,000% faster, approx. 120% faster to approx. 5,000% faster, approx. 120% faster to approx. 4,000% faster, approx. 120% faster to approx. 3,000% faster, approx. 120% faster to approx. 2,000% faster, approx. 120% faster to approx. 1,000% faster, approx. 120% faster to approx. 500% faster, approx. 120% faster to approx. 480% faster, approx. 120% faster to approx. 460% faster, approx. 120% faster to approx. 440% faster, approx. 120% faster to approx. 420% faster, approx. 120% faster to approx. 400% faster, approx. 120% faster to approx. 380% faster, approx. 120% faster to approx. 360% faster, approx. 120% faster to approx. 340% faster, approx. 120% faster to approx. 320% faster, approx. 120% faster to approx. 300% faster, approx. 120% faster to approx. 280% faster, approx. 120% faster to approx. 260% faster, approx. 120% faster to approx. 2 40% faster, 120% faster to 220% faster, 120% faster to 200% faster, 120% faster to 180% faster, 120% faster to 160% faster, 120% faster to 140% faster, 140% faster to 10,000% faster, 140% faster to 9,000% faster, 140% faster to 8,000% faster, 140% faster to 7,000% faster, 140% faster to 6,000% faster, 140% faster to 5,000% faster, 140% faster to 4,000% faster, 140% faster to 3,000% faster, 140% faster to 2,0 00% faster, approx. 140% faster to approx. 1,000% faster, approx. 140% faster to approx. 500% faster, approx. 140% faster to approx. 480% faster, approx. 140% faster to approx. 460% faster, approx. 140% faster to approx. 440% faster, approx. 140% faster to approx. 420% faster, approx. 140% faster to approx. 400% faster, approx. 140% faster to approx. 380% faster, approx. 140% faster to approx. 360% faster, approx. 140% faster to approx. 340% faster, approx. 140% faster to approx. 320% faster, approx. 140% faster to approx. 300% faster, approx. 140% faster to approx. 280% faster, approx. 140% faster to approx. 260% faster, approx. 140% faster to approx. 24 0% faster, approx. 140% faster to approx. 220% faster, approx. 140% faster to approx. 200% faster, approx. 140% faster to approx. 180% faster, approx. 140% faster to approx. 160% faster, approx. 160% faster to approx. 10,000% faster, approx. 160% faster to approx. 9,000% faster, approx. 160% faster to approx. 8,000% faster, approx. 160% faster to approx. 7,000% faster, approx. 160% faster to approx. 6,000% faster, approx. 160% faster to approx. 5,000% faster, approx. 160% faster to approx. 4,000% faster, approx. 160% faster to approx. 3,000% faster, approx. 160% faster to approx. 2,000% faster, approx. 160% faster to approx. 1,000% faster, 160% faster to 500% faster, 160% faster to 480% faster, 160% faster to 460% faster, 160% faster to 440% faster, 160% faster to 420% faster, 160% faster to 400% faster, 160% faster to 380% faster, 160% faster to 360% faster, 160% faster to 340% faster, 160% faster to 320% faster, 160% faster to 300% faster, 160% faster to 280% faster, 160% faster to 260% faster, 160% faster ~approx. 240% faster, ~approx. 160% faster~approx. 220% faster, ~approx. 160% faster~approx. 200% faster, ~approx. 160% faster~approx. 180% faster, ~approx. 180% faster~approx. 10,000% faster, ~approx. 180% faster~approx. 9,000% faster, ~approx. 180% faster~approx. 8,000% faster, ~approx. 180% faster~approx. 7,000% faster, ~approx. 180% faster~approx. 6,000% faster, ~approx. 180% faster~approx. 5,000% faster, ~approx. 180% faster~approx. 4,000% faster, ~approx. 180% faster~approx. 3,000% faster, ~approx. 180% faster~approx. 2,000% faster, ~approx. 18 0% faster to 1,000% faster, 180% faster to 500% faster, 180% faster to 480% faster, 180% faster to 460% faster, 180% faster to 440% faster, 180% faster to 420% faster, 180% faster to 400% faster, 180% faster to 380% faster, 180% faster to 360% faster, 180% faster to 340% faster, 180% faster to 320% faster, 180% faster to 300% faster, 180% faster to 280% faster, 180% faster to 260% faster , about 180% faster to about 240% faster, about 180% faster to about 220% faster, about 180% faster to about 200% faster, about 200% faster to about 10,000% faster, about 200% faster to about 9,000% faster, about 200% faster to about 8,000% faster, about 200% faster to about 7,000% faster, about 200% faster to about 6,000% faster, about 200% faster to about 5,000% faster, about 200% faster to about 4,000% faster, about 200% faster to about 3,000% faster, about 200% faster to about 2,000% faster, about 200% faster to about 1,000% faster, approx. 200% faster to approx. 500% faster, approx. 200% faster to approx. 480% faster, approx. 200% faster to approx. 460% faster, approx. 200% faster to approx. 440% faster, approx. 200% faster to approx. 420% faster, approx. 200% faster to approx. 400% faster, approx. 200% faster to approx. 380% faster, approx. 200% faster to approx. 360% faster, approx. 200% faster to approx. 340% faster, approx. 20 0% faster to approx. 320% faster, approx. 200% faster to approx. 300% faster, approx. 200% faster to approx. 280% faster, approx. 200% faster to approx. 260% faster, approx. 200% faster to approx. 240% faster, approx. 200% faster to approx. 220% faster, approx. 220% faster to approx. 10,000% faster, approx. 220% faster to approx. 9,000% faster, approx. 220% faster to approx. 8,000% faster, approx. 220% faster ~approx. 7,000% faster, ~approx. 220% faster ~approx. 6,000% faster, ~approx. 220% faster ~approx. 5,000% faster, ~approx. 220% faster ~approx. 4,000% faster, ~approx. 220% faster ~approx. 3,000% faster, ~approx. 220% faster ~approx. 2,000% faster, ~approx. 220% faster ~approx. 1,000% faster, ~approx. 220% faster ~approx. 500% faster, ~approx. 220% faster ~approx. 480% faster, ~approx. 20% faster to approx. 460% faster, approx. 220% faster to approx. 440% faster, approx. 220% faster to approx. 420% faster, approx. 220% faster to approx. 400% faster, approx. 220% faster to approx. 380% faster, approx. 220% faster to approx. 360% faster, approx. 220% faster to approx. 340% faster, approx. 220% faster to approx. 320% faster, approx. 220% faster to approx. 300% faster, approx. 220% faster to approx. 280, % faster, approx. 220% faster to approx. 260% faster, approx. 220% faster to approx. 240% faster, approx. 240% faster to approx. 10,000% faster, approx. 240% faster to approx. 9,000% faster, approx. 240% faster to approx. 8,000% faster, approx. 240% faster to approx. 7,000% faster, approx. 240% faster to approx. 6,000% faster, approx. 240% faster to approx. 5,000% faster, approx. 240% faster to approx. 4,000% faster, approx. 240% faster to approx. 3,000% faster, approx. 240% faster to approx. 2,000% faster, approx. 240% faster to approx. 1,000% faster, approx. 240% faster to approx. 500% faster, approx. 240% faster to approx. 4 80% faster, 240% faster to 460% faster, 240% faster to 440% faster, 240% faster to 420% faster, 240% faster to 400% faster, 240% faster to 380% faster, 240% faster to 360% faster, 240% faster to 340% faster, 240% faster to 320% faster, 240% faster to 300% faster, 240% faster to 280% faster, 240% faster to 260% faster, 260% faster to 10,000% faster, 260% faster to 9,000% faster, 260% faster to 8,000% faster, 260% faster ~approx. 7,000% faster, ~approx. 260% faster ~approx. 6,000% faster, ~approx. 260% faster ~approx. 5,000% faster, ~approx. 260% faster ~approx. 4,000% faster, ~approx. 260% faster ~approx. 3,000% faster, ~approx. 260% faster ~approx. 2,000% faster, ~approx. 260% faster ~approx. 1,000% faster, ~approx. 260% faster ~approx. 500% faster, ~approx. 260% faster ~approx. 480% faster, ~approx. 260% faster ~approx. 460% faster, ~approx. 260% faster ~approx. 440% faster, ~approx. 260% faster ~approx. 420% faster, ~approx. 260% faster ~approx. 400% faster, ~approx. 260% faster ~approx. 380% faster, ~approx. 260% faster ~approx. 36 0% faster, approx. 260% faster to approx. 340% faster, approx. 260% faster to approx. 320% faster, approx. 260% faster to approx. 300% faster, approx. 260% faster to approx. 280% faster, approx. 280% faster to approx. 10,000% faster, approx. 280% faster to approx. 9,000% faster, approx. 280% faster to approx. 8,000% faster, approx. 280% faster to approx. 7,000% faster, approx. 280% faster to approx. 6,000% faster, approx. 280% faster to approx. 5,000% faster, approx. 280% faster to approx. 4,000% faster, approx. 280% faster to approx. 3,000% faster, approx. 280% faster to approx. 2,000% faster, approx. 280% faster to approx. 1,000% faster, approx. 280% faster to approx. 500% faster, approx. 280% faster to approx. 480% faster, approx. 280% faster to approx. 460% faster, approx. 280% faster to approx. 440% faster, approx. 280% faster to approx. 420% faster, approx. 280% faster to approx. 400% faster, approx. 280% faster to approx. 380% faster, approx. 280% faster to approx. 360% faster, approx. 280% faster to approx. 340% faster, approx. 280% faster to approx. 320% faster, approx. 280% faster to approx. 300% faster, approx. 300% faster to approx. 10,000% faster, approx. 300% faster to approx. 9,000% faster, approx. 300% faster to approx. 8,000% faster, approx. 300% faster Approximately 7,000% faster, approximately 300% faster to approximately 6,000% faster, approximately 300% faster to approximately 5,000% faster, approximately 300% faster to approximately 4,000% faster, approximately 300% faster to approximately 3,000% faster, approximately 300% faster to approximately 2,000% faster, approximately 300% faster to approximately 1,000% faster, approximately 300% faster to approximately 500% faster, approximately 300% faster to approximately 480% faster, approximately 300% faster to approximately 460% faster, approximately 300% faster to approximately 440% faster, approximately 300% faster to approximately 420% faster, approximately 300% faster to approximately 400% faster, approximately 300% faster to approximately 380% faster, approximately 300% faster to approximately 360% faster, approximately 300% faster to approx. 340% faster, approx. 300% faster to approx. 320% faster, approx. 320% faster to approx. 10,000% faster, approx. 320% faster to approx. 9,000% faster, approx. 320% faster to approx. 8,000% faster, approx. 320% faster to approx. 7,000% faster, approx. 320% faster to approx. 6,000% faster, approx. 320% faster to approx. 5,000% faster, approx. 320% faster to approx. 4,000% faster, approx. 320% faster to approx. 3,000% faster, approx. 320% faster to approx. 2,000% faster, approx. 320% faster to approx. 1,000% faster, approx. 320% faster to approx. 500% faster, approx. 320% faster to approx. 480% faster, approx. 32 0% faster to approx. 460% faster, approx. 320% faster to approx. 440% faster, approx. 320% faster to approx. 420% faster, approx. 320% faster to approx. 400% faster, approx. 320% faster to approx. 380% faster, approx. 320% faster to approx. 360% faster, approx. 320% faster to approx. 340% faster, approx. 340% faster to approx. 10,000% faster, approx. 340% faster to approx. 9,000% faster, approx. 340% faster to approx. 8,000% faster, approx. 340% faster to approx. 7,000% faster, approx. 340% faster to approx. 6,000% faster, approx. 340% faster to approx. 5,000% faster, approx. 340% faster to approx. 4,000% faster, approx. 340% faster to approx. 3,000% faster, approx. 340% faster to approx. 2,000% faster, approx. 340% faster to approx. 1,000% faster, approx. 340% faster to approx. 500% faster, approx. 340% faster to approx. 480% faster, approx. 340% faster to approx. 460% faster, approx. 340% faster to approx. 440% faster, approx. 340% faster to approx. 420% faster, approx. 340% faster to approx. 400% faster, approx. 340% faster to approx. 380% faster, approx. 340% faster to approx. 360% faster, approx. 360% faster to approx. 10,000% faster, approx. 360% faster to approx. 9,000% faster, approx. 360% faster to approx. 8,000% faster, approx. 3 60% faster to approx. 7,000% faster, approx. 360% faster to approx. 6,000% faster, approx. 360% faster to approx. 5,000% faster, approx. 360% faster to approx. 4,000% faster, approx. 360% faster to approx. 3,000% faster, approx. 360% faster to approx. 2,000% faster, approx. 360% faster to approx. 1,000% faster, approx. 360% faster to approx. 500% faster, approx. 360% faster to approx. 480% faster, approx. 360% faster to approx. 460% faster, approx. 360% faster to approx. 440% faster, approx. 360% faster to approx. 420% faster, approx. 360% faster to approx. 400% faster, approx. 360% faster to approx. 380% faster, approx. 380% faster to approx. 10,000% faster, approx. 380% faster to approx. 9,000% faster, approx. 380% faster to approx. 8,000% faster, approx. 380% faster to approx. 7,000% faster, approx. 380% faster to approx. 6,000% faster, approx. 380% faster to approx. 5,000% faster, approx. 380% faster to approx. 4,000% faster, approx. 380% faster to approx. 3,000% faster, approx. 380% faster to approx. 2,000% faster, approx. 380% faster to approx. 1,000% faster, approx. 380% faster to approx. 500% faster, approx. 380% faster to approx. 480% faster, approx. 380% faster to approx. 460% faster, approx. 380% faster to approx. 440% faster, approx. 380% faster to approx. 420% faster, approx. 380% faster to approx. 400% faster, approx. 400% faster to approx. 10,000% faster, approx. 400% faster to approx. 9,000% faster, approx. 400% faster to approx. 8,000% faster, approx. 400% faster to approx. 7,000% faster, approx. 400% faster to approx. 6,000% faster, approx. 400% faster to approx. 5,000% faster, approx. 400% faster to approx. 4,000% faster, approx. 400% faster to approx. 3,000% faster, approx. 400% faster to approx. 2,000% faster, approx. 400% faster to approx. 1,000% faster, about 400% faster to about 500% faster, about 400% faster to about 480% faster, about 400% faster to about 460% faster, about 400% faster to about 440% faster, about 400% faster to about 420% faster, about 420% faster to about 10,000% faster, about 420% faster to about 9,000% faster, about 420% faster to about 8,000% faster, about 420% faster to about 7,000% faster, about 420% faster to about 6,000% faster, about 420% faster to about 5,000% faster, about 420% faster to about 4,000% faster, about 420% faster to about 3,000% faster, about 420% faster to about 2,000% faster, Approximately 420% faster to approximately 1,000% faster, approximately 420% faster to approximately 500% faster, approximately 420% faster to approximately 480% faster, approximately 420% faster to approximately 460% faster, approximately 420% faster to approximately 440% faster, approximately 440% faster to approximately 10,000% faster, approximately 440% faster to approximately 9,000% faster, approximately 440% faster to approximately 8,000% faster, approximately 440% faster to approximately 7,000% faster, approximately 440% faster to approximately 6,000% faster, approximately 440% faster to approximately 5,000% faster, approximately 440% faster to approximately 4,000% faster, approximately 440% faster to approximately 3,000% faster, approximately 440% faster to approximately 2,000% faster, approximately 440% Fast to approx. 1,000% faster, approx. 440% faster to approx. 500% faster, approx. 440% faster to approx. 480% faster, approx. 440% faster to approx. 460% faster, approx. 460% faster to approx. 10,000% faster, approx. 460% faster to approx. 9,000% faster, approx. 460% faster to approx. 8,000% faster, approx. 460% faster to approx. 7,000% faster, approx. 460% faster to approx. 6,000% faster, approx. 460% faster to approx. 5,000% faster, approx. 460% faster to approx. 4,000% faster, approx. 460% faster to approx. 3,000% faster, approx. 460% faster to approx. 2,000% faster, approx. 460% faster to approx. 1,000% faster, approx. 460% faster Approximately 500% faster, approximately 460% faster to approximately 480% faster, approximately 480% faster to approximately 10,000% faster, approximately 480% faster to approximately 9,000% faster, approximately 480% faster to approximately 8,000% faster, approximately 480% faster to approximately 7,000% faster, approximately 480% faster to approximately 6,000% faster, approximately 480% faster to approximately 5,000% faster, approximately 480% faster to approximately 4,000% faster, approximately 480% faster to approximately 3,000% faster, approximately 480% faster to approximately 2,000% faster, approximately 480% faster to approximately 1,000% faster, approximately 480% faster to approximately 500% faster, approximately 500% faster to approximately 10,000% faster, approximately 500% faster to approximately 9,000% faster, 500% faster to 8,000% faster, 500% faster to 7,000% faster, 500% faster to 6,000% faster, 500% faster to 5,000% faster, 500% faster to 4,000% faster, 500% faster to 3,000% faster, 500% faster to 2,000% faster, 500% faster to 1,000% faster, 1,000% faster to 10,000% faster, 1,000% faster to 9,000% faster, 1,000% faster to 8,000% faster, 1,000% faster to 7,000% faster, 1,000% faster to 6,000% faster , about 1,000% faster to about 5,000% faster, about 1,000% faster to about 4,000% faster, about 1,000% faster to about 3,000% faster, about 1,000% faster to about 2,000% faster, about 2,000% faster to about 10,000% faster, about 2,000% faster to about 9,000% faster, about 2,000% faster to about 8,000% faster, about 2,000% faster to about 7,000% faster, about 2,000% faster to about 6,000% faster, about 2,000% faster to about 5,000% faster, about 2,000% faster to about 4,000% faster, about 2,000% faster to about 3,000% faster, about 3,000% Fast to approx. 10,000% faster, approx. 3,000% faster to approx. 9,000% faster, approx. 3,000% faster to approx. 8,000% faster, approx. 3,000% faster to approx. 7,000% faster, approx. 3,000% faster to approx. 6,000% faster, approx. 3,000% faster to approx. 5,000% faster, approx. 3,000% faster to approx. 4,000% faster, approx. 4,000% faster to approx. 10,000% faster, approx. 4,000% faster to approx. 9,000% faster, approx. 4,000% faster to approx. 8,000% faster, approx. 4,000% faster to approx. 7,000% faster, approx. 4,000% faster to approx. 6,000% faster, approx. 4,000% faster to approx. 5,000 0% faster, approx. 5,000% faster to approx. 10,000% faster, approx. 5,000% faster to approx. 9,000% faster, approx. 5,000% faster to approx. 8,000% faster, approx. 5,000% faster to approx. 7,000% faster, approx. 5,000% faster to approx. 6,000% faster, approx. 6,000% faster to approx. 10,000% faster, approx. 6,000% faster to approx. 9,000% faster, approx. 6,000% faster to approx. 8,000% faster, approx. 6,000% faster to approx. 7,000% faster, approx. 7,000% faster to approx. 10,000% faster, approx. 7,000% faster to approx. 9,000% faster, approx. 7,000% faster to approx. 8,000% faster, approx.000% faster to approximately 10,000% faster, approximately 8,000% faster to approximately 9,000% faster, or approximately 9,000% faster to approximately 10,000% faster).

[0118] In some embodiments of any of the antibodies described herein, the dissociation constant (K) at a pH of about 4.0 to about 6.5 (e.g., any of the subranges of this range described herein) D ) at a pH of about 7.0 to about 8.0 (e.g., any of the subranges of this range described herein). Dgreater (e.g., detectably greater) than (e.g., at least 5% greater, at least 10% greater, at least 15% greater, at least 20% greater, at least 25% greater, at least 30% greater, at least 35% greater, at least 40% greater, at least 45% greater, at least 50% greater, at least 55% greater, at least 60% greater, at least 65% greater, at least 70% greater, at least 80% greater, at least 85% greater, at least 90% greater, at least 95% greater, at least 100% greater, at least 120% greater, at least 140% greater, at least 160% greater, at least 180% greater, at least 200% greater, at least 220% greater, at least 240% greater, at least 260% greater, at least 280% greater, at least 300% greater, at least 320% greater, at least 340% greater, at least 360% greater larger, at least 380% larger, at least 400% larger, at least 420% larger, at least 440% larger, at least 460% larger, at least 480% larger, at least 500% larger, at least 1,000% larger, at least 2,000% larger, at least 3,000% larger, at least 4,000% larger, at least 5,000% larger, at least 6,000% larger, at least 7,000% larger, at least 8,000% larger , at least 9,000% larger, or at least 10,000% larger, or about 5% larger to about 10,000% larger, about 5% larger to about 9,000% larger, about 5% larger to about 8,000% larger, about 5% larger to about 7,000% larger, about 5% larger to about 6,000% larger, about 5% larger to about 5,000% larger, about 5% larger to about 4,000% larger, about 5% larger to about 3,000% larger, about 5% larger to about 2,000% larger, about 5% larger to about 1,000% larger, about 5% larger to about 500% larger, about 5% larger to about 480% larger, about 5% larger to about 460% larger, about 5% larger to about 440% larger, about 5% larger to about 420% larger, about 5% larger to about 400% larger, about 5% larger to about 380% larger, about 5% larger to about 360% larger, about 5% larger to about 340% larger, about 5% larger to about 320% larger, about 5% larger to about 300% larger, about 5% larger to about 280% larger , about 5% larger to about 260% larger, about 5% larger to about 240% larger, about 5% larger to about 220% larger, about 5% larger to about 200% larger, about 5% larger to about 180% larger, about 5% larger to about 160% larger, about 5% larger to about 140% larger, about 5% larger to about 120% larger, about 5% larger to about 100% larger, about 5% larger to about 95% larger, about 5% larger to about 90% larger, about 5% larger to about 85% larger, about 5% larger to about 80 % larger, about 5% larger to about 75% larger, about 5% larger to about 70% larger, about 5% larger to about 65% larger, about 5% larger to about 60% larger, about 5% larger to about 55% larger, about 5% larger to about 50% larger, about 5% larger to about 45% larger, about 5% larger to about 40% larger, about 5% larger to about 35% larger, about 5% larger to about 30% larger, about 5% larger to about 25% larger, about 5% larger to about 20% larger, about 5% larger to about 15% larger , about 5% larger to about 10% larger, about 10% larger to about 10,000% larger, about 10% larger to about 9,000% larger, about 10% larger to about 8,000% larger, about 10% larger to about 7,000% larger, about 10% larger to about 6,000% larger, about 10% larger to about 5,000% larger, about 10% larger to about 4,000% larger, about 10% larger to about 3,000% larger, about 10% larger to about 2,000% larger, about 10% larger to about 1,000% larger, about 10% larger to about 500% larger, about 10% larger to about 480% larger, about 10% larger to about 460% larger, about 10% larger to about 440% larger, about 10% larger to about 420% larger, about 10% larger to about 400% larger, about 10% larger to about 380% larger, about 10% larger to about 360% larger, about 10% larger to about 340% larger, about 10% larger to about 320% larger, about 10% larger to about 300% larger, about 10% larger to about 280% larger, 10% larger to 260% larger, 10% larger to 240% larger, 10% larger to 220% larger, 10% larger to 200% larger, 10% larger to 180% larger, 10% larger to 160% larger, 10% larger to 140% larger, 10% larger to 120% larger, 10% larger to 100% larger, 10% larger to 95% larger, 10% larger to 90% larger, 10% larger to 85% larger Large, about 10% larger to about 80% larger, about 10% larger to about 75% larger, about 10% larger to about 70% larger, about 10% larger to about 65% larger, about 10% larger to about 60% larger, about 10% larger to about 55% larger, about 10% larger to about 50% larger, about 10% larger to about 45% larger, about 10% larger to about 40% larger, about 10% larger to about 35% larger, about 10% larger to about 30% larger, about 10% larger to about 25% larger, about 10% larger to about 2 0% larger, about 10% larger to about 15% larger, about 15% larger to about 10,000% larger, about 15% larger to about 9,000% larger, about 15% larger to about 8,000% larger, about 15% larger to about 7,000% larger, about 15% larger to about 6,000% larger, about 15% larger to about 5,000% larger, about 15% larger to about 4,000% larger, about 15% larger to about 3,000% larger, about 15% larger to about 2,000% larger, about 15% larger to about 1,000% larger, approx. 15% larger to approx. 500% larger, approx. 15% larger to approx. 480% larger, approx. 15% larger to approx. 460% larger, approx. 15% larger to approx. 440% larger, approx. 15% larger to approx. 420% larger, approx. 15% larger to approx. 400% larger, approx. 15% larger to approx. 380% larger, approx. 15% larger to approx. 360% larger, approx. 15% larger to approx. 340% larger, approx. 15% larger to approx. 320% larger, approx. 15% larger to approx. 300% larger, approx. 15% larger Large to about 280% larger, about 15% larger to about 260% larger, about 15% larger to about 240% larger, about 15% larger to about 220% larger, about 15% larger to about 200% larger, about 15% larger to about 180% larger, about 15% larger to about 160% larger, about 15% larger to about 140% larger, about 15% larger to about 120% larger, about 15% larger to about 100% larger, about 15% larger to about 95% larger, about 15% larger to about 90% larger, about 15% larger Large to about 85% larger, about 15% larger to about 80% larger, about 15% larger to about 75% larger, about 15% larger to about 70% larger, about 15% larger to about 65% larger, about 15% larger to about 60% larger, about 15% larger to about 55% larger, about 15% larger to about 50% larger, about 15% larger to about 45% larger, about 15% larger to about 40% larger, about 15% larger to about 35% larger, about 15% larger to about 30% larger, about 15% larger to about 25% larger , about 15% larger to about 20% larger, about 20% larger to about 10,000% larger, about 20% larger to about 9,000% larger, about 20% larger to about 8,000% larger, about 20% larger to about 7,000% larger, about 20% larger to about 6,000% larger, about 20% larger to about 5,000% larger, about 20% larger to about 4,000% larger, about 20% larger to about 3,000% larger, about 20% larger to about 2,000% larger, about 20% larger to about 1,000% larger, about 20% larger to about 500% larger, about 20% larger to about 480% larger, about 20% larger to about 460% larger, about 20% larger to about 440% larger, about 20% larger to about 420% larger, about 20% larger to about 400% larger, about 20% larger to about 380% larger, about 20% larger to about 360% larger, about 20% larger to about 340% larger, about 20% larger to about 320% larger, about 20% larger to about 300% larger, about 20% larger to approximately 280% larger, approximately 20% larger to approximately 260% larger, approximately 20% larger to approximately 240% larger, approximately 20% larger to approximately 220% larger, approximately 20% larger to approximately 200% larger, approximately 20% larger to approximately 180% larger, approximately 20% larger to approximately 160% larger, approximately 20% larger to approximately 140% larger, approximately 20% larger to approximately 120% larger, approximately 20% larger to approximately 100% larger, approximately 20% larger to approximately 95% larger, approximately 20% larger to approximately 90% larger Large, about 20% larger to about 85% larger, about 20% larger to about 80% larger, about 20% larger to about 75% larger, about 20% larger to about 70% larger, about 20% larger to about 65% larger, about 20% larger to about 60% larger, about 20% larger to about 55% larger, about 20% larger to about 50% larger, about 20% larger to about 45% larger, about 20% larger to about 40% larger, about 20% larger to about 35% larger, about 20% larger to about 30% larger, about 2 0% larger to about 25% larger, about 25% larger to about 10,000% larger, about 25% larger to about 9,000% larger, about 25% larger to about 8,000% larger, about 25% larger to about 7,000% larger, about 25% larger to about 6,000% larger, about 25% larger to about 5,000% larger, about 25% larger to about 4,000% larger, about 25% larger to about 3,000% larger, about 25% larger to about 2,000% larger, about 25% larger to about 1,000% larger, about 25% larger to about 500% larger, about 25% larger to about 480% larger, about 25% larger to about 460% larger, about 25% larger to about 440% larger, about 25% larger to about 420% larger, about 25% larger to about 400% larger, about 25% larger to about 380% larger, about 25% larger to about 360% larger, about 25% larger to about 340% larger, about 25% larger to about 320% larger, about 25% larger to about 300% larger, about 25% larger to about 280% larger, about 25% larger to about 260% larger, about 25% Large to approximately 240% larger, approximately 25% larger to approximately 220% larger, approximately 25% larger to approximately 200% larger, approximately 25% larger to approximately 180% larger, approximately 25% larger to approximately 160% larger, approximately 25% larger to 140% larger, approximately 25% larger to approximately 120% larger, approximately 25% larger to approximately 100% larger, approximately 25% larger to approximately 95% larger, approximately 25% larger to approximately 90% larger, approximately 25% larger to approximately 85% larger, a...

Claims

1. An antibody, comprising: (a) a heavy chain variable domain and a light chain variable domain, (i) SEQ ID NO:5 and SEQ ID NO:6, respectively; (ii) SEQ ID NO: 7 and SEQ ID NO: 8, respectively; (iii) SEQ ID NO: 9 and SEQ ID NO: 10, respectively; (iv) SEQ ID NO:11 and SEQ ID NO:12, respectively; (v) SEQ ID NO: 13 and SEQ ID NO: 14, respectively; (vi) SEQ ID NO: 15 and SEQ ID NO: 16, respectively; (vii) SEQ ID NO: 17 and SEQ ID NO: 18, respectively; (viii) SEQ ID NO: 19 and SEQ ID NO: 20, respectively; (ix) SEQ ID NO:21 and SEQ ID NO:22, respectively; (x) SEQ ID NO: 23 and SEQ ID NO: 24, respectively; (xi) SEQ ID NO:25 and SEQ ID NO:26, respectively; (xii) SEQ ID NO:27 and SEQ ID NO:28, respectively; (xiii) SEQ ID NO:29 and SEQ ID NO:30, respectively; (xiv) SEQ ID NO:31 and SEQ ID NO:32, respectively; (xv) a heavy chain variable domain and a light chain variable domain selected from the group of SEQ ID NO: 33 and SEQ ID NO: 34, respectively; and (b) (a) the heavy chain CH1-CH2-CH3 sequence of SEQ ID NO: 155 or SEQ ID NO: 189, (i) a lysine to cysteine ​​substitution at amino acid position 105 and deletion of threonines at amino acid positions 106 and 108; (ii) a methionine to tyrosine substitution at amino acid position 135, a serine to threonine substitution at amino acid position 137, and a threonine to glutamic acid substitution at amino acid position 139; (iii) a methionine to leucine substitution at amino acid position 311 and an asparagine to serine substitution at amino acid position 317, and (iv) the heavy chain CH1-CH2-CH3 sequence of SEQ ID NO: 155 or SEQ ID NO: 189, comprising one or more of the following alanine to cysteine ​​substitutions at amino acid position 1; and / or Light chain C of SEQ ID NO: 157, comprising a valine to cysteine ​​substitution at amino acid position 98 Ｌ An antibody comprising the sequence

2. 2. The antibody of claim 1, wherein the heavy chain CH1-CH2-CH3 sequence of SEQ ID NO:155 or SEQ ID NO:189 comprises a lysine to cysteine ​​substitution at amino acid position 105 and a deletion of threonines at amino acid positions 106 and 108.

3. The antibody comprises a heavy chain sequence and a light chain sequence, (i) SEQ ID NO: 35 and SEQ ID NO: 41, respectively; (ii) SEQ ID NO: 43 and SEQ ID NO: 49, respectively; (iii) SEQ ID NO:51 and SEQ ID NO:57, respectively; (iv) SEQ ID NO:59 and SEQ ID NO:65, respectively; (v) SEQ ID NO: 67 and SEQ ID NO: 73, respectively; (vi) SEQ ID NO: 75 and SEQ ID NO: 81, respectively; (vii) SEQ ID NO: 83 and SEQ ID NO: 89, respectively; (viii) SEQ ID NO: 91 and SEQ ID NO: 97, respectively; (ix) SEQ ID NO: 99 and SEQ ID NO: 105, respectively; (x) SEQ ID NO: 107 and SEQ ID NO: 113, respectively; (xi) SEQ ID NO: 115 and SEQ ID NO: 121, respectively; (xii) SEQ ID NO: 123 and SEQ ID NO: 129, respectively; (xiii) SEQ ID NO: 131 and SEQ ID NO: 137, respectively; (xiv) SEQ ID NO: 139 and SEQ ID NO: 145, respectively; or (xv) The antibody of claim 2, comprising a heavy chain sequence and a light chain sequence selected from the group of SEQ ID NO: 147 and SEQ ID NO: 153, respectively.

4. the heavy chain CH1-CH2-CH3 sequence of SEQ ID NO: 155 or SEQ ID NO: 189 a lysine to cysteine ​​substitution at amino acid position 105 and deletion of threonines at amino acid positions 106 and 108; and 2. The antibody of claim 1, comprising a methionine to leucine substitution at amino acid position 311 and an asparagine to serine substitution at amino acid position 317.

5. The antibody comprises a heavy chain sequence and a light chain sequence, (i) SEQ ID NO: 36 and SEQ ID NO: 41, respectively; (ii) SEQ ID NO: 44 and SEQ ID NO: 49, respectively; (iii) SEQ ID NO: 52 and SEQ ID NO: 57, respectively; (iv) SEQ ID NO: 60 and SEQ ID NO: 65, respectively; (v) SEQ ID NO: 68 and SEQ ID NO: 73, respectively; (vi) SEQ ID NO: 76 and SEQ ID NO: 81, respectively; (vii) SEQ ID NO: 84 and SEQ ID NO: 89, respectively; (viii) SEQ ID NO:92 and SEQ ID NO:97, respectively; (ix) SEQ ID NO: 100 and SEQ ID NO: 105, respectively; (x) SEQ ID NO: 108 and SEQ ID NO: 113, respectively; (xi) SEQ ID NO: 116 and SEQ ID NO: 121, respectively; (xii) SEQ ID NO: 124 and SEQ ID NO: 129, respectively; (xiii) SEQ ID NO: 132 and SEQ ID NO: 137, respectively; (xiv) SEQ ID NO: 140 and SEQ ID NO: 145, respectively; or (xv) The antibody of claim 4, comprising a heavy chain sequence and a light chain sequence selected from the group consisting of SEQ ID NO: 148 and SEQ ID NO: 153, respectively.

6. the heavy chain CH1-CH2-CH3 sequence of SEQ ID NO: 155 or SEQ ID NO: 189 a lysine to cysteine ​​substitution at amino acid position 105 and deletion of threonines at amino acid positions 106 and 108; and 2. The antibody of claim 1, comprising a methionine to tyrosine substitution at amino acid position 135, a serine to threonine substitution at amino acid position 137, and a threonine to glutamic acid substitution at amino acid position 139.

7. The antibody comprises a heavy chain sequence and a light chain sequence, (i) SEQ ID NO: 37 and SEQ ID NO: 41, respectively; (ii) SEQ ID NO: 45 and SEQ ID NO: 49, respectively; (iii) SEQ ID NO: 53 and SEQ ID NO: 57, respectively; (iv) SEQ ID NO: 61 and SEQ ID NO: 65, respectively; (v) SEQ ID NO: 69 and SEQ ID NO: 73, respectively; (vi) SEQ ID NO: 77 and SEQ ID NO: 81, respectively; (vii) SEQ ID NO: 85 and SEQ ID NO: 89, respectively; (viii) SEQ ID NO: 93 and SEQ ID NO: 97, respectively; (ix) SEQ ID NO: 101 and SEQ ID NO: 105, respectively; (x) SEQ ID NO: 109 and SEQ ID NO: 113, respectively; (xi) SEQ ID NO: 117 and SEQ ID NO: 121, respectively; (xii) SEQ ID NO: 125 and SEQ ID NO: 129, respectively; (xiii) SEQ ID NO: 133 and SEQ ID NO: 137, respectively; (xiv) SEQ ID NO: 141 and SEQ ID NO: 145, respectively; or (xv) The antibody of claim 6, comprising a heavy chain sequence and a light chain sequence selected from the group of SEQ ID NO: 149 and SEQ ID NO: 153, respectively.

8. the heavy chain CH1-CH2-CH3 sequence of SEQ ID NO:155 or SEQ ID NO:189 comprises a lysine to cysteine ​​substitution at amino acid position 105 and a deletion of the threonines at amino acid positions 106 and 108; and Light chain C of SEQ ID NO: 157 Ｌ 2. The antibody of claim 1, wherein the sequence includes a valine to cysteine ​​substitution at amino acid position 98.

9. The antibody comprises a heavy chain sequence and a light chain sequence, (i) SEQ ID NO: 35 and SEQ ID NO: 42, respectively; (ii) SEQ ID NO: 43 and SEQ ID NO: 50, respectively; (iii) SEQ ID NO:51 and SEQ ID NO:58, respectively; (iv) SEQ ID NO:59 and SEQ ID NO:66, respectively; (v) SEQ ID NO: 67 and SEQ ID NO: 74, respectively; (vi) SEQ ID NO: 75 and SEQ ID NO: 82, respectively; (vii) SEQ ID NO: 83 and SEQ ID NO: 90, respectively; (viii) SEQ ID NO: 91 and SEQ ID NO: 98, respectively; (ix) SEQ ID NO: 99 and SEQ ID NO: 106, respectively; (x) SEQ ID NO: 107 and SEQ ID NO: 114, respectively; (xi) SEQ ID NO: 115 and SEQ ID NO: 122, respectively; (xii) SEQ ID NO: 123 and SEQ ID NO: 130, respectively; (xiii) SEQ ID NO: 131 and SEQ ID NO: 138, respectively; (xiv) SEQ ID NO: 139 and SEQ ID NO: 146, respectively; or (xv) The antibody of claim 8, comprising a heavy chain sequence and a light chain sequence selected from the group of SEQ ID NO: 147 and SEQ ID NO: 154, respectively.

10. the heavy chain CH1-CH2-CH3 sequence of SEQ ID NO: 155 or SEQ ID NO: 189 a lysine to cysteine ​​substitution at amino acid position 105 and deletion of threonines at amino acid positions 106 and 108; and a methionine to leucine substitution at amino acid position 311 and an asparagine to serine substitution at amino acid position 317; Light chain C of SEQ ID NO: 157 Ｌ 2. The antibody of claim 1, wherein the sequence includes a valine to cysteine ​​substitution at amino acid position 98.

11. The antibody comprises a heavy chain sequence and a light chain sequence, (i) SEQ ID NO: 36 and SEQ ID NO: 42, respectively; (ii) SEQ ID NO: 44 and SEQ ID NO: 50, respectively; (iii) SEQ ID NO:52 and SEQ ID NO:58, respectively; (iv) SEQ ID NO: 60 and SEQ ID NO: 66, respectively; (v) SEQ ID NO: 68 and SEQ ID NO: 74, respectively; (vi) SEQ ID NO: 76 and SEQ ID NO: 82, respectively; (vii) SEQ ID NO: 84 and SEQ ID NO: 90, respectively; (viii) SEQ ID NO:92 and SEQ ID NO:98, respectively; (ix) SEQ ID NO: 100 and SEQ ID NO: 106, respectively; (x) SEQ ID NO: 108 and SEQ ID NO: 114, respectively; (xi) SEQ ID NO: 116 and SEQ ID NO: 122, respectively; (xii) SEQ ID NO: 124 and SEQ ID NO: 130, respectively; (xiii) SEQ ID NO: 132 and SEQ ID NO: 138, respectively; (xiv) SEQ ID NO: 140 and SEQ ID NO: 146, respectively; or (xv) The antibody of claim 10, comprising a heavy chain sequence and a light chain sequence selected from the group of SEQ ID NO: 148 and SEQ ID NO: 154, respectively.

12. the heavy chain CH1-CH2-CH3 sequence of SEQ ID NO: 155 or SEQ ID NO: 189 a lysine to cysteine ​​substitution at amino acid position 105 and deletion of threonines at amino acid positions 106 and 108; and a methionine to tyrosine substitution at amino acid position 135, a serine to threonine substitution at amino acid position 137, and a threonine to glutamic acid substitution at amino acid position 139; Light chain C of SEQ ID NO: 157 Ｌ 2. The antibody of claim 1, wherein the sequence includes a valine to cysteine ​​substitution at amino acid position 98.

13. The antibody comprises a heavy chain sequence and a light chain sequence, (i) SEQ ID NO: 37 and SEQ ID NO: 42, respectively; (ii) SEQ ID NO: 45 and SEQ ID NO: 50, respectively; (iii) SEQ ID NO: 53 and SEQ ID NO: 58, respectively; (iv) SEQ ID NO: 61 and SEQ ID NO: 66, respectively; (v) SEQ ID NO: 69 and SEQ ID NO: 74, respectively; (vi) SEQ ID NO: 77 and SEQ ID NO: 82, respectively; (vii) SEQ ID NO: 85 and SEQ ID NO: 90, respectively; (viii) SEQ ID NO: 93 and SEQ ID NO: 98, respectively; (ix) SEQ ID NO: 101 and SEQ ID NO: 106, respectively; (x) SEQ ID NO: 109 and SEQ ID NO: 114, respectively; (xi) SEQ ID NO: 117 and SEQ ID NO: 122, respectively; (xii) SEQ ID NO: 125 and SEQ ID NO: 130, respectively; (xiii) SEQ ID NO: 133 and SEQ ID NO: 138, respectively; (xiv) SEQ ID NO: 141 and SEQ ID NO: 146, respectively; or (xv) The antibody of claim 12, comprising a heavy chain sequence and a light chain sequence selected from the group of SEQ ID NO: 149 and SEQ ID NO: 154, respectively.

14. the heavy chain CH1-CH2-CH3 sequence of SEQ ID NO: 155 or SEQ ID NO: 189 a lysine to cysteine ​​substitution at amino acid position 105 and deletion of threonines at amino acid positions 106 and 108; and 2. The antibody of claim 1, comprising an alanine to cysteine ​​substitution at amino acid position 1.

15. The antibody comprises a heavy chain sequence and a light chain sequence, (i) SEQ ID NO: 38 and SEQ ID NO: 41, respectively; (ii) SEQ ID NO: 46 and SEQ ID NO: 49, respectively; (iii) SEQ ID NO:54 and SEQ ID NO:57, respectively; (iv) SEQ ID NO: 62 and SEQ ID NO: 65, respectively; (v) SEQ ID NO: 70 and SEQ ID NO: 73, respectively; (vi) SEQ ID NO: 78 and SEQ ID NO: 81, respectively; (vii) SEQ ID NO: 86 and SEQ ID NO: 89, respectively; (viii) SEQ ID NO:94 and SEQ ID NO:97, respectively; (ix) SEQ ID NO: 102 and SEQ ID NO: 105, respectively; (x) SEQ ID NO: 110 and SEQ ID NO: 113, respectively; (xi) SEQ ID NO: 118 and SEQ ID NO: 121, respectively; (xii) SEQ ID NO: 126 and SEQ ID NO: 129, respectively; (xiii) SEQ ID NO: 134 and SEQ ID NO: 137, respectively; (xiv) SEQ ID NO: 142 and SEQ ID NO: 145, respectively; or (xv) The antibody of claim 14, comprising a heavy chain sequence and a light chain sequence selected from the group of SEQ ID NO: 150 and SEQ ID NO: 153, respectively.

16. the heavy chain CH1-CH2-CH3 sequence of SEQ ID NO: 155 or SEQ ID NO: 189 a lysine to cysteine ​​substitution at amino acid position 105 and deletion of threonines at amino acid positions 106 and 108; a methionine to leucine substitution at amino acid position 311 and an asparagine to serine substitution at amino acid position 317; and 2. The antibody of claim 1, comprising an alanine to cysteine ​​substitution at amino acid position 1.

17. The antibody comprises a heavy chain sequence and a light chain sequence, (i) SEQ ID NO: 39 and SEQ ID NO: 41, respectively; (ii) SEQ ID NO: 47 and SEQ ID NO: 49, respectively; (iii) SEQ ID NO: 55 and SEQ ID NO: 57, respectively; (iv) SEQ ID NO: 63 and SEQ ID NO: 65, respectively; (v) SEQ ID NO: 71 and SEQ ID NO: 73, respectively; (vi) SEQ ID NO: 79 and SEQ ID NO: 81, respectively; (vii) SEQ ID NO: 87 and SEQ ID NO: 89, respectively; (viii) SEQ ID NO: 95 and SEQ ID NO: 97, respectively; (ix) SEQ ID NO: 103 and SEQ ID NO: 105, respectively; (x) SEQ ID NO: 111 and SEQ ID NO: 113, respectively; (xi) SEQ ID NO: 119 and SEQ ID NO: 121, respectively; (xii) SEQ ID NO: 127 and SEQ ID NO: 129, respectively; (xiii) SEQ ID NO: 135 and SEQ ID NO: 137, respectively; (xiv) SEQ ID NO: 143 and SEQ ID NO: 145, respectively; or (xv) The antibody of claim 16, comprising a heavy chain sequence and a light chain sequence selected from the group of SEQ ID NO: 151 and SEQ ID NO: 153, respectively.

18. the heavy chain CH1-CH2-CH3 sequence of SEQ ID NO: 155 or SEQ ID NO: 189 a lysine to cysteine ​​substitution at amino acid position 105 and deletion of threonines at amino acid positions 106 and 108; a methionine to tyrosine substitution at amino acid position 135, a serine to threonine substitution at amino acid position 137, and a threonine to glutamic acid substitution at amino acid position 139; 2. The antibody of claim 1, comprising an alanine to cysteine ​​substitution at amino acid position 1.

19. The antibody comprises a heavy chain sequence and a light chain sequence, (i) SEQ ID NO: 40 and SEQ ID NO: 41, respectively; (ii) SEQ ID NO: 48 and SEQ ID NO: 49, respectively; (iii) SEQ ID NO: 56 and SEQ ID NO: 57, respectively; (iv) SEQ ID NO: 64 and SEQ ID NO: 65, respectively; (v) SEQ ID NO: 72 and SEQ ID NO: 73, respectively; (vi) SEQ ID NO: 80 and SEQ ID NO: 81, respectively; (vii) SEQ ID NO: 88 and SEQ ID NO: 89, respectively; (viii) SEQ ID NO: 96 and SEQ ID NO: 97, respectively; (ix) SEQ ID NO: 104 and SEQ ID NO: 105, respectively; (x) SEQ ID NO: 112 and SEQ ID NO: 113, respectively; (xi) SEQ ID NO: 120 and SEQ ID NO: 121, respectively; (xii) SEQ ID NO: 128 and SEQ ID NO: 129, respectively; (xiii) SEQ ID NO: 136 and SEQ ID NO: 137, respectively; (xiv) SEQ ID NO: 144 and SEQ ID NO: 145, respectively; or (xv) The antibody of claim 18, comprising a heavy chain sequence and a light chain sequence selected from the group of SEQ ID NO: 152 and SEQ ID NO: 153, respectively.

20. The antibody is conjugated to a cytotoxic agent, the antibody comprising: (a) the heavy chain CH1-CH2-CH3 sequence of SEQ ID NO: 155 or SEQ ID NO: 189, comprising amino acid substitutions and / or deletions as defined in any one of claims 2 to 19, wherein the cytotoxic agent is (i) a cysteine ​​at amino acid position 103, (ii) a cysteine ​​for lysine substitution at amino acid position 105; (iii) a cysteine ​​at amino acid position 109, (iv) the heavy chain CH1-CH2-CH3 of SEQ ID NO: 155 or SEQ ID NO: 189, which is conjugated to one or more of: (b) the light chain C L sequence of SEQ ID NO: 157, in which the cytotoxic agent is conjugated to the cysteine ​​at amino acid position 107; and / or 20. The antibody of claim 2, comprising a light chain C L sequence of SEQ ID NO: 157, which comprises a valine to cysteine ​​substitution at amino acid position 98, wherein the cytotoxic agent is conjugated to the cysteine ​​of the valine to cysteine ​​substitution at amino acid position 98.

21. 21. The antibody of any one of claims 8 to 13 and 20, wherein the antibody further comprises a cytotoxic or cytostatic drug conjugated to the cysteine ​​at position 98 of SEQ ID NO:

158.

22. 22. A pharmaceutical composition comprising an effective amount of an antibody according to any one of claims 1 to 21.

23. 23. A kit comprising at least one dose of the antibody of any one of claims 1 to 21, or the pharmaceutical composition of claim 22.

24. The pharmaceutical composition of claim 22 for use in a method for treating cancer in a subject, wherein the cancer is characterized by having a population of cancer cells that have MET or an epitope of MET displayed on their surface, and the subject is identified as having a cancer characterized by having said population of cancer cells.

Images