Antibodies against ubiquitin C-terminal hydrolase L1 (UCH-L1) and glial fibrillary acidic protein (GFAP) and related methods

Abstract

To provide reagents, devices and methods of detecting damage or injury in an individual that has a neurological condition, is suspected of having a neurological condition, or will develop a neurological condition.SOLUTION: The invention provides anti-UCH-L1 antibodies and anti-GFAP antibodies, and their use in in vitro detection of UCH-L1 and GFAP, respectively, in a sample from an individual, such as an individual known as or suspected of having brain injury or damage, e.g., neurological damage such as mild traumatic brain injury. Also provided are: methods, systems and kits for diagnosing brain injury or damage, such as neurological damage, in an individual with the antibodies; and compositions comprising the anti-UCH-L1 antibodies and anti-GFAP antibodies.SELECTED DRAWING: None

Description

[Technical Field]

[0001] [Cross-reference of related applications] This application claims priority to U.S. Provisional Application No. 62 / 414,569, filed on 28 October 2016, entitled “Antibodies to Ubiquitin C-Terminal Hydrolase (UCH-L1) and Glial Fibrillary Acidic Protein (GFAP) and Related Methods,” the contents of which are incorporated by reference in their entirety.

[0002] [Submission of array list in ASCII text file] The following submission, in computer-readable format (CRF) on an ASCII text file (filename: 750582000140SeqList.txt, date of submission: October 23, 2017, size: 133,320 bytes), is incorporated herein by reference in its entirety.

[0003] [Information Technology Field] This disclosure relates to anti-UCH-L1 antibodies and anti-GFAP antibodies, as well as methods, systems, and kits for detecting UCH-L1 and GFAP in samples from individuals having or suspected of having brain injury, for example, for diagnosing brain injury in individuals. [Background technology]

[0004] A wide variety of injuries, diseases, and disorders can result in nerve damage, and if not detected promptly, can lead to more severe damage. For example, initial injuries resulting from traumatic, ischemic, and neurotoxic chemical trauma can result in nerve damage. Diseases or disorders affecting nerve cells (or other brain cells, e.g., glial cells) can also result in injuries or disorders that lead to the development of a neurological condition. Common methods for diagnosing neurological conditions typically involve neurological testing and assigning a Glasgow Coma Score to the individual. These methods have limited value and often prevent nuanced diagnoses due to the subjectivity of the tests and the patient's ability to deliberately alter their true responses to achieve desired outcomes. To obtain a diagnosis of a neurological condition resulting from an injury or disorder, neuroimaging techniques such as computed tomography (CT) and magnetic resonance imaging (MRI) are widely used to help determine the extent of the injury and the potential for intervention. However, these tests are expensive, time-consuming, and may not be as sensitive as biomarker tests. [Overview of the project] [Problems that the invention aims to solve]

[0005] Therefore, there remains a need for reagents, devices, and methods for detecting injury or damage in individuals who have, are suspected of having, or are developing a neurological condition. In particular, reagents, devices, and methods that enable rapid and / or early in vitro detection of damage in individuals can facilitate treatment and diagnosis to prevent or reduce the progression of neurological conditions. Embodiments that satisfy such needs are provided herein. [Means for solving the problem]

[0006] This specification provides for anti-ubiquitin C-terminal hydrolase L1 (UCH-L1) antibodies and glial fibrillary acidic protein (GFAP) antibodies, including their antigen-binding fragments, compositions comprising such antibodies or antigen-binding fragments, combinations comprising such antibodies or antigen-binding fragments, and methods of using them. In certain embodiments, the antibodies or antigen-binding fragments are used in a method for diagnosing brain injury or damage in a subject and / or predicting whether the subject requires neuroimaging.

[0007] In this specification, antibodies or antigen-binding fragments are provided that specifically bind to UCH-L1, for example, human UCH-L1, wherein the antibody or antigen-binding fragment includes specific complementarity-determining regions (CDRs), including heavy chain CDRs (i.e., CDR-H1, CDR-H2, and / or CDR-H3) and light chain CDRs (i.e., CDR-L1, CDR-L2, and / or CDR-L3), for example, any as described herein. In some embodiments, the antibody or antigen-binding fragment includes heavy chain variable regions and light chain variable regions, for example, any as described herein.

[0008] In some embodiments, an antibody or antigen-binding fragment thereof that specifically binds to UCH-L1 (e.g., human UCH-L1) is provided herein, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising an amino acid sequence having at least 85% identity with an amino acid sequence selected from any one of SEQ ID NOs. 51 to 63; and / or a light chain variable region comprising an amino acid sequence having at least 85% identity with an amino acid sequence selected from any one of SEQ ID NOs. 64 to 76. In some embodiments, the heavy chain variable region comprises an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with an amino acid sequence selected from any one of SEQ ID NOs. 51 to 63; or comprises an amino acid sequence selected from any one of SEQ ID NOs. 51 to 63. In some of the embodiments herein, the light chain variable region comprises an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with an amino acid sequence selected from any one of the SEQ ID NOs. In some of the embodiments herein, the heavy chain variable region comprises (i) CDR-H1 comprising an amino acid sequence selected from SEQ ID NOs: 1 to 8; (ii) CDR-H2 comprising an amino acid sequence selected from SEQ ID NOs: 9 to 19; and (iii) CDR-H3 comprising an amino acid sequence selected from SEQ ID NOs: 20 to 27; and / or the light chain variable region comprises (i) CDR-L1 comprising an amino acid sequence selected from SEQ ID NOs: 28 to 36; (ii) CDR-L2 comprising an amino acid sequence selected from SEQ ID NOs: 37 to 44; and (iii) CDR-L3 comprising an amino acid sequence selected from SEQ ID NOs: 45 to 50.In some of the embodiments herein, the heavy chain variable region comprises CDR-H1, CDR-H2, and CDR-H3, each comprising the amino acid sequences of CDR-H1, CDR-H2, and CDR-H3 contained within a heavy chain variable region amino acid sequence selected from any one of SEQ ID NOs. 51 to 63; and / or the light chain variable region comprises CDR-L1, CDR-L2, and CDR-L3, each comprising the amino acid sequences of CDR-L1, CDR-L2, and CDR-L3 contained within a light chain variable region amino acid sequence selected from any one of SEQ ID NOs. 64 to 76.

[0009] In some embodiments, the Specified herein provides an antibody or antigen-binding fragment that specifically binds to UCH-L1 (e.g., human UCH-L1), wherein the antibody or antigen-binding fragment comprises a heavy chain variable region having at least 85% identity with an amino acid sequence selected from any one of SEQ ID NOs. 53 to 62; and / or a light chain variable region having at least 85% identity with an amino acid sequence selected from any one of SEQ ID NOs. 66 to 75. In some embodiments, the heavy chain variable region contains at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with an amino acid sequence selected from any one of SEQ ID NOs. 53 to 62, or contains an amino acid sequence shown in any one of SEQ ID NOs. 53 to 62; and / or, the light chain variable region contains at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with an amino acid sequence selected from any one of SEQ ID NOs. 66 to 75, or contains a light chain variable region containing an amino acid sequence shown in any one of SEQ ID NOs.In some of the embodiments herein, the heavy chain variable region comprises (i) CDR-H1 comprising an amino acid sequence selected from SEQ ID NOs: 3-8; (ii) CDR-H2 comprising an amino acid sequence selected from SEQ ID NOs: 11-18; and (iii) CDR-H3 comprising an amino acid sequence selected from SEQ ID NOs: 20-27; and / or the light chain variable region comprises (i) CDR-L1 comprising an amino acid sequence selected from SEQ ID NOs: 30-36; (ii) CDR-L2 comprising an amino acid sequence selected from SEQ ID NOs: 37-44; and (iii) an amino acid sequence selected from SEQ ID NOs: 45-49 The heavy chain variable region includes CDR-L3 containing an acid sequence; or the heavy chain variable region includes CDR-H1, CDR-H2, and CDR-H3, and each includes the amino acid sequences of CDR-H1, CDR-H2, and CDR-H3 contained within a heavy chain variable region amino acid sequence selected from any one of SEQ ID NOs. 53 to 62, and / or the light chain variable region includes CDR-L1, CDR-L2, and CDR-L3, and each includes the amino acid sequences of CDR-L1, CDR-L2, and CDR-L3 contained within a light chain variable region amino acid sequence selected from any one of SEQ ID NOs. 66 to 75.

[0010] In some embodiments, the Specified herein provides an antibody or antigen-binding fragment that specifically binds to UCH-L1 (e.g., human UCH-L1), wherein the antibody or antigen-binding fragment comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising (i) CDR-H1 comprising an amino acid sequence selected from SEQ ID NOs: 1 to 8; (ii) CDR-H2 comprising an amino acid sequence selected from SEQ ID NOs: 9 to 18; and (iii) CDR-H3 comprising an amino acid sequence selected from SEQ ID NOs: 20 to 27; and / or the light chain variable region comprising (i) CDR-L1 comprising an amino acid sequence selected from SEQ ID NOs: 28 to 36; (ii) CDR-L2 comprising an amino acid sequence selected from SEQ ID NOs: 37 to 44; and (iii) CDR-L3 comprising an amino acid sequence selected from SEQ ID NOs: 45 to 49.

[0011] In some of the embodiments herein, the antibody or antigen-binding fragment that specifically binds to UCH-L1 is (a) a heavy chain variable region containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 1, SEQ ID NO: 9, and SEQ ID NO: 20, and / or a light chain variable region containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 28, SEQ ID NO: 37, and SEQ ID NO: 45, and / or (b) the C of SEQ ID NO: 2, SEQ ID NO: 10, and SEQ ID NO: 21, respectively. (c) Heavy chain variable region containing the DR-H1, CDR-H2, and CDR-H3 amino acid sequences, and / or light chain variable region containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 29, SEQ ID NO: 38, and SEQ ID NO: 46, respectively; (c) Heavy chain variable region containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 3, SEQ ID NO: 11, and SEQ ID NO: 20, and / or CDR-L1, CDR- (d) Light chain variable regions containing L2 and CDR-L3 amino acid sequences; (d) Heavy chain variable regions containing CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 4, SEQ ID NO: 12, and SEQ ID NO: 22, respectively, and / or Light chain variable regions containing CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 31, SEQ ID NO: 39, and SEQ ID NO: 47, respectively; (e) CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 5, SEQ ID NO: 13, and SEQ ID NO: 23, respectively (f) Heavy chain variable regions containing sequences, and / or light chain variable regions containing CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 32, SEQ ID NO: 39, and SEQ ID NO: 47, respectively; (f) Heavy chain variable regions containing CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 6, SEQ ID NO: 14, and SEQ ID NO: 24, respectively, and / or light chain variable regions containing CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 33, SEQ ID NO: 40, and SEQ ID NO: 48, respectively;(g) Heavy chain variable regions containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 6, SEQ ID NO: 14, and SEQ ID NO: 24, respectively, and / or Light chain variable regions containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 34, SEQ ID NO: 41, and SEQ ID NO: 48, respectively; (h) Heavy chain variable regions containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 6, SEQ ID NO: 15, and SEQ ID NO: 24, respectively, and / or CDR- Light chain variable regions containing L1, CDR-L2, and CDR-L3 amino acid sequences; (i) heavy chain variable regions containing CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 6, SEQ ID NO: 14, and SEQ ID NO: 24, and / or light chain variable regions containing CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 35, SEQ ID NO: 41, and SEQ ID NO: 48, and / or heavy chain variable regions containing CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 6, SEQ ID NO: 16, and SEQ ID NO: 25, and / or (k) The light chain variable region containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NOs. 34, SEQ ID NOs. 42, and SEQ ID NOs. 48, respectively; (k) The heavy chain variable region containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NOs. 7, SEQ ID NOs. 17, and SEQ ID NOs. 26, respectively, and / or The light chain variable region containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NOs. 36, SEQ ID NOs. 43, and SEQ ID NOs. 49, respectively; (l) The CDR-H1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NOs. 8, SEQ ID NOs. 18, and SEQ ID NOs. 27, respectively. A heavy chain variable region containing H2 and CDR-H3 amino acid sequences, and / or a light chain variable region containing CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 36, SEQ ID NO: 44, and SEQ ID NO: 49, respectively; or (m) a heavy chain variable region containing CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 1, SEQ ID NO: 19, and SEQ ID NO: 20, respectively, and / or a light chain variable region containing CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 28, SEQ ID NO: 37, and SEQ ID NO: 50, respectively.

[0012] In some of the embodiments described herein, the antibody or antigen-binding fragment that specifically binds to UCH-L1 comprises: (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 51 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 51; and / or a light chain variable region comprising the amino acid sequence of SEQ ID NO: 64 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 64; (b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 52 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 52; and / or a light chain variable region comprising the amino acid sequence of SEQ ID NO: 65 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 65; (c) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 53 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 53; and / or a light chain variable region comprising the amino acid sequence of SEQ ID NO: 66 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 66; and (d) an amino acid sequence of at least 85% identity with the amino acid sequence of SEQ ID NO: 54 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 54. (a) A heavy chain variable region containing an amino acid sequence having 5% identity; and / or a light chain variable region containing the amino acid sequence of SEQ ID NO: 67 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 67; (e) A heavy chain variable region containing the amino acid sequence of SEQ ID NO: 55 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 55; and / or a light chain variable region containing the amino acid sequence of SEQ ID NO: 68 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 68; (f) A heavy chain variable region containing the amino acid sequence of SEQ ID NO: 56 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 56; and / or a light chain variable region containing the amino acid sequence of SEQ ID NO: 69 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 69; (g) A heavy chain variable region containing the amino acid sequence of SEQ ID NO: 57 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 57; and / or a light chain variable region containing the amino acid sequence of SEQ ID NO: 70 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 70;(h) A heavy chain variable region containing the amino acid sequence of SEQ ID NO: 58 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 58; and / or a light chain variable region containing the amino acid sequence of SEQ ID NO: 71 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 71; (i) A heavy chain variable region containing the amino acid sequence of SEQ ID NO: 59 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 59; and / or a light chain variable region containing the amino acid sequence of SEQ ID NO: 72 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 72; (j) A heavy chain variable region containing the amino acid sequence of SEQ ID NO: 60 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 60; and / or the amino acid sequence of SEQ ID NO: 73 or an amino acid sequence of SEQ ID NO: 73 (k) A light chain variable region containing an amino acid sequence having at least 85% identity with the sequence; (k) A heavy chain variable region containing the amino acid sequence of SEQ ID NO: 61 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 61; and / or A light chain variable region containing the amino acid sequence of SEQ ID NO: 74 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 74; (l) A heavy chain variable region containing the amino acid sequence of SEQ ID NO: 62 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 62; and / or A light chain variable region containing the amino acid sequence of SEQ ID NO: 75 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 75; or (m) A heavy chain variable region containing the amino acid sequence of SEQ ID NO: 63 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 63;and / or a light chain variable region comprising the amino acid sequence of SEQ ID NO: 76 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 76. In some of the embodiments herein, an antibody or antigen-binding fragment that specifically binds to UCH-L1 includes (a) a heavy chain variable region comprising an amino acid sequence having at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the sequence of any of the above-mentioned SEQ ID NOs.

[0013] In some of the embodiments herein, the antibody or antigen-binding fragment that specifically binds to UCH-L1 is: (a) a heavy chain variable region containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 1, SEQ ID NO: 9, and SEQ ID NO: 20, and / or a light chain variable region containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 28, SEQ ID NO: 37, and SEQ ID NO: 45, respectively; (b) a heavy chain variable region containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 2, SEQ ID NO: 10, and SEQ ID NO: 21, and / or a light chain variable region containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 29, SEQ ID NO: 38, and SEQ ID NO: 4; (c) CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 4, SEQ ID NO: 12, and SEQ ID NO: 22, respectively. (d) A heavy chain variable region containing the DR-H3 amino acid sequence, and / or a light chain variable region containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 31, SEQ ID NO: 39, and SEQ ID NO: 47, respectively; (d) A heavy chain variable region containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 6, SEQ ID NO: 14, and SEQ ID NO: 24, respectively, and / or a light chain variable region containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 33, SEQ ID NO: 40, and SEQ ID NO: 48, respectively; or (e) A heavy chain variable region containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 5, SEQ ID NO: 13, and SEQ ID NO: 23, respectively, and / or a light chain variable region containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 32, SEQ ID NO: 39, and SEQ ID NO: 47, respectively.

[0014] In some of the embodiments herein, the antibody or antigen-binding fragment that specifically binds to UCH-L1 includes: (a) a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 51 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 51; and / or a light chain variable region containing the amino acid sequence of SEQ ID NO: 64 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 64; (b) a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 52 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 52; and / or a light chain variable region containing the amino acid sequence of SEQ ID NO: 65 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 65; and (c) an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 54 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 54. (d) A heavy chain variable region containing an amino acid sequence having a property; and / or a light chain variable region containing the amino acid sequence of SEQ ID NO: 67 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 67; (d) A heavy chain variable region containing the amino acid sequence of SEQ ID NO: 56 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 56; and / or a light chain variable region containing the amino acid sequence of SEQ ID NO: 69 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 69; or (e) A heavy chain variable region containing the amino acid sequence of SEQ ID NO: 55 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 55; and / or a light chain variable region containing the amino acid sequence of SEQ ID NO: 68 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 68.In some of the embodiments herein, an antibody or antigen-binding fragment that specifically binds to UCH-L1 includes (a) a heavy chain variable region comprising an amino acid sequence having at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of any of the above-mentioned SEQ ID NOs.

[0015] In some of the embodiments herein, an antibody or antigen-binding fragment that specifically binds to UCH-L1 includes (a) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 51 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 51; and / or a light chain variable region comprising the amino acid sequence of SEQ ID NO: 64 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 64; or (b) a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 52 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 52; and / or a light chain variable region comprising the amino acid sequence of SEQ ID NO: 65 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 65. In some of the embodiments herein, an antibody or antigen-binding fragment that specifically binds to UCH-L1 includes (a) a heavy chain variable region comprising an amino acid sequence having at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of any of the above-mentioned SEQ ID NOs.

[0016] In some of the embodiments herein, an antibody or antigen-binding fragment that specifically binds to UCH-L1 includes a heavy chain variable region containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 1, SEQ ID NO: 19, and SEQ ID NO: 20, and / or a light chain variable region containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 28, SEQ ID NO: 37, and SEQ ID NO: 50, respectively.

[0017] In some of the embodiments herein, the antibody or antigen-binding fragment that specifically binds to UCH-L1 includes a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 63 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 63; and / or a light chain variable region comprising the amino acid sequence of SEQ ID NO: 76 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 76. In some of the embodiments herein, an antibody or antigen-binding fragment that specifically binds to UCH-L1 includes (a) a heavy chain variable region comprising an amino acid sequence having at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO: 63, and / or a light chain variable region comprising an amino acid sequence having at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO: 76.

[0018] In some of the embodiments herein, the antibody or antigen-binding fragment that specifically binds to UCH-L1 is (a) a heavy chain variable region containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 3, SEQ ID NO: 11, and SEQ ID NO: 20, and / or a light chain variable region containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 30, SEQ ID NO: 37, and SEQ ID NO: 45, respectively; or (b) SEQ ID NO: 4, SEQ ID NO: 12, and SEQ ID NO: 22, respectively (c) Heavy chain variable region containing CDR-H1, CDR-H2 and CDR-H3 amino acid sequences, and / or Light chain variable region containing CDR-L1, CDR-L2 and CDR-L3 amino acid sequences of SEQ ID NO: 31, SEQ ID NO: 39 and SEQ ID NO: 47, respectively; or (c) Heavy chain variable region containing CDR-H1, CDR-H2 and CDR-H3 amino acid sequences of SEQ ID NO: 5, SEQ ID NO: 13 and SEQ ID NO: 23, respectively, and / or CDR-L1, CDR- Light chain variable region containing L2 and CDR-L3 amino acid sequences; or (d) heavy chain variable region containing CDR-H1, CDR-H2 and CDR-H3 amino acid sequences of SEQ ID NO: 6, SEQ ID NO: 14 and SEQ ID NO: 24, respectively, and / or light chain variable region containing CDR-L1, CDR-L2 and CDR-L3 amino acid sequences of SEQ ID NO: 33, SEQ ID NO: 40 and SEQ ID NO: 48, respectively; or (e) heavy chain variable region containing CDR-H1, CDR-H2 and CDR-H3 amino acid sequences of SEQ ID NO: 6, SEQ ID NO: 14 and SEQ ID NO: 24, respectively (f) A heavy chain variable region containing a column, and / or a light chain variable region containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 34, SEQ ID NO: 41, and SEQ ID NO: 48, respectively; or (f) A heavy chain variable region containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 6, SEQ ID NO: 15, and SEQ ID NO: 24, and / or a light chain variable region containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 34, SEQ ID NO: 42, and SEQ ID NO: 48, respectively;or (g) heavy chain variable regions containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 6, SEQ ID NO: 14, and SEQ ID NO: 24, respectively, and / or light chain variable regions containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 35, SEQ ID NO: 41, and SEQ ID NO: 48, respectively; or (h) heavy chain variable regions containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 6, SEQ ID NO: 16, and SEQ ID NO: 25, respectively, and / or light chain variable regions containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 34, SEQ ID NO: 42, and SEQ ID NO: 48, respectively; also (i) a heavy chain variable region containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NOs. 7, SEQ ID NOs. 17, and SEQ ID NOs. 26, respectively, and / or a light chain variable region containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NOs. 36, SEQ ID NOs. 43, and SEQ ID NOs. 49, respectively; or (j) a heavy chain variable region containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NOs. 8, SEQ ID NOs. 18, and SEQ ID NOs. 27, respectively, and / or a light chain variable region containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NOs. 36, SEQ ID NOs. 44, and SEQ ID NOs. 49, respectively.

[0019] In some of the embodiments described herein, the antibody or antigen-binding fragment that specifically binds to UCH-L1 includes: (a) a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 53 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 53; and / or a light chain variable region containing the amino acid sequence of SEQ ID NO: 66 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 66; or (b) a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 54 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 54; and / or a light chain variable region containing the amino acid sequence of SEQ ID NO: 67 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 67; or (c) a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 55 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 55; and / or a light chain variable region containing the amino acid sequence of SEQ ID NO: 68 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 68; or (d) an amino acid sequence of SEQ ID NO: 56 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 56 (a) Heavy chain variable region containing an amino acid sequence having 85% identity with the amino acid sequence of SEQ ID NO: 69 or a light chain variable region containing an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 69; (e) Heavy chain variable region containing an amino acid sequence(h) A heavy chain variable region including the amino acid sequence of SEQ ID NO: 60 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 60; and / or a light chain variable region including the amino acid sequence of SEQ ID NO: 73 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 73; (i) A heavy chain variable region including the amino acid sequence of SEQ ID NO: 61 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 61; and / or a light chain variable region including the amino acid sequence of SEQ ID NO: 74 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 74; or (k) A heavy chain variable region including the amino acid sequence of SEQ ID NO: 62 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 62; and / or a light chain variable region including the amino acid sequence of SEQ ID NO: 75 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 75. In some of the embodiments herein, an antibody or antigen-binding fragment that specifically binds to UCH-L1 includes (a) a heavy chain variable region comprising an amino acid sequence having at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence shown in any of the above-mentioned SEQ ID NOs: and / or a light chain variable region comprising an amino acid sequence having at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence shown in any of the above-mentioned SEQ ID NOs:

[0020] In some of these arbitrary embodiments, the antibody or antigen-binding fragment is 1.0 × 10⁻⁶ -10 M, 2.0×10 -10 M, 3.0×10 -10 M, 4.0×10 -10M, 5.0×10 -10 M, 6.0×10 -10 M, 7.0×10 -10 M, 8.0×10 -10 M, 9.0×10 -10 M, 1.0×10 -11 M, 2.0×10 -11 M, 3.0×10 -11 M, 4.0×10 -11 M, 5.0×10 -11 M, 6.0×10 -11 M, 7.0×10 -11 M, 8.0×10 -11 M, 9.0×10 -11 M, 1.0×10 -12 M or less than or about less than or lower than the dissociation constant (K D ) that binds to UCH-LI with a binding affinity; or, the antibody or antigen-binding fragment is 2.0×10 -10 M to 5.0×10 -12 M or about that range, e.g., 2.0×10 -10 M to 1.0×10 -12 M, 2.0×10 -10 M to 5.0×10 -11 M, 2.0×10 -10 M to 1.0×10 -11 M, 2.0×10 -10 M to 5.0×10 -10 M, 5.0×10 -10 M to 1.0×10 -12 M, 5.0×10 -10 M to 5.0×10 -11 M, 5.0×10 -10 M to 1.0×10 -11 M, 1.0×10<000....037>M to 1.0×10 -12 M, 1.0×10 -11 M to 5.0×10 -11 M or 5.0×10 -11 M to 1.0×10 -12 M or about that range, e.g., 2.0×'0 -10 M 2.0×10 -10 M to 4.0×10 -10 M, 1.0×10 -11 M to 9.0×10 -11 M, 1.0×10 It should be noted that there seems to be an incomplete tag -11 in the original text which might cause some issues in a complete understanding. Also, the "2.0×'0" in line 76 might be a typo. You may want to double-check the original text for accuracy.-12 M~5.0×10 -12 M or the dissociation constant (K) in approximately that range D ), or 1.0 × 10 -12 M, 2.0×10 -10 It binds to UCH-L1 via M.

[0021] In some of these arbitrary embodiments, the antibody or antigen-binding fragment binds to an epitope that is or contains residues 28-36, 98-106, 138-145, and / or 142-149 of the UCH-L1 protein, corresponding to the amino acid positions shown in SEQ ID NO: 207.

[0022] In some embodiments, the Specified Information provides an antibody or antigen-binding fragment that specifically binds to UCH-L1 (e.g., human UCH-L1), where the antibody or antigen-binding fragment binds to an epitope within or containing residues 98-106 of the UCH-L1 protein, corresponding to the amino acid position shown in SEQ ID NO: 207. In some embodiments, the antibody or antigen-binding fragment comprises (a) a heavy chain variable region containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 1, SEQ ID NO: 9, and SEQ ID NO: 20, respectively, and / or a light chain variable region containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 28, SEQ ID NO: 37, and SEQ ID NO: 45, respectively; and (b) a light chain variable region containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 3, SEQ ID NO: 11, and SEQ ID NO: 20, respectively. (c) A heavy chain variable region and / or a light chain variable region containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 30, SEQ ID NO: 37, and SEQ ID NO: 45, respectively; or (c) a heavy chain variable region containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 1, SEQ ID NO: 19, and SEQ ID NO: 20, respectively, and / or a light chain variable region containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 28, SEQ ID NO: 37, and SEQ ID NO: 50, respectively.

[0023] In some embodiments, the Specified Information provides an antibody or antigen-binding fragment that specifically binds to UCH-L1 (e.g., human UCH-L1), wherein the antibody or antigen-binding fragment binds to an epitope in or containing residues 28-36 of UCH-L1, corresponding to the amino acid positions of UCH-L1 shown in SEQ ID NO: 207. In some embodiments, the antibody or antigen-binding fragment includes: (a) a heavy chain variable region containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 2, SEQ ID NO: 10, and SEQ ID NO: 21, and / or a light chain variable region containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 29, SEQ ID NO: 38, and SEQ ID NO: 46, respectively; (b) a heavy chain variable region containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 6, SEQ ID NO: 14, and SEQ ID NO: 24, and / or a light chain variable region containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 33, SEQ ID NO: 40, and SEQ ID NO: 48, respectively; (c) a heavy chain variable region containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 6, SEQ ID NO: 14, and SEQ ID NO: 24, respectively. (d) Heavy chain variable regions including columns, and / or light chain variable regions including the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 34, SEQ ID NO: 41, and SEQ ID NO: 48, respectively; (d) Heavy chain variable regions including the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 6, SEQ ID NO: 15, and SEQ ID NO: 24, respectively, and / or light chain variable regions including the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 34, SEQ ID NO: 42, and SEQ ID NO: 48, respectively; (e) Heavy chain variable regions including the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 6, SEQ ID NO: 14, and SEQ ID NO: 24, respectively, and / or light chain variable regions including the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 35, SEQ ID NO: 41, and SEQ ID NO: 48, respectively;(f) Heavy chain variable regions containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 6, SEQ ID NO: 16, and SEQ ID NO: 25, respectively, and / or Light chain variable regions containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 34, SEQ ID NO: 42, and SEQ ID NO: 48, respectively; (g) Heavy chain variable regions containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 7, SEQ ID NO: 17, and SEQ ID NO: 26, respectively, and / or (h) a light chain variable region containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 36, SEQ ID NO: 43, and SEQ ID NO: 49, respectively; or (h) a heavy chain variable region containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 8, SEQ ID NO: 18, and SEQ ID NO: 27, respectively, and / or a light chain variable region containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 36, SEQ ID NO: 44, and SEQ ID NO: 49, respectively.

[0024] In some embodiments, the Specified Information provides an antibody or antigen-binding fragment that specifically binds to UCH-L1 (e.g., human UCH-L1), where the antibody or antigen-binding fragment binds to an epitope within or containing residues 138-145 of the UCH-L1 protein, corresponding to the amino acid position shown in SEQ ID NO: 207. In some embodiments, the antibody or antigen-binding fragment includes a heavy chain variable region containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 4, SEQ ID NO: 12, and SEQ ID NO: 22, respectively, and / or a light chain variable region containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 31, SEQ ID NO: 39, and SEQ ID NO: 47, respectively.

[0025] In some embodiments, the Specified Information provides an antibody or antigen-binding fragment that specifically binds to UCH-L1 (e.g., human UCH-L1), where the antibody or antigen-binding fragment binds to an epitope within or containing residues 142-149 of the UCH-L1 protein, corresponding to the amino acid position shown in SEQ ID NO: 207. In some embodiments, the antibody or antigen-binding fragment includes a heavy chain variable region containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 5, SEQ ID NO: 13, and SEQ ID NO: 23, respectively, and / or a light chain variable region containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 32, SEQ ID NO: 39, and SEQ ID NO: 47, respectively.

[0026] In some arbitrary embodiments herein, UCH-L1 (e.g., human UCH-L1) is recombinant UCH-L1 (e.g., recombinant human UCH-L1). In some arbitrary embodiments herein, UCH-L1 (e.g., human UCH-L1) is native UCH-L1 (e.g., native human UCH-L1). In some further embodiments, native UCH-L1 is present in or obtained from serum, plasma, blood, cerebrospinal fluid (CSF), urine, sweat, or saliva.

[0027] This specification provides antibodies or antigen-binding fragments comprising GFAP, for example, human GFAP, which specifically bind to GFAP, wherein the antibody or antigen-binding fragment comprises specific complementarity-determining regions (CDRs), including, for example, any heavy chain CDRs (i.e., CDR-H1, CDR-H2, and / or CDR-H3) and light chain CDRs (i.e., CDR-L1, CDR-L2, and / or CDR-L3) as described herein. In some embodiments, the antibody or antigen-binding fragment comprises, for example, any heavy chain variable region and light chain variable region as described herein.

[0028] In some embodiments, an antibody or antigen-binding fragment thereof that specifically binds to GFAP (e.g., human GFAP) is provided herein, wherein the antibody or antigen-binding fragment comprises a heavy chain variable region comprising an amino acid sequence having at least 85% identity with an amino acid sequence selected from any one of SEQ ID NOs. 172-188; and / or a light chain variable region comprising an amino acid sequence having at least 85% identity with an amino acid sequence selected from any one of SEQ ID NOs. 189-206. In some embodiments, the heavy chain variable region comprises an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with an amino acid sequence selected from any one of SEQ ID NOs. 172-188. In some of the embodiments described herein, the light chain variable region comprises an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with an amino acid sequence selected from any one of SEQ ID NOs: 189 to 206, or comprises an amino acid sequence selected from any one of SEQ ID NOs: 189 to 206. In some embodiments, the heavy chain variable region includes (i) CDR-H1 containing an amino acid sequence selected from SEQ ID NOs: 77-90; (ii) CDR-H2 containing an amino acid sequence selected from SEQ ID NOs: 91-107; and (iii) CDR-H3 containing an amino acid sequence selected from SEQ ID NOs: 108-124; and / or the light chain variable region includes (i) CDR-L1 containing an amino acid sequence selected from SEQ ID NOs: 125-141; (ii) CDR-L2 containing an amino acid sequence selected from SEQ ID NOs: 142-156; and (iii) CDR-L3 containing an amino acid sequence selected from SEQ ID NOs: 157-171.In some embodiments, the heavy chain variable region comprises CDR-H1, CDR-H2, and CDR-H3, each containing the amino acid sequences of CDR-H1, CDR-H2, and CDR-H3 within a heavy chain variable region amino acid sequence selected from any one of SEQ ID NOs. 172 to 188; and / or, the light chain variable region comprises CDR-L1, CDR-L2, and CDR-L3, each containing the amino acid sequences of CDR-L1, CDR-L2, and CDR-L3 within a light chain variable region amino acid sequence selected from any one of SEQ ID NOs. 189 to 206.

[0029] In some embodiments, an antibody or antigen-binding fragment thereof that specifically binds to GFAP (e.g., human GFAP) is provided herein, wherein the antibody or antigen-binding fragment comprises an amino acid sequence having at least 85% identity with an amino acid sequence selected from any one of SEQ ID NOs: 174-188; and / or the light chain variable region comprises an amino acid sequence having at least 85% identity with an amino acid sequence selected from any one of SEQ ID NOs: 191-206. In some embodiments, the heavy chain variable region comprises at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with an amino acid sequence selected from any one of SEQ ID NOs: 174-188; and / Alternatively, the light chain variable region contains at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with an amino acid sequence selected from any one of SEQ ID NOs. 191-206, or contains a light chain variable region containing an amino acid sequence shown in any one of SEQ ID NOs.In some embodiments, the heavy chain variable region includes (i) CDR-H1 containing an amino acid sequence selected from SEQ ID NOs. 79-90; (ii) CDR-H2 containing an amino acid sequence selected from SEQ ID NOs. 93-107; and (iii) CDR-H3 containing an amino acid sequence selected from SEQ ID NOs. 110-124; and / or the light chain variable region includes (i) CDR-L1 containing an amino acid sequence selected from SEQ ID NOs. 127-141; (ii) CDR-L2 containing an amino acid sequence selected from SEQ ID NOs. 144-156; and (iii) an amino acid sequence selected from SEQ ID NOs. 159-171 The heavy chain variable region includes CDR-L3 containing a column; or the heavy chain variable region includes CDR-H1, CDR-H2, and CDR-H3, and each includes the amino acid sequences of CDR-H1, CDR-H2, and CDR-H3 contained within a heavy chain variable region amino acid sequence selected from any one of SEQ ID NOs. 174 to 188, and / or the light chain variable region includes CDR-L1, CDR-L2, and CDR-L3, and each includes the amino acid sequences of CDR-L1, CDR-L2, and CDR-L3 contained within a light chain variable region amino acid sequence selected from any one of SEQ ID NOs. 191 to 206.

[0030] In some embodiments, the Specified herein provides an antibody or antigen-binding fragment that specifically binds to GFAP (e.g., human GFAP), wherein the antibody or antigen-binding fragment comprises a heavy chain variable region and a light chain variable region, the heavy chain variable region comprising (i) CDR-H1 comprising an amino acid sequence selected from SEQ ID NOs. 77-90; (ii) CDR-H2 comprising an amino acid sequence selected from SEQ ID NOs. 91-107; and (iii) CDR-H3 comprising an amino acid sequence selected from SEQ ID NOs. 108-124; and / or the light chain variable region comprising (i) CDR-L1 comprising an amino acid sequence selected from SEQ ID NOs. 125-141; (ii) CDR-L2 comprising an amino acid sequence selected from SEQ ID NOs. 142-156; and (iii) CDR-L3 comprising an amino acid sequence selected from SEQ ID NOs. 157-171.

[0031] In some of these arbitrary embodiments, the antibody or antigen-binding fragment that specifically binds to GFAP is (a) a heavy chain variable region comprising the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 77, SEQ ID NO: 91, and SEQ ID NO: 108, respectively, and / or a light chain variable region comprising the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 125, SEQ ID NO: 142, and SEQ ID NO: 157, respectively; (b) each of SEQ ID NO: 78, SEQ ID NO: 92, and SEQ ID NO: 109 (c) Heavy chain variable region containing CDR-H1, CDR-H2 and CDR-H3 amino acid sequences, and / or light chain variable region containing CDR-L1, CDR-L2 and CDR-L3 amino acid sequences of SEQ ID NO: 126, SEQ ID NO: 143 and SEQ ID NO: 158, respectively; (c) Heavy chain variable region containing CDR-H1, CDR-H2 and CDR-H3 amino acid sequences of SEQ ID NO: 79, SEQ ID NO: 93 and SEQ ID NO: 110, respectively, and / or CDR-L1, CDR-H3 and CDR-H3 amino acid sequences of SEQ ID NO: 127, SEQ ID NO: 144 and SEQ ID NO: 159, respectively - Light chain variable region containing L2 and CDR-L3 amino acid sequences; (d) Heavy chain variable region containing CDR-H1, CDR-H2 and CDR-H3 amino acid sequences of SEQ ID NO: 77, SEQ ID NO: 94 and SEQ ID NO: 111, and / or Light chain variable region containing CDR-L1, CDR-L2 and CDR-L3 amino acid sequences of SEQ ID NO: 128, SEQ ID NO: 145 and SEQ ID NO: 160, and / or Light chain variable region containing CDR-L1, CDR-L2 and CDR-L3 amino acid sequences of SEQ ID NO: 80, SEQ ID NO: 95 and SEQ ID NO: 112, and / or Light chain variable region containing CDR-H1, CDR-H2 and CDR-H3 amino acid sequences (f) Heavy chain variable regions including columns, and / or light chain variable regions including the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 126, SEQ ID NO: 142, and SEQ ID NO: 158, respectively; (f) Heavy chain variable regions including the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 81, SEQ ID NO: 96, and SEQ ID NO: 113, respectively, and / or light chain variable regions including the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 129, SEQ ID NO: 146, and SEQ ID NO: 161, respectively;(g) Heavy chain variable regions containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 77, SEQ ID NO: 94, and SEQ ID NO: 111, respectively, and / or Light chain variable regions containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 130, SEQ ID NO: 145, and SEQ ID NO: 160, respectively; (h) Heavy chain variable regions containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 82, SEQ ID NO: 97, and SEQ ID NO: 114, respectively, and / Or, a light chain variable region containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 131, SEQ ID NO: 147, and SEQ ID NO: 162, respectively; (i) a heavy chain variable region containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 83, SEQ ID NO: 98, and SEQ ID NO: 115, respectively, and / or a light chain variable region containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 132, SEQ ID NO: 148, and SEQ ID NO: 163, respectively; ( j) Heavy chain variable regions containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 84, SEQ ID NO: 99, and SEQ ID NO: 116, respectively, and / or Light chain variable regions containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 133, SEQ ID NO: 149, and SEQ ID NO: 164, respectively; (k) Heavy chain variable regions containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 85, SEQ ID NO: 100, and SEQ ID NO: 117, respectively, and / (i) Light chain variable regions containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 134, SEQ ID NO: 150, and SEQ ID NO: 165, respectively; (l) Heavy chain variable regions containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 86, SEQ ID NO: 101, and SEQ ID NO: 118, respectively, and / or Light chain variable regions containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 135, SEQ ID NO: 151, and SEQ ID NO: 166, respectively;(m) Heavy chain variable regions containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 78, SEQ ID NO: 102, and SEQ ID NO: 119, respectively, and / or Light chain variable regions containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 136, SEQ ID NO: 152, and SEQ ID NO: 167, respectively; (n) Heavy chain variable regions containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 78, SEQ ID NO: 103, and SEQ ID NO: 120, respectively, and / (o) Light chain variable regions containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 137, SEQ ID NO: 142, and SEQ ID NO: 158, respectively; (o) Heavy chain variable regions containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 87, SEQ ID NO: 104, and SEQ ID NO: 121, respectively, and / or Light chain variable regions containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 138, SEQ ID NO: 153, and SEQ ID NO: 168, respectively; (p) (q) Heavy chain variable regions containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NOs. 88, SEQ ID NOs. 105, and SEQ ID NOs. 122, respectively, and / or Light chain variable regions containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NOs. 139, SEQ ID NOs. 154, and SEQ ID NOs. 169, respectively; (q) Heavy chain variable regions containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NOs. 89, SEQ ID NOs. 106, and SEQ ID NOs. 123, respectively, and / or A light chain variable region containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 140, SEQ ID NO: 155, and SEQ ID NO: 170, respectively; or (r) a heavy chain variable region containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 90, SEQ ID NO: 107, and SEQ ID NO: 124, respectively, and / or a light chain variable region containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 141, SEQ ID NO: 156, and SEQ ID NO: 171, respectively.

[0032] In some of these arbitrary embodiments, the antibody or antigen-binding fragment that specifically binds to GFAP includes: (a) a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 172 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 172; and / or a light chain variable region containing the amino acid sequence of SEQ ID NO: 189 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 189; (b) a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 173 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 173; and / or a light chain variable region containing the amino acid sequence of SEQ ID NO: 190 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 190; (c) a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 174 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 174; and / or a light chain variable region containing the amino acid sequence of SEQ ID NO: 191 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 191; and (d) a sequence (a) A heavy chain variable region containing an amino acid sequence that is at least 85% identical to the amino acid sequence of sequence number 175 or sequence number 175; and / or a light chain variable region containing an amino acid sequence that is at least 85% identical to the amino acid sequence of sequence number 192 or sequence number 192; (e) A heavy chain variable region containing an amino acid sequence that is at least 85% identical to the amino acid sequence of sequence number 176 or sequence number 176; and / or a light chain variable region containing an amino acid sequence that is at least 85% identical to the amino acid sequence of sequence number 193 or sequence number 193; (f) A heavy chain variable region containing an amino acid sequence that is at least 85% identical to the amino acid sequence of sequence number 177 or sequence number 177; and / or a light chain variable region containing an amino acid sequence that is at least 85% identical to the amino acid sequence of sequence number 194 or sequence number 194; (g) A heavy chain variable region containing an amino acid sequence that is at least 85% identical to the amino acid sequence of sequence number 175 or sequence number 175;(h) A light chain variable region containing the amino acid sequence of SEQ ID NO: 195 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 195; (i) A heavy chain variable region containing the amino acid sequence of SEQ ID NO: 179 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 179; and / or A light chain variable region containing the amino acid sequence of SEQ ID NO: 197 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 197; (j) A heavy chain variable region containing the amino acid sequence of SEQ ID NO: 180 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 180; and / or A light chain variable region containing the amino acid sequence of SEQ ID NO: 198 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 198 Region; (k) Heavy chain variable region containing the amino acid sequence of SEQ ID NO: 181 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 181; and / or Light chain variable region containing the amino acid sequence of SEQ ID NO: 199 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 199; (l) Heavy chain variable region containing the amino acid sequence of SEQ ID NO: 182 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 182; and / or Light chain variable region containing the amino acid sequence of SEQ ID NO: 200 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 200; (m) Heavy chain variable region containing the amino acid sequence of SEQ ID NO: 183 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 183; and / or Light chain variable region containing the amino acid sequence of SEQ ID NO: 201 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 201; (n) Heavy chain variable region containing the amino acid sequence of SEQ ID NO: 184 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 184;(o) a light chain variable region containing the amino acid sequence of SEQ ID NO: 202 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 202; (o) a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 185 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 185; and / or a light chain variable region containing the amino acid sequence of SEQ ID NO: 203 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 203; (p) a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 186 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 186; (q) a light chain variable region containing the amino acid sequence of SEQ ID NO: 204 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 204; (q) a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 187 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 187; and / or a light chain variable region containing the amino acid sequence of SEQ ID NO: 205 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 205; or (r) a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 188 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 188;and / or a light chain variable region comprising the amino acid sequence of SEQ ID NO: 206 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 206. In some of the embodiments herein, an antibody or antigen-binding fragment that specifically binds to GFAP includes (a) a heavy chain variable region comprising an amino acid sequence having at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of any of the above-mentioned SEQ ID NOs: and / or a light chain variable region comprising an amino acid sequence having at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence shown in any of the above-mentioned SEQ ID NOs:

[0033] In some of these arbitrary embodiments, the antibody or antigen-binding fragment that specifically binds to GFAP includes a heavy chain variable region comprising the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 77, SEQ ID NO: 91, and SEQ ID NO: 108, respectively, and / or a light chain variable region comprising the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 125, SEQ ID NO: 142, and SEQ ID NO: 157, respectively.

[0034] In some of these arbitrary embodiments, the antibody or antigen-binding fragment that specifically binds to GFAP includes a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 172 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 172; and / or a light chain variable region comprising the amino acid sequence of SEQ ID NO: 189 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 189. In some of the embodiments herein, an antibody or antigen-binding fragment that specifically binds to GFAP includes (a) a heavy chain variable region comprising an amino acid sequence having at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO: 172, and / or a light chain variable region comprising an amino acid sequence having at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO: 189.

[0035] In some of these arbitrary embodiments, the antibody or antigen-binding fragment that specifically binds to GFAP includes a heavy chain variable region comprising the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 78, SEQ ID NO: 92, and SEQ ID NO: 109, respectively, and / or a light chain variable region comprising the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 126, SEQ ID NO: 143, and SEQ ID NO: 158, respectively.

[0036] In some of these arbitrary embodiments, the antibody or antigen-binding fragment that specifically binds to GFAP includes a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 173 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 173; and / or a light chain variable region comprising the amino acid sequence of SEQ ID NO: 190 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 190. In some of the embodiments herein, an antibody or antigen-binding fragment that specifically binds to GFAP includes (a) a heavy chain variable region comprising an amino acid sequence having at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence of SEQ ID NO: 173, and / or a light chain variable region comprising an amino acid sequence having at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence provided in SEQ ID NO: 190.

[0037] In some of these arbitrary embodiments herein, the antibody or antigen-binding fragment that specifically binds to GFAP is (a) a heavy chain variable region comprising the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 79, SEQ ID NO: 93, and SEQ ID NO: 110, and / or a light chain variable region comprising the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 127, SEQ ID NO: 144, and SEQ ID NO: 159, respectively; (b) each of SEQ ID NO: 77, SEQ ID NO: 94, and SEQ ID NO: 111 (c) Heavy chain variable region containing CDR-H1, CDR-H2 and CDR-H3 amino acid sequences, and / or light chain variable region containing CDR-L1, CDR-L2 and CDR-L3 amino acid sequences of SEQ ID NO: 128, SEQ ID NO: 145 and SEQ ID NO: 160, respectively; (c) Heavy chain variable region containing CDR-H1, CDR-H2 and CDR-H3 amino acid sequences of SEQ ID NO: 80, SEQ ID NO: 95 and SEQ ID NO: 112, and / or CDR-L1, CDR-H3 and CDR-H3 amino acid sequences of SEQ ID NO: 126, SEQ ID NO: 142 and SEQ ID NO: 158, respectively - Light chain variable region containing L2 and CDR-L3 amino acid sequences; (d) Heavy chain variable region containing CDR-H1, CDR-H2 and CDR-H3 amino acid sequences of SEQ ID NO: 81, SEQ ID NO: 96 and SEQ ID NO: 113, and / or Light chain variable region containing CDR-L1, CDR-L2 and CDR-L3 amino acid sequences of SEQ ID NO: 129, SEQ ID NO: 146 and SEQ ID NO: 161, and / or Light chain variable region containing CDR-L1, CDR-L2 and CDR-L3 amino acid sequences of SEQ ID NO: 77, SEQ ID NO: 94 and SEQ ID NO: 111, and / or Light chain variable region containing CDR-H1, CDR-H2 and CDR-H3 amino acid sequences (f) Heavy chain variable regions including columns, and / or light chain variable regions including the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 130, SEQ ID NO: 145, and SEQ ID NO: 160, respectively; (f) Heavy chain variable regions including the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 82, SEQ ID NO: 97, and SEQ ID NO: 114, respectively, and / or light chain variable regions including the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 131, SEQ ID NO: 147, and SEQ ID NO: 162, respectively;(g) Heavy chain variable regions containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 83, SEQ ID NO: 98, and SEQ ID NO: 115, respectively, and / or Light chain variable regions containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 132, SEQ ID NO: 148, and SEQ ID NO: 163, respectively; (h) Heavy chain variable regions containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 84, SEQ ID NO: 99, and SEQ ID NO: 116, respectively, and / Or, a light chain variable region containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 133, SEQ ID NO: 149, and SEQ ID NO: 164, respectively; (i) a heavy chain variable region containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 85, SEQ ID NO: 100, and SEQ ID NO: 117, respectively, and / or a light chain variable region containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 134, SEQ ID NO: 150, and SEQ ID NO: 165, respectively; ( j) Heavy chain variable regions containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 86, SEQ ID NO: 101, and SEQ ID NO: 118, respectively, and / or light chain variable regions containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 135, SEQ ID NO: 151, and SEQ ID NO: 166, respectively; (k) Heavy chain variable regions containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 78, SEQ ID NO: 102, and SEQ ID NO: 119, respectively, and / or, light chain variable regions containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 136, SEQ ID NO: 152, and SEQ ID NO: 167, respectively; (l) heavy chain variable regions containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 78, SEQ ID NO: 103, and SEQ ID NO: 120, respectively, and / or, light chain variable regions containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 137, SEQ ID NO: 142, and SEQ ID NO: 158, respectively;(n) Heavy chain variable regions containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 87, SEQ ID NO: 104, and SEQ ID NO: 121, respectively, and / or Light chain variable regions containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 138, SEQ ID NO: 153, and SEQ ID NO: 168, respectively; (o) Heavy chain variable regions containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 88, SEQ ID NO: 105, and SEQ ID NO: 122, respectively, and / or Light chain variable regions containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 139, SEQ ID NO: 154, and SEQ ID NO: 169, respectively; (p) A heavy chain variable region containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NOs. 89, 106, and 123, respectively, and / or a light chain variable region containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NOs. 140, 155, and 170, respectively; or (q) a heavy chain variable region containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NOs. 90, 107, and 124, respectively, and / or a light chain variable region containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NOs. 141, 156, and 171, respectively.

[0038] In some of these arbitrary embodiments, the antibody or antigen-binding fragment that specifically binds to GFAP includes: (a) a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 174 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 174; and / or a light chain variable region containing the amino acid sequence of SEQ ID NO: 191 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 191; (b) a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 175 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 175; and / or a light chain variable region containing the amino acid sequence of SEQ ID NO: 192 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 192; (c) a heavy chain variable region containing the amino acid sequence of SEQ ID NO: 176 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 176; and / or a light chain variable region containing the amino acid sequence of SEQ ID NO: 193 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 193; and (d) a sequence (a) A heavy chain variable region containing an amino acid sequence that is at least 85% identical to the amino acid sequence of sequence number 177 or sequence number 177; and / or a light chain variable region containing an amino acid sequence that is at least 85% identical to the amino acid sequence of sequence number 194 or sequence number 194; (b) A heavy chain variable region containing an amino acid sequence that is at least 85% identical to the amino acid sequence of sequence number 175 or sequence number 175; and / or a light chain variable region containing an amino acid sequence that is at least 85% identical to the amino acid sequence of sequence number 195 or sequence number 195; (c) A heavy chain variable region containing an amino acid sequence that is at least 85% identical to the amino acid sequence of sequence number 178 or sequence number 178; and / or a light chain variable region containing an amino acid sequence that is at least 85% identical to the amino acid sequence of sequence number 196 or sequence number 196; (d) A heavy chain variable region containing an amino acid sequence that is at least 85% identical to the amino acid sequence of sequence number 179 or sequence number 179;(h) A light chain variable region containing the amino acid sequence of SEQ ID NO: 197 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 197; (i) A heavy chain variable region containing the amino acid sequence of SEQ ID NO: 180 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 180; and / or A light chain variable region containing the amino acid sequence of SEQ ID NO: 198 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 198; (j) A heavy chain variable region containing the amino acid sequence of SEQ ID NO: 182 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 182; and / or A light chain variable region containing the amino acid sequence of SEQ ID NO: 200 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 200 Region; (k) Heavy chain variable region containing the amino acid sequence of SEQ ID NO: 183 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 183; and / or Light chain variable region containing the amino acid sequence of SEQ ID NO: 201 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 201; (l) Heavy chain variable region containing the amino acid sequence of SEQ ID NO: 184 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 184; and / or Light chain variable region containing the amino acid sequence of SEQ ID NO: 202 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 202; (n) Heavy chain variable region containing the amino acid sequence of SEQ ID NO: 185 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 185; and / or Light chain variable region containing the amino acid sequence of SEQ ID NO: 203 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 203; (o) Heavy chain variable region containing the amino acid sequence of SEQ ID NO: 186 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 186;(p) A light chain variable region including the amino acid sequence of SEQ ID NO: 204 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 204; (p) A heavy chain variable region including the amino acid sequence of SEQ ID NO: 187 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 187; and / or A light chain variable region including the amino acid sequence of SEQ ID NO: 205 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 205; or (q) A heavy chain variable region including the amino acid sequence of SEQ ID NO: 188 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 188; and / or A light chain variable region including the amino acid sequence of SEQ ID NO: 206 or an amino acid sequence having at least 85% identity with the amino acid sequence of SEQ ID NO: 206. In some of the embodiments herein, an antibody or antigen-binding fragment that specifically binds to GFAP includes (a) a heavy chain variable region comprising an amino acid sequence having at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence shown in any of the listed SEQ ID NOs: and / or a light chain variable region comprising an amino acid sequence having at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence shown in any of the listed SEQ ID NOs:

[0039] In some of these arbitrary embodiments, the antibody or antigen-binding fragment is 1.0 × 10⁻⁶ -8 M, 2.0×10 -8 M, 3.0×10 -8 M, 4.0×10 -8 M, 5.0×10 -8 M, 6.0×10 -8 M, 7.0×10 -8M, 8.0×10 -8 M, 9.0×10 -8 M, 1.0×10 -9 M, 2.0×10 -9 M, 3.0×10 -9 M, 4.0×10 -9 M, 5.0×10 -9 M, 6.0×10 -9 M, 7.0×10 -9 M, 8.0×10 -9 M, 9.0×10 -9 M, 1.0×10​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​-11 M, 1.0×10 -11 M~1.0×10 -12 M, for example, 1.0 × 10 -8 M~2.0×10 -8 M, 1.0×10 -9 M~6.0×10 -9 M, 2.0×10 -10 M~9.0×10 -10 M, 1.0×10 -11 M~8.0×10 -11 M, 1.0×10 -12 M~5.0×10 -12 M, or 1.0 × 10 -8 M~1.0×10 -12 M or the dissociation constant (K) in approximately that range D It binds to GFAP.

[0040] In some of the most arbitrary embodiments herein, the antibody or antigen-binding fragment that binds to GFAP binds to an epitope in or including residues 92-106, 190-202, 16-35 and / or 380, 119 and / or 190, 380-391, 119-130, 210-221, 320-329, 346-357 and / or 376-387 of the GFAP protein, and / or in residues 138-149 of the GFAP protein, corresponding to the amino acid positions shown in SEQ ID NO: 212.

[0041] In some embodiments, the Specified Classification provides an antibody or antigen-binding fragment that specifically binds to human GFAP, wherein the antibody or antigen-binding fragment binds to an epitope within residues 92-106 of the GFAP protein corresponding to the amino acid position shown in SEQ ID NO: 212. In some embodiments, the antibody or antigen-binding fragment includes a heavy chain variable region comprising the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 77, SEQ ID NO: 91, and SEQ ID NO: 108, respectively, and / or a light chain variable region comprising the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 125, SEQ ID NO: 142, and SEQ ID NO: 157, respectively.

[0042] In some embodiments, the Specified Classification provides an antibody or antigen-binding fragment that specifically binds to human GFAP, wherein the antibody or antigen-binding fragment binds to an epitope within residues 190-202 of the GFAP protein corresponding to the amino acid position shown in SEQ ID NO: 212. In some embodiments, the antibody or antigen-binding fragment includes a heavy chain variable region comprising the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 78, SEQ ID NO: 92, and SEQ ID NO: 109, respectively, and / or a light chain variable region comprising the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 126, SEQ ID NO: 143, and SEQ ID NO: 158, respectively.

[0043] In some embodiments, the Specified Classification provides an antibody or antigen-binding fragment that specifically binds to human GFAP, wherein the antibody or antigen-binding fragment binds to an epitope in residues 16-35 and / or 380 of the GFAP protein corresponding to the amino acid position shown in SEQ ID NO: 212. In some embodiments, the antibody or antigen-binding fragment includes a heavy chain variable region containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 79, SEQ ID NO: 93, and SEQ ID NO: 110, respectively, and / or a light chain variable region containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 127, SEQ ID NO: 144, and SEQ ID NO: 159, respectively.

[0044] In some embodiments, the Specified Classification provides an antibody or antigen-binding fragment that specifically binds to human GFAP, wherein the antibody or antigen-binding fragment binds to an epitope in residues 119 and / or 190 of the GFAP protein corresponding to the amino acid positions shown in SEQ ID NO: 212. In some embodiments, the antibody or antigen-binding fragment includes a heavy chain variable region comprising the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 80, SEQ ID NO: 95, and SEQ ID NO: 112, respectively, and / or a light chain variable region comprising the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 126, SEQ ID NO: 142, and SEQ ID NO: 158, respectively.

[0045] In some embodiments, the Specified Classification of Antibodies or Antigen-Binding Fragments thereof that specifically bind to human GFAP, wherein the antibody or antigen-binding fragment binds to an epitope within residues 380-391 of the GFAP protein corresponding to the amino acid position shown in SEQ ID NO: 212. In some embodiments, the antibody or antigen-binding fragment comprises (a) a heavy chain variable region containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 77, SEQ ID NO: 94, and SEQ ID NO: 111, respectively, and / or a light chain variable region containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 128, SEQ ID NO: 145, and SEQ ID NO: 160, respectively; and (b) a light chain variable region containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 77, SEQ ID NO: 94, and SEQ ID NO: 111, respectively. (c) A heavy chain variable region and / or a light chain variable region containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 130, SEQ ID NO: 145, and SEQ ID NO: 160, respectively; or (c) a heavy chain variable region containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 82, SEQ ID NO: 97, and SEQ ID NO: 114, respectively, and / or a light chain variable region containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 131, SEQ ID NO: 147, and SEQ ID NO: 162, respectively.

[0046] In some embodiments, the Specified herein provides an antibody or antigen-binding fragment that specifically binds to human GFAP, wherein the antibody or antigen-binding fragment binds to an epitope within residues 119-130 of the GFAP protein corresponding to the amino acid position shown in SEQ ID NO: 212. In some embodiments, the antibody or antigen-binding fragment comprises: (a) a heavy chain variable region containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 81, SEQ ID NO: 96, and SEQ ID NO: 113, and / or a light chain variable region containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 129, SEQ ID NO: 146, and SEQ ID NO: 161, respectively; (b) a heavy chain variable region containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 84, SEQ ID NO: 99, and SEQ ID NO: 116, and / or a light chain variable region containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 133, SEQ ID NO: 149, and SEQ ID NO: 164, respectively; (c) a heavy chain variable region containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 85, SEQ ID NO: 100, and SEQ ID NO: 117, respectively. (d) a chain variable region and / or a light chain variable region containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 134, SEQ ID NO: 150, and SEQ ID NO: 165, respectively; (d) a heavy chain variable region containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 89, SEQ ID NO: 106, and SEQ ID NO: 123, respectively, and / or a light chain variable region containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 140, SEQ ID NO: 155, and SEQ ID NO: 170, respectively; or (e) a heavy chain variable region containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 90, SEQ ID NO: 107, and SEQ ID NO: 124, respectively, and / or a light chain variable region containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 141, SEQ ID NO: 156, and SEQ ID NO: 171, respectively.

[0047] In some embodiments, the Specified Classification of Antibodies or Antigen-Binding Fragments thereof that specifically bind to human GFAP, wherein the antibody or antigen-binding fragment binds to an epitope within residues 210-221 of the GFAP protein corresponding to the amino acid position shown in SEQ ID NO: 212. In some embodiments, the antibody or antigen-binding fragment comprises (a) a heavy chain variable region containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 86, SEQ ID NO: 101, and SEQ ID NO: 118, respectively, and / or a light chain variable region containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 135, SEQ ID NO: 151, and SEQ ID NO: 166, respectively; and (b) a light chain variable region containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 78, SEQ ID NO: 102, and SEQ ID NO: 119, respectively. (c) A heavy chain variable region and / or a light chain variable region containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 136, SEQ ID NO: 152, and SEQ ID NO: 167, respectively; or (c) a heavy chain variable region containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 78, SEQ ID NO: 103, and SEQ ID NO: 120, respectively, and / or a light chain variable region containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 137, SEQ ID NO: 142, and SEQ ID NO: 158, respectively.

[0048] In some embodiments, the Specified herein provides an antibody or antigen-binding fragment that specifically binds to human GFAP, wherein the antibody or antigen-binding fragment binds to an epitope within residues 320-329 of the GFAP protein corresponding to the amino acid position shown in SEQ ID NO: 212. In some embodiments, the antibody or antigen-binding fragment includes (a) a heavy chain variable region containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 87, SEQ ID NO: 104, and SEQ ID NO: 121, respectively, and / or a light chain variable region containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 138, SEQ ID NO: 153, and SEQ ID NO: 168, respectively; or (b) a heavy chain variable region containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 88, SEQ ID NO: 105, and SEQ ID NO: 122, respectively, and / or a light chain variable region containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 139, SEQ ID NO: 154, and SEQ ID NO: 169, respectively.

[0049] In some embodiments, the Specified Classification provides an antibody or antigen-binding fragment that specifically binds to human GFAP, wherein the antibody or antigen-binding fragment binds to an epitope in residues 346-357 and / or 376-387 of the GFAP protein corresponding to the amino acid position shown in SEQ ID NO: 212. In some embodiments, the antibody or antigen-binding fragment includes a heavy chain variable region containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 88, SEQ ID NO: 105, and SEQ ID NO: 122, respectively, and / or a light chain variable region containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 139, SEQ ID NO: 154, and SEQ ID NO: 169, respectively.

[0050] In some embodiments, the Specified Classification provides an antibody or antigen-binding fragment that specifically binds to human GFAP, wherein the antibody or antigen-binding fragment binds to an epitope within residues 138-149 of the GFAP protein corresponding to the amino acid position shown in SEQ ID NO: 212. In some embodiments, the antibody or antigen-binding fragment includes a heavy chain variable region containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 89, SEQ ID NO: 106, and SEQ ID NO: 123, respectively, and / or a light chain variable region containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 140, SEQ ID NO: 155, and SEQ ID NO: 170, respectively.

[0051] In some of the embodiments described herein, the antibody or antigen-binding fragment does not bind to an epitope within or containing residues 190-202 of the human GFAP protein corresponding to the amino acid position shown in SEQ ID NO: 212; and / or does not bind to an epitope identical to or overlapping with a reference antibody containing the variable heavy chain shown in SEQ ID NO: 173 and the variable light chain shown in SEQ ID NO: 190; and / or does not compete with the reference antibody containing the variable heavy chain shown in SEQ ID NO: 173 and the variable light chain shown in SEQ ID NO: 190 for binding to GFAP.

[0052] In some arbitrary embodiments herein, GFAP (e.g., human GFAP) is recombinant GFAP (e.g., recombinant human GFAP). In some arbitrary embodiments herein, GFAP (e.g., human GFAP) is native GFAP (e.g., native human GFAP). In some further embodiments, native GFAP is present in or obtained from serum, plasma, blood, cerebrospinal fluid (CSF), urine, sweat, or saliva.

[0053] In some of the embodiments described herein, the antibody or antigen-binding fragment is isolated. In some of the embodiments described herein, the antibody is a humanized antibody, a chimeric antibody, or a human antibody. In some of the embodiments described herein, the antibody is a Muulin antibody.

[0054] In some of the embodiments described herein, the antibody is its antigen-binding fragment. In further embodiments, the antigen-binding fragment is a Fab, Fab'-SH, Fv, scFv, or (Fab')2 fragment.

[0055] In some of the embodiments described herein, the antibody is full-length or intact.

[0056] In some of the embodiments herein, the antibody further comprises a heavy chain constant domain and / or a light chain constant domain. In further embodiments, the heavy chain and / or light chain constant domain is Muulin or human. In some further embodiments, the heavy chain constant domain is IgG1, IgG2a, IgG2b, or IgM.

[0057] In some of the embodiments described herein, the antibody is a monoclonal antibody.

[0058] In some of the available embodiments described herein, the antibody is attached to a label. In further embodiments, the label is a fluorescent dye, a fluorescent protein, a radioisotope, a chromophore, a metal ion, gold particles, silver particles, magnetic particles, a polypeptide, an enzyme, streptavidin, biotin, a luminescent compound, or an oligonucleotide.

[0059] In some embodiments, nucleic acids encoding antibodies or antigen-binding fragments described herein are provided herein. In some embodiments, vectors encoding such nucleic acids are provided herein. In further embodiments, the vector is an expression vector. In some embodiments, host cells containing such nucleic acids or vectors are provided herein.

[0060] In some embodiments, nucleic acids encoding heavy chains including the heavy variable region described herein are provided herein. In some embodiments, vectors encoding such nucleic acids are provided herein. In further embodiments, the vector is an expression vector. In some embodiments, host cells containing such nucleic acids or vectors are provided herein.

[0061] In some embodiments, nucleic acids encoding a light chain containing a lightly variable region described herein are provided herein. In some embodiments, vectors encoding such nucleic acids are provided herein. In further embodiments, the vector is an expression vector. In some embodiments, host cells containing such nucleic acids or vectors are provided herein.

[0062] In some embodiments, a method for producing an antibody or antigen-binding fragment thereof (e.g., an anti-UCH-L1 antibody or an anti-GFAP antibody) as described herein is provided herein, comprising the step of culturing host cells as described herein under conditions for the production of the antibody or antigen-binding fragment. In further embodiments, the method further comprises the step of recovering the antibody or antigen-binding fragment produced by the host cells. In some embodiments, an anti-UCH-L1 antibody or its antigen-binding fragment produced by such a method is provided herein. In some embodiments, an anti-GFAP antibody or its antigen-binding fragment produced by such a method is provided herein.

[0063] In some embodiments, compositions comprising the antibody or its antigen-binding fragment described herein (e.g., anti-UCH-L1 antibody or anti-GFAP antibody) are provided herein. In some embodiments, the composition further comprises a pharmaceutically acceptable carrier.

[0064] In some embodiments, a combination of antibodies or antigen-binding fragments is provided herein, the combination comprising two or more anti-UCH-L1 antibodies or antigen-binding fragments as described herein. In some embodiments, the two or more antibodies or antigen-binding fragments comprise one or more first antibodies or antigen-binding fragments that bind to a first epitope or region in UCH-L1; and one or more second antibodies or antigen-binding fragments that bind to a second epitope or region in UCH-L1. In some further embodiments, the one or more first antibodies or antigen-binding fragments and the one or more second antibodies or antigen-binding fragments bind to non-overlapping epitopes or regions of UCH-L1 (e.g., human UCH-L1) and / or do not compete for binding to UCH-L1.

[0065] In some arbitrary such embodiments, (i) the one or more first antibodies or antigen-binding fragments thereof bind to epitopes in or containing residues 28-36, 98-106, 138-145, and / or 142-149 of the UCH-L1 protein, corresponding to the amino acid positions shown in SEQ ID NO: 207; and (ii) the one or more second antibodies or antigen-binding fragments thereof bind to epitopes that are not identical to or do not overlap with the epitopes in (i). In some arbitrary embodiments, (i) the one or more first antibodies or antigen-binding fragments bind to an epitope in or containing residues 28-36 and / or 98-106 of the UCH-L1 protein corresponding to the amino acid positions shown in SEQ ID NO: 207; and (ii) the one or more second antibodies or antigen-binding fragments bind to an epitope in or containing residues 138-145 and / or 142-149 of the UCH-L1 protein corresponding to the amino acid positions shown in SEQ ID NO: 207.

[0066] In some embodiments, at least one of the two or more anti-UCH-L1 antibody or antigen-binding fragment combinations described herein, optionally one or more of the first antibody or its antigen-binding fragment, or one or more of the second antibody or its antigen-binding fragment, is conjugated to a label. In some embodiments, at least one of the antibody or antigen-binding fragments, optionally one or more of the first antibody or its antigen-binding fragment, or one or more of the second antibody or its antigen-binding fragment, is attached to or immobilized on a solid support. In some embodiments, one or more of the first or second antibody or antigen-binding fragment is attached to or immobilized on a solid support, and the other of the one or more of the first or second antibody or antigen-binding fragment is conjugated to a label. In some embodiments, the label is a fluorescent dye, a fluorescent protein, a radioisotope, a chromophore, a metal ion, gold particles, silver particles, magnetic particles, a polypeptide, an enzyme, streptavidin, biotin, a luminescent compound, or an oligonucleotide. In some embodiments, the solid support is a bead, column, array, assay plate, microwell, stick, filter, or strip.

[0067] In some embodiments, a combination of antibodies or antigen-binding fragments is provided herein, the combination comprising two or more anti-GFAP antibodies or antigen-binding fragments as described herein. In some embodiments, the two or more antibodies or antigen-binding fragments comprising one or more first antibodies or antigen-binding fragments that bind to a first epitope or region in GFAP; and one or more second antibodies or antigen-binding fragments that bind to a second epitope or region in GFAP. In some further embodiments, the one or more first antibodies or antigen-binding fragments and the one or more second antibodies or antigen-binding fragments bind to non-overlapping epitopes or regions of GFAP (e.g., human GFAP) and / or do not compete for binding to GFAP.

[0068] In some arbitrary such embodiments, (i) the one or more first antibodies or antigen-binding fragments bind to an epitope that is or contains the residues of the GFAP protein corresponding to the amino acid positions shown in SEQ ID NO: 212, specifically residues 92-106, 190-202, 16-35 and / or 380, 119 and / or 190, 380-391, 119-130, 210-221, 320-329, 346-357 and / or 376-387 and / or 138-149; and (ii) the one or more second antibodies or antigen-binding fragments bind to an epitope that is not identical to or does not overlap with the epitope in (i). In some arbitrary such embodiments, (i) the one or more first antibodies or their antigen-binding fragments bind to epitopes in or containing amino acid residues 190-202 of the GFAP protein corresponding to the amino acid positions shown in SEQ ID NO: 212; and (ii) the one or more second antibodies or their antigen-binding fragments bind to epitopes in or containing residues 92-106, 16-35 and / or 380, 119 and / or 190, 380-391, 119-130, 210-221, 320-329, 346-357 and / or 376-387 and / or 138-149 of the GFAP protein, corresponding to the amino acid positions shown in SEQ ID NO: 212.

[0069] In some embodiments, at least one of the two or more anti-GFAP antibody or antigen-binding fragment combinations described herein, optionally one or more of the first antibody or its antigen-binding fragment, or one or more of the second antibody or its antigen-binding fragment, is conjugated to a label. In some embodiments, at least one of the antibody or antigen-binding fragments, optionally one or more of the first antibody or its antigen-binding fragment, or one or more of the second antibody or its antigen-binding fragment, is attached to or immobilized on a solid support. In some embodiments, one or more of the first or second antibody or antigen-binding fragment is attached to or immobilized on a solid support, and the other of the one or more of the first or second antibody or antigen-binding fragment is conjugated to a label. In some embodiments, the label is a fluorescent dye, a fluorescent protein, a radioisotope, a chromophore, a metal ion, gold particles, silver particles, magnetic particles, a polypeptide, an enzyme, streptavidin, biotin, a luminescent compound, or an oligonucleotide. In some embodiments, the solid support is a bead, column, array, assay plate, microwell, stick, filter, or strip.

[0070] In some embodiments, combinations of antibodies or antigen-binding fragments thereof are provided herein, the combinations comprising at least one anti-UCH-L1 antibody, for example, at least one anti-UCH-L1 antibody described herein or a combination of anti-UCH-L1 antibodies shown herein; and at least one anti-GFAP antibody, for example, at least one anti-GFAP antibody described herein or a combination of anti-GFAP antibodies shown herein.

[0071] In some embodiments, a solid support is provided herein and comprises an antibody or antigen-binding fragment described herein (e.g., anti-UCH-L1 antibody and / or anti-GFAP antibody) immobilized thereon. In further embodiments, the solid support is a bead, column, array, assay plate, microwell, stick, filter, or strip.

[0072] In some embodiments, devices comprising a solid support as described herein are provided herein. In further embodiments, the device is a rapid detection device or a rapid diagnostic device.

[0073] In some embodiments, a kit is provided herein that includes an antibody or antigen-binding fragment described herein (e.g., anti-UCH-L1 antibody and / or anti-GFAP antibody), a composition described herein or a combination of the antibody or antigen-binding fragment described herein, and optionally, instructions for use. In some embodiments, the kit further includes a solid support or a device comprising a solid support. In further embodiments, the solid support is a bead, column, array, assay plate, microwell, stick, filter, or strip. In some embodiments herein, the device is a rapid detection device or a rapid diagnostic device. In some of such embodiments herein, the instructions specify an assay for detecting UCH-L1 or GFAP in a sample and / or for determining the amount of UCH-L1 or GFAP in a sample.

[0074] In some embodiments, a method for detecting UCH-L1 in a human subject is provided herein, the method comprising: (a) contacting a sample with one or more first antibodies or antigen-binding fragments, e.g., one or more described herein (e.g., anti-UCH-L1 antibodies), under conditions that form a complex comprising an antibody or antigen-binding fragment and UCH-L1; and (b) detecting the presence or absence of the complex in the sample, thereby detecting UCH-L1 in the sample. In further embodiments, the detection method includes an immunoassay. In further embodiments, the immunoassay is an enzyme-linked immunosorbent assay (ELISA). In further embodiments, the ELISA is a sandwich ELISA. In some arbitrary such embodiments, the step of detecting the presence or absence of the complex in step (b) includes (i) contacting the complex of step (a) with one or more second antibodies or antigen-binding fragments under conditions that bind to UCH-L1 in the complex (the one or more second antibodies or antigen-binding fragments are conjugated to a label capable of producing a detectable signal); and (ii) evaluating the presence or absence of a detectable signal. In further embodiments, the one or more second antibodies or antigen-binding fragments include one or more antibodies or antigen-binding fragments described herein (e.g., anti-UCH-L1 antibodies).

[0075] In some embodiments, a method for detecting human UCH-L1 in a sample derived from a subject is provided herein, the method comprising: (a) contacting a sample with one or more first antibodies or antigen-binding fragments that specifically bind to human UCH-L1 under conditions that form a complex comprising an antibody or antigen-binding fragment and UCH-L1; and (b) detecting the presence or absence of the complex in the sample, wherein the detecting step comprises: (i) contacting the complex of step (a) with one or more second antibodies or antigen-binding fragments that specifically bind to UCH-L1 under conditions that bind to UCH-L1 in the complex (the one or more second antibodies or antigen-binding fragments are conjugated to a label capable of producing a detectable signal); and (ii) evaluating the presence or absence of a detectable signal to thereby detect UCH-L1 in the sample, wherein at least one of the one or more first antibodies or antigen-binding fragments and one or more second antibodies or antigen-binding fragments include antibodies or antigen-binding fragments described herein (e.g., anti-UCH-L1 antibodies). In further embodiments, the one or more second antibodies or antigen-binding fragments bind to an epitope of UCH-L1 that is not identical to or does not overlap with the epitope bound by the antibody or antigen-binding fragment of (a). In some arbitrary such embodiments, (1) the one or more first antibodies or antigen-binding fragments bind to an epitope in or containing residues 28-36, 98-106, 138-145, and / or 142-149 of the UCH-L1 protein, corresponding to the amino acid positions shown in SEQ ID NO: 207; and (2) the one or more second antibodies or antigen-binding fragments bind to an epitope that is not identical to or does not overlap with the epitope of (1).In some arbitrary such embodiments, (1) the one or more first antibodies or antigen-binding fragments bind to an epitope in or containing residues 28-36 and / or 98-106 of the UCH-L1 protein, corresponding to the amino acid positions shown in SEQ ID NO: 207; and (2) the one or more second antibodies or antigen-binding fragments bind to an epitope in or containing residues 138-145 and / or 142-149 of the UCH-L1 protein, corresponding to the amino acid positions shown in SEQ ID NO: 207.

[0076] In some embodiments, a method for detecting GFAP in a human subject is provided herein, the method comprising: (a) contacting a sample with one or more first antibodies or antigen-binding fragments, e.g., one or more described herein (e.g., anti-GFAP antibodies), under conditions that form a complex comprising an antibody or antigen-binding fragment and GFAP; and (b) detecting the presence or absence of the complex in the sample, thereby detecting GFAP in the sample. In further embodiments, the detection method comprises an immunoassay. In further embodiments, the immunoassay is an enzyme-linked immunosorbent assay (ELISA). In further embodiments, the ELISA is a sandwich ELISA. In some arbitrary such embodiments, the step of detecting the presence or absence of the complex in step (b) comprises: (i) contacting the complex of step (a) with one or more second antibodies or antigen-binding fragments, under conditions that bind to GFAP in the complex (the one or more second antibodies or antigen-binding fragments are conjugated to a label capable of producing a detectable signal); and (ii) evaluating the presence or absence of a detectable signal. In further embodiments, the one or more second antibodies or antigen-binding fragments described herein include one or more antibodies or antigen-binding fragments (e.g., anti-GFAP antibodies).

[0077] In some embodiments, a method for detecting human GFAP in a sample derived from a subject is provided herein, the method comprising: (a) contacting a sample with one or more first antibodies or antigen-binding fragments that specifically bind to human GFAP under conditions that form a complex comprising an antibody or antigen-binding fragment and GFAP; and (b) detecting the presence or absence of the complex in the sample, wherein the detecting step comprises: (i) contacting the complex of step (a) with one or more second antibodies or antigen-binding fragments that specifically bind to GFAP under conditions that bind to GFAP in the complex (the one or more second antibodies or antigen-binding fragments are conjugated to a label capable of producing a detectable signal); and (ii) evaluating the presence or absence of a detectable signal to thereby detect GFAP in the sample, wherein at least one of the one or more first antibodies or antigen-binding fragments and one or more second antibodies or antigen-binding fragments include antibodies or antigen-binding fragments described herein (e.g., anti-GFAP antibodies). In a further embodiment, the one or more second antibodies or antigen-binding fragments bind to an epitope of GFAP that is not identical to or does not overlap with the epitope bound by the antibody or antigen-binding fragment of (a).In some arbitrary such embodiments, (1) the one or more first antibodies or antigen-binding fragments bind to an epitope that is or contains the residues of the GFAP protein corresponding to the amino acid positions shown in SEQ ID NO: 212, specifically residues 92-106, 190-202, 16-35 and / or 380, 119 and / or 190, 380-391, 119-130, 210-221, 320-329, 346-357 and / or 376-387 and / or 138-149; and (2) the one or more second antibodies or antigen-binding fragments bind to an epitope that is not identical to or does not overlap with the epitope in (1). In some arbitrary such embodiments, (1) the one or more first antibodies or their antigen-binding fragments bind to an epitope in or containing amino acid residues 190-202 of the GFAP protein corresponding to the amino acid positions shown in SEQ ID NO: 212; and (2) the one or more second antibodies or their antigen-binding fragments bind to an epitope in or containing residues 92-106, 16-35 and / or 380, 119 and / or 190, 380-391, 119-130, 210-221, 320-329, 346-357 and / or 376-387 and / or 138-149 of the GFAP protein, corresponding to the amino acid positions shown in SEQ ID NO: 212.

[0078] In some embodiments of the method for detecting (e.g., UCH-L1 and / or GFAP), the complex formed in step (a) is separated or washed from a sample not contained in the complex before step (b). In some embodiments of the method, the one or more first antibodies or their antigen-binding fragments are attached to or immobilized on a solid support. In some embodiments of the method, the one or more second antibodies or their antigen-binding fragments not bound to the complex are removed before step (b)(ii). In some arbitrary such embodiments, the sample is isolated or obtained from an individual. In some arbitrary such embodiments, the sample is serum, plasma, blood, cerebrospinal fluid (CSF), urine, sweat, or saliva. In some arbitrary such embodiments, the method further includes the step of (c) determining the amount of UCH-L1 to be detected in the sample. In some arbitrary such embodiments, the method further includes the step of (c) determining the amount of GFAP to be detected in the sample.

[0079] In some embodiments, a method for diagnosing brain injury or damage in a subject is provided herein, the method comprising the steps of: (i) diagnosing the subject as having brain injury or damage or at risk of having brain injury or damage if the amount of UCH-L1 in the sample is greater than, equal to, or about the UCH-L1 threshold level; or (ii) diagnosing the subject as not having brain injury or damage or not at risk of having brain injury or damage if the amount of UCH-L1 in the sample is below the UCH-L1 threshold level. In some embodiments, if the subject is identified as having brain injury or damage or at risk of having brain injury or damage, the subject is administered a therapeutic agent to treat the brain injury or damage. In some arbitrary embodiments, if the subject is identified as having brain injury or damage or at risk of having brain injury or damage, the brain of the subject is subjected to neuroimaging. In any such embodiment, if a subject is identified as not having brain injury or damage, or not at risk of having brain injury or damage, then the subject's brain is not subjected to neuroimaging.

[0080] In some embodiments, a method for diagnosing brain injury or damage in a subject is provided herein, the method comprising the steps of: (i) if the amount of GFAP in the sample is greater than, equal to, or about the GFAP threshold level, the subject is diagnosed as having brain injury or damage or at risk of having brain injury or damage; or (ii) if the amount of GFAP in the sample is below the GFAP threshold level, the subject is diagnosed as not having brain injury or damage or at risk of having brain injury or damage. In some embodiments, if the subject is identified as having brain injury or damage or at risk of having brain injury or damage, the subject is administered a therapeutic agent to treat the brain injury or damage. In some arbitrary embodiments, if the subject is identified as having brain injury or damage or at risk of having brain injury or damage, the brain of the subject is subjected to neuroimaging. In any such embodiment, if a subject is identified as not having brain injury or damage, or not at risk of having brain injury or damage, then the subject's brain is not subjected to neuroimaging.

[0081] In some embodiments, a method for diagnosing brain injury in a subject is provided herein, the method comprising: (a) performing a method for detecting UCH-L1, such as a detection method described herein, thereby determining the amount of UCH-L1 in a sample; and (b) performing a method for detecting GFAP, such as a detection method described herein, thereby determining the amount of GFAP in a sample; and (i) diagnosing the subject as having or being at risk of having brain injury or damage if the amount of UCH-L1 in the sample is greater than, equal to, or about the UCH-L1 threshold level, and / or the amount of GFAP in the sample is greater than, equal to, or about the GFAP threshold level; or (ii) diagnosing the subject as not having or being at risk of having brain injury or damage if the amount of UCH-L1 in the sample is below the UCH-L1 threshold level, and / or the amount of GFAP in the sample is below the GFAP threshold level. In some embodiments, if a subject is identified as having or being at risk of having a brain injury or injury, the subject is administered a therapeutic agent to treat the brain injury or injury. In some arbitrary embodiments of such embodiments, if a subject is identified as having or being at risk of having a brain injury or injury, the subject's brain is subjected to neuroimaging. In some embodiments of such embodiments, if a subject is identified as not having or being at risk of having a brain injury or injury, the subject's brain is not subjected to neuroimaging.

[0082] In some embodiments, a method for treating a subject for brain injury or damage is provided herein, comprising the steps of: a) performing a diagnostic method such as the method described herein; and b) administering a therapeutic agent to the subject to treat brain injury or damage if the subject is identified as having or being at risk of having brain injury or damage. In further embodiments, the therapeutic agent is selected from N-methyl-D-aspartate (NMDA) receptor antagonists, sodium channel antagonists, nitric oxide synthase (NOS) inhibitors, glycine site antagonists, potassium channel openers, AMPA / kainate receptor antagonists, calcium channel antagonists, GABA-A receptor modulators, anti-inflammatory agents, or combinations thereof.

[0083] In some embodiments, a method is provided herein for predicting whether a subject needs neuroimaging for suspected brain injury or damage, the method comprising: (a) performing a method for detecting UCH-L1, such as the detection method described herein, thereby determining the amount of UCH-L1 in a sample; and / or (b) performing a method for detecting GFAP, such as the detection method described herein, thereby determining the amount of GFAP in a sample; wherein (i) if the amount of UCH-L1 in the sample is greater than, equal to, or about the UCH-L1 threshold level, and / or if the amount of GFAP in the sample is greater than, equal to, or about the GFAP threshold level, the subject is predicted to need neuroimaging; or (ii) if the amount of UCH-L1 in the sample is below the UCH-L1 threshold level, and / or if the amount of GFAP in the sample is below the GFAP threshold level, the subject is predicted not to need neuroimaging.

[0084] In some embodiments, a method is provided herein for predicting whether a subject requires neuroimaging in relation to a predicted brain injury or damage, comprising the steps of: a) performing a method for diagnosing or detecting UCH-L1 and / or GFAP, such as a method for diagnosis or detection described herein; and b) predicting that if the subject is identified as having or at risk of having a brain injury or damage, the subject will require neuroimaging. In some embodiments, the method further comprises the step of performing neuroimaging on the subject's brain.

[0085] In any such embodiment of some of the methods described herein, the neuroimaging is performed by computed tomography (CT) or magnetic resonance imaging (MRI).

[0086] In any such embodiment of some of the methods described herein, the UCH-L1 threshold level is 30 pg / mL or about 30 pg / mL, 40 mg / mL or about 40 mg / mL, 60 pg / mL or about 60 pg / mL, 80 pg / mL or about 80 pg / mL, 100 pg / mL or about 100 pg / mL, 150 pg / mL or about 150 pg / mL, 200 pg / mL or about 200 pg / mL, 250 pg / mL or about 250 pg / mL, 300 pg / mL or about 300 pg / mL, 400 pg / mL or about 400 pg / mL, or 500 pg / mL or about 500 pg / mL. In some embodiments, the UCH-L1 threshold level is 100 pg / mL or about 100 pg / mL. In some embodiments, the UCH-L1 threshold level is 200 pg / ml or approximately 200 pg / ml.

[0087] In any such embodiment of some of the methods described herein, the GFAP threshold level is 10 pg / mL or about 10 pg / mL, 20 pg / mL or about 20 pg / mL, 30 pg / mL or about 30 pg / mL, 40 pg / mL or about 40 pg / mL, 50 pg / mL or about 50 pg / mL, 60 pg / mL or about 60 pg / mL, and 70 pg / mL. The GFAP threshold level is approximately 70 pg / mL, 80 pg / mL or approximately 80 pg / mL, 90 pg / mL or approximately 90 pg / mL, 100 pg / mL or approximately 100 pg / mL, 150 pg / mL or approximately 150 pg / mL, 200 pg / mL or approximately 200 pg / mL, 250 pg / mL or approximately 250 pg / mL, or 300 pg / mL or approximately 300 pg / mL. In some embodiments, the GFAP threshold level is 50 pg / mL or approximately 50 pg / mL. In some embodiments, the GFAP threshold level is 70 pg / mL or approximately 70 pg / mL.

[0088] In some of these arbitrary embodiments described herein, the UCH-L1 threshold level is 200 pg / mL and the GFAP threshold level is 70 pg / mL.

[0089] In any such embodiment of some of the methods described herein, brain injury or damage is associated with or results from mechanical injury, hypoxia, infectious disease, neuronal disease, toxic injury, or neurological disease or condition. In some embodiments, mechanical injury is traumatic brain injury or chronic traumatic encephalopathy. In further embodiments, brain injury or damage is traumatic brain injury. In further embodiments, traumatic brain injury is mild traumatic brain injury. In some embodiments, hypoxia is associated with stroke, vasculitis, ischemia, or heart disease. In some embodiments, infectious disease includes infection by Mycobacterium bacteria, Neisseria meningitidis, herpesviruses, poliovirus, mumps virus, Enteroviridiae virus, West Nile virus, or tick-borne encephalitis virus. In some embodiments, neuronal disease is Alzheimer's disease, Lewy body dementia, vascular dementia, diabetic dementia, Parkinson's disease, ALS, or prion disease. In some embodiments, toxic damage is associated with exposure to nerve agents, alcohol-induced dementia, heavy metal poisoning, psychostimulants, chemotherapeutic agents, biological agents, or antibiotics.

[0090] In any such embodiment of some of the methods described herein, the sample is obtained from the subject within approximately 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 12 hours, 24 hours, or 48 hours after brain injury or injury or suspected brain injury or injury.

[0091] In any such embodiment of some of the methods described herein, the sample is obtained from the subject within approximately 8 hours after brain injury or injury or suspected brain injury or injury.

[0092] In any such embodiment of some of the methods described herein, the sample is serum.

[0093] In any such embodiment of some of the methods described herein, the sample is CSF.

[0094] In any such embodiment of some of the methods described herein, the method is carried out in vitro.

[0095] It should be understood that one, some, or all characteristics of the various embodiments described herein may be combined to form other embodiments of the present invention. These and other aspects of the present invention will be apparent to those skilled in the art. These and other embodiments of the present invention are further described by the following detailed description. [Modes for carrying out the invention]

[0096] Antibodies that bind to ubiquitin C-terminal hydrolase L1 (UCH-L1) are provided, comprising antigen-binding fragments of such antibodies, nucleic acids encoding such antibodies and antigen-binding fragments, and cells such as recombinant cells for expressing and producing these antibodies and antigen-binding fragments. Antibodies that bind to glial fibrillary acidic protein (GFAP) are also provided herein, comprising antigen-binding fragments of such antibodies, nucleic acids encoding such antibodies and antigen-binding fragments, and cells such as recombinant cells for expressing and producing these antibodies and antigen-binding fragments. Methods for producing and using antibodies and antigen-binding fragments, such as in methods for detecting UCH-L1 and / or GFAP in samples derived from an individual, methods for diagnosing brain injury or neurological conditions in an individual, and methods for predicting the likelihood that such an individual may require neuroimaging (e.g., computed tomography scans) and / or therapeutic intervention.

[0097] All references cited herein, including patent applications, patent publications, and scientific literature and databases, are incorporated herein by reference in whole for all purposes to the same extent that each individual reference is suggested to be incorporated by reference in particular and individually.

[0098] For clarity of disclosure and without limitation, the detailed explanation is divided into the following subsections. The section headings used herein are for organizational purposes only and should not be construed as limiting the contents described herein.

[0099] [I. Definition] Unless otherwise defined, all terms, notations, and other technical and scientific or specialized terms used herein are intended to have the same meaning as that generally understood by one skilled in the art to which the claims relate. Where applicable, terms having a generally understood meaning are defined herein for clarity and / or for immediate reference, and the inclusion of such definitions herein should not necessarily be construed as representing a substantial difference from that generally understood in the art.

[0100] Before describing the present invention in detail, it should be understood that the present invention is not limited to any particular composition or biological system and, of course, can be modified. It should also be understood that the technical terms used herein are for the purpose of describing a particular embodiment only and are not intended to limit it.

[0101] In this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context explicitly indicates otherwise. Thus, for example, a reference to "a molecule" may optionally include combinations of two or more such molecules.

[0102] As used herein, the term “about” refers to the normal range of error for each value that is readily known to those skilled in the art. In this specification, references to “about” values ​​or parameters include (and describe) embodiments relating to the value or parameter itself.

[0103] The aspects and embodiments of the present invention described herein are understood to include aspects and embodiments that "include," "consist of," and "essentially consist of."

[0104] As used herein, “optional” or “optionally” means whether or not the event or situation described thereafter occurs, and such description includes both cases in which such event or situation occurs and cases in which it does not. For example, “optionally substituted” means that the base is either unsubstituted or substituted.

[0105] As used herein, “antibody” refers to immunoglobulins and immunoglobulin fragments, whether naturally occurring, partially or entirely synthetic, produced, for example by recombinant means, and includes any fragment thereof that contains at least a portion of the variable heavy and / or light chain regions of an immunoglobulin molecule sufficient to form an antigen-binding site, and, if assembled, specifically refers to the binding antigen. Thus, an antibody contains any protein having a binding domain that is homologous or substantially homologous to the immunoglobulin antigen-binding domain (antibody-binding site). Typically, an antibody is a variable heavy (V H ) Chain and / or variable light (V L ) Contains all or at least a portion of the chain. Generally, V H and V L When they pair together, they form an antigen-binding site, but in some cases, a single V H or V LThe domain is sufficient for antigen binding. Furthermore, the antibody may contain all or part of the constant region. Therefore, in this specification, references to antibodies are understood to include full-length antibodies and antigen-binding fragments, including those that specifically bind to UCH-L1 or GFAP. The term “antibody” also includes antibody compositions having polyepitope specificity, multispecific antibodies (e.g., bispecific antibodies), diabodies, and single-chain molecules. Antibodies include polyclonal or monoclonal antibodies. Antibodies also include synthetic antibodies or antibodies produced by recombinant means. The term “immunoglobulin” (Ig) is used interchangeably with “antibody” in this specification.

[0106] Therefore, the term “antibody” includes the full-length antibody and a portion thereof, including antibody fragments, for example, the heavy chain or a portion thereof and / or the light chain or a portion thereof. An antibody may comprise two heavy chains (which may be represented as H and H') and two light chains (which may be represented as L and L'). Each L chain is attached to the H chain by one covalent disulfide bond, while the two H chains are attached to each other by one or more disulfide bonds depending on the H chain isotype. Each H and L chain also has regularly spaced intrachain disulfide bridges. Each H chain has a variable domain (V) at its N-terminus. H ) followed by three constant domains (CH1, CH2, and CH3) for the α and γ chains respectively, and four C for the μ and ε isotypes. H It has domains (CH1, CH2, CH3, and CH4). Each L chain has a variable domain (V) at its N-terminus. L ) followed by a constant domain (C) at the other end. L) are present. In some cases, the heavy chain may be a full-length immunoglobulin heavy chain or a portion of it sufficient to form an antigen-binding site (e.g., the heavy chain may include, but is not limited to, VH chains, VH-CH1 chains and VH-CH1-CH2-CH3 chains), and / or each light chain may be a full-length light chain or a portion of it sufficient to form an antigen-binding site (e.g., the light chain may include, but is not limited to, VL chains and VL-CL chains). For the structures and properties of different classes of antibodies, see, for example, Basic and Clinical Immunology, 8th Edition, Daniel P. Sties, Abba I. Terr and Tristram G. Parsolw (eds), Appleton & Lange, Norwalk, CT, 1994, p. 71 and Chapter 6. Each heavy chain (H and H') is paired with one light chain (L and L', respectively).

[0107] The terms “full-length antibody,” “intact antibody,” or “whole antibody” are used interchangeably and refer to an antibody in its substantially intact form, unlike an antibody fragment. A full-length antibody is an antibody that typically has two full-length heavy chains (e.g., VH-CH1-CH2-CH3 or VH-CH1-CH2-CH3-CH4) and two full-length light chains (VL-CL) and a hinge region, such as antibodies produced by antibody-secreting B cells from mammalian species (e.g., humans, mice, rats, rabbits, non-human primates, etc.) and synthetically produced antibodies with the same domain. In particular, a whole antibody includes those having heavy and light chains containing an Fc region. The constant domain may be the constant domain of the native sequence (e.g., the constant domain of the human native sequence) or an amino acid sequence mutation thereof. In some cases, an intact antibody may have one or more effector functions.

[0108] An "antibody fragment" includes a portion of an intact antibody, an antigen-binding and / or variable region of an intact antibody. Antibody fragments include, but are not limited to, Fab fragments, Fab' fragments, F(ab')2 fragments, Fv fragments, disulfide-bound Fv(dsFv), Fd fragments, Fd' fragments; diabodies; and linear antibodies (US Patent No. 5,641,870, Example 2; Zapata et al., Protein Eng.). 8(10) See 1057-1062

[1995] ); single-chain antibody molecules including single-chain Fvs (scFv) or single-chain Fab (scFab); and antigen-binding fragments of any of the above and multispecific antibodies derived from antibody fragments.

[0109] "Fv" consists of one heavy chain and one light chain variable domain linked by a non-covalent association. From the folding of these two domains, six complementarity-determining regions (CDRs) (three from the heavy chain and three from the light chain in each) are generated, contributing amino acid residues for antigen binding and giving the antibody antigen-binding specificity. However, even a single variable domain (or half of Fv containing only the three antigen-specific CDRs) has the ability to recognize and bind to the antigen, but in some cases, with lower affinity than the entire binding site.

[0110] "dsFv" refers to Fv having a modified intermolecular disulfide bond, V H -V L Stabilize the pair.

[0111] "Fd fragment" is one of the constant region domains (C) of the antibody heavy chain. H 1) and variable domain (V H It is a fragment of an antibody containing ).

[0112] A "Fab fragment" is an antibody fragment resulting from the digestion of full-length immunoglobulins by papain, or a fragment with the same structure that is synthetically produced, for example, by a recombinant method. Fab fragments have a light chain (V L and CL (including), and one constant region domain of the heavy chain (C H 1) and the variable domain of the heavy chain (V H Includes another chain containing ).

[0113] An "F(ab')2 fragment" is an antibody fragment resulting from the digestion of immunoglobulins by pepsin at pH 4.0-4.5, or an identically structured fragment produced synthetically, for example, by recombinant methods. An F(ab')2 fragment essentially contains two Fab fragments, where each heavy chain portion contains a few more amino acids, including cysteine ​​residues that form a disulfide bond connecting the two fragments.

[0114] A "Fab' fragment" is a fragment that contains half of an F(ab')2 fragment (one heavy chain and one light chain).

[0115] An "Fd' fragment" is an antibody fragment that contains one of the heavy chain segments of an F(ab')2 fragment.

[0116] "Fv' fragment" is the V of the antibody molecule. H and V L This is a fragment that contains only the domain.

[0117] "scFv fragments" are variable light chains (V) covalently bonded in any order by polypeptide linkers. L ) and variable heavy chain (V H This refers to an antibody fragment containing a linker. The linker is of a length such that the two variable domains are cross-linked with virtually no interference. An exemplary linker is a Glu-Ser (Gly-Ser) with a small amount of Glu or Lys residues dispersed throughout to increase solubility. n It is a residue.

[0118] A "diabody" is a dimerized scFv; diabodies typically have shorter peptide linkers than scFvs and preferentially dimerize.

[0119] As used herein, the “variable domain” of an antibody is a specific Ig domain of the antibody heavy chain or light chain, which is generally the most variable part of the antibody (compared to other antibodies of the same class). The amino-terminal domain of each heavy chain and each light chain has one variable region domain. The variable domains of the heavy chain and light chain are each referred to as “V H " and "V L It can be called a 'variable region'. Each variable region includes a complementarity-determining region (CDR) and a framework region (FR), which are parts of the antigen-binding site domain. The variable domain containing the antigen-binding site provides antigen specificity and is therefore responsible for antigen recognition.

[0120] The term "complementarity-determining region" or "CDR" refers to a sequence of amino acids within the antibody's variable region that interacts with a co-origin antigen to derive antigen specificity and / or binding affinity. CDRs are located within or found within the antibody's "hypervariable region" or "HVR," are hypervariable in sequence, and / or form structurally defined loops ("hypervariable loops"). In some cases, CDRs are also called hypervariable regions or hypervariable loops. Generally, there are three CDRs (CDR-H1, CDR-H2, CDR-H3) within each heavy chain variable region, and three CDRs (CDR-L1, CDR-L2, CDR-L3) within each light chain variable region.

[0121] "Framework region" and "FR" refer to variable domain residues in the variable regions of the heavy and light chains other than CDR residues, as defined herein. Generally, there are four FRs (FR-H1, FR-H2, FR-H3, and FR-H4) in each full-length heavy chain variable region, and four FRs (FR-L1, FR-L2, FR-L3, and FR-L4) in each full-length light chain variable region.

[0122] Identifying the amino acid sequence boundaries of a given CDR or FR using any many well-known schemes is within the realm of the art, including: “Sequences of Proteins of Immunological Interest,” 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, described by Kabat et al. (1991) (“Kabat” numbering scheme); Al-Lazikani et al., (1997) JMB 273, 927-948 (“Chothia” numbering scheme); MacCallum et al., J.Mol.Biol.262:732-745 (1996), “Antibody-antigen interactions: Contact analysis and binding site topography,” J.Mol.Biol.262, 732-745 (“Contact” numbering scheme); Lefranc MP et al., “IMGT unique numbering for immunoglobulin and T cell receptor variable domains and Ig "Superfamily V-like domains", Dev Comp Immunol, 2003 Jan;27(1):55-77 ("IMGT" numbering scheme), Honegger A and Pluckthun A, "Yet another numbering scheme for immunoglobulin variable domains: an automatic modeling and analysis tool", J Mol Biol, 2001 Jun 8;309(3):657-70 ("Aho" numbering scheme), and Martin et al., "Modeling antibody hypervariable loops: a combined algorithm", PNAS, 1989, 86(23):9268-9272 ("AbM" numbering scheme).

[0123] The boundaries of a given CDR or FR can vary depending on the scheme used for identification. For example, the Kabat scheme is based on structural alignment, while the Chothia scheme is based on structural information. Numbering for both the Kabat and Chothia schemes is based on the length of the most common antibody region sequence, with insertions indicated by insertion letters such as "30a," and deletions appearing in some antibodies. The two schemes place specific insertions and deletions ("indels") in different positions, resulting in differential numbering. The Contact scheme is based on the analysis of complex crystal structures and is similar in many ways to the Chothia numbering scheme.

[0124] Table 1 provides an exemplary numbering scheme known to those skilled in the art for identifying CDR and FR in antibodies. Kabat's designation is the most commonly used, based on structural alignment and sequence variability (Kabat et al., Sequences of Proteins of Immunological Interest, 5 th Ed. Public Health Service, National Institute of Health, Bethesda, MD (1991). Chothia's designation is based on structural information regarding the position of structural loops (Chothia and Lesk J. Mol. Biol. 196:901-917 (1987)). The "contact" designation is based on the analysis of available complex crystal structures. AbM designation is another standard to describe CDR and is used by Oxford's Molecular AbM antibody modeling software. JPEG0007832969000001.jpg90166

[0125] Unless otherwise indicated, variable domain residues (CDR residues and framework region residues) are numbered according to Kabat et al. (above). It is within the realm of the art to readily determine CDR and FR variable domain residues according to any other well-known numbering scheme and designation. Embodiments described with respect to Kabat CDRs are also understood to be provided herein based on any other alternative known standard or scheme for describing or classifying antibody CDRs or hypervariable loops.

[0126] The expressions “Kabat variable domain residue numbering,” “Kabat amino acid position numbering,” or “Kabat-based numbering,” and their variations, refer to the numbering system used for the heavy-chain or light-chain variable domains of antibody compilation in Kabat et al. (above). Using this numbering system, the actual linear amino acid sequence may contain fewer or more amino acids corresponding to the shortening or insertion of the HVR or FR of the variable domain. For example, the heavy-chain variable domain may contain a single amino acid insertion after H2 residue 52 (Kabat-based residue 52a) and an insertion residue after heavy-chain FR residue 82 (e.g., Kabat-based residues 82a, 82b, and 82c). The Kabat numbering of residues can be determined for a given antibody by aligning it with a “standard” Kabat numbering sequence in the homology region of the antibody sequence.

[0127] As used herein, constant region domains are domains within antibody heavy or light chains that contain amino acid sequences relatively conserved among antibodies compared to variable region domains. Each light chain has a single light chain constant region (CL) domain of either type κ or λ. Each heavy chain contains one or more heavy chain constant region (CH) domains that can be assigned to different classes or isotypes. There are five classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, each having a heavy chain designated as α, δ, ε, γ, and μ, respectively. Full-length IgA, IgD, and IgG isotypes contain CH1, CH2, CH3, and hinge regions, while IgE and IgM contain CH1, CH2, CH3, and CH4. The γ and α classes are further divided into subclasses based on relatively small differences in CH sequence and function; for example, humans express the following subclasses: IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. IgG1 antibodies can exist in numerous polymorphic variations called allotypes (reviewed in Jefferis and Lefranc 2009.mAbs Vol 1 Issue 4 1-7), and all of them are appropriate. The antibody constant region may include the Fc region. While the boundaries of the Fc region of immunoglobulin heavy chains can vary, the human IgG heavy chain Fc region typically includes the CH2 and CH3 domains and the hinge region, e.g., the region containing amino acid residues from Cys226 or Pro230 to its carboxyl terminus.

[0128] An “isolated” antibody is one that has been identified, separated, and / or recovered from the components of its production environment (e.g., naturally or recombinantly). In some embodiments, the isolated polypeptide is free from association with all other components from its production environment. Components of contaminants in its production environment, e.g., those arising from recombinant transfected cells, are materials that typically interfere with research, diagnostic, or therapeutic use of the antibody and may include enzymes, hormones, and other proteinaceous or non-proteinaceous solutes. In some embodiments, the polypeptide is purified to (1) more than 95% by weight of the antibody, and in some embodiments, more than 99% by weight, as determined by, for example, the Lowry method; (1) to a degree sufficient to obtain at least 15 residues of the N-terminal or internal amino acid sequence by using a spinning cup sequencer; or (3) to homogeneity by SDS-PAGE under non-reducible or reducing conditions using Coomassie blue or silver staining. The isolated antibody contains the antibody in situ within recombinant cells, since at least one component of the antibody’s natural environment is absent. However, typically, isolated polypeptides or antibodies are prepared by at least one purification step.

[0129] As used herein, the term "monoclonal antibody" refers to an antibody obtained from a substantially homogeneous population of antibodies; that is, individual antibodies within the population are identical except for possible spontaneous mutations and / or post-translational modifications (e.g., isomerization, amidation) that may be present in small amounts. In some embodiments, the monoclonal antibody has a C-terminal cleavage in the heavy chain and / or light chain. For example, amino acid residues 1, 2, 3, 4, or 5 are cleaved at the C-terminus of the heavy chain and / or light chain. In some embodiments, the C-terminal cleavage removes the C-terminal lysine from the heavy chain. In some embodiments, the monoclonal antibody has an N-terminal cleavage in the heavy chain and / or light chain. For example, amino acid residues 1, 2, 3, 4, or 5 are cleaved at the N-terminus of the heavy chain and / or light chain. In some embodiments, truncated forms of the monoclonal antibody can be produced by recombinant techniques. In some embodiments, the monoclonal antibody is highly specific and directed to a single antigenic site. In some embodiments, monoclonal antibodies are highly specific and directed to a number of antigenic sites (e.g., bispecific or multispecific antibodies). The modifier “monoclonal” describes the characterization of antibodies obtained from a substantially homogeneous population of antibodies and should not be construed as requiring antibody production by any particular method. For example, monoclonal antibodies provided herein may be produced by a variety of techniques, including, for example, hybridoma methods, recombinant DNA methods, phage display techniques, and other techniques known to those skilled in the art for creating or producing antibodies.

[0130] The term "monoclonal antibody" as used herein includes, in particular, "chimeric" antibodies (immunoglobulins) in which a portion of the heavy and / or light chain is identical or homogeneous to a corresponding sequence in an antibody derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is identical or homogeneous to a corresponding sequence in an antibody derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies insofar as they exhibit the desired biological activity (U.S. Patent No. 4,816,567; Morrison et al., Proc. Natl. Acad. Sci. USA, 81:6851-6855 (1984)). The term "humanized antibody" as used herein is used as a subset of "chimeric antibody".

[0131] The "humanized" form of a non-human (e.g., Muulin) antibody is a chimeric antibody containing a minimal sequence derived from a non-human immunoglobulin. In one embodiment, the humanized antibody is a human immunoglobulin (recipient antibody) in which residues derived from the recipient's CDR are replaced with residues derived from a non-human species (donor antibody), e.g., mouse, rat, rabbit, or non-human primate CDR, having the desired specificity, affinity, and / or capabilities. In some cases, FR residues of the human immunoglobulin are replaced with corresponding non-human residues. Furthermore, the humanized antibody may contain residues not found in the recipient antibody or donor antibody. These modifications may be made to further improve antibody performance, such as binding affinity. Generally, the humanized antibody contains at least one, typically two, substantially all of the variable domains, with all or substantially all of the CDRs and all or substantially all of the FR regions corresponding to those of the non-human immunoglobulin sequence being from the human immunoglobulin sequence, but the FR regions may contain one or more individual FR residue substitutions that improve antibody performance, such as binding affinity, isomerization, and immunogenicity. In some embodiments, the number of these amino acid substitutions in FR is no more than 6 in the H chain and no more than 3 in the L chain. The humanized antibody may optionally include at least a portion of the immunoglobulin constant region (Fc), typically that of human immunoglobulin. For further details, see, for example, Jones et al., Nature 321:522-525 (1986); Riechmann et al., Nature 332:323-329 (1988); and Presta, Curr. Op. Struct. Biol. 2:593-596 (1992). See also, for example, Vaswani and Hamilton, Ann. Allergy, Asthma & Immunol. 1:105-115 (1998); Harris, Biochem. Soc. Transactions 23:1035-1038 (1995); Hurle and Gross, Curr. Op. Biotech. 5:428-433 (1994); and U.S. Patent Nos. 6,982,321 and 7,087,409. In some embodiments, the humanized antibody is directed to a single antigenic site.In some embodiments, the humanized antibody is directed to multiple antigenic sites. Alternative humanization methods are described in U.S. Patent No. 7,981,843 and U.S. Patent Application No. 2006 / 0134098.

[0132] The "amino acid sequence identity percentage (%)" relative to a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical to amino acid residues in the reference polypeptide sequence after the sequences have been aligned and gaps introduced where necessary to achieve the maximum possible sequence identity percentage, without considering any conservative substitutions as part of the sequence identity. Alignment for the purpose of determining the amino acid sequence identity percentage can be achieved in various ways within the scope of the art, for example, by using publicly available computer software such as BLAST, BLAST-2, ALIGN, or Megalign (DNASTAR) software. Those skilled in the art can determine appropriate parameters for aligning the sequences, including any algorithm required to achieve the maximum alignment over the entire length of the sequences being compared. For example, the amino acid sequence identity percentage of a given amino acid sequence A to or against a given amino acid sequence B (or a given amino acid sequence A that has or contains a specific amino acid sequence identity percentage to or against a given amino acid sequence B) is calculated as follows:

[0133] 100 x fraction X / Y

[0134] Here, X is the number of amino acid residues scored as identical matches by sequence in the alignment of A and B in their respective programs, and Y is the total number of amino acid residues in B. If the length of amino acid sequence A is not equal to the length of amino acid sequence B, then it is understood that the amino acid sequence identity % of A to B is not equal to the amino acid sequence identity % of B to A.

[0135] An antibody that "bounds to," "specifically binds to," or "is specific with respect to" a particular polypeptide or epitope on a particular polypeptide is one that binds to that particular polypeptide or epitope on a particular polypeptide without substantially binding to any other polypeptide or polypeptide epitope. In some embodiments, the binding of the anti-UCH-L1 antibodies described herein to unrelated, non-UCH-L1 polypeptides is less than 10% of the binding of antibodies that bind to UCH-L1 as measured by methods known in the art (e.g., enzyme-linked immunosorbent assay (ELISA)). In some embodiments, the binding of the anti-GFAP antibodies described herein to unrelated, non-GFAP polypeptides is less than 10% of the binding of antibodies that bind to GFAP as measured by methods known in the art (e.g., enzyme-linked immunosorbent assay (ELISA)). Typically, an antibody that immunospecifically binds (or specifically binds) to UCH-L1 or GFAP is 1 × 10⁻⁶ -7 M or 1×10 -8 M or a dissociation constant less than (K) D )(or approximately or 1 x 10 7 M -1 or 1 × 10 8 M -1 Or a higher affinity constant K A ) is something that connects to it.

[0136] As used herein, “binding affinity” refers to the strength of the non-covalent interaction between a single binding site of a molecule (e.g., an antibody) and its binding partner (e.g., an antigen). In some embodiments, the affinity of an antibody to UCH-L1 or GFAP is typically expressed as the dissociation constant (K). D Affinity can be expressed by ( ). Affinity can be measured by common methods known in the art, including those described herein.

[0137] As used herein, the term "UCH-L1" refers to the human UCH-L1 protein or its isoforms or variants, including spontaneously occurring variants of human UCH-L1, such as splice variants or allele variants. An exemplary amino acid sequence of human UCH-L1 is shown in SEQ ID NO: 207. Another exemplary amino acid sequence of human UCH-L1 is shown in SEQ ID NO: 208. Yet another exemplary amino acid sequence of human UCH-L1 is shown in SEQ ID NO: 209. An exemplary amino acid sequence of human UCH-L1 is shown in SEQ ID NO: 210. Yet another exemplary amino acid sequence of human UCH-L1 is shown in SEQ ID NO: 211. In some embodiments, human UCH-L1 may refer to allele variants or splice variants that exhibit at least or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with any of SEQ ID NOs: 207, 208, 209, 210, or 211. In some embodiments, it is understood that the provided antibody or antigen-binding fragment may exhibit cross-reactive binding to the UCH-L1 protein of another mammal, e.g., Muulin UCH-L1 or Primate UCH-L1.

[0138] Human UCH-L1 isoform 1 amino acid sequence MQLKPMEINPEMLNKVLSRLGVAGQWRFVDVLGLEEESLGSVPAPACALLLLFPLTAQHENFRKKQIEELKGQEVSPKVYFMKQTIGNSCGTIGLIHAVANNQDKLGFEDGSVLKQFLSETEKMSPEDRAKCFEKNEAIQAAHDAVAQEGQCRVDDKVNFHFILFNNVDGHLYELDGRMPFPVNHGASSEDTLLKDAAKVCREFTEREQGEVRFSAVALCKAA (Sequence ID 207)

[0139] Human UCH-L1 isoform 2 amino acid sequence MQLKPMEINPEMLNKVLSRLGVAGQWRFVDVLGLEEESLGSVPAPACALLLLFPLTAQHENFRKKQIEELKGQEVSPKVYFMKQTIGNSCGTIGLIHAVANNQDKLGFEDGSVLKQFLSETEKMSPEDRAKCFEKNEAIQAAHDAVAQEGQCRVDDKVNFHFILFNNVDGHLYELDGRMPFPVNHGASSEDTLLKDAAKALKHKQSAQLSTGPLWCELQMVKHSPQCMSCIRYLTL (Sequence ID 208)

[0140] Human UCH-L1 isoform 3 amino acid sequence MQLKPMEINPEMLNKVLSRLGVAGQWRFVDVLGLEEESLGSVPAPACALLLLFPLTAQHENFRKKQIEELKGQEVSPKVYFMKQTIGNSCGTIGLIHAVANNQDKLGFEDGSVLKQFLSETEKMSPEDRAKCFEKNEAIQAAHDAVAQEGQCRVDDKMDECLFR(Sequence ID 209)

[0141] Human UCH-L1 isoform 4 amino acid sequence MQLKPMEINPEMLNKVLSRLGVAGQWRFVDVLGLEEESLGSVPAPACALLLLFPLTAQHENFRKKQIEELKGQEVSPKVYFMKQTIGNSCGTIGLIHAVANNQDKLGFEDGSVLKQFLSETEKMSPEDRAKCFEKNEAIQAAHDAVAQEGQCRVDDKTLPRSAENSPSVSKEKSASLPWLSARQPNALWEGLC (Sequence ID 210)

[0142] Human UCH-L1 isoform 5 amino acid sequences MQLKPMEINPEMLNKVLSRLGVAGQWRFVDVLGLEEESLGSVPAPACALLLLFPLTAQHENFRKKQIEELKGQEVSPKVYFMKQTIGNSCGTIGLIHAVANNQDKLGFEDGSVLKQFLSETEKMSPEDRAKCFEKNEAIQAAHDAVAQEGQCRVDDKTLPRHLSTSRVHSCPLGHCGVSFRW (Sequence ID 211)

[0143] As used herein, the terms “glial fiber acidic protein” or “GFAP” refer to the human GFAP protein or its isoforms, fragments, or variants, including spontaneously occurring variants of human GFAP, such as splice variants or allelic variants. An example amino acid sequence of human GFAP is shown in SEQ ID NO: 212. Another example amino acid sequence of human GFAP is shown in SEQ ID NO: 213. Yet another example amino acid sequence of human GFAP is shown in SEQ ID NO: 214. In some embodiments, human GFAP may refer to variants such as allelic variants or splice variants that exhibit at least or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with any of SEQ ID NOs: 212, 213, or 214. In some embodiments, it is understood that the provided antibody or antigen-binding fragment may exhibit cross-reactive binding with another mammalian GFAP protein, such as Muulin GFAP or primate GFAP.

[0144] Human GFAP isoform 1 amino acid sequence MERRRITSAARRSYVSSGEMMVGGLAPGRRLGPGTRLSLAARMPPPLPTRVDFSLAGALNAGFKETRASERAEMMELNDRFASYIEKVRFLEQQNKALAAELNQLRAKEPTKLADVYQAELRELRLRLDQLTANSARLEVERDNLAQDLATVRQKLQDETNLRLEAEENNLAAYRQEADEATLARLDLERKIESLEEEIRFLRKIHEEEVRELQEQLARQQVH VELDVAKPDLTAALKEIRTQYEAMASSNMHEAEEWYRSKFADLTDAAARNAELLRQAKHEANDYRRQLQSLTCDLESLRGTNESLERQMREQEERHVREAASYQEALARLEEEGQSLKDEMARHLQEYQDLLNVKLALDIEIATYRKLLEGEENRITIPVQTFSNLQIRETSLDTKSVSEGHLKRNIVVKTVEMRDGEVIKESKQEHKDVM (Sequence ID 212).

[0145] Human GFAP isoform 2 amino acid sequence MERRRITSAARRSYVSSGEMMVGGLAPGRRLGPGTRLSLAARMPPPLPTRVDFSLAGALNAGFKETRASERAEMMELNDRFASYIEKVRFLEQQNKALAAELNQLRAKEPTKLADVYQAELRELRLRLDQLTANSARLEVERDNLAQDLATVRQKLQDETNLRLEAENNLAAYRQEADEATLARLDLERKIESLEEEIRFLRKIHEEEVRELQEQLARQQV HVELDVAKPDLTAALKEIRTQYEAMASSNMHEAEEWYRSKFADLTDAAARNAELLRQAKHEANDYRRQLQSLTCDLESLRGTNESLERQMREQEERHVREAASYQEALARLEEEGQSLKDEMARHLQEYQDLLNVKLALDIEIATYRKLLEGEENRITIPVQTFSNLQIRGGKSTKDGENHKVTRYLKSLTIRVIPIQAHQIVNGTPPARG (Sequence ID 213).

[0146] Human GFAP isoform 3 amino acid sequence MERRRITSAARRSYVSSGEMMVGGLAPGRRLGPGTRLSLARMPPPLPTRVDFSLAGALNAGFKETRASERAEMMELNDRFASYIEKVRFLEQQNKALAAELNQLRAKEPTKL ADVYQAELRELRLRLDQLTANSARLEVERDNLAQDLATVRQKLQDETNLRLEAENNLAAYRQEADEATLARLDLERKIESLEEEIRFLRKIHEEEVRELQEQLARQQVHVEL DVAKPDLTAALKEIRTQYEAMASSNMHEAEEWYRSKFADLTDAAARNAELLRQAKHEANDYRRQLQSLTCDLESLRGTNESLERQMREQEERHVREAASYQEALARLEEEGQSLKDEMARHLQEYQDLLNVKLALDIEIATYRKLLEGEENRITIPVQTFSNLQIRGQYSRASWEGHWSPAPSSRACRLLQTGTEDQGKGIQLSLGAFVTLQRS (Sequence ID 214).

[0147] In this specification, the descriptions of an amino acid sequence as "corresponding," "at a corresponding position," or "corresponding to" an amino acid position within a disclosed sequence, such as those listed in a sequence list, refer to an amino acid position identified when aligning with the disclosed sequence to maximize identity using a standard alignment algorithm. In some embodiments, exemplary corresponding residues of UCH-L1 can be identified by sequence alignment with the exemplary UCH-L1 sequence shown in SEQ ID NO: 207. In some embodiments, exemplary corresponding residues of the GFAP protein can be identified by sequence alignment with the exemplary GFAP sequence shown in SEQ ID NO: 212. By aligning sequences, those skilled in the art can identify corresponding residues, for example, by using conserved and identical amino acid residues as guides. Generally, to identify corresponding positions, amino acid sequences are arranged to obtain the highest-order match (see, for example: Computational Molecular Biology, Lesk, AM, ed., Oxford University Press, New York, 1988; Biocomputing: Informatics and Genome Projects, Smith, DW, ed., Academic Press, New York, 1993; Computer Analysis of Sequence Data, Part I, Griffin, AM, and Griffin, HG, eds., Humana Press, New Jersey, 1994; Sequence Analysis in Molecular Biology, von Heinje, G., Academic Press, 1987; and Sequence Analysis Primer, Gribskov, M. and Devereux, J., eds., Stockton Press, New York, 1991; Carrillo et al. (1988) SIAM J Applied Math 48:1073).

[0148] In this specification, an “isolated” nucleic acid molecule encoding an antibody or antibody chain (L or H chain) is a nucleic acid molecule that has been identified and isolated from at least one contaminating nucleic acid molecule that would normally be present in the environment in which it was produced. In some embodiments, the isolated nucleic acid is unrelated to all components associated with the production environment. In this specification, an isolated nucleic acid molecule encoding polypeptides and antibodies is a form other than that found in nature or in a setting. Isolated nucleic acid molecules are therefore distinguished from nucleic acids encoding polypeptides and antibodies that are naturally present in cells as described herein.

[0149] The term "naked antibody" refers to an antibody that is not partially or completely conjugated with a label.

[0150] As used herein, "antibody conjugate" refers to an antibody attached to a portion or label via covalent or non-covalent interactions.

[0151] As used herein, the terms “conjugated to an antibody,” “bound to an antibody,” or “attached to an antibody,” or other variations thereof, when referring to the attachment of a portion to an antibody or its antigen-binding fragment (such as a label or other portion), mean that the portion is attached to the antibody or its antigen-binding fragment by any known method for conjugating molecules, including through covalent or non-covalent interactions. Conjugation may be performed using any variety of binders resulting in conjugation, but is not limited to peptides or compound linkers or chemical crosslinkers. In some embodiments, attachment is performed by any known method for conjugating peptides, for example, by the production of a fusion protein by recombinant means, or by chemical means after translation.

[0152] As used herein, detection includes methods that enable visualization (by eye or instrument) of proteins. Proteins can be visualized using antibodies specific for the protein. Detection of proteins can also be facilitated by fusion of the protein with an epitope tag or a tag that includes a label.

[0153] The term "label" means any moiety that can be attached or bound, either directly or indirectly, to an antibody and that functions to (i) provide a detectable signal; (ii) interact with a second label to modify the detectable signal provided by the first or second label, e.g., FRET (fluorescence resonance energy transfer); (iii) stabilize an interaction with or increase the binding affinity for an antigen or ligand; (iv) affect mobility, e.g., electrophoretic mobility, or cell permeability by charge, hydrophobicity, shape, or other physical parameters; or (v) provide a capture moiety for modulating ligand affinity, antibody / antigen binding, or ion complexation.

[0154] As used herein, "solid-phase binding assay" refers to an in vitro assay in which an antigen is contacted with a ligand, and one of the antigen or ligand is bound to a solid support. During the antigen-ligand interaction, unwanted or non-specific components can be removed (e.g., by washing), and the antigen-ligand complex is detected.

[0155] "Solid support" means a non-aqueous matrix to which an antibody according to the disclosure provided can adhere or attach. For example, solid supports include, but are not limited to, microtiter plates, membranes (e.g., nitrocellulose), beads, dipsticks, thin layer chromatography plates, or other solid media.

[0156] The term “composition” refers to any mixture of two or more products, substances, or compounds, including antibodies. It may be a solution, suspension, liquid, powder, paste, aqueous, non-aqueous, or any combination thereof. A formulation is generally a form that allows the biological activity of the active ingredient (e.g., antibody) to be effective.

[0157] As used herein, "carrier" includes pharmaceutically acceptable carriers, excipients, or stabilizers that are nontoxic to cells or mammals to which they are exposed at the dose and concentration used. Acceptable carriers, excipients, or stabilizers suitable for use in diagnostic or detection assays are also included. Acceptable carriers are often aqueous pH-buffered solutions. Examples of acceptable carriers include buffers such as phosphoric acid, citrate, and other organic acids; antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptides; proteins such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrin; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and / or nonionic surfactants such as TWEEN®, polyethylene glycol (PEG), and Pluronic®.

[0158] As used herein, "combination" refers to any relationship between or within two or more items. A combination may be two or more distinct items, for example, two compositions or two collections, a mixture thereof, for example, a single mixture of two or more items, or any variation thereof. The elements of a combination are generally functionally related or associated.

[0159] The kits used herein are packaged combinations that may optionally include other elements, such as further reagents and their combinations or instructions for use, for purposes including, but not limited to, the detection, diagnosis, and / or evaluation of biological activity or properties.

[0160] As used herein, “article of manufacture” refers to a product that is manufactured and sold. As used throughout this application, the term is intended to encompass any antibodies provided herein, including compositions and combinations thereof contained in a package.

[0161] As used herein, an individual “at risk” of developing a disability may or may not have a detectable disease or symptom of a disease, and may or may not have a manifested detectable disease or symptom of a disease. “At risk” means that an individual has one or more risk factors associated with the occurrence of brain injury or injury, e.g., traumatic brain injury or other neurological injury or condition known in the art. Non-limiting examples of such risk factors include, for example, a bolt or jolt to the head, penetrating head injury, alteration of mental state or consciousness (short or long duration), memory loss, or other similar signs or consequences that may indicate brain injury. An individual having one or more of these risk factors is more likely to develop a disability than an individual not having one or more of these risk factors.

[0162] As used herein, the term “treatment” refers to a clinical intervention designed to alter the natural processes of an individual or cell being treated during the course of clinicopathology. Desired effects of treatment include a reduction in the rate of disease progression, improvement or mitigation of symptoms, and remission or improved prognosis. An individual is successfully “treated” if, for example, one or more symptoms associated with a disorder (e.g., an eosinophil-mediated disease) are reduced or eliminated. An individual is successfully “treated” if, for example, the treatment results in an increase in the quality of life of the person with the disease, a reduction in the dosage of other drugs required to treat the disease, a decrease in the frequency of disease relapses, a decrease in the severity of the disease, a delay in the onset or progression of the disease, and / or an extension of the individual’s survival.

[0163] "Effective dose" refers to the minimum effective amount in terms of duration and dosage required to achieve a desired or suggested effect, including therapeutic or prophylactic outcomes. An effective dose may be provided in one or more doses. "Therapeutic effective dose" is the minimum concentration required to produce a measurable improvement in a particular disorder. The therapeutic effective dose as used herein may vary depending on factors such as the patient's condition, age, sex, and weight, and the antibody's ability to induce a desired response in the individual. A therapeutic effective dose may also be such that the therapeutically beneficial effects outweigh any toxic or adverse effects of the antibody. "Prophylactic effective dose" refers to the effective amount in terms of duration and dosage required to achieve a desired prophylactic outcome. Typically, but not always, prophylactic doses are used in subjects before or in the early stages of a disease, so a prophylactic effective dose may be less than a therapeutic effective dose.

[0164] As used herein, “individual” or “subject” refers to a mammal. “Mammal” for therapeutic purposes includes humans, domesticated and livestock animals, and zoo animals, exercise animals, or pet animals, such as dogs, horses, rabbits, cattle, pigs, hamsters, gerbils, mice, ferrets, rats, and cats. In some embodiments, the individual or subject is a human.

[0165] [II. Anti-UCH-L1 antibody and anti-GFAP antibody] Anti-GFAP antibodies and anti-UCH-L1 antibodies are provided herein. In some embodiments, the antibodies provided detect GFAP and UCH-L1, respectively, in samples derived from individuals, such as human patients. In some embodiments, the samples are derived from individuals who have or are suspected of having brain damage resulting from neurodegenerative diseases, strokes, or injuries or trauma, such as mild, moderate, or severe traumatic brain injury, as described herein.

[0166] In some embodiments, GFAP and UCH-L1 have been shown to be associated with nerve injury or brain injury (see, for example, US2011 / 0143375). Cells in the brain, including nerve cells and non-nerve cells (e.g., glial cells), can be directly and / or indirectly harmed as a result of injury or disease. Several proteins, including GFAP and UCH-L1, may be released from harmed brain cells or from unharmed brain cells associated with harmed brain cells. For example, directly harmed brain cells may release proteins that indicate direct damage. Or, simultaneously, unharmed brain cells may respond to harm in surrounding brain cells and release proteins that indicate damage in their area.

[0167] GFAP is a member of the cytoskeletal protein family and is the major 8-9 nanometer intermediate filament of glial cells such as mature astrocytes in the central nervous system (CNS). GFAP is a monomeric molecule with molecular masses of 35-40 and 53 kDa and isoelectric points of 5.7-5.8. GFAP is a highly brain-specific protein and is not normally found outside the CNS in visible amounts. GFAP can be released into the body, such as into the blood and cerebrospinal fluid (CSF), immediately after brain injury. For example, in some cases, after injury, as a result of trauma, disease, genetic disorder, or chemical injury, astrocytes in the CNS can become reactive in a way characterized by the rapid synthesis of GFAP through a process called astrogliosis or gliosis. In some embodiments, GFAP may readily undergo protein degradation modifications, which may, in some cases, result in GFAP degradation products (see, e.g., Papa et al. (2012) Ann Emerg. Med., 59:10 and McMahon et al. (2015) J. Neurotrauma, 32:527-533). In some cases, calpain hyperactivation at the site of injury or damage may result in the release of GFAP degradation products. In some cases, existing methods for detecting GFAP in body fluids are not optimal.

[0168] UCH-L1 is present in neurons and elevates upon neuronal injury. It is commonly used as a biomarker in the study of the mammalian central nervous system (CNS). Several isoforms of UCH-L1 exist alongside a prototype UCH-L1, known to be approximately 25 kDa in size. While UCH-L1 is considered a good candidate as a biomarker for detecting brain injury, elevated levels of UCH-L1 are difficult to reliably detect, partly due to its complex structure. This is a result of a tangled tertiary structure that folds on itself, obscuring the binding site from detection antibodies against UCH-L1. In some cases, existing methods for detecting UCH-L1 in bodily fluids are not optimal.

[0169] The antibodies provided overcome these problems. Exemplary anti-GFAP or anti-UCH-L1 antibodies are described in the following subsections. In some embodiments, one or more of the provided anti-UCH-L1 antibodies and / or one or more of the provided anti-GFAP antibodies may be used alone or together in a method for detecting or diagnosing brain injury resulting from a neurological condition or other condition associated with brain injury, and / or in a method for predicting whether a subject needs it, for example, whether or not a CT scan is necessary.

[0170] A. Anti-UCH-L1 antibody In one embodiment, an antibody that binds to human UCH-L1 is provided, comprising a fragment, isoform, or variant of the human UCH-L1 protein. In some embodiments, the human UCH-L1 protein is released from damaged cells or tissues and / or is present in body fluids (e.g., serum, cerebrospinal fluid, or other body fluids described) as a result of brain injury or injury. In some embodiments, the anti-UCH-L1 antibody binds to the human UCH-L1 protein comprising an amino acid sequence selected from any of SEQ ID NOs. 207-211, or a variant thereof having an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence selected from SEQ ID NOs. 207-211.

[0171] In some embodiments, a UCH-L1 variant is UCH-L1 having at least about 80% amino acid sequence identity with the UCH-L1 amino acid sequence, which is: (i) the full-length native human UCH-L1 amino acid sequence shown, for example, in any of SEQ ID NOs. 207-211; (ii) the full-length recombinant human UCH-L1 amino acid sequence shown, for example, in any of SEQ ID NOs. 207-211; (iii) the UCH-L1 amino acid sequence of (i) or (ii) with a signal peptide deleted; or (iv) any other fragment of the full-length UCH-L1 amino acid sequence of (i) or (ii), for example, encoded by a nucleic acid representing only a portion of the complete coding sequence relating to the full-length UCH-L1 protein. Such a UCH-L1 variant comprises a polypeptide in which one or more amino acid residues are added to or deleted from the N- or C-terminus of the full-length native amino acid sequence or the full-length recombinant amino acid sequence. Typically, UCH-L1 mutants have at least approximately 80% amino acid sequence identity, or at least approximately 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% amino acid sequence identity, with the full-length native UCH-L1 amino acid sequence (e.g., shown in SEQ ID NOs. 207-211), the full-length recombinant UCH-L1 amino acid sequence (e.g., shown in SEQ ID NOs. 207-211), or those UCH-L1 amino acid sequences lacking a signal peptide, or any other fragment of such a full-length UCH-L1 amino acid sequence. In some embodiments, the UCH-L1 variant containing a full-length sequence fragment is at least about 10 amino acids long, or at least about 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220 amino acids long, or more.In some embodiments, the UCH-L1 variant has one or fewer conserved amino acid substitutions compared to the native UCH-L1 amino acid sequence or the recombinant UCH-L1 amino acid sequence, or two, three, four, five, six, seven, eight, nine, or ten or fewer conserved amino acid substitutions compared to the native UCH-L1 amino acid sequence or the recombinant UCH-L1 amino acid sequence.

[0172] In some embodiments, the anti-UCH-L1 antibody binds to an epitope or region corresponding to an epitope or region contained within the human UCH-L1 protein shown in SEQ ID NO: 207, or to the same epitope or region within an isoform, fragment, or variant of the UCH-L1 protein shown in SEQ ID NO: 207.

[0173] In some embodiments, the UCH-L1 protein (e.g., human UCH-L1 protein) is a recombinant UCH-L1 protein, such as a recombinant UCH-L1 protein produced in a bacterial host cell (e.g., E. coli cell) or a mammalian host cell (e.g., CHO cell). In some embodiments, the UCH-L1 protein (e.g., human UCH-L1 protein) is a native UCH-L1 protein, such as a native UCH-L1 protein present in or obtained in an individual (e.g., human) in serum, plasma, blood (e.g., whole blood), cerebrospinal fluid, urine, sweat, saliva, or any other biological fluid. In some embodiments, the anti-UCH-L1 antibody binds to glycosylated UCH-L1.

[0174] In some embodiments, the anti-UCH-L1 antibody described herein binds to a linear epitope of UCH-L1 (e.g., human UCH-L1). In some embodiments, the anti-UCH-L1 antibody described herein binds to a structural epitope of UCH-L1 (e.g., human UCH-L1).

[0175] In some embodiments, the anti-UCH-L1 antibody binds to a specific epitope or region of UCH-L1. In some embodiments, the anti-UCH-L1 antibody binds to an epitope that comprises, consists of, or consists essentially of one or more amino acids of a portion of UCH-L1 corresponding to positions 98-106 of human UCH-L1 as set forth in SEQ ID NO: 207. In some embodiments, the anti-UCH-L1 antibody binds to an epitope that comprises, consists of, or consists essentially of one or more amino acids of a portion of UCH-L1 corresponding to positions 28-36 of human UCH-L1 as set forth in SEQ ID NO: 207. In some embodiments, the anti-UCH-L1 antibody binds to an epitope that comprises, consists of, or consists essentially of one or more amino acids of a portion of UCH-L1 corresponding to positions 138-145 of human UCH-L1 as set forth in SEQ ID NO: 207. In some embodiments, the anti-UCH-L1 antibody binds to an epitope that comprises, consists of, or consists essentially of one or more amino acids of a portion of UCH-L1 corresponding to positions 142-149 of human UCH-L1 as set forth in SEQ ID NO: 207. For example, in some embodiments, the anti-UCH-L1 antibody binds to an epitope that comprises, consists of, or consists essentially of a portion of UCH-L1 corresponding to positions 98-106 of human UCH-L1 as set forth in SEQ ID NO: 207.

[0176] In some embodiments, among the antibodies provided, there are antibodies that bind to the same or overlapping epitopes as one or more of the other antibodies provided, and / or antibodies that compete with one or more of the other antibodies provided for binding to UCH-L1. In some embodiments, among the antibodies provided, there are antibodies that bind to different or distinct epitopes compared to one or more of the other antibodies provided, and / or antibodies that do not compete with one or more of the other antibodies provided for binding to UCH-L1. For example, in some embodiments, antibodies are provided that bind to a distinct epitope and / or do not compete for binding to UCH-L1 compared to the antibodies designated as UCH-L1-1 and UCH-L1-2 as described herein. In some embodiments, antibodies are provided that bind to a distinct epitope and / or do not compete for binding to UCH-L1 compared to the antibody designated as UCH-L1-5 as described herein.

[0177] In some embodiments, the antibody binds to an epitope of UCH-L1 that is conserved among UCH-L1 from different species. In some embodiments, the antibody binds to an epitope of UCH-L1 that is present in human UCH-L1 or its isoforms or variants but not in one or more other non-human species.

[0178] In some embodiments, an anti-UCH-L1 antibody comprising a heavy chain variable region and a light chain variable region is provided herein, wherein the heavy chain variable region comprises CDR-H3 comprising an amino acid sequence selected from SEQ ID NOs. 20-27. In some embodiments, the heavy chain variable region further comprises CDR-H1 comprising an amino acid sequence selected from SEQ ID NOs. 1-8 and / or CDR-H2 comprising an amino acid sequence selected from SEQ ID NOs. 9-19.

[0179] In some embodiments, an anti-UCH-L1 antibody comprising a heavy chain variable region and a light chain variable region is provided herein, wherein the light chain variable region comprises CDR-L3 comprising an amino acid sequence selected from SEQ ID NOs. 45-50. In some embodiments, the light chain variable region further comprises CDR-L1 comprising an amino acid sequence selected from SEQ ID NOs. 28-36 and / or CDR-L2 comprising an amino acid sequence selected from SEQ ID NOs. 37-44.

[0180] In some embodiments, the heavy chain CDR sequence is as follows: a) CDR-H1 as shown in Sequence ID No. 1 or Sequence ID No. 2; b) CDR-H2 as shown in SEQ ID NO: 9 or SEQ ID NO: 10; and / or c) CDR-H3 as shown in Sequence ID No. 20 or Sequence ID No. 21 Includes.

[0181] In some embodiments, the heavy chain CDR sequence is as follows: a) CDR-H1 as shown in SEQ ID NO: 3; SEQ ID NO: 4; SEQ ID NO: 5; SEQ ID NO: 6; SEQ ID NO: 7 or SEQ ID NO: 8; b) CDR-H2 as shown in SEQ ID NO: 11; SEQ ID NO: 12; SEQ ID NO: 13; SEQ ID NO: 14; SEQ ID NO: 15; SEQ ID NO: 16; SEQ ID NO: 17 or SEQ ID NO: 18; and / or c) CDR-H3 as shown in Schematic Code 20; Schematic Code 22; Schematic Code 23; Schematic Code 24; Schematic Code 25; Schematic Code 26; or Schematic Code 27 Includes.

[0182] In some embodiments, the heavy chain CDR sequence is as follows: a) CDR-H1 as shown in Sequence ID No. 1; b) CDR-H2 as shown in Sequence ID No. 19; and / or c) CDR-H3 shown in Sequence ID No. 20 Includes.

[0183] In some embodiments, the light chain CDR sequence is as follows: a) CDR-L1 as shown in Sequence ID No. 28 or Sequence ID No. 29; b) CDR-L2 as shown in Sequence ID No. 37 or Sequence ID No. 38; and / or c) CDR-L3 as shown in Sequence ID No. 45 or Sequence ID No. 46 Includes.

[0184] In some embodiments, the light chain CDR sequence is as follows: a) CDR-L1 as shown in SEQ ID NO: 30; SEQ ID NO: 31; SEQ ID NO: 32; SEQ ID NO: 33; SEQ ID NO: 34; SEQ ID NO: 35; or SEQ ID NO: 36; b) CDR-L2 as shown in SEQ ID NOs. 37, 39; 40; 41; 42; 43; or 44; and / or c) CDR-L3 as shown in SEQ ID NO: 45; SEQ ID NO: 47; or SEQ ID NO: 49 Includes.

[0185] In some embodiments, the light chain CDR sequence is as follows: a) CDR-L1 as shown in Sequence ID No. 28; b) CDR-L2 as shown in Sequence ID No. 37; and / or c) CDR-L3 shown in Sequence ID No. 50 Includes.

[0186] Also provided are antibodies containing the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and / or CDR-L3 sequences, which are identical to any of the above-mentioned CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and / or CDR-L3 sequences by at least or approximately 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, respectively.

[0187] In one embodiment, an anti-UCH-L1 antibody comprising a heavy chain variable region and a light chain variable region is provided herein, wherein the heavy chain variable region comprises (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1, (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 9, and (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 20; and / or the light chain variable region comprises (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 28, (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 37, and (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 45. In some embodiments, the antibody described herein binds to an epitope corresponding to an epitope that is or comprises the human UCH-L1 residues 98-106 shown in SEQ ID NO: 207.

[0188] In one embodiment, an anti-UCH-L1 antibody comprising a heavy chain variable region and a light chain variable region is provided herein, wherein the heavy chain variable region comprises (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 2, (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 10, and (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 21; and / or the light chain variable region comprises (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 29, (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 38, and (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 46. In some embodiments, the antibody described herein binds to an epitope corresponding to the epitope that is or comprises the human UCH-L1 within residues 28-36 shown in SEQ ID NO: 207.

[0189] In one embodiment, an anti-UCH-L1 antibody comprising a heavy chain variable region and a light chain variable region is provided herein, wherein the heavy chain variable region comprises (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 3, (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 11, and (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 20; and / or, the light chain variable region comprises (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 30, (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 37, and (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 45. In some embodiments, the antibody described herein binds to an epitope corresponding to the epitope of human UCH-L1, which is or comprises residues 98-106 of SEQ ID NO: 207.

[0190] In another embodiment, an anti-UCH-L1 antibody comprising a heavy chain variable region and a light chain variable region is provided herein, wherein the heavy chain variable region comprises (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 4, (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 12, and (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 22; and / or the light chain variable region comprises (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 31, (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 39, and (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 47. In some embodiments, the antibody described herein binds to an epitope corresponding to an epitope that is or comprises human UCH-L1 within residues 138-145 as shown in SEQ ID NO: 207.

[0191] In another embodiment, an anti-UCH-L1 antibody comprising a heavy chain variable region and a light chain variable region is provided herein, wherein the heavy chain variable region comprises (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 5, (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 13, and (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 23; and / or the light chain variable region comprises (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 32, (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 39, and (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 47. In some embodiments, the antibody described herein binds to an epitope corresponding to the epitope that is or comprises the human UCH-L1 within residues 142-149 shown in SEQ ID NO: 207.

[0192] In another embodiment, an anti-UCH-L1 antibody comprising a heavy chain variable region and a light chain variable region is provided herein, the heavy chain variable region comprising (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 6, (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 14, and (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 24; and / or the light chain variable region comprising (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 33, (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 40, and (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 48. In some embodiments, the antibody described herein binds to an epitope corresponding to the epitope that is or comprises the human UCH-L1 within residues 28-36 shown in SEQ ID NO: 207.

[0193] In another embodiment, an anti-UCH-L1 antibody comprising a heavy chain variable region and a light chain variable region is provided herein, wherein the heavy chain variable region comprises (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 6, (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 14, and (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 24; and / or the light chain variable region comprises (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 34, (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 41, and (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 48. In some embodiments, the antibody described herein binds to an epitope corresponding to the epitope that is or comprises the human UCH-L1 within residues 28-36 shown in SEQ ID NO: 207.

[0194] In another embodiment, an anti-UCH-L1 antibody comprising a heavy chain variable region and a light chain variable region is provided herein, wherein the heavy chain variable region comprises (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 6, (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 15, and (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 24; and / or the light chain variable region comprises (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 34, (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 42, and (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 48. In some embodiments, the antibody described herein binds to an epitope corresponding to the epitope that is or comprises the human UCH-L1 within residues 28-36 shown in SEQ ID NO: 207.

[0195] In another embodiment, an anti-UCH-L1 antibody comprising a heavy chain variable region and a light chain variable region is provided herein, wherein the heavy chain variable region comprises (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 6, (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 14, and (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 24; and / or the light chain variable region comprises (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 35, (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 41, and (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 48. In some embodiments, the antibody described herein binds to an epitope corresponding to the epitope that is or comprises the human UCH-L1 within residues 28-36 shown in SEQ ID NO: 207.

[0196] In another embodiment, an anti-UCH-L1 antibody comprising a heavy chain variable region and a light chain variable region is provided herein, wherein the heavy chain variable region comprises (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 6, (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 16, and (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 25; and / or the light chain variable region comprises (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 34, (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 42, and (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 48. In some embodiments, the antibody described herein binds to an epitope corresponding to the epitope that is or comprises the human UCH-L1 within residues 28-36 shown in SEQ ID NO: 207.

[0197] In another embodiment, an anti-UCH-L1 antibody comprising a heavy chain variable region and a light chain variable region is provided herein, the heavy chain variable region comprising (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 7, (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 17, and (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 26; and / or the light chain variable region comprising (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 36, (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 43, and (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 49. In some embodiments, the antibody described herein binds to an epitope corresponding to the epitope that is or comprises the human UCH-L1 within residues 28-36 shown in SEQ ID NO: 207.

[0198] In another embodiment, an anti-UCH-L1 antibody comprising a heavy chain variable region and a light chain variable region is provided herein, wherein the heavy chain variable region comprises (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 8, (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 18, and (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 27; and / or the light chain variable region comprises (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 36, (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 44, and (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 49. In some embodiments, the antibody described herein binds to an epitope corresponding to an epitope that is or comprises the human UCH-L1 within residues 28-36 shown in SEQ ID NO: 207.

[0199] In another embodiment, an anti-UCH-L1 antibody comprising a heavy chain variable region and a light chain variable region is provided herein, wherein the heavy chain variable region comprises (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 1, (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 19, and (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 20; and / or the light chain variable region comprises (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 28, (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 37, and (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 50. In some embodiments, the antibody described herein binds to an epitope corresponding to the epitope that is or comprises the human UCH-L1 within residues 98-106 shown in SEQ ID NO: 207.

[0200] In some embodiments, anti-UCH-L1 includes a heavy chain variable region containing CDR-H1, CDR-H2, and CDR-H3, and each includes the amino acid sequences of CDR-H1, CDR-H2, and CDR-H3 contained within a heavy chain variable region amino acid sequence selected from any one of SEQ ID NOs. 51 to 63. In some embodiments, anti-UCH-L1 includes a heavy chain variable region containing CDR-H1, CDR-H2, and CDR-H3, and each includes the amino acid sequences of CDR-H1, CDR-H2, and CDR-H3 contained within a heavy chain variable region amino acid sequence selected from any one of SEQ ID NOs. 51 or 52. In some embodiments, anti-UCH-L1 includes a heavy chain variable region containing CDR-H1, CDR-H2, and CDR-H3, and each includes the amino acid sequences of CDR-H1, CDR-H2, and CDR-H3 contained within a heavy chain variable region amino acid sequence selected from any one of SEQ ID NOs. 53 to 62. In some embodiments, anti-UCH-L1 includes a heavy chain variable region comprising CDR-H1, CDR-H2, and CDR-H3, each comprising the amino acid sequences of CDR-H1, CDR-H2, and CDR-H3 contained within a heavy chain variable region amino acid sequence selected from any one of SEQ ID NOs.63.

[0201] In some embodiments, anti-UCH-L1 includes CDR-L1, CDR-L2, and CDR-L3, each comprising the amino acid sequences of CDR-L1, CDR-L2, and CDR-L3 contained within a light chain variable region amino acid sequence selected from any one of SEQ ID NOs.64 to 76. In some embodiments, anti-UCH-L1 includes CDR-L1, CDR-L2, and CDR-L3, each comprising the amino acid sequences of CDR-L1, CDR-L2, and CDR-L3 contained within a light chain variable region amino acid sequence selected from any one of SEQ ID NOs.64 or 65. In some embodiments, anti-UCH-L1 includes CDR-L1, CDR-L2, and CDR-L3, each comprising the amino acid sequences of CDR-L1, CDR-L2, and CDR-L3 contained within a light chain variable region amino acid sequence selected from any one of SEQ ID NOs.66 to 75. In some embodiments, anti-UCH-L1 comprises CDR-L1, CDR-L2, and CDR-L3, each comprising the amino acid sequences of CDR-L1, CDR-L2, and CDR-L3 contained within a light chain variable region amino acid sequence selected from any one of SEQ ID NOs.76.

[0202] The anti-UCH-L1 antibodies described herein may contain any suitable framework variable domain sequence, as long as the antibody retains the ability to bind to UCH-L1 (e.g., human UCH-L1). In use herein, the heavy chain framework region is designated as "HC-FR1-FR4" and the light chain framework region is designated as "LC-FR1-FR4".

[0203] In some embodiments, anti-UCH-L1 antibodies are provided herein that include a heavy chain variable domain comprising an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with an amino acid sequence selected from SEQ ID NOs. In some embodiments, anti-UCH-L1 antibodies are provided herein that include a heavy chain variable domain comprising an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with an amino acid sequence selected from SEQ ID NOs. In some embodiments, anti-UCH-L1 antibodies are provided herein that include a heavy chain variable domain comprising an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with an amino acid sequence selected from SEQ ID NOs. In some embodiments, anti-UCH-L1 antibodies are provided herein that include a heavy chain variable domain comprising an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with an amino acid sequence selected from SEQ ID NOs. In some embodiments, amino acids having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity include substitutions, insertions, or deletions compared to the reference sequence, but antibodies containing that amino acid sequence retain the ability to bind to UCH-L1 (e.g., human UCH-L1). In some embodiments, the substitutions, insertions, or deletions (e.g., 1, 2, 3, 4, or 5 amino acids) occur in the outer region of the CDR (i.e., in the FR).

[0204] In some embodiments, the anti-UCH-L1 antibody includes a heavy chain variable domain containing an amino acid sequence selected from SEQ ID NOs. 51 to 63. In some embodiments, the anti-UCH-L1 antibody includes a heavy chain variable domain containing the amino acid sequence of SEQ ID NO. 51. In some embodiments, the anti-UCH-L1 antibody includes a heavy chain variable domain containing the amino acid sequence of SEQ ID NO. 52. In some embodiments, the anti-UCH-L1 antibody includes a heavy chain variable domain containing the amino acid sequence of SEQ ID NO. 53. In some embodiments, the anti-UCH-L1 antibody includes a heavy chain variable domain containing the amino acid sequence of SEQ ID NO. 54. In some embodiments, the anti-UCH-L1 antibody includes a heavy chain variable domain containing the amino acid sequence of SEQ ID NO. 55. In some embodiments, the anti-UCH-L1 antibody includes a heavy chain variable domain containing the amino acid sequence of SEQ ID NO. 56. In some embodiments, the anti-UCH-L1 antibody includes a heavy chain variable domain containing the amino acid sequence of SEQ ID NO. 57. In some embodiments, the anti-UCH-L1 antibody includes a heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 58. In some embodiments, the anti-UCH-L1 antibody includes a heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 59. In some embodiments, the anti-UCH-L1 antibody includes a heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 60. In some embodiments, the anti-UCH-L1 antibody includes a heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 61. In some embodiments, the anti-UCH-L1 antibody includes a heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 62. In some embodiments, the anti-UCH-L1 antibody includes a heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 63.

[0205] In some embodiments, anti-UCH-L1 antibodies are provided herein that include a light chain variable domain comprising an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with an amino acid sequence selected from SEQ ID NOs.64 to 76. In some embodiments, anti-UCH-L1 antibodies are provided herein that include a light chain variable domain comprising an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with an amino acid sequence selected from SEQ ID NOs.64 or 65. In some embodiments, anti-UCH-L1 antibodies are provided herein that include a light chain variable domain comprising an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with an amino acid sequence selected from SEQ ID NOs. In some embodiments, anti-UCH-L1 antibodies are provided herein that include a light chain variable domain comprising an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with an amino acid sequence selected from SEQ ID NOs. In some embodiments, an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity includes substitutions, insertions, or deletions compared to the reference sequence, but an antibody containing that amino acid sequence retains the ability to bind to UCH-L1 (e.g., human UCH-L1). In some embodiments, the substitutions, insertions, or deletions (e.g., 1, 2, 3, 4, or 5 amino acids) occur in the outer region of the CDR (i.e., in the FR).

[0206] In some embodiments, the anti-UCH-L1 antibody includes a light chain variable domain containing amino acids selected from SEQ ID NOs. 64 to 76. In some embodiments, the anti-UCH-L1 antibody includes a light chain variable domain containing the amino acid sequence of SEQ ID NO. 64. In some embodiments, the anti-UCH-L1 antibody includes a light chain variable domain containing the amino acid sequence of SEQ ID NO. 65. In some embodiments, the anti-UCH-L1 antibody includes a light chain variable domain containing the amino acid sequence of SEQ ID NO. 66. In some embodiments, the anti-UCH-L1 antibody includes a light chain variable domain containing the amino acid sequence of SEQ ID NO. 67. In some embodiments, the anti-UCH-L1 antibody includes a light chain variable domain containing the amino acid sequence of SEQ ID NO. 68. In some embodiments, the anti-UCH-L1 antibody includes a light chain variable domain containing the amino acid sequence of SEQ ID NO. 69. In some embodiments, the anti-UCH-L1 antibody includes a light chain variable domain containing the amino acid sequence of SEQ ID NO. 70. In some embodiments, the anti-UCH-L1 antibody includes a light chain variable domain containing the amino acid sequence of SEQ ID NO. 71. In some embodiments, the anti-UCH-L1 antibody includes a light chain variable domain containing the amino acid sequence of SEQ ID NO: 72. In some embodiments, the anti-UCH-L1 antibody includes a light chain variable domain containing the amino acid sequence of SEQ ID NO: 73. In some embodiments, the anti-UCH-L1 antibody includes a light chain variable domain containing the amino acid sequence of SEQ ID NO: 74. In some embodiments, the anti-UCH-L1 antibody includes a light chain variable domain containing the amino acid sequence of SEQ ID NO: 75. In some embodiments, the anti-UCH-L1 antibody includes a light chain variable domain containing the amino acid sequence of SEQ ID NO: 76.

[0207] In one embodiment, an anti-UCH-L1 antibody is provided herein that includes a heavy chain variable domain containing an amino acid sequence selected from SEQ ID NOs. 51 to 63, and / or a light chain variable domain containing an amino acid sequence selected from SEQ ID NOs. 64 to 76. In some embodiments, the anti-UCH-L1 antibody includes a heavy chain variable domain containing an amino acid sequence selected from SEQ ID NOs. 51 or 52, and / or a light chain variable domain containing an amino acid sequence selected from SEQ ID NOs. 64 or 65. In some embodiments, the anti-UCH-L1 antibody includes a heavy chain variable domain containing an amino acid sequence selected from SEQ ID NOs. 53 to 62, and / or a light chain variable domain containing an amino acid sequence selected from SEQ ID NOs. 66 to 75. In some embodiments, the anti-UCH-L1 antibody includes a heavy chain variable domain containing an amino acid sequence selected from SEQ ID NOs. 63, and / or a light chain variable domain containing an amino acid sequence selected from SEQ ID NOs. 76. Antibodies are also provided that contain heavy chain variable domains and / or light chain variable domain sequences that are at least or approximately 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any of the heavy chain variable domains and / or light chain variable domain sequences described above.

[0208] In some embodiments, anti-UCH-L1 antibodies, such as UCH-L1-1, UCH-L1-2, etc., comprising the heavy chain variable domain and / or light chain variable domain of the antibodies listed in Table 6, are provided herein.

[0209] In some embodiments, the anti-UCH-L1 antibody includes a heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 51, and / or a light chain variable domain containing the amino acid sequence of SEQ ID NO: 64. In some embodiments, the anti-UCH-L1 antibody includes a heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 52, and / or a light chain variable domain containing the amino acid sequence of SEQ ID NO: 65. In some embodiments, the anti-UCH-L1 antibody includes a heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 53, and / or a light chain variable domain containing the amino acid sequence of SEQ ID NO: 66. In some embodiments, the anti-UCH-L1 antibody includes a heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 54, and / or a light chain variable domain containing the amino acid sequence of SEQ ID NO: 67. In some embodiments, the anti-UCH-L1 antibody includes a heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 55, and / or a light chain variable domain containing the amino acid sequence of SEQ ID NO: 68. In some embodiments, the anti-UCH-L1 antibody includes a heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 56, and / or a light chain variable domain containing the amino acid sequence of SEQ ID NO: 69. In some embodiments, the anti-UCH-L1 antibody includes a heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 57, and / or a light chain variable domain containing the amino acid sequence of SEQ ID NO: 70. In some embodiments, the anti-UCH-L1 antibody includes a heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 58, and / or a light chain variable domain containing the amino acid sequence of SEQ ID NO: 71. In some embodiments, the anti-UCH-L1 antibody includes a heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 59, and / or a light chain variable domain containing the amino acid sequence of SEQ ID NO: 72. In some embodiments, the anti-UCH-L1 antibody includes a heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 60, and / or a light chain variable domain containing the amino acid sequence of SEQ ID NO: 73. In some embodiments, the anti-UCH-L1 antibody includes a heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 61 and / or a light chain variable domain containing the amino acid sequence of SEQ ID NO: 74.In some embodiments, the anti-UCH-L1 antibody includes a heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 62 and / or a light chain variable domain containing the amino acid sequence of SEQ ID NO: 75. In some embodiments, the anti-UCH-L1 antibody includes a heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 73 and / or a light chain variable domain containing the amino acid sequence of SEQ ID NO: 76.

[0210] In one embodiment, the anti-UCH-L1 antibody described herein is an antibody fragment (including an antigen-binding fragment), such as Fab, Fab'-SH, Fv, scFv, or (Fab')2 fragment.

[0211] In any embodiment of this specification, the antibody may include a heavy chain constant domain. In some embodiments, the heavy chain constant domain is a non-human mammal. In some embodiments, the heavy chain constant domain is a non-human primate. In some embodiments, the heavy chain constant domain is a non-human primate. In some embodiments, the heavy chain constant domain is Muulin (e.g., mouse or rat). In some embodiments, the Muulin heavy chain constant domain is IgG1, IgG2a, IgG2b, or IgM. In some embodiments, the Muulin heavy chain constant domain is Muulin IgG1. In some embodiments, Muulin IgG1 includes the amino acid sequence of SEQ ID NO: 215 or its isoforms or variants having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 215. In some embodiments, the murin heavy chain constant domain is murin IgG2a. In some embodiments, murin IgG2a includes the amino acid sequence of SEQ ID NO: 216 or its isoforms or variants having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 216. In some embodiments, the murin heavy chain constant domain is murin IgG2b. In some embodiments, murin IgG2b includes the amino acid sequence of SEQ ID NO: 217 or its isoforms or variants having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 217. In some embodiments, the murin heavy chain constant domain is murin IgM. In some embodiments, murin IgM includes the amino acid sequence of SEQ ID NO: 223 or its isoforms or variants having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 223. In some embodiments, the heavy chain constant domain is human. In some embodiments, the human heavy chain constant domain is human IgG1.In some embodiments, human IgG1 includes the amino acid sequence of SEQ ID NO: 218 or its isoforms or variants having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 218. In some embodiments, the human heavy chain constant domain is human IgM. In some embodiments, human IgM includes the amino acid sequence of SEQ ID NO: 224 or its isoforms or variants having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 224.

[0212] Based on the amino acid sequences of those constant domains, two types of light chains, κ and λ, exist. In any embodiment herein, the antibodies provided herein may include a light chain constant domain. In some embodiments, the light chain constant domain is a non-human mammal. In some embodiments, the light chain constant domain is a non-human primate. In some embodiments, the light chain constant domain is a non-human primate. In some embodiments, the light chain constant domain is murin (e.g., mouse or rat). In some embodiments, the murin light chain constant domain is murin κ or murin λ. In some embodiments, murin κ includes the amino acid sequence of SEQ ID NO: 219 or its isoforms or variants having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 219. In some embodiments, murin λ includes the amino acid sequence of SEQ ID NO: 220 or its isoforms or variants having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 220. In some embodiments, the light chain constant domain is human. In some embodiments, the human light chain constant domain is human κ or human λ. In some embodiments, human κ includes the amino acid sequence of SEQ ID NO: 221 or its isoforms or variants having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 221. In some embodiments, human λ includes the amino acid sequence of SEQ ID NO: 222 or its isoforms or variants having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 222.

[0213] In one embodiment, the anti-UCH-L1 antibody described herein is a monoclonal antibody. In one embodiment, the anti-UCH-L1 antibody described herein is a humanized antibody, a chimeric antibody, or a human antibody. In one embodiment, the anti-UCH-L1 antibody described herein is a mouse antibody, a rabbit antibody, a rat antibody, or a non-human primate antibody. In some embodiments, any anti-UCH-L1 antibody is recombinant. In one embodiment, any anti-UCH-L1 antibody described herein is isolated or purified.

[0214] In some embodiments, the anti-UCH-L1 antibody provided herein is 10 -8 M or less, for example, 10 -8 M~10 -13 M, for example, 10 -9 M~10 -13 M, for example, 10 -10 M~10 -12 The dissociation constant (K) of M D ) has binding affinity. In some embodiments, the anti-UCH-L1 antibody provided herein has a dissociation constant (K) of 1 μM or less, 150 nM or less, 100 nM or less, 50 nM or less, 10 nM or less, 1 nM or less, 0.1 nM or less, 0.01 nM or less, or 0.001 nM or less. D ) has. In some embodiments, the anti-UCH-L1 antibody provided herein is 1.0 × 10 -10 M, 2.0×10 -10 M, 3.0×10 -10 M, 4.0×10 -10 M, 5.0×10 -10 M, 6.0×10 -10 M, 7.0×10 -10 M, 8.0×10 -10 M, 9.0×10 -10 M, 1.0×10 -11 M, 2.0×10 -11 M, 3.0×10 -11 M, 4.0×10 -11 M, 5.0×10 -11 M, 6.0×10 -11 M, 7.0×10 -11 M, 8.0×10 -11 M, 9.0×10 -11M, or 1.0 × 10 -12 Dissociation constant (K) less than or approximately less than M D ) has.

[0215] In some embodiments, the anti-UCH-L1 antibody provided herein is 2.0 × 10⁻⁶ -10 M~5.0×10 -12 M or approximately its range, for example, 2.0 × 10 -10 M~1.0×10 -12 M, 2.0×10 -10 M~5.0×10 -11 M, 2.0×10 -10 M~1.0×10 -11 M, 2.0×10 -10 M~5.0×10 -10 M, 5.0×10 -10 M~1.0×10 -12 M, 5.0×10 -10 M~5.0×10 -11 M, 5.0×10 -10 M~1.0×10 -11 M, 1.0×10 -11 M~1.0×10 -12 M, 1.0×10 -11 M~5.0×10 -11 M or 5.0×10 -11 M~1.0×10 -12 M, or the dissociation constant (K) in approximately that range. D ) has affinity. In some embodiments, the anti-UCH-L1 antibody provided herein has 2 × 10 -10 M ~ approx. 1×10 -12 M or the dissociation constant (K) in approximately that range D ) has. In some embodiments, the anti-UCH-L1 antibody provided herein is 2.0 × 10 -10 M~4.0×10 -10 M, 1.0×10 -11 M~9.0×10 -11 M, or 1.0 × 10 -12 M~5.0×10 -12 M, or the dissociation constant (K) in approximately that range. D) has. In some embodiments, the anti-UCH-L1 antibodies provided herein are antibodies shown in Table 4, for example, UCH-L1-1, UCH-L1-2, etc., with a dissociation constant (K D ) has.

[0216] In one embodiment, a nucleic acid encoding an anti-UCH-L1 antibody is provided. In some embodiments, the nucleic acid may encode an anti-UCH-L1 antibody or antigen-binding fragment provided herein. In some embodiments, the nucleic acid may encode a heavy chain containing a heavy chain variable region of an anti-UCH-L1 antibody or antigen-binding fragment provided herein. In some embodiments, the nucleic acid may encode a light chain containing a light chain variable region of an anti-UCH-L1 antibody or antigen-binding fragment provided herein.

[0217] In certain embodiments, a vector such as an expression vector containing a nucleic acid encoding an anti-UCH-L1 antibody is provided. In certain embodiments, a host cell containing such nucleic acid and / or vector is provided. For example, a host cell provided herein may include a vector containing a nucleic acid encoding the heavy chain of the anti-UCH-L1 antibody or antigen-binding fragment provided herein. In some embodiments, such a host cell may further include a vector containing a nucleic acid encoding the light chain of the anti-UCH-L1 antibody or antigen-binding fragment provided herein.

[0218] In another aspect of the present invention, a composition comprising an anti-UCH-L1 antibody or a nucleic acid encoding an anti-UCH-L1 antibody is provided. In certain embodiments, the compositions provided herein may be used for the detection of UCH-L1, for the diagnosis of brain injury or injury (e.g., resulting from a neurological condition, stroke, or traumatic brain injury) in an individual having or suspected of having brain injury or injury, and / or for predicting whether the subject requires a CT scan, such as in the methods enumerated herein. In some embodiments, the provided anti-UCH-L1 antibody may be used in combination with any one or more anti-GFAP antibodies provided herein.

[0219] B. Anti-GFAP antibody In one embodiment, antibodies conjugating to human GFAP protein, comprising fragments, isoforms, or variants of human GFAP protein, are provided herein. In some embodiments, the human GFAP protein is released from damaged cells or tissues and / or present in body fluids (e.g., serum, cerebrospinal fluid, or other body fluids described) as a result of brain injury or injury. In some embodiments, the anti-GFAP antibody conjugates to human GFAP protein comprising an amino acid sequence selected from any of SEQ ID NOs. 212-214, or a variant thereof having an amino acid sequence having at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence selected from SEQ ID NOs. 212-214.

[0220] In some embodiments, a GFAP variant is a GFAP having at least about 80% amino acid sequence identity with the GFAP amino acid sequence, and is: (i) a full-length native GFAP amino acid sequence as shown in any of SEQ ID NOs. 212-214; (ii) a full-length recombinant GFAP amino acid sequence as shown in any of SEQ ID NOs. 212-214; (iii) a GFAP amino acid sequence of (i) or (ii) lacking a signal peptide; or (iv) encoded by any other fragment of the full-length GFAP amino acid sequence of (i) or (ii), for example, a nucleic acid representing only a small portion of the complete coding sequence for the full-length GFAP protein. Such GFAP variants include, for example, polypeptides in which one or more amino acid residues are added or deleted at the N- or C-terminus of the full-length native amino acid sequence or the full-length recombinant amino acid sequence. Typically, GFAP variants have at least approximately 80% amino acid sequence identity, or at least approximately 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% amino acid sequence identity, with the full-length native GFAP amino acid sequence (e.g., shown in SEQ ID NOs. 212-214), the full-length recombinant GFAP amino acid sequence (e.g., shown in SEQ ID NOs. 212-214), or any other fragment of the GFAP amino acid sequence lacking a signal peptide or any other fragment of the full-length GFAP amino acid sequence. In some embodiments, GFAP variants containing full-length sequence fragments are at least about 10 amino acids long, or at least about 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430 amino acids long, or longer.In some embodiments, the GFAP variant has one or fewer conserved amino acid substitutions compared to the native GFAP amino acid sequence or the recombinant GFAP amino acid sequence, or two, three, four, five, six, seven, eight, nine, or ten or fewer conserved amino acid substitutions compared to the native GFAP amino acid sequence or the recombinant GFAP amino acid sequence.

[0221] In some embodiments, the anti-GFAP antibody binds to an epitope or region corresponding to an epitope or region contained within the human GFAP protein shown in SEQ ID NO: 212, or to the same epitope or region within an isoform, fragment, or variant of the GFAP protein shown in SEQ ID NO: 212.

[0222] In some embodiments, the GFAP protein (e.g., human GFAP protein) is a recombinant GFAP protein, such as a recombinant GFAP protein produced in bacterial host cells (e.g., E. coli cells) or mammalian host cells (e.g., CHO cells). In some embodiments, the GFAP protein (e.g., human GFAP protein) is a native GFAP protein, such as a native GFAP protein present in or obtained in serum, plasma, blood (e.g., whole blood), cerebrospinal fluid, urine, sweat, saliva, or any other biological fluid present in or obtained in an individual (e.g., human). In some embodiments, the anti-GFAP antibody binds to GFAP modified by citrullination, glycosylation, phosphorylation, or other modifications.

[0223] In some embodiments, the anti-GFAP antibody described herein binds to a linear epitope of GFAP (e.g., human GFAP). In some embodiments, the anti-GFAP antibody described herein binds to a structural epitope of GFAP (e.g., human GFAP).

[0224] In some embodiments, the anti-GFAP antibody binds to a specific epitope or region of GFAP. In some embodiments, the anti-GFAP antibody binds to an epitope that contains, or includes (or is entirely contained within) one or more amino acids, which is a portion of GFAP corresponding to positions 92-106 of the human GFAP protein shown in SEQ ID NO: 212. In some embodiments, the anti-GFAP antibody binds to an epitope that contains, or includes (or is entirely contained within) one or more amino acids, which is a portion of GFAP corresponding to positions 190-202 of the human GFAP protein shown in SEQ ID NO: 212. In some embodiments, the anti-GFAP antibody binds to an epitope that contains, or includes (or is entirely contained within) one or more amino acids, which is a portion of GFAP corresponding to positions 16-35 and / or 380 of the human GFAP protein shown in SEQ ID NO: 212. In some embodiments, the anti-GFAP antibody binds to an epitope containing, or including (or entirely containing) one or more amino acids, the portion of GFAP corresponding to positions 119 and / or 190 of the human GFAP protein shown in SEQ ID NO: 212. In some embodiments, the anti-GFAP antibody binds to an epitope containing, or including (or entirely containing) one or more amino acids, the portion of GFAP corresponding to positions 380-391 of the human GFAP protein shown in SEQ ID NO: 212. In some embodiments, the anti-GFAP antibody binds to an epitope containing, or including (or entirely containing) one or more amino acids, the portion of GFAP corresponding to positions 119-130 of the human GFAP protein shown in SEQ ID NO: 212. In some embodiments, the anti-GFAP antibody binds to an epitope containing, or including (or entirely containing) one or more amino acids, the portion of GFAP corresponding to positions 210-221 of the human GFAP protein shown in SEQ ID NO: 212.In some embodiments, the anti-GFAP antibody binds to an epitope that includes, or contains (or is entirely contained within) one or more amino acids, which is a portion of the GFAP protein corresponding to positions 320-329, 346-357, and / or 376-387, as shown in SEQ ID NO: 212. In some embodiments, the anti-GFAP antibody binds to an epitope that includes, or contains (or is entirely contained within) one or more amino acids, which is a portion of the GFAP protein corresponding to positions 138-149, as shown in SEQ ID NO: 212.

[0225] In some embodiments, among the antibodies provided, the antibodies bind to epitopes that are identical to or overlap with one or more of the other antibodies provided, and / or compete with one or more of the other antibodies provided for binding to GFAP. In some embodiments, among the antibodies provided, the antibodies bind to different or distinct epitopes compared to one or more of the other antibodies provided, and / or do not compete with one or more of the other antibodies provided for binding to GFAP. For example, in some embodiments, the antibodies provided bind to distinct epitopes and / or do not compete with the antibodies designated as GFAP-2 as described herein for binding to GFAP. In some embodiments, the antibodies provided bind to distinct epitopes and / or do not compete with the antibodies designated as GFAP-6 as described herein for binding to GFAP.

[0226] In some embodiments, the antibody binds to GFAP epitopes that are conserved among GFAPs from different species. In some embodiments, the antibody binds to GFAP epitopes that are present in human GFAP or its isoforms or variants but not in one or more other non-human species.

[0227] In one embodiment, an anti-GFAP antibody comprising a heavy chain variable region and a light chain variable region is provided herein, wherein the heavy chain variable region comprises CDR-H3 comprising an amino acid sequence selected from SEQ ID NOs: 108-124. In some embodiments, the heavy chain variable region further comprises CDR-H1 comprising an amino acid sequence selected from SEQ ID NOs: 77-90 and / or CDR-H2 comprising an amino acid sequence selected from SEQ ID NOs: 91-107.

[0228] In one embodiment, an anti-GFAP antibody comprising a heavy chain variable region and a light chain variable region is provided herein, wherein the light chain variable region comprises CDR-L3 comprising an amino acid sequence selected from SEQ ID NOs. 157-171. In some embodiments, the heavy chain variable region further comprises CDR-L1 comprising an amino acid sequence selected from SEQ ID NOs. 125-141 and / or CDR-L2 comprising an amino acid sequence selected from SEQ ID NOs. 142-156.

[0229] In some embodiments, the heavy chain CDR sequence includes: a) CDR-H1 as shown in SEQ ID NOs. 77; 78; 79; 80; 81; 82; 83; 84; 85; 86; 87; 88; 89 or 90; b) CDR-H2 as shown in SEQ ID NOs. 91; SEQ ID NOs. 92; SEQ ID NOs. 93; SEQ ID NOs. 94; SEQ ID NOs. 95; SEQ ID NOs. 96; SEQ ID NOs. 97; SEQ ID NOs. 98; SEQ ID NOs. 99; SEQ ID NOs. 100; SEQ ID NOs. 101, SEQ ID NOs. 102; SEQ ID NOs. 103; SEQ ID NOs. 104; SEQ ID NOs. 105; SEQ ID NOs. 106 or SEQ ID NOs. 107; and c) CDR-H3 as shown in SEQ ID NOs: 108; 109; 110; 111; 112; 113; 114; 115; 116; 117; 118; 119; 120; 121; 122; 123 or 124.

[0230] In some embodiments, the heavy chain CDR sequence includes: a) CDR-H1 as shown in SEQ ID NOs. 77; 78; 79; 80; 81; 82; 83; 84; 85; 86; 87; 88; 89 or 90; b) CDR-H2 as shown in SEQ ID NOs. 93; SEQ ID NOs. 94; SEQ ID NOs. 95; SEQ ID NOs. 96; SEQ ID NOs. 97; SEQ ID NOs. 98; SEQ ID NOs. 99; SEQ ID NOs. 100; SEQ ID NOs. 101, SEQ ID NOs. 102; SEQ ID NOs. 103; SEQ ID NOs. 104; SEQ ID NOs. 105; SEQ ID NOs. 106 or SEQ ID NOs. 107; and c) CDR-H3 as shown in SEQ ID NO: 110; SEQ ID NO: 111; SEQ ID NO: 112; SEQ ID NO: 113; SEQ ID NO: 114; SEQ ID NO: 115; SEQ ID NO: 116; SEQ ID NO: 117; SEQ ID NO: 118; SEQ ID NO: 119; SEQ ID NO: 120; SEQ ID NO: 121; SEQ ID NO: 122; SEQ ID NO: 123 or SEQ ID NO: 124.

[0231] In some embodiments, the heavy chain CDR sequence includes: a) CDR-H shown in Sequence ID 77; b) CDR-H2 as shown in Sequence ID No. 91; and c) CDR-H3 as shown in Sequence ID No. 108.

[0232] In some embodiments, the heavy chain CDR sequence includes: a) CDR-H1 as shown in Sequence ID No. 78; b) CDR-H2 as shown in Sequence ID No. 92; and c) CDR-H3 as shown in Sequence ID No. 109.

[0233] In some embodiments, the light chain CDR sequence includes: a) CDR-L1 as shown in SEQ ID NOs. 125; 126; 127; 128; 129; 130; 131; 132; 133; 134; 135; 136; 137; 138; 139; 140 or 141; b) CDR-L2 as shown in SEQ ID NOs. 142; SEQ ID NOs. 143, 144; SEQ ID NOs. 145; SEQ ID NOs. 146; SEQ ID NOs. 147; SEQ ID NOs. 148; SEQ ID NOs. 149; SEQ ID NOs. 150; SEQ ID NOs. 151; SEQ ID NOs. 152; SEQ ID NOs. 153; SEQ ID NOs. 154; SEQ ID NOs. 155 or SEQ ID NOs. 156; and c) CDR-L3 as shown in SEQ ID NO: 157; SEQ ID NO: 158; SEQ ID NO: 159; SEQ ID NO: 160; SEQ ID NO: 161; SEQ ID NO: 162; SEQ ID NO: 163; SEQ ID NO: 164; SEQ ID NO: 165; SEQ ID NO: 166; SEQ ID NO: 167; SEQ ID NO: 168; SEQ ID NO: 169; SEQ ID NO: 170 or SEQ ID NO: 171.

[0234] In some embodiments, the light chain CDR sequence includes: a) CDR-L1 as shown in SEQ ID NO: 126; SEQ ID NO: 127; SEQ ID NO: 128; SEQ ID NO: 129; SEQ ID NO: 130; SEQ ID NO: 131; SEQ ID NO: 132; SEQ ID NO: 133; SEQ ID NO: 134; SEQ ID NO: 135; SEQ ID NO: 136; SEQ ID NO: 137; SEQ ID NO: 138; SEQ ID NO: 139; SEQ ID NO: 140 or SEQ ID NO: 141; b) CDR-L2 as shown in SEQ ID NO: 142; SEQ ID NO: 144; SEQ ID NO: 145; SEQ ID NO: 146; SEQ ID NO: 147; SEQ ID NO: 148; SEQ ID NO: 149; SEQ ID NO: 150; SEQ ID NO: 151; SEQ ID NO: 152; SEQ ID NO: 153; SEQ ID NO: 154; SEQ ID NO: 155 or SEQ ID NO: 156; and c) CDR-L3 as shown in SEQ ID NO: 158; SEQ ID NO: 159; SEQ ID NO: 160; SEQ ID NO: 161; SEQ ID NO: 162; SEQ ID NO: 163; SEQ ID NO: 164; SEQ ID NO: 165; SEQ ID NO: 166; SEQ ID NO: 167; SEQ ID NO: 168; SEQ ID NO: 169; SEQ ID NO: 170 or SEQ ID NO: 171.

[0235] In some embodiments, the light chain CDR sequence includes: a) CDR-L1 as shown in Sequence ID No. 125; b) CDR-L2 as shown in Sequence ID No. 142; and c) CDR-L3 as shown in Sequence ID No. 157.

[0236] In some embodiments, the light chain CDR sequence includes: a) CDR-L1 as shown in Sequence ID No. 126; b) CDR-L2 as shown in Sequence ID No. 143; and c) CDR-L3 as shown in sequence number 158.

[0237] Antibodies are also provided that contain the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and / or CDR-L3 sequences, which are identical to any of the above-mentioned CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and / or CDR-L3 sequences by at least or approximately 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%, respectively.

[0238] In one embodiment, an anti-GFAP antibody comprising a heavy chain variable region and a light chain variable region is provided herein, wherein the heavy chain variable region comprises (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 77, (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 91, and (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 108; and / or the light chain variable region comprises (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 125, (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 142, and (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 157. In some embodiments, the antibody described herein binds to an epitope corresponding to an epitope that is or comprises human GFAP within residues 92-106 shown in SEQ ID NO: 212.

[0239] In one embodiment, an anti-GFAP antibody comprising a heavy chain variable region and a light chain variable region is provided herein, wherein the heavy chain variable region comprises (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 78, (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 92, and (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 109; and / or the light chain variable region comprises (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 126, (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 143, and (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 158. In some embodiments, the antibody described herein binds to an epitope corresponding to an epitope that is or comprises human GFAP within residues 190-202 shown in SEQ ID NO: 212.

[0240] In one embodiment, an anti-GFAP antibody comprising a heavy chain variable region and a light chain variable region is provided herein, wherein the heavy chain variable region comprises (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 79, (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 93, and (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 110; and / or the light chain variable region comprises (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 127, (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 144, and (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 159. In some embodiments, the antibody described herein binds to an epitope corresponding to an epitope that is or comprises human GFAP within residues 16-35 and / or 380 of SEQ ID NO: 212.

[0241] In another embodiment, an anti-GFAP antibody comprising a heavy chain variable region and a light chain variable region is provided herein, the heavy chain variable region comprising (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 77, (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 94, and (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 111; and / or the light chain variable region comprising (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 128, (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 145, and (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 160. In some embodiments, the antibody described herein binds to an epitope corresponding to the epitope that is or comprises the human GFAP shown in SEQ ID NO: 212, specifically within residues 119 and / or 190.

[0242] In another embodiment, an anti-GFAP antibody comprising a heavy chain variable region and a light chain variable region is provided herein, wherein the heavy chain variable region comprises (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 80, (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 95, and (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 112; and / or the light chain variable region comprises (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 126, (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 142, and (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 158. In some embodiments, the antibody described herein binds to an epitope corresponding to the epitope that is or comprises the human GFAP within residues 119-130 shown in SEQ ID NO: 212.

[0243] In another embodiment, an anti-GFAP antibody comprising a heavy chain variable region and a light chain variable region is provided herein, wherein the heavy chain variable region comprises (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 81, (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 96, and (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 113; and / or the light chain variable region comprises (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 129, (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 146, and (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 161. In some embodiments, the antibody described herein binds to an epitope corresponding to an epitope that is or comprises human GFAP within residues 380-391 shown in SEQ ID NO: 212.

[0244] In another embodiment, an anti-GFAP antibody comprising a heavy chain variable region and a light chain variable region is provided herein, the heavy chain variable region comprising (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 77, (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 94, and (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 111; and / or the light chain variable region comprising (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 130, (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 145, and (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 160. In some embodiments, the antibody described herein binds to an epitope corresponding to an epitope that is or comprises human GFAP within residues 380-391 as shown in SEQ ID NO: 212.

[0245] In another embodiment, an anti-GFAP antibody comprising a heavy chain variable region and a light chain variable region is provided herein, wherein the heavy chain variable region comprises (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 82, (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 97, and (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 114; and / or the light chain variable region comprises (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 131, (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 147, and (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 162. In some embodiments, the antibody described herein binds to an epitope corresponding to an epitope that is or comprises human GFAP within residues 380-391 as shown in SEQ ID NO: 212.

[0246] In another embodiment, an anti-GFAP antibody comprising a heavy chain variable region and a light chain variable region is provided herein, wherein the heavy chain variable region comprises (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 83, (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 98, and (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 115; and / or the light chain variable region comprises (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 132, (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 148, and (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 163.

[0247] In another embodiment, an anti-GFAP antibody comprising a heavy chain variable region and a light chain variable region is provided herein, wherein the heavy chain variable region comprises (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 84, (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 99, and (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 116; and / or the light chain variable region comprises (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 133, (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 149, and (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 164. In some embodiments, the antibody described herein binds to an epitope corresponding to the epitope that is or comprises the human GFAP residues 119-130 shown in SEQ ID NO: 212.

[0248] In another embodiment, an anti-GFAP antibody comprising a heavy chain variable region and a light chain variable region is provided herein, wherein the heavy chain variable region comprises (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 85, (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 100, and (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 117; and / or the light chain variable region comprises (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 134, (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 150, and (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 165. In some embodiments, the antibody described herein binds to an epitope corresponding to the epitope that is or comprises the human GFAP residues 119-130 shown in SEQ ID NO: 212.

[0249] In another embodiment, an anti-GFAP antibody comprising a heavy chain variable region and a light chain variable region is provided herein, wherein the heavy chain variable region comprises (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 86, (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 101, and (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 118; and / or the light chain variable region comprises (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 135, (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 151, and (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 166. In some embodiments, the antibody described herein binds to an epitope corresponding to an epitope that is or comprises human GFAP within residues 210-221 shown in SEQ ID NO: 212.

[0250] In another embodiment, an anti-GFAP antibody comprising a heavy chain variable region and a light chain variable region is provided herein, wherein the heavy chain variable region comprises (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 78, (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 102, and (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 119; and / or the light chain variable region comprises (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 136, (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 152, and (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 167. In some embodiments, the antibody described herein binds to an epitope corresponding to an epitope that is or comprises the human GFAP residues 210-221 shown in SEQ ID NO: 212.

[0251] In another embodiment, an anti-GFAP antibody comprising a heavy chain variable region and a light chain variable region is provided herein, wherein the heavy chain variable region comprises (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 78, (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 103, and (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 120; and / or the light chain variable region comprises (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 137, (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 142, and (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 158. In some embodiments, the antibody described herein binds to an epitope corresponding to an epitope that is or comprises the human GFAP residues 210-221 shown in SEQ ID NO: 212.

[0252] In another embodiment, an anti-GFAP antibody comprising a heavy chain variable region and a light chain variable region is provided herein, wherein the heavy chain variable region comprises (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 87, (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 104, and (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 121; and / or the light chain variable region comprises (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 138, (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 153, and (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 168. In some embodiments, the antibody described herein binds to an epitope corresponding to an epitope that is or comprises human GFAP within residues 320-329 shown in SEQ ID NO: 212.

[0253] In another embodiment, an anti-GFAP antibody comprising a heavy chain variable region and a light chain variable region is provided herein, wherein the heavy chain variable region comprises (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 88, (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 105, and (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 122; and / or the light chain variable region comprises (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 139, (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 154, and (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 169. In some embodiments, the antibody described herein binds to an epitope corresponding to an epitope that is or comprises the human GFAP residues 320-329, 346-357 and / or 376-387 shown in SEQ ID NO: 212.

[0254] In another embodiment, an anti-GFAP antibody comprising a heavy chain variable region and a light chain variable region is provided herein, the heavy chain variable region comprising (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 89, (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 106, and (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 123; and / or the light chain variable region comprising (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 140, (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 155, and (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 170. In some embodiments, the antibody described herein binds to an epitope corresponding to an epitope that is or comprises human GFAP residues 119-130 and / or 138-149 shown in SEQ ID NO: 212.

[0255] In another embodiment, an anti-GFAP antibody comprising a heavy chain variable region and a light chain variable region is provided herein, wherein the heavy chain variable region comprises (i) CDR-H1 comprising the amino acid sequence of SEQ ID NO: 90, (ii) CDR-H2 comprising the amino acid sequence of SEQ ID NO: 107, and (iii) CDR-H3 comprising the amino acid sequence of SEQ ID NO: 124; and / or the light chain variable region comprises (i) CDR-L1 comprising the amino acid sequence of SEQ ID NO: 141, (ii) CDR-L2 comprising the amino acid sequence of SEQ ID NO: 156, and (iii) CDR-L3 comprising the amino acid sequence of SEQ ID NO: 171. In some embodiments, the antibody described herein binds to an epitope corresponding to an epitope that is or comprises human GFAP within residues 119-130 of SEQ ID NO: 212.

[0256] In some embodiments, anti-GFAP includes a heavy chain variable region containing CDR-H1, CDR-H2, and CDR-H3, and each contains the amino acid sequences of CDR-H1, CDR-H2, and CDR-H3 contained within a heavy chain variable region amino acid sequence selected from any one of SEQ ID NOs. 172 to 188. In some embodiments, anti-GFAP includes a heavy chain variable region containing CDR-H1, CDR-H2, and CDR-H3, and each contains the amino acid sequences of CDR-H1, CDR-H2, and CDR-H3 contained within a heavy chain variable region amino acid sequence selected from any one of SEQ ID NOs. 174 to 188. In some embodiments, anti-GFAP includes a heavy chain variable region containing CDR-H1, CDR-H2, and CDR-H3, and each contains the amino acid sequences of CDR-H1, CDR-H2, and CDR-H3 contained within the heavy chain variable region amino acid sequence of SEQ ID NO. 172. In some embodiments, anti-GFAP includes a heavy chain variable region comprising CDR-H1, CDR-H2, and CDR-H3, and each comprises the amino acid sequences of CDR-H1, CDR-H2, and CDR-H3 contained within the heavy chain variable region amino acids of SEQ ID NO: 173.

[0257] In some embodiments, anti-GFAP includes CDR-L1, CDR-L2, and CDR-L3, each containing the amino acid sequences of CDR-L1, CDR-L2, and CDR-L3 within a light chain variable region amino acid sequence selected from any one of SEQ ID NOs. 189 to 206. In some embodiments, anti-GFAP includes CDR-L1, CDR-L2, and CDR-L3, each containing the amino acid sequences of CDR-L1, CDR-L2, and CDR-L3 within a light chain variable region amino acid sequence selected from any one of SEQ ID NOs. 191 to 206. In some embodiments, anti-GFAP includes CDR-L1, CDR-L2, and CDR-L3, each containing the amino acid sequences of CDR-L1, CDR-L2, and CDR-L3 within the light chain variable region amino acid sequence of SEQ ID NO. 189. In some embodiments, anti-GFAP comprises CDR-L1, CDR-L2, and CDR-L3, each containing the amino acid sequences of CDR-L1, CDR-L2, and CDR-L3 within the light chain variable region amino acid sequence of SEQ ID NO: 190.

[0258] The anti-GFAP antibodies described herein may contain any suitable framework variable domain sequence, as long as the antibody retains the ability to bind to GFAP (e.g., human GFAP). As used herein, the heavy chain framework region is designated as "HC-FR1-FR4" and the light chain framework region is designated as "LC-FR1-FR4".

[0259] In some embodiments, anti-GFAP antibodies are provided herein that include a heavy chain variable domain comprising an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with an amino acid sequence selected from SEQ ID NOs.172-188. In some embodiments, anti-GFAP antibodies are provided herein that include a heavy chain variable domain comprising an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with an amino acid sequence selected from SEQ ID NOs.174-188. In some embodiments, anti-GFAP antibodies are provided herein that include a heavy chain variable domain comprising an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with the amino acid sequence of SEQ ID NO: 172. In some embodiments, anti-GFAP antibodies are provided herein that include a heavy chain variable domain comprising an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with the amino acid sequence of SEQ ID NO: 173. In some embodiments, an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity includes substitutions, insertions, or deletions compared to the reference sequence, but an antibody containing that amino acid sequence retains the ability to bind to GFAP (e.g., human GFAP). In some embodiments, the substitutions, insertions, or deletions (e.g., 1, 2, 3, 4, or 5 amino acids) occur in the outer region of the CDR (i.e., in the FR).

[0260] In some embodiments, the anti-GFAP antibody includes a heavy chain variable domain containing an amino acid sequence selected from SEQ ID NOs: 172-188. In some embodiments, the anti-GFAP antibody includes a heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 172. In some embodiments, the anti-GFAP antibody includes a heavy chain variable domain containing an amino acid sequence selected from SEQ ID NO: 173. In some embodiments, the anti-GFAP antibody includes a heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 174. In some embodiments, the anti-GFAP antibody includes a heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 175. In some embodiments, the anti-GFAP antibody includes a heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 176. In some embodiments, the anti-GFAP antibody includes a heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 177. In some embodiments, the anti-GFAP antibody includes a heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 178. In some embodiments, the anti-GFAP antibody includes a heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 179. In some embodiments, the anti-GFAP antibody includes a heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 180. In some embodiments, the anti-GFAP antibody includes a heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 181. In some embodiments, the anti-GFAP antibody includes a heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 182. In some embodiments, the anti-GFAP antibody includes a heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 183. In some embodiments, the anti-GFAP antibody includes a heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 184. In some embodiments, the anti-GFAP antibody includes a heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 185. In some embodiments, the anti-GFAP antibody includes a heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 186. In some embodiments, the anti-GFAP antibody includes a heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 187. In some embodiments, the anti-GFAP antibody includes a heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 188.

[0261] In some embodiments, anti-GFAP antibodies are provided herein that include a light chain variable domain comprising an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with an amino acid sequence selected from SEQ ID NOs.189-206. In some embodiments, anti-GFAP antibodies are provided herein that include a light chain variable domain comprising an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with an amino acid sequence selected from SEQ ID NOs.191-206. In some embodiments, anti-GFAP antibodies are provided herein that include a light chain variable domain comprising an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with the amino acid sequence of SEQ ID NO: 189. In some embodiments, anti-GFAP antibodies are provided herein that include a light chain variable domain comprising an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with the amino acid sequence of SEQ ID NO: 190. In some embodiments, an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity includes substitutions, insertions, or deletions compared to the reference sequence, but an antibody containing that amino acid sequence retains the ability to bind to GFAP (e.g., human GFAP). In some embodiments, the substitutions, insertions, or deletions (e.g., 1, 2, 3, 4, or 5 amino acids) occur in the outer region of the CDR (i.e., in the FR).

[0262] In some embodiments, the anti-GFAP antibody includes a light chain variable domain containing an amino acid sequence selected from SEQ ID NOs: 189-206. In some embodiments, the anti-GFAP antibody includes a light chain variable domain containing the amino acid sequence of SEQ ID NO: 189. In some embodiments, the anti-GFAP antibody includes a light chain variable domain containing the amino acid sequence of SEQ ID NO: 190. In some embodiments, the anti-GFAP antibody includes a light chain variable domain containing the amino acid sequence of SEQ ID NO: 191. In some embodiments, the anti-GFAP antibody includes a light chain variable domain containing the amino acid sequence of SEQ ID NO: 192. In some embodiments, the anti-GFAP antibody includes a light chain variable domain containing the amino acid sequence of SEQ ID NO: 193. In some embodiments, the anti-GFAP antibody includes a light chain variable domain containing the amino acid sequence of SEQ ID NO: 194. In some embodiments, the anti-GFAP antibody includes a light chain variable domain containing the amino acid sequence of SEQ ID NO: 195. In some embodiments, the anti-GFAP antibody includes a light chain variable domain containing the amino acid sequence of SEQ ID NO: 196. In some embodiments, the anti-GFAP antibody includes a light chain variable domain containing the amino acid sequence of SEQ ID NO: 197. In some embodiments, the anti-GFAP antibody includes a light chain variable domain containing the amino acid sequence of SEQ ID NO: 198. In some embodiments, the anti-GFAP antibody includes a light chain variable domain containing the amino acid sequence of SEQ ID NO: 199. In some embodiments, the anti-GFAP antibody includes a light chain variable domain containing the amino acid sequence of SEQ ID NO: 200. In some embodiments, the anti-GFAP antibody includes a light chain variable domain containing the amino acid sequence of SEQ ID NO: 201. In some embodiments, the anti-GFAP antibody includes a light chain variable domain containing the amino acid sequence of SEQ ID NO: 202. In some embodiments, the anti-GFAP antibody includes a light chain variable domain containing the amino acid sequence of SEQ ID NO: 203. In some embodiments, the anti-GFAP antibody includes a light chain variable domain containing the amino acid sequence of SEQ ID NO: 204. In some embodiments, the anti-GFAP antibody includes a light chain variable domain containing the amino acid sequence of SEQ ID NO: 205. In some embodiments, the anti-GFAP antibody includes a light chain variable domain containing the amino acid sequence of SEQ ID NO: 206.

[0263] In one embodiment, an anti-GFAP antibody is provided herein that includes a heavy chain variable domain containing an amino acid sequence selected from SEQ ID NOs: 172-188, and / or a light chain variable domain containing an amino acid sequence selected from SEQ ID NOs: 189-206. In some embodiments, the anti-GFAP antibody includes a heavy chain variable domain containing an amino acid sequence selected from SEQ ID NOs: 174-188, and / or a light chain variable domain containing an amino acid sequence selected from SEQ ID NOs: 191-206. In some embodiments, the anti-GFAP antibody includes a heavy chain variable domain containing an amino acid sequence selected from SEQ ID NOs: 172, and / or a light chain variable domain containing an amino acid sequence selected from SEQ ID NOs: 189. In some embodiments, the anti-GFAP antibody includes a heavy chain variable domain containing an amino acid sequence selected from SEQ ID NOs: 173, and / or a light chain variable domain containing an amino acid sequence selected from SEQ ID NOs: 190. Also provided are antibodies containing a heavy chain variable domain and / or light chain variable domain sequence that is at least or approximately 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to any of the heavy chain variable domain and / or light chain variable domain sequences described above.

[0264] In some embodiments, anti-GFAP antibodies comprising the heavy chain variable domain and / or light chain variable domain of the antibodies shown in Table 10 (e.g., GFAP-2, GFAP-6, etc.) are provided herein.

[0265] In some embodiments, the anti-GFAP antibody includes a heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 172, and / or a light chain variable domain containing the amino acid sequence of SEQ ID NO: 189. In some embodiments, the anti-GFAP antibody includes a heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 173, and / or a light chain variable domain containing the amino acid sequence of SEQ ID NO: 190. In some embodiments, the anti-GFAP antibody includes a heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 174, and / or a light chain variable domain containing the amino acid sequence of SEQ ID NO: 191. In some embodiments, the anti-GFAP antibody includes a heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 175, and / or a light chain variable domain containing the amino acid sequence of SEQ ID NO: 192. In some embodiments, the anti-GFAP antibody includes a heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 176, and / or a light chain variable domain containing the amino acid sequence of SEQ ID NO: 193. In some embodiments, the anti-GFAP antibody includes a heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 177 and / or a light chain variable domain containing the amino acid sequence of SEQ ID NO: 194. In some embodiments, the anti-GFAP antibody includes a heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 175 and / or a light chain variable domain containing the amino acid sequence of SEQ ID NO: 195. In some embodiments, the anti-GFAP antibody includes a heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 178 and / or a light chain variable domain containing the amino acid sequence of SEQ ID NO: 196. In some embodiments, the anti-GFAP antibody includes a heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 179 and / or a light chain variable domain containing the amino acid sequence of SEQ ID NO: 197. In some embodiments, the anti-GFAP antibody includes a heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 180 and / or a light chain variable domain containing the amino acid sequence of SEQ ID NO: 198. In some embodiments, the anti-GFAP antibody includes a heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 181 and / or a light chain variable domain containing the amino acid sequence of SEQ ID NO: 199.In some embodiments, the anti-GFAP antibody includes a heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 182, and / or a light chain variable domain containing the amino acid sequence of SEQ ID NO: 200. In some embodiments, the anti-GFAP antibody includes a heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 183, and / or a light chain variable domain containing the amino acid sequence of SEQ ID NO: 201. In some embodiments, the anti-GFAP antibody includes a heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 184, and / or a light chain variable domain containing the amino acid sequence of SEQ ID NO: 202. In some embodiments, the anti-GFAP antibody includes a heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 185, and / or a light chain variable domain containing the amino acid sequence of SEQ ID NO: 203. In some embodiments, the anti-GFAP antibody includes a heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 186, and / or a light chain variable domain containing the amino acid sequence of SEQ ID NO: 204. In some embodiments, the anti-GFAP antibody includes a heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 187 and / or a light chain variable domain containing the amino acid sequence of SEQ ID NO: 205. In some embodiments, the anti-GFAP antibody includes a heavy chain variable domain containing the amino acid sequence of SEQ ID NO: 188 and / or a light chain variable domain containing the amino acid sequence of SEQ ID NO: 206.

[0266] In some embodiments, the anti-GFAP antibody does not include a variable heavy chain comprising CDR-H1, CDR-H2, and CDR-H3 as shown in SEQ ID NOs. 78, 92, and 109, respectively, and a variable light chain comprising CDR-L1, CDR-L2, and CDR-L3 as shown in SEQ ID NOs. 126, 143, and 158, respectively. In some embodiments, the anti-GFAP antibody does not include a variable heavy chain as shown in SEQ ID NO. 173 and a variable light chain as shown in SEQ ID NO. 190. In some embodiments, the anti-GFAP antibody is not an antibody designated as GFAP-2.

[0267] In one embodiment, the anti-GFAP antibody described herein is a monoclonal antibody. In one embodiment, the anti-GFAP antibody described herein is an antibody fragment (including an antigen-binding fragment), for example, Fab, Fab'-SH, Fv, scFv, or (Fab')2 fragment.

[0268] In any embodiment of this specification, the antibody may include a heavy chain constant domain. In some embodiments, the heavy chain constant domain is a non-human mammal. In some embodiments, the heavy chain constant domain is a non-human primate. In some embodiments, the heavy chain constant domain is a non-human primate. In some embodiments, the heavy chain constant domain is Muulin (e.g., mouse or rat). In some embodiments, the Muulin heavy chain constant domain is IgG1, IgG2a, or IgG2b. In some embodiments, the Muulin heavy chain constant domain is Muulin IgG1. In some embodiments, Muulin IgG1 includes the amino acid sequence of SEQ ID NO: 215, or its isoforms or variants having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 215. In some embodiments, the Muulin heavy chain constant domain is Muulin IgG2a. In some embodiments, murin IgG2a includes the amino acid sequence of SEQ ID NO: 216, or its isoforms or variants having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 216. In some embodiments, the murin heavy chain constant domain is murin IgG2b. In some embodiments, murin IgG2b includes the amino acid sequence of SEQ ID NO: 217, or its isoforms or variants having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 217. In some embodiments, the heavy chain constant domain is human. In some embodiments, the human heavy chain constant domain is human IgG1. In some embodiments, human IgG1 includes the amino acid sequence of SEQ ID NO: 218, or its isoforms or variants having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 218.

[0269] Based on the amino acid sequences of those constant domains, there are two types of light chains, κ and λ. In any embodiment provided herein, the antibodies provided herein may include a light chain constant domain. In some embodiments, the light chain constant domain is a non-human mammal. In some embodiments, the light chain constant domain is a non-human primate. In some embodiments, the light chain constant domain is a non-human primate. In some embodiments, the light chain constant domain is murin (e.g., mouse or rat). In some embodiments, the murin light chain constant domain is κ or λ. In some embodiments, murin κ includes the amino acid sequence of SEQ ID NO: 219, or its isoform or variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 219. In some embodiments, murin λ includes the amino acid sequence of SEQ ID NO: 220, or its isoform or variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 220. In some embodiments, the light chain constant domain is human. In some embodiments, the human light chain constant domain is κ or λ. In some embodiments, human κ includes the amino acid sequence of SEQ ID NO: 221, or its isoform or variant having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 221. In some embodiments, human λ includes the amino acid sequence of SEQ ID NO: 222, or its isoforms or variants having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity with SEQ ID NO: 222.

[0270] In one embodiment, the anti-GFAP antibody described herein is a monoclonal antibody. In one embodiment, the anti-GFAP antibody described herein is a humanized antibody, a chimeric antibody, or a human antibody. In one embodiment, the anti-GFAP antibody described herein is a mouse antibody, a rabbit antibody, a rat antibody, or a non-human primate antibody. In some embodiments, any anti-GFAP antibody is recombinant. In one embodiment, any anti-GFAP antibody described herein is isolated or purified.

[0271] In some embodiments, the anti-GFAP antibody provided herein is 10 -8 M or less, for example, 10 -8 M~10 -13 M, for example, 10 -8 M~10 -12 M, for example, 10 -9 M~10 -13 The dissociation constant (K) of M D ) has binding affinity. In some embodiments, the anti-GFAP antibody provided herein has a dissociation constant (K) of 1 μM or less, 150 nM or less, 100 nM or less, 50 nM or less, 10 nM or less, 1 nM or less, 0.1 nM or less, 0.01 nM or less, or 0.001 nM or less. D ) has. In some embodiments, the anti-GFAP antibody provided herein is 1.0 × 10 -8 M, 2.0×10 -8 M, 3.0×10 -8 M, 4.0×10 -8 M, 5.0×10 -8 M, 6.0×10 -8 M, 7.0×10 -8 M, 8.0×10 -8 M, 9.0×10 -8 M, 1.0×10 -9 M, 2.0×10 -9 M, 3.0×10 -9 M, 4.0×10 -9 M, 5.0×10 -9 M, 6.0×10 -9 M, 7.0×10 -9 M, 8.0×10 -9 M, 9.0×10 -9 M, 1.0×10-10 M, 2.0×10 -10 M, 3.0×10 -10 M, 4.0×10 -10 M, 5.0×10 -10 M, 6.0×10 -10 M, 7.0×10 -10 M, 8.0×10 -10 M, 9.0×10 -10 M, 1.0×10 -11 M, 2.0×10 -11 M, 3.0×10 -11 M, 4.0×10 -11 M, 5.0×10 -11 M, 6.0×10 -11 M, 7.0×10 -11 M, 8.0×10 -11 M, 9.0×10 -11 M, or 1.0 × 10 -12 Dissociation constant (K) less than or approximately less than M D ) has.

[0272] In some embodiments, the anti-GFRAP antibody provided herein is 1.0 × 10⁶ -8 M~5.0×10 -12 M, 1.0×10 -8 M~1.0×10 -12 M, 1.0×10 -8 M~1.0×10 -11 M, 1.0×10 -8 M~1.0×10 -11 M, 1.0×10 -8 M~1.0×10 -10 M, 1.0×10 -10 M~1.0×10 -12 M, 1.0×10 -10 M~1.0×10 -11 M, 1.0×10 -11 M~1.0×10 -12 M or the dissociation constant (K) in approximately that range D ) has. In some embodiments, the anti-GFAP antibody provided herein is 1.0 × 10 -8 M~1.0×10 -12 M or the dissociation constant (K) in approximately that range D) has. In some embodiments, the anti-GFAP antibody provided herein is 1.0 × 10 -8 M~2.0×10 -8 M, 1.0×10 -9 M~6.0×10 -9 M, 2.0×10 -10 M~9.0×10 -10 M, 1.0×10 -11 M~8.0×10 -11 M, or 1.0 × 10 -12 M~5.0×10 -12 M or the dissociation constant (K) in approximately that range D ) has. In some embodiments, the anti-GFAP antibodies provided herein are antibodies shown in Table 8, for example, GFAP-1, GFAP-2, etc., with a dissociation constant (K D ) has.

[0273] In one embodiment, a nucleic acid encoding an anti-GFAP antibody is provided. In some embodiments, the nucleic acid may encode an anti-GFAP antibody or antigen-binding fragment provided herein. In some embodiments, the nucleic acid may encode a heavy chain containing a heavy chain variable region of an anti-GFAP antibody or antigen-binding fragment provided herein. In some embodiments, the nucleic acid may encode a light chain containing a light chain variable region of an anti-GFAP antibody or antigen-binding fragment provided herein.

[0274] In certain embodiments, a vector, such as an expression vector, is provided, which contains a nucleic acid encoding an anti-GFAP antibody. In certain embodiments, a host cell containing such a nucleic acid and / or vector is provided. For example, a host cell provided herein may contain a vector containing a nucleic acid encoding the heavy chain of the anti-GFAP antibody or antigen-binding fragment provided herein. In some embodiments, such a host cell may further contain a vector containing a nucleic acid encoding the light chain of the anti-GFAP antibody or antigen-binding fragment provided herein.

[0275] In another aspect of the present invention, a composition comprising an anti-GFAP antibody or a nucleic acid encoding an anti-GFAP antibody is provided. In certain embodiments, the compositions provided herein may be used for the detection of GFAP, for the diagnosis of brain injury or injury (e.g., resulting from a neurological condition, stroke, or traumatic brain injury) in an individual having or suspected of having brain injury or injury, and / or for predicting whether the subject requires a CT scan, such as in the methods enumerated herein. In some embodiments, the provided anti-GFAP antibody may be used in combination with any one or more anti-UCH-L1 antibodies provided herein.

[0276] C. Method for evaluating exemplary characteristics The antibodies provided exhibit one or more exemplary properties as described. Evaluating the properties of the antibodies according to the provided description is within the realm of those skilled in the art. This section provides a description of exemplary methods that may be used to evaluate affinity, epitope specificity, and one or more other properties of the antibodies provided.

[0277] In some embodiments, the provided antibody or fragment may be evaluated for binding to UCH-L1 or GFAP, or for binding to their variants or isoforms containing fragments of UCH-L1 or GFAP. Binding may be evaluated in vitro (e.g., immunoassay) or ex vivo. In some embodiments, binding is evaluated by immunoassay. Immunoassays are not limited to, but include, Western blot or immunoblot, e.g., quantitative Western blot; radioimmunoassay; ELISA (enzyme-linked immunosorbent assay); MesoScalebDiscovery (MSD, Gaithersburg, Maryland); "sandwich" immunoassay; immunoprecipitation assay; ELISPOT; precipitation reaction; gel diffusion precipitation reaction; immunodiffusion assay; agglutination assay; complement fixation assay; immunoradiometric assay; fluorescence immunoassay; protein A immunoassay; immunohistochemistry; and competitive and non-competitive assay systems using techniques such as immunoelectron microscopy or liposome immunoassay (LIA). Such assays are routine and well-known in the art (see, for example, Ausubel et al., Eds, 1994, Current Protocols in Molecular Biology, Vol. 1, John Wiley & Sons, Inc., New York).

[0278] In some cases, depending on the quantitative assay selected to measure antibody binding, absolute binding may be expressed in terms of optical density (OD) measured by, for example, concentration measurement or spectrophotometric measurement; arbitrary fluorescence units (AFU) measured by, for example, fluorescence measurement; or lumens measured by, for example, chemiluminescence measurement. In some examples, specific activity is calculated by dividing the absolute binding signal by the antibody protein concentration. In some embodiments, binding activity may be normalized relative to a reference antibody.

[0279] In some embodiments, binding activity may be measured in terms of binding affinity, and the binding rate (k a or k on ) and / or dissociation rate (k d or k off) such as the binding reaction rate, and the maximum half-effective concentration (EC2) 50 ) values ​​and / or thermodynamic data (e.g., Gibbs free energy (ΔG), enthalpy (ΔH), entropy (-TΔS), and / or coupling constant (K A ) or dissociation constant (K D It can be determined from the perspective of measuring the binding reaction rate (k). Typically, determining the binding reaction rate requires known antibody and antigen or substrate protein concentrations. a ) and coupling constant (K A ) is positively correlated with binding affinity. In contrast, the dissociation rate (k) is positively correlated with binding affinity. d ), dissociation constant (K D ) and EC 50 The value is negatively correlated with binding affinity. Therefore, higher binding affinity corresponds to lower kd and K D and EC 50 It is represented by a value.

[0280] Assays for determining antibody binding affinity are well known in the art (see Chen, Y., et al., (1999) J. Mol. Biol. 293:865-881 and Scatchard, G., Ann. NYAcad. Sci. 51:660 (1947)). The affinity constant is expressed in units of reciprocal molar concentration (i.e., M -1 The binding affinity of an antibody can be calculated from the rate constant for the binding-dissociation reaction, which is measured by standard kinetic methodologies for antibody reactions (e.g., immunoassay, surface plasmon resonance, biolayer interferometry, or other kinetic interaction assays known in the art). The binding affinity of an antibody can be calculated from the dissociation constant, or K D It can also be expressed as follows: The dissociation constant is the reciprocal of the coupling constant (K D = 1 / K A Therefore, the affinity constant is K DThe affinity constant can also be expressed by standard kinetic methodologies for antibody reactions, such as immunoassays, surface plasmon resonance (SPR) (Rich and Myszka (2000) Curr. Opin. Biotechnol 11:54; Englebienne (1998) Analyst. 123:1599), isothermal titration calorimetry (ITC), biolayer interferometry (Tobias et al., Biomolecular Binding Kinetic Assays in the Octet Platform, Application Note 14, ForteBio, Div. of Paul Life Sciences, 2013) or other kinetic interaction assays known in the art (e.g., Paul, ed., Fundamental Immunology, 2nd ed., Raven Press, New York, pages 2013). See 332-336 (1989); also see U.S. Patent No. 7,229,619 for a description of exemplary SPR and ITC methods for calculating antibody binding affinity. Instruments and methods for monitoring and real-time detection of binding rate are known and commercially available (e.g., BIAcore 2000, BIAcore AB, Upsala, Sweden and GE Healthcare Life Sciences; Malmqvist (2000) Biochem. Soc. Trans. 27:335; Octet QK). e (ForteBio).

[0281] In one embodiment, the binding affinity of an anti-UCH-L1 antibody or anti-GFAP antibody is determined by a biolayer interference assay. For example, a UCH-L1-His tagged protein is immobilized on a capture sensor (ForteBio) and incubated with increasing concentrations of anti-UCH-L1 antibody or anti-UCH-L1 Fab, e.g., Octet QK e Affinity measurements are obtained using equipment such as the System (ForteBio).

[0282] In some embodiments, the provided anti-UCH-L1 or anti-GFAP antibody binds to a specific epitope within UCH-L1 or GFAP, respectively, such as an epitope that is part of, within, or contains the described UCH-L1 or GFAP region. Assays for mapping the epitopes bound by the antibody and the reference antibody may be used and are known. In some embodiments, the epitope may be a linear epitope. In some embodiments, the epitope may be a structural epitope.

[0283] In an exemplary epitope mapping assay, a protein antigen, such as recombinant human UCH-L1 or recombinant human GFAP of a particular fragment, is added to a microplate and incubated so that the protein coats the wells on the plate. In some embodiments, one or more different truncations of a protein may be evaluated, each representing or different from one or more other truncated proteins by the presence or absence of a particular region or sequence of amino acids. In some embodiments, multiple overlapping truncated proteins may be produced, each deleting up to 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 150, 200, 250 or more N- or C-terminal amino acid residues. For comparison, binding to full-length proteins may also be compared. Each truncated fragment or full-length protein may be contacted with a specific test antibody, and binding may be evaluated or determined using known techniques.

[0284] In some embodiments, the provided antibody (e.g., the first antibody) binds to a distinct and non-overlapping epitope compared to a reference antibody (e.g., the second antibody). In some embodiments, the two antibodies specifically bind to different or non-overlapping epitopes if all or essentially all amino acid mutations in the antigen that reduce or eliminate binding of one antibody do not reduce or eliminate binding of the other antibody. In some embodiments, the two antibodies do not specifically bind to overlapping epitopes if at least some of the amino acid mutations in the antigen that reduce or eliminate binding of one antibody to the antigen do not reduce or eliminate binding of the other antibody to the antigen.

[0285] In some embodiments, whether an antibody “competes for binding” to a particular antigen or substrate (e.g., UCH-L1 or GFAP) can be evaluated using a competition assay. An antibody “competes for binding” to an antigen (e.g., UCH-L1 or GFAP) if it competitively inhibits the binding of a reference antibody to the antigen, and / or if the reference antibody competitively inhibits the binding of the antibody to the antigen. An antibody competitively inhibits the binding of a reference antibody to an antigen if the excess of the antibody detectably inhibits (blocks) the binding of other antibodies to that antigen. A certain degree of inhibition can be defined. In some embodiments, the addition of an excess of the provided antibody, such as a 1, 2, 5, 10, 50, or 100-fold excess compared to the amount or concentration of the reference antibody, can be used to evaluate whether one inhibits the binding of the other to the antigen. In some embodiments, an antibody competes for binding if the inhibition of binding is at least 50%, and in some embodiments, at least 75%, 90%, or 99%. In some embodiments, the antibody does not compete for binding if the inhibition of binding is less than 50%, for example, less than 40%, 30%, 20%, 10%, or less in some embodiments. In some embodiments, competitive inhibition is measured in a competitive binding assay (see, e.g., Junghans et al., Cancer Res. 1990:50:1495-1502).

[0286] In some embodiments, the antibodies provided are antibodies that do not compete for binding with one or more other reference antibodies. In some embodiments, antibodies that bind to the same antigen (e.g., UCH-L1 or GFAP) but do not compete for binding to it may be used as paired antibodies in an assay (e.g., sandwich ELISA) to detect or measure UCH-L1 or GFAP in the described sample.

[0287] In some embodiments, in order to determine which of the anti-UCH-L1 antibodies can be used as a pair, each of the anti-UCH-L1 antibodies provided above may be labeled with a detectable label (e.g., HRP) and tested individually in a sandwich configuration with each of the other anti-UCH-L1 antibodies provided.

[0288] In some embodiments, in order to determine which of the anti-GFAP antibodies can be used as a pair, each of the anti-GFAP antibodies provided above may be labeled with a detectable label (e.g., HRP) and tested individually in a sandwich configuration with each of the other anti-GFAP antibodies provided.

[0289] [III. Antibody Production and Preparation] In some embodiments, the provided antibody or fragment is prepared using techniques available in the art for producing antibodies, exemplary methods of which are described in detail in the following sections. [A. Antibody format and modification] 1. Antibody fragment Among the antibodies offered, antibody fragments are provided. Antibody fragments can be produced by traditional methods such as enzymatic digestion or by recombinant technology. In certain situations, antibody fragments are preferable to the whole antibody. For a review of specific antibody fragments, see Hudson et al. (2003) Nat. Med. 9:129-134.

[0290] Various techniques have been developed for the production of antibody fragments. Traditionally, these fragments were obtained via the proteolytic digestion of intact antibodies (see, e.g., Morimoto et al., Journal of Biochemical and Biophysical Methods 24:107-117 (1992); and Brennan et al., Science, 229:81 (1985)). However, these fragments can now be produced directly by recombinant host cells. Fab, Fv, and ScFv antibody fragments can all be expressed in E. coli and secreted from there, thus enabling the easy production of large quantities of these fragments. Antibody fragments can be isolated from the antibody phage libraries mentioned above. Alternatively, Fab'-SH fragments can be recovered directly from E. coli and chemically bound to form F(ab')2 fragments (Carter et al., Bio / Technology 10:163-167 (1992)). According to another approach, F(ab')2 fragments can be isolated directly from recombinant host cell cultures. Fab and F(ab')2 fragments with an extended in vivo half-life containing salvage receptor-binding epitope residues are described in U.S. Patent No. 5,869,046. Other techniques for the production of antibody fragments are apparent to those skilled in the art. In certain embodiments, the antibody is a single-chain Fv fragment (scFv). See WO93 / 16185; U.S. Patent Nos. 5,571,894; and 5,587,458. Fv and scFv are the only species that have intact binding sites with a deleted constant region; therefore, they may be suitable for reducing non-specific binding during in vivo use. scFv fusion proteins can be constructed to result in the fusion of an effector protein at either the amino or carboxyl terminus of the scFv. See Antibody Engineering, ed. Borrebaeck (above). The antibody fragment may be, for example, a "linear antibody" as described in U.S. Patent No. 5,641,870. Such a linear antibody may be monospecific or bispecific.

[0291] 2. Humanized antibodies Among the antibodies offered, humanized antibodies are available. Various methods for humanizing non-human antibodies are known in the art. For example, a humanized antibody may have one or more amino acid residues introduced into it from a non-human source. These non-human amino acid residues are often called “import” residues, and they are typically obtained from an “import” variable domain. Humanization can be carried out in essence by substituting the hypervariable region sequence with respect to the corresponding sequence of the human antibody, according to Winter’s method (Jones et al. (1986) Nature 321:522-525; Riechmann et al. (1988) Nature 332:323-327; Verhoeyen et al. (1988) Science 239:1534-1536). Thus, such a “humanized” antibody is a chimeric antibody (US Patent No. 4,816,567), where a substantially less than intact human variable domain is substituted with a corresponding sequence from a non-human species. In practice, humanized antibodies are typically human antibodies in which some hypervariable region residues and, in some cases, some FR residues are substituted with residues derived from similar partials in rodent antibodies.

[0292] The selection of human variable domains used in the production of humanized antibodies, both in the light and heavy chains, can be crucial for reducing antigenicity. Using a so-called "best-fit" method, the sequences of variable domains in rodent (e.g., mouse) antibodies are screened against an entire library of known human variable domain sequences. The human sequence most closely resembling that of rodents is then recognized as the human framework for humanized antibodies (Sims et al. (1993) J.Immunol. 151:2296; Chothia et al. (1987) J.Mol.Biol. 196:901). Another method uses a specific framework derived from the consensus sequences of all human antibodies of a particular subgroup of light or heavy chains. The same framework can be used for several different humanized antibodies (Carter et al. (1992) Proc.Natl.Acad.Sci.USA, 89:4285; Presta et al. (1993) J.Immunol., 151:2623).

[0293] Furthermore, it is generally desirable that antibodies be humanized while retaining high affinity for the antigen and other desirable biological properties. To achieve this objective, according to one method, humanized antibodies are prepared by a process of analyzing the parental sequence and various conceptual humanized products using three-dimensional models of the parental and humanized sequences. Three-dimensional immunoglobulin models are generally available and familiar to those skilled in the art. Computer programs are available that depict and display the possible three-dimensional structures of selected candidate immunoglobulin sequences. Scrutiny of these displays allows for the analysis of what appears to be the role of residues in the function of the candidate immunoglobulin sequence, i.e., the analysis of residues that affect the candidate immunoglobulin's ability to bind to its antigen. In this way, FR residues may be selected and combined from recipient and import sequences so that desired antibody properties, such as increased affinity for the target antigen(s), are achieved. In general, hypervariable region residues are directly and most substantially involved in the effect of antigen binding.

[0294] 3. Human antibodies Of the antibodies offered, human antibodies are available. Human anti-UCH-L1 antibodies and / or human anti-GFAP antibodies can be produced by hybridoma. Human myeloma and mouse-human heterozygous myeloma cell lines for the production of human monoclonal antibodies are described, for example, by Kozbor J. Immunol., 133:3001 (1984); Brodeur et al., Monoclonal Antibody Production Techniques and Applications, pp. 51-63 (Marcel Dekker, Inc., New York, 1987); and Boerner et al., J. Immunol., 147:86 (1991).

[0295] Gene shuffling can also be used to obtain human antibodies from non-human (e.g., rodent) antibodies, where the human antibody has similar affinity and specificity to the starting non-human antibody. According to this method, also known as “epitope imprinting,” the heavy or light chain variable region of a non-human antibody fragment obtained by the phage display technique described herein is replaced with a repertoire of human V domain genes to create a population of non-human / human scFv or Fab chimeras. Antigen selection leads to the isolation of the non-human / human chimera scFv or Fab, where the human chain restores the antigen-binding site that is destroyed during the removal of the corresponding non-human chain in the primary phage display clone; i.e., the epitope governs the selection of the human chain partner. The process is repeated to replace the remaining non-human chain to obtain a human antibody (see PCTWO93 / 06213, published April 1, 1993). Unlike traditional humanization of non-human antibodies using CDR grafts, this technology provides fully human antibodies that do not contain non-human FR or CDR residues.

[0296] 4. Bispecific antibodies In some embodiments, bispecific antibodies are provided herein, which are monoclonal antibodies having binding specificity with respect to at least two different antigens. In certain embodiments, the bispecific antibody is human or a humanized antibody. In certain embodiments, one binding specificity is with respect to UCH-L1 and the other is with respect to any other antigen (e.g., GFAP). In certain embodiments, one binding specificity is with respect to GFAP and the other is with respect to any other antigen (e.g., UCH-L1). In certain embodiments, the bispecific antibody may bind to two different epitopes of UCH-L1. In certain embodiments, the bispecific antibody may bind to two different epitopes of GFAP. The bispecific antibody may be used to localize a cytotoxic agent to cells expressing UCH-L1 and / or GFAP. The bispecific antibody may be prepared as a full-length antibody or an antibody fragment (e.g., F(ab')2 bispecific antibody).

[0297] Methods for producing bispecific antibodies are known in the art. See Milstein and Cuello, Nature, 305:537 (1983), WO93 / 08829, published May 13, 1993, and Traunecker et al., EMBO J., 10:3655 (1991). For further details on the production of bispecific antibodies, see, for example, Suresh et al., Methods in Enzymology, 121:210 (1986). Bispecific antibodies include crosslinked or "heteroconjugate" antibodies. For example, one antibody in a heteroconjugate may be bound to avidin and the other to biotin. Heteroconjugate antibodies can be produced using any convenient crosslinking method. Suitable crosslinking agents are well known in the art and are disclosed in U.S. Patent No. 4,676,980 along with many crosslinking techniques.

[0298] 5. Single-domain antibodies In some embodiments, the antibody relating to the provided disclosure is a single-domain antibody. A single-domain antibody is a single polypeptide chain comprising all or part of the heavy chain variable domains or all or part of the light chain variable domains of an antibody. In certain embodiments, the single-domain antibody is a human single-domain antibody (see, for example, Domantis, Inc., Waltham, Mass.; U.S. Patent No. 6,248,516B1). In one embodiment, the single-domain antibody consists of all or part of the heavy chain variable domains of an antibody.

[0299] 6. Antibody variants In some embodiments, the amino acid sequence modifications (one or more) of antibodies described herein are considered. For example, it may be desirable to improve the binding affinity and / or other biological properties of the antibody. Amino acid sequence variants of antibodies can be prepared by introducing appropriate changes into the nucleotide sequence encoding the antibody, or by peptide synthesis. Such modifications include, for example, deletions from and / or insertions into residues in the amino acid sequence of the antibody, and / or substitutions therein. Any combination of deletions, insertions, and substitutions may be made to reach a final construct, insofar as the final construct possesses the desired characteristics. Amino acid changes can be introduced into the amino acid sequence of the antibody in question when the sequence is constructed.

[0300] A useful method for identifying specific residues or regions of an antibody that are favorable sites for mutagenesis is called "alanine scan mutagenesis," as described by Cunningham and Wells (1989) Science, 244:1081-1085. Here, residues or target residue groups are identified (e.g., charged residues such as arg, asp, his, lys, and glu) and substituted with neutral or negatively charged amino acids (e.g., alanine or polyalanine) to affect the interaction between the antigen and the amino acid. These amino acid positions that exhibit functional sensitivity to substitution are then examined by introducing further or other mutations at or related to the substitution site. Thus, while the site to introduce amino acid sequence mutations is predetermined, the nature of the mutation itself does not need to be predetermined. For example, to analyze the performance of a mutation at a given site, an ala scan or random mutagenesis is performed at a target codon or region, and the expressed immunoglobulin is screened for desired activity.

[0301] Amino acid sequence insertions include amino- and / or carboxyl-terminal fusions ranging in length from one residue to polypeptides containing 100 or more residues, as well as intrasequence insertions of single or multiple amino acid residues. Examples of terminal insertions include antibodies with an N-terminal methionyl residue.

[0302] In certain embodiments, the antibodies of the present invention are modified to increase or decrease the degree to which the antibody is glycosylated. Polypeptide glycosylation is typically either N-linked or O-linked. N-linking refers to the attachment of a carbohydrate moiety to the side chain of an asparagine residue. The tripeptide sequences asparagine-X-serine and asparagine-X-threonine (where X is any amino acid except proline) are recognition sequences for the enzymatic attachment of the carbohydrate moiety to the asparagine side chain. Therefore, the presence of either of these tripeptide sequences in a polypeptide creates a potential glycosylation site. O-linked glycosylation refers to the attachment of one of the sugars N-acetylgalactosamine, galactose, or xylose to a hydroxyamino acid, most commonly serine or threonine, but 5-hydroxyproline or 5-hydroxylysine may also be used.

[0303] The addition or deletion of glycosylation sites to an antibody is preferably achieved by modifying the amino acid sequence such that one or more of the aforementioned tripeptide sequences (for N-linked glycosylation sites) are created or removed. The modification may be made by adding, deleting, or substituting one or more serine or threonine residues into the original antibody sequence (for O-linked glycosylation sites).

[0304] Another type of mutant is the amino acid substitution mutant. These mutants have at least one amino acid residue in the antibody molecule that is substituted by a different residue. Target sites for substitutional mutagenesis include hypervariable regions, but FR changes are also considered. Conservative substitutions are shown in Table 2 under the heading "Preferred Substitutions". If such substitutions result in desirable changes in biological activity, more substantial changes (indicated as "Exemplary Substitutions" in Table 2, or further described below with reference to amino acid classes) may be introduced and the product may be screened. JPEG0007832969000002.jpg182166

[0305] Substantial modification of the biological properties of antibodies is achieved by selecting substitutions that significantly differ in (a) the structure of the polypeptide backbone within the region of substitution, e.g., sheet or helical structure, (b) the charge or hydrophobicity of the molecule at the target site, or (c) their effect on the maintenance of most of the side chains. Amino acids can be grouped according to the similarity in the properties of their side chains (ALLehninger, Biochemistry, second ed., pp. 73-75, Worth Publishers, New York (1975)): (1) Non-polar: Ala(A), Val(V), Leu(L), Ile(I), Pro(P), Phe(F), Trp(W), Met(M) (2) Non-charged polarity: Gly(G), Ser(S), Thr(T), Cys(C), Tyr(Y), Asn(N), Gln(Q) (3) Acidic: Asp(D), Glu(E) (4) Basic: Lys(K), Arg(R), His(H)

[0306] Alternatively, naturally occurring residues can be grouped based on their general side-chain properties: (1) Hydrophobic: norleucine, Met, Ala, Val, Leu, Ile; (2) Neutral hydrophilic: Cys, Ser, Thr, Asn, Gln; (3) Acidic: Asp, Glu; (4) Basicity: His, Lys, Arg; (5) Residues that affect chain orientation: Gly, Pro; (6) Aromatic: Trp, Tyr, Phe.

[0307] Non-conservative substitutions require the exchange of one member of one of these classes with another. Such substitution residues may be introduced within a conservative substitution site or within the remaining (non-conservative) site.

[0308] One type of substitution mutant involves the substitution of one or more hypervariable region residues in the parent antibody (e.g., a humanized or human antibody). Generally, the resulting mutant(s) selected for further development have altered (e.g., improved) biological properties compared to the parent antibody from which they are produced. A convenient method for generating such substitution mutants involves affinity maturation using phage display. Briefly, several hypervariable region sites (e.g., 6-7 sites) are mutated to produce all possible amino acid substitutions at each site. Antibodies thus produced are presented by filamentous phage particles as fusions to at least a portion of the phage coat protein (e.g., the gene III product of M13) packaged within each particle. The mutants presented by the phage are then screened for their biological activity (e.g., binding affinity). To identify candidate hypervariable region sites for modification, scan mutagenesis (e.g., alanine scan) can be performed to identify hypervariable region residues that significantly contribute to antigen binding. Alternatively, or in addition, it may be beneficial to analyze the crystal structure of the antigen-antibody complex to identify contact sites between the antibody and the antigen. Such contact residues and adjacent residues are candidates for substitution by techniques known in the art, including those constructed herein. Once such variants are produced, a panel of variants may be screened using techniques known in the art, including those described herein, and antibodies exhibiting superior properties in one or more relevant assays may be selected for further development.

[0309] Nucleic acid molecules encoding amino acid sequence mutations in antibodies are prepared by a variety of methods known in the art. These methods include, but are not limited to, isolation from natural sources (in the case of naturally occurring amino acid sequence mutations), or preparation by (or site-directed) mutagenesis mediated by earlier prepared mutant or non-mutant versions of oligonucleotides of antibodies, PCR mutagenesis, and cassette mutagenesis.

[0310] It may be desirable to introduce one or more amino acid modifications into the constant domain of the antibody of the present invention to thereby generate a constant domain variant. The constant domain variant may include a human constant domain sequence (e.g., human IgG1, IgG2, IgG3, or IgG4 constant domain) or a Muhrin constant domain sequence (e.g., Muhrin IgG1, IgG2a, IgG2b, IgG2c, and IgG3 constant domains) that includes amino acid modifications (e.g., substitutions) at one or more amino acid positions, including those of hinge cysteine.

[0311] [B. Vectors, host cells, and recombination methods] For the recombinant production of the antibody of the present invention, the nucleic acid encoding it is isolated and inserted into a replicable vector for further cloning (DNA amplification) or expression. The antibody-encoding DNA is readily isolated and sequenced using conventional procedures (e.g., by using oligonucleotide probes capable of specifically binding to the genes encoding the heavy and light chains of the antibody). Many vectors are available. The choice of vector is partially dependent on the host cell used. Generally, the host cell is of either prokaryotic or eukaryotic (usually mammalian) origin. It is understood that any isotype constant region, including IgG, IgM, IgA, IgD, and IgE constant regions, can be used for this purpose, and that such constant regions can be obtained from any human or animal species (e.g., mouse, non-human primate, etc.). [1. Antibody production using prokaryotic host cells:] a) Vector construction The polynucleotide sequences encoding the polypeptide components of the antibody of the present invention can be obtained using standard recombinant techniques. The desired polynucleotide sequence can be isolated and sequenced from antibody-producing cells such as hybridoma cells. Alternatively, the polynucleotide can be synthesized using a nucleotide synthesizer or PCR technique. Once obtained, the polypeptide-encoding sequence is inserted into a recombinant vector capable of replicating and expressing heterologous polynucleotides within a prokaryotic host. Many vectors available and known in the art can be used for the purposes of the present invention. The selection of a suitable vector depends primarily on the size of the nucleic acid to be inserted into the vector and the specific host cell to be transformed by the vector. Each vector contains a variety of components depending on its function (amplification or expression of heterologous polynucleotides, or both) and the specific host cell in which it resides and its compatibility. Vector components generally include, but are not limited to: an origin of replication, a selection marker gene, a promoter, a ribosome-binding site (RBS), a signal sequence, a heterologous nucleic acid insertion, and a transcription termination sequence.

[0312] Generally, plasmid vectors containing replicons and regulatory sequences derived from a species compatible with the host cell are used for these hosts. The vectors typically possess marking sequences and replication sites that can provide phenotypic selection in transformed cells. For example, E. coli is typically transformed using pBR322 (a plasmid derived from the E. coli species). pBR322 contains genes encoding ampicillin (Amp) and tetracycline (Tet) resistance, thus providing a simple means for identifying transformed cells. pBR322, its derivatives, or other microbial plasmids or bacteriophages may contain, or be modified to contain, promoters that can be used by microorganisms for the expression of endogenous proteins. Examples of pBR322 derivatives used for the expression of specific antibodies are described in detail in Carter et al., U.S. Patent No. 5,648,237.

[0313] In addition, phage vectors containing replicons and regulatory sequences compatible with host microorganisms can be used as transformation vectors for those hosts. For example, bacteriophages such as λGEM.TM.-11 can be used to create recombinant vectors that can be used to transform sensitive host cells such as E. coli LE392.

[0314] The expression vector of the present invention may include two or more promoter-cistron pairs encoding each of the polypeptide components. The promoter is an untranslated regulatory sequence located upstream (5') of the cistron that regulates its expression. Prokaryotic promoters are typically classified into two classes: inducible and constitutive. Inducible promoters are promoters that initiate transcription of cistrons at increased levels under their control in response to changes in culture conditions, such as the presence or absence of nutrients or temperature changes.

[0315] Numerous promoters are well known that are recognized by a variety of potential host cells. Selective promoters can be operably ligated to cistron DNA encoding a light or heavy chain by removing the promoter from the original DNA via restriction enzyme digestion and insertion of the isolated promoter sequence into the vector of the present invention. Both native promoter sequences and many heterologous prom...

Claims

1. An antibody or its antigen-binding fragment that specifically binds to human glial fiber acidic protein (GFAP), The aforementioned antibody or antigen-binding fragment is (a) Heavy chain variable regions containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 77, SEQ ID NO: 91, and SEQ ID NO: 108, respectively, and light chain variable regions containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 125, SEQ ID NO: 142, and SEQ ID NO: 157, respectively; (b) Heavy chain variable regions containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 78, SEQ ID NO: 92, and SEQ ID NO: 109, respectively, and light chain variable regions containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 126, SEQ ID NO: 143, and SEQ ID NO: 158, respectively; (c) Heavy chain variable regions containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 79, SEQ ID NO: 93, and SEQ ID NO: 110, respectively, and light chain variable regions containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 127, SEQ ID NO: 144, and SEQ ID NO: 159, respectively; (d) Heavy chain variable regions containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 77, SEQ ID NO: 94, and SEQ ID NO: 111, respectively, and light chain variable regions containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 128, SEQ ID NO: 145, and SEQ ID NO: 160, respectively; (e) Heavy chain variable regions containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 80, SEQ ID NO: 95, and SEQ ID NO: 112, respectively, and light chain variable regions containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 126, SEQ ID NO: 142, and SEQ ID NO: 158, respectively; (f) Heavy chain variable regions containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 81, SEQ ID NO: 96, and SEQ ID NO: 113, respectively, and light chain variable regions containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 129, SEQ ID NO: 146, and SEQ ID NO: 161, respectively; (g) Heavy chain variable regions containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 77, SEQ ID NO: 94, and SEQ ID NO: 111, respectively, and light chain variable regions containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 130, SEQ ID NO: 145, and SEQ ID NO: 160, respectively; (h) Heavy chain variable regions containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 82, SEQ ID NO: 97, and SEQ ID NO: 114, respectively, and light chain variable regions containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 131, SEQ ID NO: 147, and SEQ ID NO: 162, respectively; (i) Heavy chain variable regions containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 83, SEQ ID NO: 98, and SEQ ID NO: 115, respectively, and light chain variable regions containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 132, SEQ ID NO: 148, and SEQ ID NO: 163, respectively; (j) Heavy chain variable regions containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 84, SEQ ID NO: 99, and SEQ ID NO: 116, respectively, and light chain variable regions containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 133, SEQ ID NO: 149, and SEQ ID NO: 164, respectively; (k) Heavy chain variable regions containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 85, SEQ ID NO: 100, and SEQ ID NO: 117, respectively, and light chain variable regions containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 134, SEQ ID NO: 150, and SEQ ID NO: 165, respectively; (l) Heavy chain variable regions containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 86, SEQ ID NO: 101, and SEQ ID NO: 118, respectively, and light chain variable regions containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 135, SEQ ID NO: 151, and SEQ ID NO: 166, respectively; (m) Heavy chain variable regions containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 78, SEQ ID NO: 102, and SEQ ID NO: 119, respectively, and light chain variable regions containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 136, SEQ ID NO: 152, and SEQ ID NO: 167, respectively; (n) Heavy chain variable regions containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 78, SEQ ID NO: 103, and SEQ ID NO: 120, respectively, and light chain variable regions containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 137, SEQ ID NO: 142, and SEQ ID NO: 158, respectively; (o) Heavy chain variable regions containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 87, SEQ ID NO: 104, and SEQ ID NO: 121, respectively, and light chain variable regions containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 138, SEQ ID NO: 153, and SEQ ID NO: 168, respectively; (p) Heavy chain variable regions containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 88, SEQ ID NO: 105, and SEQ ID NO: 122, respectively, and light chain variable regions containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 139, SEQ ID NO: 154, and SEQ ID NO: 169, respectively; (q) Heavy chain variable regions containing the CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 89, SEQ ID NO: 106, and SEQ ID NO: 123, respectively, and light chain variable regions containing the CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 140, SEQ ID NO: 155, and SEQ ID NO: 170, respectively; or (r) Heavy chain variable regions containing CDR-H1, CDR-H2, and CDR-H3 amino acid sequences of SEQ ID NO: 90, SEQ ID NO: 107, and SEQ ID NO: 124, respectively, and light chain variable regions containing CDR-L1, CDR-L2, and CDR-L3 amino acid sequences of SEQ ID NO: 141, SEQ ID NO: 156, and SEQ ID NO: 171, respectively, Antibody or antigen-binding fragments containing such fragments.

2. The antibody or antigen-binding fragment is 5.0 × 10 －１０ Equilibrium dissociation constant (K) less than M Ｄ ) binds to GFAP, The antibody or antigen-binding fragment according to claim 1.

3. The antibody or antigen-binding fragment is 1.0 × 10 －１２ Equilibrium dissociation constant (K) less than M Ｄ ) binds to GFAP, The antibody or antigen-binding fragment according to claim 1 or 2.

4. The antibody or antigen-binding fragment binds to an epitope that is or contains residues 92-106, 190-202, 16-35 and / or 380, 119 and / or 190, 380-391, 119-130, 210-221, 320-390, 346-357 and / or 376-387, or 138-149 of the GFAP protein. The antibody or antigen-binding fragment according to any one of claims 1 to 3.

5. The antibody or antigen-binding fragment is (a) Heavy chain variable region containing the amino acid sequence of SEQ ID NO: 172; and light chain variable region containing the amino acid sequence of SEQ ID NO: 189; (b) Heavy chain variable region containing the amino acid sequence of SEQ ID NO: 173; and light chain variable region containing the amino acid sequence of SEQ ID NO: 190; (c) Heavy chain variable region containing the amino acid sequence of SEQ ID NO: 174; and light chain variable region containing the amino acid sequence of SEQ ID NO: 191; (d) Heavy chain variable region containing the amino acid sequence of SEQ ID NO: 175; and light chain variable region containing the amino acid sequence of SEQ ID NO: 192; (e) Heavy chain variable region containing the amino acid sequence of SEQ ID NO: 176; and light chain variable region containing the amino acid sequence of SEQ ID NO: 193; (f) Heavy chain variable region containing the amino acid sequence of SEQ ID NO: 177; and light chain variable region containing the amino acid sequence of SEQ ID NO: 194; (g) Heavy chain variable region containing the amino acid sequence of SEQ ID NO: 175; and light chain variable region containing the amino acid sequence of SEQ ID NO: 195; (h) Heavy chain variable region containing the amino acid sequence of SEQ ID NO: 178; and light chain variable region containing the amino acid sequence of SEQ ID NO: 196; (i) Heavy chain variable region containing the amino acid sequence of SEQ ID NO: 179; and light chain variable region containing the amino acid sequence of SEQ ID NO: 197; (j) Heavy chain variable region containing the amino acid sequence of SEQ ID NO: 180; and the a of SEQ ID NO: 198 Light chain variable region containing a mino acid sequence; (k) Heavy chain variable region containing the amino acid sequence of SEQ ID NO: 181; and light chain variable region containing the amino acid sequence of SEQ ID NO: 199; (l) Heavy chain variable region containing the amino acid sequence of SEQ ID NO: 182; and light chain variable region containing the amino acid sequence of SEQ ID NO: 200; (m) Heavy chain variable region containing the amino acid sequence of SEQ ID NO: 183; and light chain variable region containing the amino acid sequence of SEQ ID NO: 201; (n) Heavy chain variable region containing the amino acid sequence of SEQ ID NO: 184; and light chain variable region containing the amino acid sequence of SEQ ID NO: 202; (o) Heavy chain variable region containing the amino acid sequence of SEQ ID NO: 185; and light chain variable region containing the amino acid sequence of SEQ ID NO: 203; (p) Heavy chain variable region containing the amino acid sequence of SEQ ID NO: 186; and light chain variable region containing the amino acid sequence of SEQ ID NO: 204; (q) Heavy chain variable region containing the amino acid sequence of SEQ ID NO: 187; and light chain variable region containing the amino acid sequence of SEQ ID NO: 205; or (r) Heavy chain variable region containing the amino acid sequence of SEQ ID NO: 188; and light chain variable region containing the amino acid sequence of SEQ ID NO: 206, including, The antibody or antigen-binding fragment according to any one of claims 1 to 4.

6. A nucleic acid encoding an antibody or antigen-binding fragment according to any one of claims 1 to 5.

7. A vector comprising the nucleic acid described in claim 6.

8. A nucleic acid according to claim 6 or a vector according to claim 7, host cell.

9. A method for producing an antibody or its antigen-binding fragment, The method includes culturing the host cells described in claim 8 under conditions that produce the antibody or antigen-binding fragment, method.

10. A collection comprising two or more antibodies or antigen-binding fragments according to any one of claims 1 to 5, kit.

11. The two or more antibodies or antigen-binding fragments are One or more first antibodies or their antigen-binding fragments that bind to a first epitope or region within GFAP; and One or more secondary antibodies or their antigen-binding fragments that bind to a second epitope or region within GFAP. The kit according to claim 10, comprising:

12. The one or more first antibodies or their antigen-binding fragments, and the one or more second antibodies or their antigen-binding fragments, bind to non-overlapping epitopes or regions of human GFAP and / or do not compete for binding to GFAP. The kit according to claim 11.

13. A method for detecting GFAP in a human subject, The aforementioned method, (a) The step of contacting one or more first antibodies or antigen-binding fragments according to any one of claims 1 to 5 with a sample isolated from the human subject under conditions that form a complex comprising the antibody or antigen-binding fragment and GFAP; and (b) A step of detecting the presence or absence of the complex in the sample, thereby detecting GFAP in the sample. including, method.

14. The step of detecting the presence or absence of the complex in step (b) is: (i) a step of contacting the complex of step (a) with one or more second antibodies or antigen-binding fragments under conditions that the complex is bound to GFAP, wherein the one or more second antibodies or antigen-binding fragments are conjugated with a label capable of producing a detectable signal; and (ii) A step of evaluating the presence or absence of the detectable signal, including, The method according to claim 13.

15. (c) further comprising the step of determining the amount of GFAP detected in the sample, The method according to claim 13 or 14.

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