Anti-CD112R antibodies and uses thereof

Abstract

The present invention provides an anti-CD112R antibody and its use, specifically providing an anti-CD112R antibody or an antigen-binding fragment thereof, wherein the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 contained therein are as described herein. The present invention also provides a composition comprising the anti-CD112R antibody or its antigen-binding fragment, a nucleic acid molecule encoding the antibody or its antigen-binding fragment, a vector and a host cell for expressing the antibody or its antigen-binding fragment, and a pharmaceutical use of the antibody or its antigen-binding fragment.

Description

Technical Field

[0001] The present invention provides an antibody or an antigen-binding fragment thereof that specifically binds to CD112R and a composition comprising the same. Also provided are nucleic acid molecules encoding the antibody or its antigen-binding fragment of the present invention, vectors and host cells for expressing the antibody or its antigen-binding fragment of the present invention, and treatment and diagnosis methods and uses of the antibody or its antigen-binding fragment of the present invention. Background Art

[0002] The immune system is a highly complex system composed of many cell types, including but not limited to T cells, B cells, natural killer cells, antigen presenting cells, dendritic cells, monocytes and macrophages. These cells possess a complex and delicate system to control their interactions and responses. Cells utilize activation and inhibition mechanisms and feedback loops to keep responses under control and not allow for the negative consequences of uncontrolled immune responses (e.g., autoimmune diseases).

[0003] CD112R (PVRIG), also known as poliovirus receptor-associated immunoglobulin domain-containing protein, Q6DKI7 or C7orf15, is a 326-amino acid transmembrane domain protein with a signal peptide (spanning amino acids 1 to 40), an extracellular domain (spanning amino acids 41 to 171), a transmembrane domain (spanning amino acids 172 to 190) and a cytoplasmic domain (spanning amino acids 191 to 326). CD112R binds to poliovirus receptor-associated protein 2 (PVLR2, also known as nectin-2, CD112 or herpesvirus entry mediator B (HVEB), human plasma membrane glycoprotein), the binding partner of CD112R.

[0004] Administration of anti-CD112R immunotherapy provides an opportunity to increase, enhance, and maintain immune responses. CD112R is an inhibitory receptor expressed primarily by T cells and NK cells and competes with the activating receptor CD226 for binding to CD112. CD112 interacts with CD112R with higher affinity than with CD226, effectively modulating CD226-mediated cell activation. Anti-CD112R antibodies that block interaction with CD112 directly limit inhibitory signaling downstream of CD112R while promoting greater immune cell activation by increasing CD226 interaction with CD112.

[0005] Treatment with anti-CD112R antibodies provides an opportunity to downregulate inhibitory signals that may occur when CD112R-expressing immune cells bind to CD112 on tumor cells and / or myeloid cells within the tumor microenvironment and may enhance, increase, and sustain anti-tumor immune responses.

[0006] Currently, the only anti-CD112R monoclonal antibody drug is the preclinical SRF813 (Surface Oncology), and more new anti-CD112R antibodies are still needed. Summary of the invention

[0007] The present invention provides an anti-CD112R antibody or an antigen-binding fragment thereof, which has advantages such as high affinity and high specificity for human CD112R. The anti-CD112R antibody or an antigen-binding fragment thereof provided by the present invention can be used as an independent therapy or in combination with other therapies / or other anticancer agents for the treatment of cancer, for example.

[0008] In one aspect, the present invention provides an anti-CD112R antibody or an antigen-binding fragment thereof, comprising a heavy chain variable region and / or a light chain variable region:

[0009] The heavy chain variable region comprises:

[0010] (I) HCDR1, HCDR2 and HCDR3 with amino acid sequences as shown in SEQ ID NO:1, SEQ ID NO:2 and SEQ ID NO:3, respectively; or HCDR1, HCDR2 and HCDR3 with 1, 2 or 3 amino acid differences with the amino acid sequences as shown in SEQ ID NO:1, SEQ ID NO:2 and SEQ ID NO:3, respectively; or

[0011] (II) HCDR1, HCDR2 and HCDR3 with amino acid sequences as shown in SEQ ID NO:7, SEQ ID NO:8 and SEQ ID NO:9, respectively; or HCDR1, HCDR2 and HCDR3 with 1, 2 or 3 amino acid differences with the amino acid sequences as shown in SEQ ID NO:7, SEQ ID NO:8 and SEQ ID NO:9, respectively; or

[0012] (III) HCDR1, HCDR2 and HCDR3 with amino acid sequences as shown in SEQ ID NO: 13, SEQ ID NO: 14 and SEQ ID NO: 15, respectively; or HCDR1, HCDR2 and HCDR3 with 1, 2 or 3 amino acid differences with the amino acid sequences as shown in SEQ ID NO: 13, SEQ ID NO: 14 and SEQ ID NO: 15, respectively; or

[0013] (IV) HCDR1, HCDR2 and HCDR3 with amino acid sequences as shown in SEQ ID NO: 16, SEQ ID NO: 17 and SEQ ID NO: 18, respectively; or HCDR1, HCDR2 and HCDR3 with 1, 2 or 3 amino acid differences with the amino acid sequences as shown in SEQ ID NO: 16, SEQ ID NO: 17 and SEQ ID NO: 18, respectively; or

[0014] (V) HCDR1, HCDR2 and HCDR3 with amino acid sequences as shown in SEQ ID NO:22, SEQ ID NO:23 and SEQ ID NO:24, respectively; or HCDR1, HCDR2 and HCDR3 with 1, 2 or 3 amino acid differences with the amino acid sequences as shown in SEQ ID NO:22, SEQ ID NO:23 and SEQ ID NO:24, respectively; or

[0015] (VI) HCDR1, HCDR2 and HCDR3 with amino acid sequences as shown in SEQ ID NO:28, SEQ ID NO:29 and SEQ ID NO:30, respectively; or HCDR1, HCDR2 and HCDR3 with 1, 2 or 3 amino acid differences with the amino acid sequences as shown in SEQ ID NO:28, SEQ ID NO:29 and SEQ ID NO:30, respectively; or

[0016] (VII) HCDR1, HCDR2 and HCDR3 with amino acid sequences as shown in SEQ ID NO:34, SEQ ID NO:35 and SEQ ID NO:36, respectively; or HCDR1, HCDR2 and HCDR3 with 1, 2 or 3 amino acid differences with the amino acid sequences as shown in SEQ ID NO:34, SEQ ID NO:35 and SEQ ID NO:36, respectively; or

[0017] (VIII) HCDR1, HCDR2 and HCDR3 with amino acid sequences as shown in SEQ ID NO:40, SEQ ID NO:41 and SEQ ID NO:42, respectively; or HCDR1, HCDR2 and HCDR3 with 1, 2 or 3 amino acid differences with the amino acid sequences as shown in SEQ ID NO:40, SEQ ID NO:41 and SEQ ID NO:42, respectively; or

[0018] (IX) HCDR1, HCDR2 and HCDR3 with amino acid sequences as shown in SEQ ID NO:49, SEQ ID NO:50 and SEQ ID NO:51, respectively; or HCDR1, HCDR2 and HCDR3 with 1, 2 or 3 amino acid differences with the amino acid sequences as shown in SEQ ID NO:49, SEQ ID NO:50 and SEQ ID NO:51, respectively; or

[0019] (X) HCDR1, HCDR2 and HCDR3 with amino acid sequences as shown in SEQ ID NO:55, SEQ ID NO:56 and SEQ ID NO:57, respectively; or HCDR1, HCDR2 and HCDR3 with 1, 2 or 3 amino acid differences with the amino acid sequences as shown in SEQ ID NO:55, SEQ ID NO:56 and SEQ ID NO:57, respectively; or

[0020] (XI) HCDR1, HCDR2 and HCDR3 with amino acid sequences as shown in SEQ ID NO:61, SEQ ID NO:62 and SEQ ID NO:63, respectively; or HCDR1, HCDR2 and HCDR3 with 1, 2 or 3 amino acid differences with the amino acid sequences as shown in SEQ ID NO:61, SEQ ID NO:62 and SEQ ID NO:63, respectively; or

[0021] (XII) HCDR1, HCDR2 and HCDR3 with amino acid sequences as shown in SEQ ID NO:67, SEQ ID NO:68 and SEQ ID NO:69, respectively; or HCDR1, HCDR2 and HCDR3 with 1, 2 or 3 amino acid differences with the amino acid sequences as shown in SEQ ID NO:67, SEQ ID NO:68 and SEQ ID NO:69, respectively; or

[0022] (XIII) HCDR1, HCDR2 and HCDR3 with amino acid sequences as shown in SEQ ID NO:73, SEQ ID NO:74 and SEQ ID NO:75, respectively; or HCDR1, HCDR2 and HCDR3 with 1, 2 or 3 amino acid differences with the amino acid sequences as shown in SEQ ID NO:73, SEQ ID NO:74 and SEQ ID NO:75, respectively; or

[0023] (XIV) HCDR1, HCDR2 and HCDR3 with amino acid sequences as shown in SEQ ID NO:79, SEQ ID NO:80 and SEQ ID NO:81, respectively; or HCDR1, HCDR2 and HCDR3 with 1, 2 or 3 amino acid differences with the amino acid sequences as shown in SEQ ID NO:79, SEQ ID NO:80 and SEQ ID NO:81, respectively; or

[0024] (XV) HCDR1, HCDR2 and HCDR3 with amino acid sequences as shown in SEQ ID NO: 143, SEQ ID NO: 144 and SEQ ID NO: 145, respectively; or HCDR1, HCDR2 and HCDR3 with 1, 2 or 3 amino acid differences with the amino acid sequences as shown in SEQ ID NO: 143, SEQ ID NO: 144 and SEQ ID NO: 145, respectively;

[0025] The light chain variable region comprises:

[0026] (I) LCDR1, LCDR2 and LCDR3 with amino acid sequences as shown in SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6, respectively; or LCDR1, LCDR2 and LCDR3 with 1, 2 or 3 amino acid differences with the amino acid sequences as shown in SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6, respectively; or

[0027] (II) LCDR1, LCDR2 and LCDR3 whose amino acid sequences are shown in SEQ ID NO:10, SEQ ID NO:11 and SEQ ID NO:12, respectively; or LCDR1, LCDR2 and LCDR3 whose amino acid sequences differ from those of SEQ ID NO:10, SEQ ID NO:11 and SEQ ID NO:12, respectively, by 1, 2 or 3 amino acids; or

[0028] (III) LCDR1, LCDR2 and LCDR3 whose amino acid sequences are shown in SEQ ID NO: 19, SEQ ID NO: 20 and SEQ ID NO: 21, respectively; or LCDR1, LCDR2 and LCDR3 whose amino acid sequences differ from those of SEQ ID NO: 19, SEQ ID NO: 20 and SEQ ID NO: 21, respectively, by 1, 2 or 3 amino acids; or

[0029] (IV) LCDR1, LCDR2 and LCDR3 whose amino acid sequences are as shown in SEQ ID NO:25, SEQ ID NO:26 and SEQ ID NO:27, respectively; or LCDR1, LCDR2 and LCDR3 whose amino acid sequences differ from those of SEQ ID NO:25, SEQ ID NO:26 and SEQ ID NO:27, respectively, by 1, 2 or 3 amino acids; or

[0030] (V) LCDR1, LCDR2 and LCDR3 whose amino acid sequences are shown in SEQ ID NO:31, SEQ ID NO:32 and SEQ ID NO:33, respectively; or LCDR1, LCDR2 and LCDR3 whose amino acid sequences differ from those of SEQ ID NO:31, SEQ ID NO:32 and SEQ ID NO:33, respectively, by 1, 2 or 3 amino acids; or

[0031] (VI) LCDR1, LCDR2 and LCDR3 whose amino acid sequences are shown in SEQ ID NO:37, SEQ ID NO:38 and SEQ ID NO:39, respectively; or LCDR1, LCDR2 and LCDR3 whose amino acid sequences differ from those of SEQ ID NO:37, SEQ ID NO:38 and SEQ ID NO:39, respectively, by 1, 2 or 3 amino acids; or

[0032] (VII) LCDR1, LCDR2 and LCDR3 with amino acid sequences as shown in SEQ ID NO:43, SEQ ID NO:44 and SEQ ID NO:45, respectively; or LCDR1, LCDR2 and LCDR3 with 1, 2 or 3 amino acid differences with the amino acid sequences as shown in SEQ ID NO:43, SEQ ID NO:44 and SEQ ID NO:45, respectively; or

[0033] (VIII) LCDR1, LCDR2 and LCDR3 whose amino acid sequences are shown in SEQ ID NO:46, SEQ ID NO:47 and SEQ ID NO:48, respectively; or LCDR1, LCDR2 and LCDR3 whose amino acid sequences differ from those of SEQ ID NO:46, SEQ ID NO:47 and SEQ ID NO:48, respectively, by 1, 2 or 3 amino acids; or

[0034] (IX) LCDR1, LCDR2 and LCDR3 with amino acid sequences as shown in SEQ ID NO:52, SEQ ID NO:53 and SEQ ID NO:54, respectively; or LCDR1, LCDR2 and LCDR3 with 1, 2 or 3 amino acid differences with the amino acid sequences as shown in SEQ ID NO:52, SEQ ID NO:53 and SEQ ID NO:54, respectively; or

[0035] (X) LCDR1, LCDR2 and LCDR3 whose amino acid sequences are shown in SEQ ID NO:58, SEQ ID NO:59 and SEQ ID NO:60, respectively; or LCDR1, LCDR2 and LCDR3 whose amino acid sequences differ from those of SEQ ID NO:58, SEQ ID NO:59 and SEQ ID NO:60, respectively, by 1, 2 or 3 amino acids; or

[0036] (XI) LCDR1, LCDR2 and LCDR3 whose amino acid sequences are shown in SEQ ID NO:64, SEQ ID NO:65 and SEQ ID NO:66, respectively; or LCDR1, LCDR2 and LCDR3 whose amino acid sequences differ from those of SEQ ID NO:64, SEQ ID NO:65 and SEQ ID NO:66, respectively, by 1, 2 or 3 amino acids; or

[0037] (XII) LCDR1, LCDR2 and LCDR3 whose amino acid sequences are as shown in SEQ ID NO:70, SEQ ID NO:71 and SEQ ID NO:72, respectively; or LCDR1, LCDR2 and LCDR3 whose amino acid sequences differ from those of SEQ ID NO:70, SEQ ID NO:71 and SEQ ID NO:72, respectively, by 1, 2 or 3 amino acids; or

[0038] (XIII) LCDR1, LCDR2 and LCDR3 with amino acid sequences as shown in SEQ ID NO:76, SEQ ID NO:77 and SEQ ID NO:78, respectively; or LCDR1, LCDR2 and LCDR3 with 1, 2 or 3 amino acid differences with the amino acid sequences as shown in SEQ ID NO:76, SEQ ID NO:77 and SEQ ID NO:78, respectively; or

[0039] (XIV) LCDR1, LCDR2 and LCDR3 whose amino acid sequences are shown in SEQ ID NO:82, SEQ ID NO:83 and SEQ ID NO:84, respectively; or LCDR1, LCDR2 and LCDR3 whose amino acid sequences have 1, 2 or 3 amino acid differences with the amino acid sequences shown in SEQ ID NO:82, SEQ ID NO:83 and SEQ ID NO:84, respectively.

[0040] In some embodiments, the antibody or antigen-binding fragment thereof of the present invention comprises:

[0041] (I) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 having amino acid sequences as shown in SEQ ID NO:1, SEQ ID NO:2 and SEQ ID NO:3, respectively; and a light chain variable region comprising LCDR1, LCDR2 and LCDR3 having amino acid sequences as shown in SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6, respectively; or

[0042] (II) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 having amino acid sequences as shown in SEQ ID NO:7, SEQ ID NO:8 and SEQ ID NO:9, respectively; and a light chain variable region comprising LCDR1, LCDR2 and LCDR3 having amino acid sequences as shown in SEQ ID NO:10, SEQ ID NO:11 and SEQ ID NO:12, respectively; or

[0043] (III) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 having amino acid sequences as shown in SEQ ID NO:13, SEQ ID NO:14 and SEQ ID NO:15, respectively; and a light chain variable region comprising LCDR1, LCDR2 and LCDR3 having amino acid sequences as shown in SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6, respectively; or

[0044] (IV) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 having amino acid sequences as shown in SEQ ID NO:16, SEQ ID NO:17 and SEQ ID NO:18, respectively; and a light chain variable region comprising LCDR1, LCDR2 and LCDR3 having amino acid sequences as shown in SEQ ID NO:19, SEQ ID NO:20 and SEQ ID NO:21, respectively; or

[0045] (V) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 with amino acid sequences as shown in SEQ ID NO:22, SEQ ID NO:23 and SEQ ID NO:24, respectively; and a light chain variable region comprising LCDR1, LCDR2 and LCDR3 with amino acid sequences as shown in SEQ ID NO:25, SEQ ID NO:26 and SEQ ID NO:27, respectively; or

[0046] (VI) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 with amino acid sequences as shown in SEQ ID NO:28, SEQ ID NO:29 and SEQ ID NO:30, respectively; and a light chain variable region comprising LCDR1, LCDR2 and LCDR3 with amino acid sequences as shown in SEQ ID NO:31, SEQ ID NO:32 and SEQ ID NO:33, respectively; or

[0047] (VII) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 having amino acid sequences as shown in SEQ ID NO:34, SEQ ID NO:35 and SEQ ID NO:36, respectively; and a light chain variable region comprising LCDR1, LCDR2 and LCDR3 having amino acid sequences as shown in SEQ ID NO:37, SEQ ID NO:38 and SEQ ID NO:39, respectively; or

[0048] (VIII) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 as shown in the amino acid sequences of SEQ ID NO:40, SEQ ID NO:41 and SEQ ID NO:42, respectively; and a light chain variable region comprising LCDR1, LCDR2 and LCDR3 as shown in the amino acid sequences of SEQ ID NO:43, SEQ ID NO:44 and SEQ ID NO:45, respectively; or

[0049] (IX) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO:28, SEQ ID NO:29 and SEQ ID NO:30, respectively; and a light chain variable region comprising LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO:46, SEQ ID NO:47 and SEQ ID NO:48, respectively; or

[0050] (X) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 as shown in the amino acid sequences of SEQ ID NO:49, SEQ ID NO:50 and SEQ ID NO:51, respectively; and a light chain variable region comprising LCDR1, LCDR2 and LCDR3 as shown in the amino acid sequences of SEQ ID NO:52, SEQ ID NO:53 and SEQ ID NO:54, respectively; or

[0051] (Ⅺ) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 as shown in the amino acid sequences of SEQ ID NO:55, SEQ ID NO:56 and SEQ ID NO:57, respectively; and a light chain variable region comprising LCDR1, LCDR2 and LCDR3 as shown in the amino acid sequences of SEQ ID NO:58, SEQ ID NO:59 and SEQ ID NO:60, respectively; or

[0052] (XII) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 having amino acid sequences as shown in SEQ ID NO:61, SEQ ID NO:62 and SEQ ID NO:63, respectively; and a light chain variable region comprising LCDR1, LCDR2 and LCDR3 having amino acid sequences as shown in SEQ ID NO:64, SEQ ID NO:65 and SEQ ID NO:66, respectively; or

[0053] (XIII) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 as shown in the amino acid sequences of SEQ ID NO:67, SEQ ID NO:68 and SEQ ID NO:69, respectively; and a light chain variable region comprising LCDR1, LCDR2 and LCDR3 as shown in the amino acid sequences of SEQ ID NO:70, SEQ ID NO:71 and SEQ ID NO:72, respectively; or

[0054] (XIV) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 as shown in the amino acid sequences of SEQ ID NO:73, SEQ ID NO:74 and SEQ ID NO:75, respectively; and a light chain variable region comprising LCDR1, LCDR2 and LCDR3 as shown in the amino acid sequences of SEQ ID NO:76, SEQ ID NO:77 and SEQ ID NO:78, respectively; or

[0055] (XV) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 with amino acid sequences as shown in SEQ ID NO:79, SEQ ID NO:80 and SEQ ID NO:81, respectively; and a light chain variable region comprising LCDR1, LCDR2 and LCDR3 with amino acid sequences as shown in SEQ ID NO:82, SEQ ID NO:83 and SEQ ID NO:84, respectively; or

[0056] (XVI) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO:13, SEQ ID NO:14 and SEQ ID NO:15, respectively; and a light chain variable region comprising LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO:43, SEQ ID NO:44 and SEQ ID NO:45, respectively; or

[0057] (XVII) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 as shown in the amino acid sequences of SEQ ID NO:13, SEQ ID NO:14 and SEQ ID NO:15, respectively; and a light chain variable region comprising LCDR1, LCDR2 and LCDR3 as shown in the amino acid sequences of SEQ ID NO:52, SEQ ID NO:53 and SEQ ID NO:54, respectively; or

[0058] (XVIII) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 as shown in the amino acid sequences of SEQ ID NO:13, SEQ ID NO:14 and SEQ ID NO:15, respectively; and a light chain variable region comprising LCDR1, LCDR2 and LCDR3 as shown in the amino acid sequences of SEQ ID NO:70, SEQ ID NO:71 and SEQ ID NO:72, respectively; or

[0059] (XIX) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 as shown in the amino acid sequences of SEQ ID NO:40, SEQ ID NO:41 and SEQ ID NO:42, respectively; and a light chain variable region comprising LCDR1, LCDR2 and LCDR3 as shown in the amino acid sequences of SEQ ID NO:52, SEQ ID NO:53 and SEQ ID NO:54, respectively; or

[0060] (XX) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO:40, SEQ ID NO:41 and SEQ ID NO:42, respectively; and a light chain variable region comprising LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO:70, SEQ ID NO:71 and SEQ ID NO:72, respectively; or

[0061] (XXⅠ) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 as shown in the amino acid sequences of SEQ ID NO:49, SEQ ID NO:50 and SEQ ID NO:51, respectively; and a light chain variable region comprising LCDR1, LCDR2 and LCDR3 as shown in the amino acid sequences of SEQ ID NO:43, SEQ ID NO:44 and SEQ ID NO:45, respectively; or (XXⅡ) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 as shown in the amino acid sequences of SEQ ID NO:49, SEQ ID NO:50 and SEQ ID NO:51, respectively; and a light chain variable region comprising LCDR1, LCDR2 and LCDR3 as shown in the amino acid sequences of SEQ ID NO:70, SEQ ID NO:71 and SEQ ID NO:72, respectively; or (XXⅢ) a heavy chain variable region comprising an amino acid sequence as shown in SEQ ID NO:67, SEQ ID NO:68 and SEQ ID NO:69, respectively. NO:69; and a light chain variable region comprising LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO:43, SEQ ID NO:44 and SEQ ID NO:45, respectively; or (XXIV) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO:67, SEQ ID NO:68 and SEQ ID NO:69, respectively; and a light chain variable region comprising LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO:52, SEQ ID NO:53 and SEQ ID NO:54, respectively; or (XXV) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO:143, SEQ ID NO:144 and SEQ ID NO:145, respectively; and a light chain variable region comprising amino acid sequences as shown in SEQ ID NO:19, SEQ ID NO:20 and SEQ ID NO:21, respectively. LCDR1, LCDR2 and LCDR3 shown in NO:21.

[0062] In some embodiments, the antibodies of the present invention are murine antibodies or chimeric antibodies.

[0063] In some embodiments, the antibody or antigen-binding fragment thereof of the present invention comprises a heavy chain variable region and a light chain variable region:

[0064] (I) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO:85, or an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence as set forth in SEQ ID NO:85; and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO:86, or an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence as set forth in SEQ ID NO:86; or

[0065] (II) the heavy chain variable region comprises the amino acid sequence as shown in SEQ ID NO:87, or comprises an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity with the amino acid sequence as shown in SEQ ID NO:87; and the light chain variable region comprises the amino acid sequence as shown in SEQ ID NO:88, or comprises an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity with the amino acid sequence as shown in SEQ ID NO:88; or

[0066] (III) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO:89, or comprises an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence as set forth in SEQ ID NO:89; and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO:90, or comprises an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence as set forth in SEQ ID NO:90; or

[0067] (IV) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO:91, or comprises an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence as set forth in SEQ ID NO:91; and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO:92, or comprises an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence as set forth in SEQ ID NO:92; or

[0068] (V) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO:93, or an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence as set forth in SEQ ID NO:93; and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO:94, or an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence as set forth in SEQ ID NO:94; or

[0069] (VI) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO:95, or an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence as set forth in SEQ ID NO:95; and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO:96, or an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence as set forth in SEQ ID NO:96; or

[0070] (VII) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO:97, or an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence as set forth in SEQ ID NO:97; and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO:98, or an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence as set forth in SEQ ID NO:98; or

[0071] (VIII) the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:99, or comprises an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:99; and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO:100, or comprises an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:100; or (IX) the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:101, or comprises an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:101; and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO:102, or comprises an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:102; or

[0072] (X) the heavy chain variable region comprises the amino acid sequence as shown in SEQ ID NO:103, or an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence as shown in SEQ ID NO:103; and the light chain variable region comprises the amino acid sequence as shown in SEQ ID NO:104, or an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence as shown in SEQ ID NO:104; or

[0073] (Ⅺ) the heavy chain variable region comprises the amino acid sequence as shown in SEQ ID NO:105, or an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence as shown in SEQ ID NO:105; and the light chain variable region comprises the amino acid sequence as shown in SEQ ID NO:106, or an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence as shown in SEQ ID NO:106; or

[0074] (XII) the heavy chain variable region comprises the amino acid sequence as shown in SEQ ID NO:107, or an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence as shown in SEQ ID NO:107; and the light chain variable region comprises the amino acid sequence as shown in SEQ ID NO:108, or an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence as shown in SEQ ID NO:108; or

[0075] (XIII) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO:109, or an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence as set forth in SEQ ID NO:109; and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO:110, or an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence as set forth in SEQ ID NO:110; or

[0076] (XIV) the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:111, or an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:111; and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO:112, or an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:112; or

[0077] (XV) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO:113, or an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence as set forth in SEQ ID NO:113; and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO:114, or an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence as set forth in SEQ ID NO:114; or

[0078] (XVI) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO:99, or an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence as set forth in SEQ ID NO:99; and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO:110, or an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence as set forth in SEQ ID NO:110; or

[0079] (XVII) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO:103, or an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence as set forth in SEQ ID NO:103; and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO:110, or an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence as set forth in SEQ ID NO:110; or

[0080] (XVIII) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO:103, or an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence as set forth in SEQ ID NO:103; and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO:100, or an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence as set forth in SEQ ID NO:100; or

[0081] (XIX) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO:109, or an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence as set forth in SEQ ID NO:109; and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO:100, or an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence as set forth in SEQ ID NO:100; or

[0082] (XX) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO:109, or an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence as set forth in SEQ ID NO:109; and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO:104, or an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence as set forth in SEQ ID NO:104; or

[0083] (XXI) the heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:142, or an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity with the amino acid sequence shown in SEQ ID NO:142; and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:92, or an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity with the amino acid sequence shown in SEQ ID NO:92.

[0084] In some embodiments, the antibodies described herein are humanized antibodies.

[0085] In some embodiments, the antibody or antigen-binding fragment thereof of the present invention comprises:

[0086] (I) a heavy chain variable region comprising an amino acid sequence as shown in any one of SEQ ID NO: 115, 116, 117, 118, 119, 120, 121, 124, 125, 128, 129 or 130; and

[0087] A light chain variable region comprising an amino acid sequence as shown in any one of SEQ ID NO: 122, 123, 126, 127, 131 or 132; or

[0088] (II) a heavy chain variable region comprising an amino acid sequence having at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence shown in any one of SEQ ID NO: 115, 116, 117, 118, 119, 120, 121, 124, 125, 128, 129 or 130; and

[0089] A light chain variable region comprising an amino acid sequence having at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence shown in any one of SEQ ID NO: 122, 123, 126, 127, 131 or 132; or

[0090] (III) a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO: 118 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO: 127; or

[0091] (IV) a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO: 124 or 125 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO: 126; or

[0092] (V) a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO: 128 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO: 126, 127, 131 or 132; or

[0093] (VI) a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO: 129 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO: 122, 123, 127, 131 or 132; or

[0094] (VII) a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO: 118 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO: 127; or

[0095] (VIII) a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO: 128 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO: 127; or

[0096] (IX) a heavy chain variable region having an amino acid sequence as shown in SEQ ID NO: 129 and a light chain variable region having an amino acid sequence as shown in SEQ ID NO: 131.

[0097] In some embodiments, the antibody or antigen-binding fragment thereof of the present invention comprises:

[0098] (I) a heavy chain comprising the amino acid sequence shown in any one of SEQ ID NO: 134, 135, 137, 138, 140 or 141, and

[0099] A light chain comprising the amino acid sequence shown in any one of SEQ ID NO: 133, 136 or 139; or

[0100] (II) a heavy chain comprising an amino acid sequence having at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence shown in any one of SEQ ID NO: 134, 135, 137, 138, 140 or 141, and

[0101] A light chain comprising an amino acid sequence having at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence shown in any one of SEQ ID NO: 133, 136 or 139; or

[0102] (III) a heavy chain having an amino acid sequence as shown in SEQ ID NO: 134 or 135, and a light chain having an amino acid sequence as shown in SEQ ID NO: 133; or

[0103] (IV) a heavy chain having an amino acid sequence as shown in SEQ ID NO: 137 or 138, and a light chain having an amino acid sequence as shown in SEQ ID NO: 136; or

[0104] (V) a heavy chain having an amino acid sequence as shown in SEQ ID NO: 140 or 141, and a light chain having an amino acid sequence as shown in SEQ ID NO: 139.

[0105] In some embodiments, the antibody or antigen-binding fragment thereof described in the present invention is a murine antibody, a chimeric antibody, a humanized antibody, or a fully human antibody, or an antigen-binding fragment thereof.

[0106] In some embodiments, the antibody or antigen-binding fragment thereof described in the present invention, wherein the antigen-binding fragment is Fab, Fab', F(ab')2, Fv, scFv or sdAb.

[0107] In some embodiments, the antibody or antigen-binding fragment thereof described in the present invention, wherein the antibody or antigen-binding fragment thereof is any IgG subtype, such as IgG1, IgG2, IgG3 or IgG4, preferably IgG1 subtype or IgG4 subtype.

[0108] In another aspect, the present invention provides an isolated anti-CD112R antibody or antigen-binding fragment thereof having one or more of the following properties:

[0109] (1) the epitope of the human CD112R protein bound is identical to, completely overlaps with, or partially overlaps with the anti-CD112R antibody or antigen-binding fragment thereof described herein;

[0110] (2) competing with the anti-CD112R antibody or antigen-binding fragment thereof described herein for binding to the epitope of the human CD112R protein.

[0111] In some embodiments, the antibodies or antigen-binding fragments thereof described herein have one or more of the following characteristics:

[0112] (1) Binds to human / cynomolgus monkey CD112R protein with high affinity;

[0113] (2) Inhibit or block the binding of human CD112R protein to human CD112 or cells expressing human CD112.

[0114] In some embodiments, the antibodies described herein are monoclonal antibodies.

[0115] The present invention also provides a multispecific antibody comprising a light chain variable region and a heavy chain variable region of the antibody or antigen-binding fragment thereof described herein.

[0116] The present invention also provides a single-chain antibody comprising a light chain variable region and a heavy chain variable region of the antibody or antigen-binding fragment thereof described herein.

[0117] The present invention also provides an immunoconjugate comprising the antibody or antigen-binding fragment thereof described herein conjugated to a therapeutic agent or a diagnostic agent.

[0118] In yet another aspect, the present invention provides a polynucleotide molecule encoding the anti-CD112R antibody or antigen-binding fragment thereof described herein.

[0119] In yet another aspect, the present invention provides an expression vector comprising the polynucleotide molecule described herein, preferably, the vector is a eukaryotic expression vector.

[0120] In yet another aspect, the present invention provides a host cell comprising the polynucleotide molecule described herein or the expression vector described herein. Preferably, the host cell is a eukaryotic cell, more preferably a mammalian cell.

[0121] In yet another aspect, the present invention provides a method for preparing the anti-CD112R antibody or its antigen-binding fragment described herein, the method comprising expressing the antibody or its antigen-binding fragment in a host cell described herein under conditions suitable for expression of the antibody or its antigen-binding fragment, and recovering the expressed antibody or its antigen-binding fragment from the host cell.

[0122] In yet another aspect, the present invention provides a pharmaceutical composition comprising the anti-CD112R antibody or antigen-binding fragment thereof described herein, the polynucleotide molecule described herein, the expression vector described herein, the host cell described herein, and a pharmaceutically acceptable carrier or excipient.

[0123] In yet another aspect, the present invention provides a pharmaceutical combination comprising an antibody or antigen-binding fragment thereof or a pharmaceutical composition as described herein, and one or more additional therapeutic agents.

[0124] In some embodiments, in the drug combination described in the present invention, the additional therapeutic agent is selected from one or more of anti-PD-1 antibodies, PD-L1 antibodies and anti-TIGIT antibodies; preferably, the additional therapeutic agent is an anti-TIGIT antibody, or a combination of an anti-TIGIT antibody and a PD-1 antibody.

[0125] In another aspect, the present invention provides the use of the antibody or antigen-binding fragment thereof described herein, the polynucleotide molecule described herein, the expression vector described herein, the host cell described herein, the pharmaceutical composition described herein or the drug combination described herein in the preparation of a medicament for treating and / or preventing a disease or condition mediated by CD112R, preferably the disease or condition is cancer, more preferably the cancer is selected from melanoma, renal cancer, prostate cancer, breast cancer, colon cancer, lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, uterine cancer, ovarian cancer and rectal cancer.

[0126] In another aspect, the present invention provides an antibody or antigen-binding fragment thereof as described herein, a polynucleotide molecule as described herein, an expression vector as described herein, a host cell as described herein, a pharmaceutical composition as described herein, or a drug combination as described herein, for treating and / or preventing a CD112R-mediated disease or condition, preferably the disease or condition is cancer, more preferably the cancer is selected from melanoma, renal cancer, prostate cancer, breast cancer, colon cancer, lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, uterine cancer, ovarian cancer and rectal cancer.

[0127] In another aspect, the present invention provides a method for treating and / or preventing a CD112R-mediated disease or condition, comprising administering to a subject in need thereof a therapeutically or prophylactically effective amount of an antibody or antigen-binding fragment thereof as described herein, a polynucleotide molecule as described herein, an expression vector as described herein, a host cell as described herein, a pharmaceutical composition as described herein, or a drug combination as described herein, wherein the disease or condition is preferably cancer, and more preferably the cancer is selected from melanoma, renal cancer, prostate cancer, breast cancer, colon cancer, lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, uterine cancer, ovarian cancer, and rectal cancer.

[0128] In some embodiments, the antibody or antigen-binding fragment thereof of the present invention is administered in combination with an additional therapeutic agent, and the additional therapeutic agent is selected from one or more of anti-PD-1 antibodies, PD-L1 antibodies and anti-TIGIT antibodies; preferably, the additional therapeutic agent is an anti-TIGIT antibody, or a combination of an anti-TIGIT antibody and an anti-PD-1 antibody.

[0129] In yet another aspect, the present invention provides a pharmaceutical combination comprising the antibody or antigen-binding fragment thereof described herein, the polynucleotide molecule described herein, the expression vector described herein, the host cell described herein or the pharmaceutical composition described herein, and one or more additional therapeutic agents.

[0130] In another aspect, the present invention provides a kit comprising the antibody or antigen-binding fragment thereof described herein, the polynucleotide molecule described herein, the expression vector described herein, the host cell described herein, the pharmaceutical composition described herein, or the drug combination described herein, preferably further comprising a drug delivery device.

[0131] In yet another aspect, the present invention provides a method for detecting the presence of CD112R in a sample using the antibody or antigen-binding fragment thereof described herein or a detection composition containing the antibody or antigen-binding fragment thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0132] Figure 1 : Activity detection of hybridoma antibodies combined with anti-TIGIT antibodies in a dual reporter gene system.

[0133] Figure 2 : Activity of hybridoma antibodies combined with anti-TIGIT antibodies and anti-PD-1 antibodies in a triple reporter gene system.

[0134] Figure 3 : FACS method was used to detect the binding of anti-CD112R chimeric antibody to CHO-hCD112 expressing cells.

[0135] Figure 4 : ELISA was used to detect the binding of anti-CD112R chimeric antibody to cynomolgus monkey CD112R.

[0136] Figure 5 : FACS method was used to detect the blocking effect of anti-CD112R chimeric antibody on the binding of CD112R protein to human CHO-CD112 cells.

[0137] Figure 6 : Activity of anti-CD112R chimeric antibody in CD112R / CD112 reporter gene assay system.

[0138] Figure 7 : ELISA was used to detect the binding of anti-CD112R humanized antibody to cynomolgus monkey and mouse CD112R.

[0139] Figure 8 : Activity of anti-CD112R humanized antibody combined with anti-TIGIT antibody in a dual reporter gene system.

[0140] Figure 9: The activity of anti-CD112R humanized antibody in combination with anti-TIGIT antibody and anti-PD-1 antibody in the triple reporter gene system.

[0141] Figure 10 : Tumor growth inhibitory effects of anti-CD112R humanized antibodies, anti-TIGIT antibodies and their combination. DETAILED DESCRIPTION

[0142] definition

[0143] The practice of the present invention will employ, unless otherwise indicated, conventional techniques of molecular biology (including recombinant techniques), microbiology, cell biology, biochemistry and immunology, which are within the skill of the art.

[0144] In order to make it easier to understand the present invention, some scientific and technological terms are specifically defined as follows. Unless otherwise clearly defined in other parts of this article, the scientific and technological terms used herein have the meanings commonly understood by ordinary technicians in the field to which the present invention belongs. Regarding the definitions and terms in this area, professionals can specifically refer to Current Protocols in Molecular Biology (Ausubel). The abbreviations of amino acid residues are standard 3-letter and / or 1-letter codes used in the art to refer to one of the 20 commonly used L-amino acids. The singular form used herein (including the claims) includes its corresponding plural form unless otherwise clearly specified in the text.

[0145] The term "about" when used in conjunction with a numerical value is meant to encompass the numerical value within a range having a lower limit that is 5% less than the specified numerical value and an upper limit that is 5% greater than the specified numerical value, including but not limited to ±5%, ±2%, ±1%, and ±0.1%, as such variations are appropriate for performing the disclosed methods.

[0146] The term "and / or" should be understood to mean any one of the optional items or a combination of any two or more of the optional items.

[0147] As used herein, the term "or" should be understood to have the same meaning as "and / or" as defined above. For example, when separating items in a list, "or" or "and / or" should be interpreted as inclusive, that is, including at least one of the numbers or elements in the list, but also including more than one, and optionally, additional unlisted items. Only when terms are clearly indicated to the contrary, such as "only one" or "exactly one" or when "consisting of..." is used in the claims, it will refer to only one number listed or one element of the list.

[0148] As used herein, the words "a" and "an" should be understood to mean "at least one" unless expressly stated to the contrary.

[0149] The terms "CD112R", "immunoglobulin domain associated with PVR", "CD112 receptor", "immunoglobulin domain associated with poliovirus receptor", "Nectin-2 receptor", "C7orfl5", "transmembrane protein PVRIG" are all used interchangeably and include variants, subtypes, species homologs of human CD112R or CD112R of other species and analogs having at least one common epitope of CD112R, unless otherwise indicated. The term includes unprocessed full-length CD112R as well as any form of CD112R produced as a result of processing in the cell. The term encompasses "full-length" unprocessed CD112R as well as any form of CD112R or any fragment thereof, such as a splice variant or allelic variant, produced by intracellular processing.

[0150] In one embodiment, CD112R refers to the full-length CD112R from human or cynomolgus monkey or a fragment thereof (such as a mature fragment lacking a signal peptide).

[0151] The term "human CD112R" refers to a human sequence CD112R, such as a complete amino acid sequence of a human CD112R with NCBI accession number NM_024070. The human CD112R sequence may be different from the human CD112R with NCBI accession number NM_024070 due to having, for example, a conservative mutation or a mutation in a non-conservative region, and CD112R has substantially the same biological function as the human CD112R with NCBI accession number NM_024070.

[0152] The term "percent (%) amino acid sequence identity" or simply "identity" is defined as the percentage of amino acid residues in a candidate amino acid sequence that are identical to the amino acid residues in a reference amino acid sequence, after the amino acid sequences are aligned (and gaps introduced where necessary) to obtain the maximum percent sequence identity, and any conservative substitutions are not considered part of the sequence identity. Sequence alignments can be performed using various methods in the art to determine percent amino acid sequence identity, for example, using publicly available computer software such as BLAST, BLAST-2, ALIGN or MEGALIGN (DNASTAR) software. One skilled in the art can determine appropriate parameters for measuring alignments, including any algorithm required to achieve maximum alignment over the entire length of the compared sequences.

[0153] The term "immune response" refers to the actions of, for example, lymphocytes, antigen presenting cells, phagocytes, granulocytes, and soluble macromolecules produced by the above cells or the liver (including antibodies, cytokines and complement), which result in the selective damage, destruction or elimination from the human body of invading pathogens, cells or tissues infected with pathogens, cancer cells, or, in the case of autoimmunity or pathological inflammation, normal human cells or tissues.

[0154] The term "signal transduction pathway" or "signal transduction activity" refers to a biochemical cause-effect relationship, usually initiated by protein-protein interactions such as the binding of a growth factor to a receptor, that results in the transmission of a signal from one part of a cell to another part of the cell. Typically, the transmission involves specific phosphorylation of one or more tyrosine, serine or threonine residues on one or more proteins in a series of reactions that lead to signal transduction. The penultimate process usually involves nuclear events, resulting in changes in gene expression.

[0155] The terms "activity" or "biological activity", or the terms "biological property" or "biological characteristics" are used interchangeably herein and include, but are not limited to, epitope / antigen affinity and specificity, the ability to neutralize or antagonize CD112R activity in vivo or in vitro, IC 50 , the in vivo stability of the antibody and the immunogenic properties of the antibody. Other identifiable biological properties or characteristics of antibodies known in the art include, for example, cross-reactivity (i.e., usually with non-human homologs of the targeted peptide, or with cross-reactivity of other proteins or tissues), and the ability to maintain high protein expression levels in mammalian cells. The aforementioned properties or characteristics are observed, measured or evaluated using techniques known in the art, including but not limited to ELISA, FACS or BIACORE plasma resonance analysis, unrestricted in vitro or in vivo neutralization assays, receptor binding, production and / or secretion of cytokines or growth factors, signal transduction, and immunohistochemistry of tissue sections from different sources (including humans, primates or any other source).

[0156] The term "antibody" refers to any form of antibody having the desired biological activity. Therefore, it is used in the broadest sense, specifically including but not limited to monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, multispecific antibodies (such as bispecific antibodies), humanized antibodies, fully human antibodies, chimeric antibodies and camelized single domain antibodies.

[0157] The term "isolated antibody" refers to the purified state of the binding compound, and in this case means that the molecule is substantially free of other biomolecules, such as nucleic acids, proteins, lipids, sugars, or other substances such as cell debris and growth medium. The term "isolated" does not imply the complete absence of such substances or the absence of water, buffers, or salts unless they are present in amounts that significantly interfere with the experimental or therapeutic use of the binding compound described herein.

[0158] The term "monoclonal antibody" refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations that may be present in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigenic epitope. In contrast, conventional (polyclonal) antibody preparations typically include a large number of antibodies directed against (or specific for) different epitopes. The modifier "monoclonal" indicates the character of the antibody as being obtained from a population of substantially homogeneous antibodies, and is not to be construed as requiring production of the antibody by any particular method.

[0159] The term "full-length antibody" refers to an immunoglobulin molecule that contains at least four peptide chains when naturally present: two heavy (H) chains and two light (L) chains interconnected by disulfide bonds. Each heavy chain consists of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region (abbreviated herein as CH). The heavy chain constant region consists of three domains, CH1, CH2, and CH3. Each light chain consists of a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region consists of one domain, CL. The VH and VL regions can be further subdivided into highly variable complementary determining regions (CDRs) and regions separated by more conservative framework regions (FRs). Each VH or VL region consists of three CDRs and four FRs arranged from the amino terminus to the carboxyl terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain binding domains that interact with antigens. The constant regions of the antibodies may mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (eg, effector cells) and the first component (Clq) of the classical complement system.

[0160] The term "antigen-binding fragment" of an antibody ("parent antibody") includes fragments or derivatives of an antibody, typically including at least one fragment of an antigen-binding region or variable region (e.g., one or more CDRs) of a parent antibody that retains at least some of the binding specificity of the parent antibody. Examples of antibody binding fragments include, but are not limited to, Fab, Fab', F(ab')2, and Fv fragments; diabodies; linear antibodies; single-chain antibody molecules, such as sc-Fv; nanobodies and multispecific antibodies formed from antibody fragments. When the binding activity of the antigen is expressed on a molar basis, the binding fragment or derivative typically retains at least 10% of its antigen-binding activity. Preferably, the binding fragment or derivative retains at least 20%, 50%, 70%, 80%, 90%, 95%, or 100% or more of the antigen-binding affinity of the parent antibody. It is also contemplated that the antigen-binding fragment of an antibody may include conservative or non-conservative amino acid substitutions that do not significantly change its biological activity (referred to as "conservative variants" or "functional conservative variants" of antibodies). The term "binding compound" refers to both antibodies and their binding fragments.

[0161] The term "single-chain Fv" or "scFv" antibody refers to an antibody fragment comprising the VH and VL domains of an antibody, wherein these domains are present in a single polypeptide chain. The Fv polypeptide generally also comprises a polypeptide linker between the VH and VL domains that enables the scFv to form the desired structure for antigen binding.

[0162] The term "domain antibody" is an immunologically functional immunoglobulin fragment containing only the variable region of the heavy chain or the variable region of the light chain. In some cases, two or more VH regions are covalently linked with a peptide linker to form a bivalent domain antibody. The two VH regions of a bivalent domain antibody can target the same or different antigens.

[0163] The term "bivalent antibody" contains two antigen binding sites. In some cases, the two binding sites have the same antigen specificity. However, a bivalent antibody can be bispecific.

[0164] The term "diabody" refers to a small antibody fragment with two antigen binding sites, which comprises a heavy chain variable domain (VH) connected to a light chain variable domain (VL) in the same polypeptide chain (VH-VL or VL-VH). By using a linker that is too short to allow pairing between the two domains on the same chain, the domains are forced to pair with the complementary domains of another chain and generate two antigen binding sites.

[0165] The term "mouse antibody" or "hybridoma antibody" in the present disclosure refers to a monoclonal antibody against human CD112R prepared according to the knowledge and skills in the art. During preparation, a test subject is injected with CD112R antigen, and then a hybridoma expressing an antibody with a desired sequence or functional properties is isolated.

[0166] The term "chimeric antibody" is an antibody having the variable domains of a first antibody and the constant domains of a second antibody, wherein the first antibody and the second antibody are from different species. Typically, the variable domains are obtained from antibodies such as rodents ("parent antibodies"), while the constant domain sequences are obtained from human antibodies, such that the resulting chimeric antibodies are less likely to induce adverse immune responses in human subjects than the parent rodent antibodies.

[0167] The term "humanized antibody" refers to an antibody form containing sequences from human and non-human (e.g., mouse, rat) antibodies. In general, a humanized antibody comprises substantially all of at least one, usually two variable domains, wherein all or substantially all of the hypervariable loops correspond to the hypervariable loops of non-human immunoglobulins, and all or substantially all of the framework (FR) regions are framework regions of human immunoglobulin sequences. A humanized antibody may optionally comprise at least a portion of a human immunoglobulin constant region (Fc).

[0168] The term "fully human antibody" refers to an antibody that contains only human immunoglobulin protein sequences. If produced in a mouse, in a mouse cell, or in a hybridoma derived from a mouse cell, a fully human antibody may contain rat sugar chains. Similarly, a "mouse antibody" refers to an antibody that contains only mouse immunoglobulin sequences. Alternatively, if produced in a rat, in a rat cell, or in a hybridoma derived from a rat cell, a fully human antibody may contain rat sugar chains. Similarly, a "rat antibody" refers to an antibody that contains only rat immunoglobulin sequences.

[0169] An "isotype" antibody refers to the class of antibody provided by the heavy chain constant region genes (e.g., IgM, IgE, IgG such as IgG1, IgG2, or IgG4). Isotypes also include modified forms of one of these classes, where the modifications have been made to alter Fc function, such as to enhance or reduce effector function or binding to Fc receptors.

[0170] The term "Fc region" herein is used to define the C-terminal region of an immunoglobulin heavy chain that includes at least a portion of a constant region. The term includes native sequence Fc regions and variant Fc regions. In some embodiments, the human IgG heavy chain Fc region extends from Cys226 or Pro230 to the carboxyl terminus of the heavy chain. However, the C-terminal lysine (Lys447) in the Fc region may or may not be present (the numbering in this paragraph is according to the EU numbering system, also referred to as the EU index, such as Rabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991).

[0171] The term "epitope" refers to a protein determinant that is capable of specific binding to an antibody. Epitopes are usually composed of various chemically active surface molecules such as amino acids or sugar side chains, and usually have specific three-dimensional structural characteristics as well as specific charge characteristics. The difference between conformational epitopes and non-conformational epitopes is that in the presence of denaturing solvents, the binding to the former but not to the latter is lost.

[0172] The term "cross-reaction" described herein refers to the combination of antigen fragments of the same target molecule of human, monkey, and / or mouse (mouse or rat). Therefore, "cross-reaction" should be understood as the inter-species reaction with the same molecule X expressed in different species. The cross-reaction specificity of the monoclonal antibody recognizing human CD112R, monkey, and / or mouse CD112R (mouse or rat) can be determined by FACS analysis.

[0173] "Affinity" or "binding affinity" refers to the intrinsic binding affinity that reflects the interaction between members of a binding pair. The affinity of a molecule X for its partner Y can generally be expressed by the equilibrium dissociation constant (K D ) represents the equilibrium dissociation constant, which is the dissociation rate constant and the association rate constant (k dis and k on ). Affinity can be measured by common methods known in the art. One specific method for measuring affinity is the ForteBio kinetic binding assay herein.

[0174] The term "not binding" to a protein or cell means that it does not bind to the protein or cell, or does not bind to it with high affinity, i.e., the K of the binding protein or cell is D 1.0×10 -6 M or more, more preferably 1.0×10 -5 M or more, more preferably 1.0×10 -4 M or higher, 1.0×10 -3 M or more, more preferably 1.0×10 -2 M or higher.

[0175] The term "high affinity" for IgG antibodies refers to the K D 1.0×10 -6 M or less, preferably 5.0×10 -8 M or less, more preferably 1.0×10 -8 M or less, 5.0×10 -9 M or less, more preferably 1.0×10 -9 M or lower. For other antibody subtypes, “high affinity” binding may vary. For example, “high affinity” binding for the IgM subtype refers to a K D For 10 -6 M or less, preferably 10-7 M or less, more preferably 10 -8 M or lower.

[0176] The terms "antibody-dependent cellular cytotoxicity," "antibody-dependent cell-mediated cytotoxicity" or "ADCC" refer to a cell-mediated immune defense in which immune system effector cells actively lyse target cells, such as cancer cells, that are bound to cell membrane surface antigens and antibodies, such as Claudin18.2 antibodies.

[0177] The term "complement dependent cytotoxicity" or "CDC" refers to the effector function of IgG and IgM antibodies, which, when bound to surface antigens, initiate the classical complement pathway, including the formation of a membrane attack complex and target cell lysis. The antibodies of the present invention, when bound to Claudin 18.2, initiate CDC against cancer cells.

[0178] The terms "nucleic acid", "polynucleotide", "nucleic acid molecule" and "polynucleotide molecule" refer to deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) and polymers thereof in single-stranded or double-stranded form. Unless expressly limited, the term includes nucleic acids containing analogs of known natural nucleotides that have similar binding properties to reference nucleic acids and are metabolized in a manner similar to naturally occurring nucleotides (see, U.S. Pat. No. 8,278,036 to Kariko et al., which discloses mRNA molecules in which uridine is replaced by pseudouridine, methods for synthesizing the mRNA molecules, and methods for delivering therapeutic proteins in vivo). Unless otherwise indicated, a specific nucleic acid sequence also implicitly includes conservatively modified variants thereof (e.g., degenerate codon substitutions), alleles, orthologs, SNPs, and complementary sequences as well as sequences explicitly indicated. Specifically, degenerate codon substitutions can be achieved by generating sequences in which the third position of one or more selected (or all) codons is substituted with mixed-base and / or deoxyinosine residues (Batzer et al., Nucleic Acid Res. 19:5081 (1991); Ohtsuka et al., J. Biol. Chem. 260:2605-2608 (1985); and Rossolini et al., Mol. Cell. Probes 8:91-98 (1994)).

[0179] "Construct" refers to any recombinant polynucleotide molecule (such as a plasmid, cosmid, virus, autonomously replicating polynucleotide molecule, bacteriophage, or linear or circular single-stranded or double-stranded DNA or RNA polynucleotide molecule), derived from any source, capable of integrating with a genome or autonomously replicating, constituting a polynucleotide molecule in which one or more polynucleotide molecules have been linked (i.e., operably linked) in a functionally operable manner. Recombinant constructs will typically include a polynucleotide of the invention operably linked to a transcription initiation regulatory sequence that directs transcription of the polynucleotide in a host cell. Both heterologous and non-heterologous (i.e., endogenous) promoters can be used to direct expression of the nucleic acids of the invention.

[0180] "Vector" refers to any recombinant polynucleotide construct that can be used for the purpose of transformation (i.e., introducing heterologous DNA into a host cell). One type of vector is a "plasmid", which refers to a circular double-stranded DNA loop into which additional DNA segments can be connected. Another type of vector is a viral vector, in which additional DNA segments can be connected to the viral genome. Certain vectors are capable of autonomous replication in the host cell into which they are introduced (e.g., bacterial vectors with bacterial replication origins and episomal mammalian vectors). After introduction into the host cell, other vectors (e.g., non-episomal mammalian vectors) are integrated into the genome of the host cell and are therefore replicated together with the host genome. In addition, certain vectors are capable of directing the expression of operatively connected genes. Such vectors are referred to herein as "expression vectors".

[0181] The term "expression vector" as used herein refers to a nucleic acid molecule that can replicate and express a target gene when transformed, transfected or transduced into a host cell. The expression vector comprises one or more phenotypic selection markers and an origin of replication to ensure maintenance of the vector and to provide amplification in the host when necessary.

[0182] "Activation," "stimulation," and "treatment" as used for a cell or receptor may have the same meaning, e.g., a cell or receptor is activated, stimulated, or treated with a ligand, unless the context otherwise or clearly dictates. "Ligand" includes natural and synthetic ligands, such as cytokines, cytokine variants, analogs, muteins, and binding compounds derived from antibodies. "Ligand" also includes small molecules, such as peptide mimetics of cytokines and peptide mimetics of antibodies. "Activation" may refer to cell activation regulated by internal mechanisms as well as external or environmental factors. "Response / reaction," such as the response of a cell, tissue, organ, or organism, includes changes in biochemical or physiological behavior (e.g., concentration, density, adhesion or migration within a biological compartment, gene expression rate, or differentiation state), where the change is related to activation, stimulation, or treatment, or to internal mechanisms such as genetic programming.

[0183] As used herein, the term "treatment" or "treating" of any disease or condition refers to improving the disease or condition (i.e., slowing down or preventing or reducing the progression of the disease or at least one of its clinical symptoms) in one embodiment. In another embodiment, "treatment" or "treating" refers to alleviating or improving at least one physical parameter, including those physical parameters that may not be discerned by the patient. In another embodiment, "treatment" or "treating" refers to regulating the disease or condition physically (e.g., stabilization of discernible symptoms), physiologically (e.g., stabilization of physical parameters), or in both aspects. Unless explicitly described herein, methods for assessing the treatment and / or prevention of a disease are generally known in the art.

[0184] "Subject" includes any human or non-human animal. The term "non-human animal" includes all vertebrates, e.g., mammals and non-mammals, such as non-human primates, sheep, dogs, cats, horses, cows, chickens, amphibians, reptiles, etc. As used herein, the term "cyno" or "cynomolgus monkey" refers to cynomolgus monkeys.

[0185] Administration "in combination with" one or more additional therapeutic agents includes simultaneous (concurrent) administration and consecutive administration in either order.

[0186] "Therapeutically effective amount", "therapeutically effective dose" and "effective amount" refer to the amount of the CD112R antibody or its antigen-binding fragment of the present invention, when administered to cells, tissues or subjects alone or in combination with other therapeutic drugs, to effectively prevent or improve the symptoms of one or more diseases or conditions or the development of the disease or condition. The therapeutically effective dose also refers to the amount of the antibody or its antigen-binding fragment sufficient to cause symptom improvement, such as the amount of the treatment, cure, prevention or improvement of the relevant medical condition or the speed of the treatment, cure, prevention or improvement of such conditions. When the active ingredient administered alone is applied to an individual, the therapeutically effective dose refers only to the ingredient. When administered in combination, the therapeutically effective dose refers to the combined amount of the active ingredients that cause the therapeutic effect, whether in combination, sequentially or simultaneously. The effective amount of the therapeutic agent will result in an increase of at least 10%, typically at least 20%, preferably at least about 30%, more preferably at least 40%, and most preferably at least 50% in the diagnostic criteria or parameters.

[0187] "Pharmaceutically acceptable carrier" refers to a component of a pharmaceutical preparation or composition other than the active ingredient that is non-toxic to the subject. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers or preservatives.

[0188] The term "cancer" is used herein to refer to a group of cells that exhibit abnormally high levels of proliferation and growth. Cancer may be benign (also known as a benign tumor), pre-malignant or malignant. Cancer cells may be solid cancer cells or leukemia cancer cells. The term "tumor" as used herein refers to one or more cells comprising a cancer. The term "tumor growth" is used herein to refer to the proliferation or growth of one or more cells comprising a cancer, which results in a corresponding increase in the size or extent of the cancer.

[0189] Anti-CD112R antibody

[0190] In one aspect, the invention provides antibodies or antigen-binding fragments thereof that specifically bind to CD112R. The term "anti-CD112R antibody", "anti-CD112R", "CD112R antibody" or "antibody in conjunction with CD112R" refers to being able to bind to CD112R protein or its fragment with sufficient affinity so that the antibody can be used as a diagnostic agent and / or therapeutic agent targeting CD112R.

[0191] In some embodiments, the present invention provides antibodies that bind to CD112R protein. In some embodiments, the present invention provides antibodies that block CD112R from binding to CD112 protein. In some embodiments, the present invention provides antibodies that enhance the activation of CD226, T cells and / or NK cells.

[0192] In some embodiments, the antibodies of the present invention bind to human or cynomolgus CD112R proteins. In some embodiments, the antibodies of the present invention bind to human CD112R and block the interaction between human CD112R and human CD112 proteins.

[0193] In some embodiments, the anti-CD112R antibody of the present invention comprises:

[0194] (I) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 having amino acid sequences as shown in SEQ ID NO:1, SEQ ID NO:2 and SEQ ID NO:3, respectively; and a light chain variable region comprising LCDR1, LCDR2 and LCDR3 having amino acid sequences as shown in SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6, respectively; or

[0195] (II) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 having amino acid sequences as shown in SEQ ID NO:7, SEQ ID NO:8 and SEQ ID NO:9, respectively; and a light chain variable region comprising LCDR1, LCDR2 and LCDR3 having amino acid sequences as shown in SEQ ID NO:10, SEQ ID NO:11 and SEQ ID NO:12, respectively; or

[0196] (III) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 having amino acid sequences as shown in SEQ ID NO:13, SEQ ID NO:14 and SEQ ID NO:15, respectively; and a light chain variable region comprising LCDR1, LCDR2 and LCDR3 having amino acid sequences as shown in SEQ ID NO:4, SEQ ID NO:5 and SEQ ID NO:6, respectively; or

[0197] (IV) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 having amino acid sequences as shown in SEQ ID NO:16, SEQ ID NO:17 and SEQ ID NO:18, respectively; and a light chain variable region comprising LCDR1, LCDR2 and LCDR3 having amino acid sequences as shown in SEQ ID NO:19, SEQ ID NO:20 and SEQ ID NO:21, respectively; or

[0198] (V) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 with amino acid sequences as shown in SEQ ID NO:22, SEQ ID NO:23 and SEQ ID NO:24, respectively; and a light chain variable region comprising LCDR1, LCDR2 and LCDR3 with amino acid sequences as shown in SEQ ID NO:25, SEQ ID NO:26 and SEQ ID NO:27, respectively; or

[0199] (VI) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 with amino acid sequences as shown in SEQ ID NO:28, SEQ ID NO:29 and SEQ ID NO:30, respectively; and a light chain variable region comprising LCDR1, LCDR2 and LCDR3 with amino acid sequences as shown in SEQ ID NO:31, SEQ ID NO:32 and SEQ ID NO:33, respectively; or

[0200] (VII) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 having amino acid sequences as shown in SEQ ID NO:34, SEQ ID NO:35 and SEQ ID NO:36, respectively; and a light chain variable region comprising LCDR1, LCDR2 and LCDR3 having amino acid sequences as shown in SEQ ID NO:37, SEQ ID NO:38 and SEQ ID NO:39, respectively; or

[0201] (VIII) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 as shown in the amino acid sequences of SEQ ID NO:40, SEQ ID NO:41 and SEQ ID NO:42, respectively; and a light chain variable region comprising LCDR1, LCDR2 and LCDR3 as shown in the amino acid sequences of SEQ ID NO:43, SEQ ID NO:44 and SEQ ID NO:45, respectively; or

[0202] (IX) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO:28, SEQ ID NO:29 and SEQ ID NO:30, respectively; and a light chain variable region comprising LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO:46, SEQ ID NO:47 and SEQ ID NO:48, respectively; or

[0203] (X) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 as shown in the amino acid sequences of SEQ ID NO:49, SEQ ID NO:50 and SEQ ID NO:51, respectively; and a light chain variable region comprising LCDR1, LCDR2 and LCDR3 as shown in the amino acid sequences of SEQ ID NO:52, SEQ ID NO:53 and SEQ ID NO:54, respectively; or

[0204] (Ⅺ) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 as shown in the amino acid sequences of SEQ ID NO:55, SEQ ID NO:56 and SEQ ID NO:57, respectively; and a light chain variable region comprising LCDR1, LCDR2 and LCDR3 as shown in the amino acid sequences of SEQ ID NO:58, SEQ ID NO:59 and SEQ ID NO:60, respectively; or

[0205] (XII) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 having amino acid sequences as shown in SEQ ID NO:61, SEQ ID NO:62 and SEQ ID NO:63, respectively; and a light chain variable region comprising LCDR1, LCDR2 and LCDR3 having amino acid sequences as shown in SEQ ID NO:64, SEQ ID NO:65 and SEQ ID NO:66, respectively; or

[0206] (XIII) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 as shown in the amino acid sequences of SEQ ID NO:67, SEQ ID NO:68 and SEQ ID NO:69, respectively; and a light chain variable region comprising LCDR1, LCDR2 and LCDR3 as shown in the amino acid sequences of SEQ ID NO:70, SEQ ID NO:71 and SEQ ID NO:72, respectively; or

[0207] (XIV) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 as shown in the amino acid sequences of SEQ ID NO:73, SEQ ID NO:74 and SEQ ID NO:75, respectively; and a light chain variable region comprising LCDR1, LCDR2 and LCDR3 as shown in the amino acid sequences of SEQ ID NO:76, SEQ ID NO:77 and SEQ ID NO:78, respectively; or

[0208] (XV) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 with amino acid sequences as shown in SEQ ID NO:79, SEQ ID NO:80 and SEQ ID NO:81, respectively; and a light chain variable region comprising LCDR1, LCDR2 and LCDR3 with amino acid sequences as shown in SEQ ID NO:82, SEQ ID NO:83 and SEQ ID NO:84, respectively; or

[0209] (XVI) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO:13, SEQ ID NO:14 and SEQ ID NO:15, respectively; and a light chain variable region comprising LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO:43, SEQ ID NO:44 and SEQ ID NO:45, respectively; or

[0210] (XVII) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 as shown in the amino acid sequences of SEQ ID NO:13, SEQ ID NO:14 and SEQ ID NO:15, respectively; and a light chain variable region comprising LCDR1, LCDR2 and LCDR3 as shown in the amino acid sequences of SEQ ID NO:52, SEQ ID NO:53 and SEQ ID NO:54, respectively; or

[0211] (XVIII) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 as shown in the amino acid sequences of SEQ ID NO:13, SEQ ID NO:14 and SEQ ID NO:15, respectively; and a light chain variable region comprising LCDR1, LCDR2 and LCDR3 as shown in the amino acid sequences of SEQ ID NO:70, SEQ ID NO:71 and SEQ ID NO:72, respectively; or

[0212] (XIX) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 as shown in the amino acid sequences of SEQ ID NO:40, SEQ ID NO:41 and SEQ ID NO:42, respectively; and a light chain variable region comprising LCDR1, LCDR2 and LCDR3 as shown in the amino acid sequences of SEQ ID NO:52, SEQ ID NO:53 and SEQ ID NO:54, respectively; or

[0213] (XX) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO:40, SEQ ID NO:41 and SEQ ID NO:42, respectively; and a light chain variable region comprising LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO:70, SEQ ID NO:71 and SEQ ID NO:72, respectively; or

[0214] (XXⅠ) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 as shown in the amino acid sequences of SEQ ID NO:49, SEQ ID NO:50 and SEQ ID NO:51, respectively; and a light chain variable region comprising LCDR1, LCDR2 and LCDR3 as shown in the amino acid sequences of SEQ ID NO:43, SEQ ID NO:44 and SEQ ID NO:45, respectively; or (XXⅡ) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 as shown in the amino acid sequences of SEQ ID NO:49, SEQ ID NO:50 and SEQ ID NO:51, respectively; and a light chain variable region comprising LCDR1, LCDR2 and LCDR3 as shown in the amino acid sequences of SEQ ID NO:70, SEQ ID NO:71 and SEQ ID NO:72, respectively; or (XXⅢ) a heavy chain variable region comprising an amino acid sequence as shown in SEQ ID NO:67, SEQ ID NO:68 and SEQ ID NO:69, respectively. NO:69; and a light chain variable region comprising LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO:43, SEQ ID NO:44 and SEQ ID NO:45, respectively; or (XXIV) a heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO:67, SEQ ID NO:68 and SEQ ID NO:69, respectively; and a light chain variable region comprising LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO:52, SEQ ID NO:53 and SEQ ID NO:54, respectively;

[0215] (XV) HCDR1, HCDR2 and HCDR3 with amino acid sequences as shown in SEQ ID NO: 143, SEQ ID NO: 144 and SEQ ID NO: 145, respectively; or HCDR1, HCDR2 and HCDR3 with 1, 2 or 3 amino acid differences with the amino acid sequences as shown in SEQ ID NO: 143, SEQ ID NO: 144 and SEQ ID NO: 145, respectively.

[0216] In some embodiments, the antibody or antigen-binding fragment thereof described herein comprises a heavy chain variable region and / or a light chain variable region:

[0217] The heavy chain variable region comprises:

[0218] (I) HCDR1, HCDR2 and HCDR3 with amino acid sequences as shown in SEQ ID NO: 13, SEQ ID NO: 14 and SEQ ID NO: 15, respectively; or

[0219] (II) HCDR1, HCDR2 and HCDR3 with amino acid sequences as shown in SEQ ID NO:40, SEQ ID NO:41 and SEQ ID NO:42, respectively; or

[0220] (III) HCDR1, HCDR2 and HCDR3 with amino acid sequences as shown in SEQ ID NO:49, SEQ ID NO:50 and SEQ ID NO:51, respectively; or

[0221] (IV) HCDR1, HCDR2 and HCDR3 with amino acid sequences as shown in SEQ ID NO:67, SEQ ID NO:68 and SEQ ID NO:69, respectively;

[0222] The light chain variable region comprises:

[0223] (I) LCDR1, LCDR2 and LCDR3 with amino acid sequences as shown in SEQ ID NO:43, SEQ ID NO:44 and SEQ ID NO:45, respectively; or

[0224] (II) LCDR1, LCDR2 and LCDR3 with amino acid sequences as shown in SEQ ID NO:52, SEQ ID NO:53 and SEQ ID NO:54, respectively; or

[0225] (III) LCDR1, LCDR2 and LCDR3 whose amino acid sequences are shown in SEQ ID NO:70, SEQ ID NO:71 and SEQ ID NO:72 respectively.

[0226] In some embodiments, the antibody or antigen-binding fragment thereof described in the present invention comprises:

[0227] (1) HCDR1, HCDR2 and HCDR3 of the heavy chain variable region as shown in SEQ ID NO: 118, and LCDR1, LCDR2 and LCDR3 of the light chain variable region as shown in SEQ ID NO: 127; or

[0228] (2) HCDR1, HCDR2 and HCDR3 of the heavy chain variable region as shown in SEQ ID NO: 124 or 125, and LCDR1, LCDR2 and LCDR3 of the light chain variable region as shown in SEQ ID NO: 126; or

[0229] (3) HCDR1, HCDR2 and HCDR3 of the heavy chain variable region as shown in SEQ ID NO: 128, and LCDR1, LCDR2 and LCDR3 of the light chain variable region as shown in SEQ ID NO: 126, 127, 131 or 132; or

[0230] (4) HCDR1, HCDR2 and HCDR3 of the heavy chain variable region as shown in SEQ ID NO: 129, and LCDR1, LCDR2 and LCDR3 of the light chain variable region as shown in SEQ ID NO: 122, 123, 127, 131 or 132.

[0231] In some embodiments, the antibody or antigen-binding fragment thereof of the present invention comprises a heavy chain variable region and a light chain variable region:

[0232] (I) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO:85, or an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence as set forth in SEQ ID NO:85; and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO:86, or an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence as set forth in SEQ ID NO:86; or

[0233] (II) the heavy chain variable region comprises the amino acid sequence as shown in SEQ ID NO:87, or comprises an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity with the amino acid sequence as shown in SEQ ID NO:87; and the light chain variable region comprises the amino acid sequence as shown in SEQ ID NO:88, or comprises an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity with the amino acid sequence as shown in SEQ ID NO:88; or

[0234] (III) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO:89, or comprises an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence as set forth in SEQ ID NO:89; and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO:90, or comprises an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence as set forth in SEQ ID NO:90; or

[0235] (IV) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO:91, or comprises an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence as set forth in SEQ ID NO:91; and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO:92, or comprises an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence as set forth in SEQ ID NO:92; or

[0236] (V) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO:93, or an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence as set forth in SEQ ID NO:93; and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO:94, or an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence as set forth in SEQ ID NO:94; or

[0237] (VI) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO:95, or an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence as set forth in SEQ ID NO:95; and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO:96, or an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence as set forth in SEQ ID NO:96; or

[0238] (VII) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO:97, or an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence as set forth in SEQ ID NO:97; and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO:98, or an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence as set forth in SEQ ID NO:98; or

[0239] (VIII) the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:99, or comprises an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:99; and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO:100, or comprises an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:100; or (IX) the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:101, or comprises an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:101; and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO:102, or comprises an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:102; or

[0240] (X) the heavy chain variable region comprises the amino acid sequence as shown in SEQ ID NO:103, or an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence as shown in SEQ ID NO:103; and the light chain variable region comprises the amino acid sequence as shown in SEQ ID NO:104, or an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence as shown in SEQ ID NO:104; or

[0241] (Ⅺ) the heavy chain variable region comprises the amino acid sequence as shown in SEQ ID NO:105, or an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence as shown in SEQ ID NO:105; and the light chain variable region comprises the amino acid sequence as shown in SEQ ID NO:106, or an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence as shown in SEQ ID NO:106; or

[0242] (XII) the heavy chain variable region comprises the amino acid sequence as shown in SEQ ID NO:107, or an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence as shown in SEQ ID NO:107; and the light chain variable region comprises the amino acid sequence as shown in SEQ ID NO:108, or an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence as shown in SEQ ID NO:108; or

[0243] (XIII) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO:109, or an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence as set forth in SEQ ID NO:109; and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO:110, or an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence as set forth in SEQ ID NO:110; or

[0244] (XIV) the heavy chain variable region comprises the amino acid sequence set forth in SEQ ID NO:111, or an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:111; and the light chain variable region comprises the amino acid sequence set forth in SEQ ID NO:112, or an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:112; or

[0245] (XV) the heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:113, or an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity with the amino acid sequence shown in SEQ ID NO:113; and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:114, or an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity with the amino acid sequence shown in SEQ ID NO:114.

[0246] (XVI) the heavy chain variable region comprises the amino acid sequence as shown in SEQ ID NO:99, or an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity with the amino acid sequence as shown in SEQ ID NO:99; and the light chain variable region comprises the amino acid sequence as shown in SEQ ID NO:110, or an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity with the amino acid sequence as shown in SEQ ID NO:110.

[0247] (XVII) the heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:103, or an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity with the amino acid sequence shown in SEQ ID NO:103; and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:110, or an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity with the amino acid sequence shown in SEQ ID NO:110.

[0248] (XVIII) the heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:103, or an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity with the amino acid sequence shown in SEQ ID NO:103; and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:100, or an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity with the amino acid sequence shown in SEQ ID NO:100.

[0249] (XIX) the heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:109, or an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity with the amino acid sequence shown in SEQ ID NO:109; and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:100, or an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity with the amino acid sequence shown in SEQ ID NO:100.

[0250] (XX) the heavy chain variable region comprises the amino acid sequence as set forth in SEQ ID NO:109, or an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence as set forth in SEQ ID NO:109; and the light chain variable region comprises the amino acid sequence as set forth in SEQ ID NO:104, or an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence as set forth in SEQ ID NO:104; or

[0251] (XXI) the heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:142, or an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity with the amino acid sequence shown in SEQ ID NO:142; and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:92, or an amino acid sequence that has at least 95%, 96%, 97%, 98% or 99% sequence identity with the amino acid sequence shown in SEQ ID NO:92.

[0252] In some embodiments, the antibodies or antigen-binding fragments thereof described herein comprise HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, respectively:

[0253] HCDR1: SYHMS (SEQ ID NO: 13);

[0254] HCDR2: AIX1X2X3X4X5X6TYYX7DTVKG (SEQ ID NO: 146), wherein X1 is N or S, X2 is S or R, X3 is N or D, X4 is D or G or V, X5 is I or D, X6 is N or S, and X7 is L or P;

[0255] HCDR3: HEDYX8GFAMDX9 (SEQ ID NO: 147), wherein X8 is Y or F, and X9 is Y or S;

[0256] LCDR1:KASQSVX 10 NDVA (SEQ ID NO: 148), wherein X 10 is T or S;

[0257] LCDR2:YVSX 11 X 12 X 13 T (SEQ ID NO: 149), wherein X 11 N or H, X 12 H or R, X 13 is Y or F;

[0258] LCDR3:X 14 QAYRSPWT (SEQ ID NO: 150), X 14 It is Q or H.

[0259] In the above substitutions, N, T and S are polar uncharged aliphatic amino acids, S, R, N and D are polar aliphatic amino acids, D, G, V and I are aliphatic amino acids, L and P are non-polar amino acids, Y and F are aromatic amino acids, Y and S are polar uncharged amino acids, N, Q and H are polar amino acids, H and R are polar charged amino acids. Therefore, these amino acids can be substituted with each other, and the resulting CDRs still retain the binding activity described herein when used to construct anti-CD112R antibodies.

[0260] In some embodiments, the antibody or antigen-binding fragment thereof described in the present invention comprises an amino acid sequence of HCDR1 as shown in SEQ ID NO:13; an amino acid sequence of HCDR2 as shown in the amino acid sequence of SEQ ID NO:14, 41, 50 or 68; an amino acid sequence of HCDR3 as shown in the amino acid sequence of SEQ ID NO:15 or 42; an amino acid sequence of LCDR1 as shown in the amino acid sequence of SEQ ID NO:43 or 52; an amino acid sequence of LCDR2 as shown in the amino acid sequence of SEQ ID NO:44, 53 or 71; and an amino acid sequence of LCDR3 as shown in the amino acid sequence of SEQ ID NO:54 or 72.

[0261] In some embodiments, the antibody or antigen-binding fragment thereof of the present invention comprises:

[0262] a heavy chain variable region comprising an amino acid sequence as shown in any one of SEQ ID NO: 115, 116, 117, 118, 119, 120, 121, 124, 125, 128, 129 or 130; and

[0263] A light chain variable region comprising the amino acid sequence shown in any one of SEQ ID NO: 122, 123, 126, 127, 131 or 132.

[0264] In some embodiments, the antibody or antigen-binding fragment thereof of the present invention comprises:

[0265] A heavy chain variable region comprising an amino acid sequence having at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence shown in any one of SEQ ID NO: 115, 116, 117, 118, 119, 120, 121, 124, 125, 128, 129 or 130; and

[0266] A light chain variable region comprising an amino acid sequence having at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence shown in any one of SEQ ID NO:122, 123, 126, 127, 131 or 132.

[0267] In some embodiments, the antibody or antigen-binding fragment thereof of the present invention comprises:

[0268] (I) a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO: 118 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO: 127; or

[0269] (II) a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO: 124 or 125 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO: 126; or

[0270] (III) a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO: 128 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO: 126, 127, 131 or 132; or

[0271] (IV) a heavy chain variable region having an amino acid sequence as shown in SEQ ID NO: 129 and a light chain variable region having an amino acid sequence as shown in SEQ ID NO: 122, 123, 127, 131 or 132.

[0272] In some embodiments, the antibody or antigen-binding fragment thereof of the present invention comprises:

[0273] (I) a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO: 118 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO: 127; or

[0274] (II) a heavy chain variable region with an amino acid sequence as shown in SEQ ID NO: 128 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO: 127; or

[0275] (III) a heavy chain variable region having an amino acid sequence as shown in SEQ ID NO: 129 and a light chain variable region having an amino acid sequence as shown in SEQ ID NO: 131.

[0276] In some embodiments, the antibody or antigen-binding fragment thereof of the present invention comprises:

[0277] A heavy chain comprising the amino acid sequence shown in any one of SEQ ID NO: 134, 135, 137, 138, 140 or 141, and

[0278] A light chain comprising the amino acid sequence shown in any one of SEQ ID NO: 133, 136 or 139.

[0279] In some embodiments, the antibody or antigen-binding fragment thereof of the present invention comprises:

[0280] A heavy chain comprising an amino acid sequence having at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence shown in any one of SEQ ID NO: 134, 135, 137, 138, 140 or 141, and

[0281] A light chain comprising an amino acid sequence having at least 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence shown in any one of SEQ ID NO:133, 136 or 139.

[0282] In some embodiments, the antibody or antigen-binding fragment thereof of the present invention comprises:

[0283] (I) a heavy chain having an amino acid sequence as shown in SEQ ID NO: 134 or 135, and a light chain having an amino acid sequence as shown in SEQ ID NO: 133; or

[0284] (II) a heavy chain having an amino acid sequence as shown in SEQ ID NO: 137 or 138, and a light chain having an amino acid sequence as shown in SEQ ID NO: 136; or

[0285] (III) a heavy chain having an amino acid sequence as shown in SEQ ID NO: 140 or 141, and a light chain having an amino acid sequence as shown in SEQ ID NO: 139.

[0286] In some embodiments, the antibody or antigen-binding fragment thereof described in the present invention is a murine antibody, a chimeric antibody, a humanized antibody, or a fully human antibody, or an antigen-binding fragment thereof.

[0287] Any suitable method for producing antibodies can be used to produce antibodies of the present invention. Any suitable form of CD112R can be used as an immunogen (antigen) for producing antibodies. By way of example and not limitation, any CD112R variant or fragment thereof can be used as an immunogen. In some embodiments, hybridoma cells producing monoclonal anti-human CD112R antibodies of mouse origin can be produced by methods well known in the art.

[0288] Antibodies derived from rodents (such as mice) may cause unwanted antibody immunogenicity when used as therapeutic drugs in vivo. Repeated use causes the human body to produce an immune response against the therapeutic antibody, which at least leads to loss of therapeutic efficacy and severe cases lead to potentially lethal allergic reactions. One method of reducing the immunogenicity of rodent antibodies includes the production of chimeric antibodies, in which the mouse variable region is fused to the human constant region (Liu et al. (1987) Proc. Natl. Acad. Sci. USA 84: 3439-43). However, the retention of intact rodent variable regions in chimeric antibodies may still cause harmful immunogenicity in patients. Transplanting the complementary determining region (CDR) loops of rodent variable domains onto human frameworks (i.e., humanization) has been used to further minimize rodent sequences (Jones et al. (1986) Nature 321: 522; Verhoeyen et al. (1988) Science 239: 1534).

[0289] The amino acid sequences of the light chain and heavy chain variable regions and CDRs of the anti-human CD112R murine antibody of the present invention are shown in Table 1.

[0290] Table 1: CDR and variable region amino acid sequences of anti-CD112R mouse antibodies (KABAT scheme)

[0291]

[0292]

[0293] 1D11VH:

[0294] EVQLQQSGPELVKPGASVKISCKASGYPFI NYNIH WLRQSRGKSLEWIG YVYPYNGVPGYNQKFKS KATLTADNSFSTAYMEFRSLTSEDSAVYFCAR ERGRDYFDS WGQGTSLTVSS (SEQ ID NO:85)

[0295] HCDR1: NYNIH (SEQ ID NO:1)

[0296] HCDR2:YVYPYNGVPGYNQKFKS (SEQ ID NO:2)

[0297] HCDR3: ERGRDYFDS (SEQ ID NO:3)

[0298] 1D11 VL: (Identical to 3D2 VL)

[0299] DIQLTQSPASLSVSVGETVTITC RVSANIYSNLV WYHQRQGKSPQLLVY GGTNLAD GVPSRFSGSGSGTQFSLKINSLQSEDFGSYHC QHFWSTPYT FGGGTKLEIK(SEQ ID NO:86)

[0300] LCDR1: RVSANIYSNLV (SEQ ID NO:4)

[0301] LCDR2: GGTNLAD (SEQ ID NO:5)

[0302] LCDR3: QHFWSTPYT (SEQ ID NO:6)

[0303] 2G10 VH:

[0304] QVQLQQSGAELVKPGASVKLSCKASGYTFT SHYMY WLKQRPGQGLEWIG EINPSNGDTKFNEKFKS KATLTVDKSSSTAYMQLSSLTSEDSAVYYCTR EKDAFSALDY WGQGTSVTDSS(SEQ ID NO:87)

[0305] HCDR1: SHYMY (SEQ ID NO:7)

[0306] HCDR2: EINPSNGDTKFNEKFKS (SEQ ID NO:8)

[0307] HCDR3: EKDAFSALDY (SEQ ID NO:9)

[0308] 2G10 VL:

[0309] DIQMIQSPSSMFASLGDRVSLSC RASQGIRGHLD WYQQKPGGTIKLLIY STSILNF GVPSRFSGSGSGSDYSLTISSLESEDFADYYC LQRNAYPLTFGAGTKLELK (SEQ ID NO:88)

[0310] LCDR1: RASQGIRGHLD (SEQ ID NO:10)

[0311] LCDR2: STSILNF (SEQ ID NO:11)

[0312] LCDR3: LQRNAYPLT (SEQ ID NO:12)

[0313] 3D2VH:

[0314] DVQLVESGGGLVKLGGSLKLSCVASGFTFS SYHMS WIRQTPEKRLELVA AINSNDI NTYYLDTVKG RFTISRDIAKNTLHLQMSSLKSEDTALYYCAR HEDYYGFAMDY WGQGTSVTVSS (SEQ ID NO:89)

[0315] HCDR1: SYHMS (SEQ ID NO:13)

[0316] HCDR2: AINSNDINTYYLDTVKG (SEQ ID NO:14)

[0317] HCDR3: HEDYYGFAMDY (SEQ ID NO:15)

[0318] 3D2VL (identical to 1D11 VL):

[0319] DIQLTQSPASLSVSVGETVTITC RVSANIYSNLV WYHQRQGKSPQLLVY GGTNLAD GVPSRFSGSGSGTQFSLKINSLQSEDFGSYHC QHFWSTPYT FGGGTKLEIK (SEQ IDNO:90)

[0320] LCDR1: RVSANIYSNLV (SEQ ID NO:4)

[0321] LCDR2: GGTNLAD (SEQ ID NO:5)

[0322] LCDR3: QHFWSTPYT (SEQ ID NO:6)

[0323] 4E2VH1:

[0324] EVQLQQSGAELVRSGTSVTLSCTASGFNIR DYFIH WVKQRPEQGLEWIG WIIPASGDTDCAPIFQG KATLTADTFSNTAYLHLNSLTSEDTAVYCNT WVWSPYAVDY WGQGTSVTVSS(SEQ ID NO:91)

[0325] HCDR1: DYFIH (SEQ ID NO:16)

[0326] HCDR2: WIIPASGDTDCAPIFQG (SEQ ID NO:17)

[0327] HCDR3: WVWSPYAVDY (SEQ ID NO:18)

[0328] 4E2VH2:

[0329] EVQLQQSGAELVKPGASVKISCKASGYTFT DYNMD WVKQSHGKSLEWIG DIHPKYDRTSYNQNFKG KATLTVDKSSRTAYMELRSLTSEDTAVYFCVR INDFDEGFAMDY WGQGTSVTVSS(SEQ ID NO:142)

[0330] HCDR1: DYNMD (SEQ ID NO:143)

[0331] HCDR2: DIHPKYDRTSYNQNFKG (SEQ ID NO:144)

[0332] HCDR3: INDFDEGFAMDY (SEQ ID NO:145)

[0333] 4E2VL:

[0334] QIVLTQSPAIMSVSPGEKVTMTC SATSSINYMH WYQQKSGTSPKRWIY DTSKLAS GVPARFSGSGSGTSYSLTISNMEAEDAATYYC QQWTSNPLT FGAGTKLELK(SEQ ID NO:92)

[0335] LCDR1: SATSSINYMH (SEQ ID NO:19)

[0336] LCDR2: DTSKLAS (SEQ ID NO:20)

[0337] LCDR3: QQWTSNPLT (SEQ ID NO:21)

[0338] 4E5VH:

[0339] EVMLVESGGGLVKPGGSLKLSCAASGFTFS NYIMS WVRQTPDMRLEWVA TISSGGSSTYYVDRVKG GFPFSRDSVKYILYVHTSSLRSADTAIYYCAK HEDWDPLYYYSMDY WGQGTSVTVSS(SEQ ID NO:93)

[0340] HCDR1: NYIMS (SEQ ID NO:22)

[0341] HCDR2: TISSGGSSTYYVDRVKG (SEQ ID NO:23)

[0342] HCDR3: HEDWDPLYYYSMDY (SEQ ID NO:24)

[0343] 4E5VL:

[0344] QIVLTQSPTVMSASPGDKVTMTC SASSSVSYMY WFQQKPGSSPRLLIY DTSHLAF GVPSRFSGSRSGTSYSLTISRMEAEDTATYYC QQWTTYPLT FGAGTKLELK(SEQ ID NO:94)

[0345] LCDR1: SASSSVSYMY (SEQ ID NO:25)

[0346] LCDR2: DTSHLAF (SEQ ID NO:26)

[0347] LCDR3: QQWTTYPLT (SEQ ID NO:27)

[0348] 5B1VH (identical to 6A6 VH):

[0349] EVQLQQSGAELVRSGTSVTLSCTASGFNIR DYFIH WVKQRPEQGLEWIG WIIPASGDTDCAPIFQGKATLTADTFSNTAYLHLNSLTSEDTAVYYCNT WVWSPYAVDY WGQGTSVTVSS(SEQ ID NO:95)

[0350] HCDR1: DYFIH (SEQ ID NO:28)

[0351] HCDR2: WIIPASGDTDCAPIFQG (SEQ ID NO:29)

[0352] HCDR3: WVWSPYAVDY (SEQ ID NO:30)

[0353] 5B1VL:

[0354] DIVMTQFPSSLSVPVGEKVTMNC KSSQSLLNSGNQKNFLA WYQQKPGQPPKLLIY GASTRES GVPYRFTGSGSGTDFTLTISSVQAEDLAVYYC QNDHSYPWT FGGGTKLEIK(SEQ ID NO:96)

[0355] LCDR1: KSSQSLLNSGNQKNFLA (SEQ ID NO:31)

[0356] LCDR2: GASTRES (SEQ ID NO:32)

[0357] LCDR3: QNDHSYPWT (SEQ ID NO:33)

[0358] 5B2VH:

[0359] EVQLQQSGPELVKPGASVRISCKASGYTFT DYNMH WVKQSHGKSLEWIG YIYPY NGGTGHNQNFKS KATLTVDKSSSTAYMEFRSLTSDDSAVYYCAR EDFRHEKMDY WGQGTSVTVSS(SEQ ID NO:97)

[0360] HCDR1: DYNMH (SEQ ID NO:34)

[0361] HCDR2: YIYPYNGGTGHNQNFKS (SEQ ID NO:35)

[0362] HCDR3: EDFRHEKMDY(SEQ ID NO:36)

[0363] 5B2VL:

[0364] DIQMTQSPASLSASVGETVTITC RTSDNIYVYLS WYQQKQGKSPQLLVY NAKTLTE NVPSRFSGSGSGTQFSLKINSLQPEDFGSYYC QHHYGTPYT FGGGTKLEIK(SEQ ID NO:98)

[0365] LCDR1: RTSDNIYVYLS (SEQ ID NO:37)

[0366] LCDR2: NAKTLTE (SEQ ID NO:38)

[0367] LCDR3: QHHYGTPYT (SEQ ID NO:39)

[0368] 5C10VH:

[0369] DVKLVESGGGLVKLGGSLKLSCAASGFTFS SYHMS WVRQTPEKRLELVA AISRDGDSTYYPDTVKG RFTISRDDAENTLYLQMSSLKSEDTALYYCSR HEDYFGFAMDS WGQGTSVTVSS(SEQ ID NO:99)

[0370] HCDR1: SYHMS (SEQ ID NO:40)

[0371] HCDR2: AISRDGDSTYYPDTVKG (SEQ ID NO:41)

[0372] HCDR3: HEDYFGFAMDS (SEQ ID NO:42)

[0373] 5C10VL:

[0374] SIVMTQTPKFLLVSAGDRVTITC KASQSVTNDVA WYQQKPGQSPKLLMY YVSNHYT GVPDRFIGSGYGTDFTFTISTVQAEDLAVYFC QQAYRSPWT FGGGTKLEIK(SEQ ID NO:100)

[0375] LCDR1: KASQSVTNDVA (SEQ ID NO:43)

[0376] LCDR2: YVSNHYT (SEQ ID NO:44)

[0377] LCDR3: QQAYRSPWT (SEQ ID NO:45)

[0378] 6A6VH (identical to 5B1 VH):

[0379] EVQLQQSGAELVRSGTSVTLSCTASGFNIR DYFIH WVKQRPEQGLEWIG WIIPASGDTDCAPIFQG KATLTADTFSNTAYLHLNSLTSEDTAVYYCNT WVWSPYAVDY WGQGTSVTVSS (SEQ ID NO:101)

[0380] HCDR1: DYFIH (SEQ ID NO:28)

[0381] HCDR2: WIIPASGDTDCAPIFQG (SEQ ID NO:29)

[0382] HCDR3: WVWSPYAVDY (SEQ ID NO:30)

[0383] 6A6VL:

[0384] DVLMTQTPLSLPVSLGDQTSISC RSSQSIVHSNGNTYLH WYLQKPGQSPKLLIY KVSNRFS GVPDRFSGSGSGTDFTLKISRVEAEDLGVYYCF QGSHVPWT FGGGTRLEIK (SEQ ID NO:102)

[0385] LCDR1: RSSQSIVHSNGNTYLH (SEQ ID NO:46)

[0386] LCDR2: KVSNRFS (SEQ ID NO:47)

[0387] LCDR3: FQGSHVPWT (SEQ ID NO:48)

[0388] 6A10VH:

[0389] DVKLVESGGGLVKLGGSLKLSCAASGFTFS SYHMS WVRQTPEKRLELVA AINSNVISTYYLDTVKG RFTISRDNAKNTLYLQMSSLKSEDTALYYCAR HEDYYGFAMDY WGQGTSVTVSS(SEQ ID NO:103)

[0390] HCDR1: SYHMS (SEQ ID NO:49)

[0391] HCDR2: AINSNVISTYYLDTVKG (SEQ ID NO:50)

[0392] HCDR3: HEDYYGFAMDY (SEQ ID NO:51)

[0393] 6A10VL:

[0394] SIVMTQTPKFLLVSAGDRVTITC KASQSVSNDVA WYQEKPGQSPKLLMY YVSHRFT GVPDRFTGSGYGTDFTFTINTVQAEDLAVYFC HQAYRSPWT FGGGTKLEIK(SEQ ID NO:104)

[0395] LCDR1: KASQSVSNDVA (SEQ ID NO:52)

[0396] LCDR2: YVSHRFT (SEQ ID NO:53)

[0397] LCDR3: HQAYRSPWT (SEQ ID NO:54)

[0398] 6C6VH:

[0399] EVQLQQSGPELVRPGASVRISCKASGYTFT DYNMN WVKQSHGKSLEWIG YIYPYNGGAGYNQNFKN KATLTVDTYSRAAYMELRSLTSEDSAVYYCAR ERGMQRDYFDY WGQGTILTVSS(SEQ ID NO:105)

[0400] HCDR1: DYNMN (SEQ ID NO:55)

[0401] HCDR2: YIYPYNGGAGYNQNFKN (SEQ ID NO:56)

[0402] HCDR3: ERGMQRDYFDY (SEQ ID NO:57)

[0403] 6C6VL:

[0404] DIQMTQSPASLSVSVGETVTITC RTSENIYSNLA WYQQKQGKSPQLLVY AATNLAD GVPSRFSGSGSGTQFSLKINSLQSGDFGSYFC QHFWGTPYT FGGGTKLEIK(SEQ ID NO:106)

[0405] LCDR1: RTSENIYSNLA (SEQ ID NO:58)

[0406] LCDR2: AATNLAD (SEQ ID NO:59)

[0407] LCDR3: QHFWGTPYT (SEQ ID NO:60)

[0408] 6D2VH:

[0409] EVQLQQSGPELVKPGASVKISCKASGYTFT DYNIH WVKQSHGKRPDWIG YNYPYNGGAGYNQNFRS RATLTVDKFSSTAYMELRSLTSEDSAVYYCA GEEVRRGPFYF WGQGTSVTVSS(SEQ ID NO:107)

[0410] HCDR1: DYNIH (SEQ ID NO:61)

[0411] HCDR2: YNYPYNGGAGYNQNFRS (SEQ ID NO:62)

[0412] HCDR3: GEEVRRGPFYF (SEQ ID NO:63)

[0413] 6D2VL:

[0414] DIQMTQSPDSLSASVGETVTITC RTSENIYSFLV WYQQKQGKSPQLLVY NAKTLAE GVPSRFSGSGSGTQFSLKINSLQPEDFGTYYC QHYYGTPYT FGGGTKLEIK(SEQ ID NO:108)

[0415] LCDR1: RTSENIYSFLV (SEQ ID NO:64)

[0416] LCDR2: NAKTLAE (SEQ ID NO:65)

[0417] LCDR3: QHYYGTPYT (SEQ ID NO:66)

[0418] 7C2VH:

[0419] DVKLVESGGGLVKLGGSLKLSCAASGFTFS SYHMS WIRQTPEKRLELVA AINSNGINTYYLDTVKG RFTISRDNAKNTLYLQMSSLKSEDTALYYCAR HEDYYGFAMDY WGQGTSVTVSS(SEQ ID NO:109)

[0420] HCDR1: SYHMS (SEQ ID NO:67)

[0421] HCDR2: AINSNGINTYYLDTVKG (SEQ ID NO:68)

[0422] HCDR3: HEDYYGFAMDY (SEQ ID NO:69)

[0423] 7C2VL:

[0424] SIVMTQTPKFLLVSAGDRVTITC KASQSVSNDVA WYQQKPGQSPKLLMY YVSNRFT GVPDRFTGSGYGTDFTFTINTVQAEDLAVYFC QQAYRSPWT FGGGTKLEIK(SEQ ID NO:110)

[0425] LCDR1: KASQSVSNDVA (SEQ ID NO:70)

[0426] LCDR2: YVSNRFT (SEQ ID NO:71)

[0427] LCDR3: QQAYRSPWT (SEQ ID NO:72)

[0428] 8D3VH:

[0429] QIQLVQSGPELKKPGETVKISCKASGYTFT DYSMH WVKQAPGKGLKWVG WISTETAQPTYADDFRG RFAFSLETSASTAYLQINNLRNEDTATYFCA TGNYGWYFSV WGAGTTVTVSS(SEQ ID NO:111)

[0430] HCDR1: DYSMH (SEQ ID NO:73)

[0431] HCDR2: WISTETAQPTYADDFRG (SEQ ID NO:74)

[0432] HCDR3: TGNYGWYFSV (SEQ ID NO:75)

[0433] 8D3VL:

[0434] ENVLTQSPAIMSASPGEKVTMTC RATSGVSSSYLF WYQQKSGASPKIWIY STSNLAS GVPTRFSGSGSGTSYSLTISSVEAEDAATYYC QQYSGYPYT FGGGTKLEIK(SEQ ID NO:112)

[0435] LCDR1: RATSGVSSSYLF (SEQ ID NO:76)

[0436] LCDR2: STSNLAS (SEQ ID NO:77)

[0437] LCDR3: QQYSGYPYT (SEQ ID NO:78)

[0438] 8H8VH:

[0439] EVKLVESGGGLVKPGGSLKVSCAASGFTFS DYPMS WVRQTPDKRLEWVA CIDTDENTYYPDSVKG RFTISRDNGRNIVNLQMSSLRSEDAAMYYCAR GWDDYAAWFAY WGQGTLVTVSA(SEQ ID NO:113)

[0440] HCDR1: DYPMS (SEQ ID NO:79)

[0441] HCDR2: CIDTDENTYYPDSVKG (SEQ ID NO:80)

[0442] HCDR3: GWDDYAAWFAY (SEQ ID NO:81)

[0443] 8H8VL:

[0444] ENVLTQFPAIMSVFLGERVTMSC RASSSVNYMY WYQQKSDASPKLWIY HTSNLAP GVPARFSGSGSGNSYSLTISSMEGEDAATYYC QQFTSSPWT FGGGTKLEIK (SEQ ID NO: 114)

[0445] LCDR1: RASSSVNYMY (SEQ ID NO:82)

[0446] LCDR2: HTSNLAP (SEQ ID NO:83)

[0447] LCDR3: QQFTSSPWT (SEQ ID NO:84)

[0448] In some embodiments, chimeric or humanized antibodies of the present invention can be prepared based on the sequence of the prepared mouse monoclonal hybridoma antibody. DNA encoding heavy and light chain immunoglobulins can be obtained from the target mouse hybridoma and engineered to contain non-mouse (e.g., human) immunoglobulin sequences using standard molecular biology techniques.

[0449] In some embodiments, the chimeric CD112R antibody of the present invention can be effectively connected to the heavy chain and light chain variable region of the immunoglobulin derived from the hybridoma using methods known in the art (see, for example, U.S. Patent No. 4,816,567 belonging to Cabilly et al.), and chimeric heavy chain and chimeric light chain are obtained for preparation. In some embodiments, the constant region included in the chimeric antibody of the present invention can be selected from any human IgG subtype, such as IgG1, IgG2, IgG3, IgG4, preferably IgG4.

[0450] In some embodiments, the chimeric CD112R antibodies of the present invention can be obtained by "mixing and matching" chimeric light chain and chimeric heavy chain expression plasmids to transfect expression cells, and the CD112R binding of such "mixed and matched" antibodies can be tested using the above-mentioned binding assays and other conventional binding assays (e.g., ELISA).

[0451] The precise amino acid sequence boundaries of the variable region CDRs of the antibodies of the invention can be determined using any of a number of well-known schemes, including Chothia (Chothia et al. (1989) Nature 342:877-883; Al-Lazikani et al., "Standard conformations for the canonical structures of immunoglobulins", Journal of Molecular Biology, 273, 927-948 (1997)), based on the three-dimensional structure of antibodies and the topology of the CDR loops, Kabat (Kabat et al., Sequences of Proteins of Immunological Interest, 4th Edition, US Department of Health and Human Services, National Institutes of Health (1987)), AbM (University of Bath), Contact (University College London), the international ImMunoGeneTics database (IMGT) (1999 Nucleic Acids Research, 27, 209-212), and the North CDR definition based on affinity propagation clustering using a large number of crystal structures.

[0452] Unless otherwise indicated, the boundaries of the CDRs of the antibodies of the invention can be determined by one skilled in the art according to any scheme in the art (eg, different assignment systems or combinations).

[0453] It should be noted that the boundaries of the CDRs of the variable regions of the same antibody obtained based on different assignment systems may be different. That is, the CDR sequences of the variable regions of the same antibody defined under different assignment systems are different. Therefore, when it comes to defining antibodies using specific CDR sequences defined in the present invention, the scope of the antibodies also covers antibodies whose variable region sequences contain the specific CDR sequences, but whose claimed CDR boundaries are different from the specific CDR boundaries defined in the present invention due to the application of different schemes (e.g., different assignment systems or combinations).

[0454] Antibodies with different specificities (i.e., different binding sites for different antigens) have different CDRs. However, although CDRs are different between antibodies, only a limited number of amino acid positions in CDRs are directly involved in antigen binding. Using at least two of Kabat, Chothia, AbM, Contact and North methods, the minimum overlapping region can be determined, thereby providing a "minimum binding unit" for antigen binding. The minimum binding unit can be a sub-portion of a CDR. As those skilled in the art will appreciate, by the structure of the antibody and protein folding, the residues of the rest of the CDR sequence can be determined. Therefore, the present invention also contemplates variants of any CDR given herein. For example, in a variant of a CDR, the amino acid residues of the minimum binding unit can remain unchanged, and the remaining CDR residues defined according to Kabat or Chothia can be replaced by conservative amino acid residues.

[0455] In the present invention, various chimeric heavy chain and light chain expression plasmids were mixed and paired to transfect expression cells to obtain 72 anti-human CD112R chimeric antibodies, and their numbers and pairing methods are shown in Table 2.

[0456] Table 2: Numbering of chimeric antibodies and the origin of their heavy and light chain variable regions

[0457] 2G10-VH 4E2-VH1 4E2-VH2 4E5-VH 5B2-VH 6A10-VH 7C2-VH 5C10-VH 3D2-VH 2G10-VL Chi-1 Chi-9 Chi-17 Chi-25 Chi-33 Chi-41 Chi-49 Chi-57 Chi-65 4E2-VL Chi-2 Chi-10 Chi-18 Chi-26 Chi-34 Chi-42 Chi-50 Chi-58 Chi-66 4E5-VL Chi-3 Chi-11 Chi-19 Chi-27 Chi-35 Chi-43 Chi-51 Chi-59 Chi-67 5B2-VL Chi-4 Chi-12 Chi-20 Chi-28 Chi-36 Chi-44 Chi-52 Chi-60 Chi-68 6A10-VL Chi-5 Chi-13 Chi-21 Chi-29 Chi-37 Chi-45 Chi-53 Chi-61 Chi-69 7C2-VL Chi-6 Chi-14 Chi-22 Chi-30 Chi-38 Chi-46 Chi-54 Chi-62 Chi-70 5C10-VL Chi-7 Chi-15 Chi-23 Chi-31 Chi-39 Chi-47 Chi-55 Chi-63 Chi-71 1D11-VL Chi-8 Chi-16 Chi-24 Chi-32 Chi-40 Chi-48 Chi-56 Chi-64 Chi-72

[0458] The humanized antibodies of the present invention can be prepared by inserting mouse CDR regions into human germline framework regions using methods known in the art, such as Winter et al. U.S. Pat. No. 5,225,539 and Queen et al. U.S. Pat. Nos. 5,530,101; 5,585,089; 5,693,762 and 6,180,370.

[0459] The amino acid sequences of the light chain and heavy chain variable regions and CDRs of the anti-human CD112R humanized antibodies of the present invention are as follows:

[0460] 3D2VH-1: SEQ ID NO: 115

[0461] EVQLVESGGGLVQPGGSLRLSCAASGFTFS SYHMS WVRQAPGKGLELVA AINSNDINTYYLDTVKG RFTISRDIAKNSLYLQMNSLRAEDTAVYYCAR HEDYYGFAMDY WGQGTLVTVSS

[0462] 3D2VH-2: SEQ ID NO: 116

[0463] EVQLVESGGGLVKPGGSLRLSCAASGFTFS SYHMS WVRQAPGKGLELVS AINSNDINTYYLDTVKG RFTISRDIAKNSLYLQMNSLRAEDTAVYYCAR HEDYYGFAMDY WGQGTLVTVSS

[0464] 3D2VH-3:SEQ ID NO:117

[0465] EVQLVESGGGLVKPGGSLRLSCAASGFTFS SYHMS WIRQAPGKGLELVS AINSNDINTYYLDTVKG RFTISRDNAKNSLYLQMNSLRAEDTAVYYCAR HEDYYGFAMDY WGQGTLVTVSS

[0466] 5C10 VH-1:SEQ ID NO:118

[0467] EVQLVESGGGLVKPGGSLRLSCAASGFTFS SYHMS WVRQAPGKGLELVS AISRDGDSTYYPDTVKG RFTISRDNAKNSLYLQMNSLRAEDTAVYYCSR HEDYFGFAMDS WGQGTLVTVSS

[0468] 5C10 VH-2:SEQ ID NO:119

[0469] EVQLVESGGGLVKPGGSLRLSCAASGFTFS SYHMS WVRQAPGKGLELVS AISRDGDSTYYPDTVKG RFTISRDDAENSLYLQMNSLRAEDTAVYYCSR HEDYFGFAMDS WGQGTLVTVSS

[0470] 5C10 VH-3:SEQ ID NO:120

[0471] EVQLVESGGGLVQPGGSLRLSCAASGFTFS SYHMS WVRQAPGKGLELVA AISRDGDSTYYPDTVKG RFTISRDNAKNSLYLQMNSLRAEDTAVYYCSR HEDYFGFAMDS WGQGTLVTVSS

[0472] 5C10 VH-4:SEQ ID NO:121

[0473] EVQLVESGGGLVQPGGSLRLSCAASGFTFS SYHMS WVRQAPGKGLELVA AISRDGDSTYYPDTVKG RFTISRDDAENSLYLQMNSLRAEDTAVYYCSR HEDYFGFAMDS WGQGTLVTVSS

[0474] 5C10 VL-1:SEQ ID NO:122

[0475] DIVMTQSPDSLAVSLGERATINC KASQSVTNDVA WYQQKPGQPPKLLIY YVSNHYT GVPDRFSGSGSGTDFTLTISSLQAEDVAVYFC QQAYRSPWT FGQGTKLEIK

[0476] 5C10 VL-2:SEQ ID NO:123

[0477] AIQMTQSPSSLSASVGDRVTITC KASQSVTNDVA WYQQKPGKAPKLLIY YVSNHYT GVPSRFSGSGSGTDFTLTISSLQPEDFATYFC QQAYRSPWT FGQGTKLEIK

[0478] 6A10 VH-1:SEQ ID NO:124

[0479] EVQLVESGGGLVQPGGSLRLSCAASGFTFS SYHMS WVRQAPGKGLELVS AINSNVISTYYLDTVKG RFTISRDNAKNSLYLQMNSLRAEDTAVYYCAR HEDYYGFAMDY WGQGTLVTVSS

[0480] 6A10 VH-2:SEQ ID NO:125

[0481] EVQLVESGGGLVKPGGSLRLSCAASGFTFS SYHMS WVRQAPGKGLELVS AINSNVISTYYLDTVKG RFTISRDNAKNSLYLQMNSLRAEDTAVYYCAR HEDYYGFAMDY WGQGTLVTVSS

[0482] 6A10 VL-1:SEQ ID NO:126

[0483] EIVMTQSPPTLSLSPGERVTLSC KASQSVSNDVA WYQEKPGQAPRLLIY YVSHRFT GIPARFSGSGSGTDFTLTISSLQPEDFAVYYC HQAYRSPWT FGQGTKLEIK

[0484] 6A10 VL-2:SEQ ID NO:127

[0485] DIVMTQSPDSLAVSLGERATINC KASQSVSNDVA WYQQKPGQPPKLLIY YVSHRF TGVPDRFSGSGSGTDFTLTISSLQAEDVAVYFCHQ AYRSPWT FGQGTKLEIK

[0486] 7C2 VH-1:SEQ ID NO:128

[0487] EVQLVESGGGLVKPGGSLRLSCAASGFTFS SYHMS WVRQAPGKGLELVS AINSNGINTYYLDTVKG RFTISRDNAKNSLYLQMNSLRAEDTAVYYCAR HEDYYGFAMDY WGQGTLVTVSS

[0488] 7C2 VH-2:SEQ ID NO:129

[0489] EVQLVESGGGLVQPGGSLRLSCAASGFTFS SYHMS WIRQAPGKGLELVA AINSNGINTYYLDTVKG RFTISRDNAKNSLYLQMNSLRAEDTAVYYCAR HEDYYGFAMDY WGQGTLVTVSS

[0490] 7C2 VH-3:SEQ ID NO:130

[0491] EVQLVESGGGLVQPGGSLRLSCAASGFTFS SYHMS WIRQAPGKGLELVA AINSNDINTYYLDTVKG RFTISRDNAKNSLYLQMNSLRAEDTAVYYCAR HEDYYGFAMDY WGQGTLVTVSS

[0492] 7C2 VL-1:SEQ ID NO:131

[0493] DIQMTQSPSSLSASVGDRVTITC KASQSVSNDVA WYQQKPGKAPKLLIY YVSNRFT GVPSRFSGSGSGTDFTLTISSLQPEDFATYFC QQAYRSPWT FQGKLEIK

[0494] 7C2 VL-2: SEQ ID NO: 132

[0495] EIVMTQSPPTLSLSPGERVTLSC KASQSVSNDVA WYQQKPGQAPRLLIY YVSNRFT GIPARFSGSGSGTTDFTLTISSLQPEDFAVYFC QQAYRSPWT FQGKLEIK

[0496] The numbers of the humanized anti-CD112R antibodies of the present invention and the sources of their heavy chain and light chain variable regions are shown in Table 3.

[0497] Table 3: Numbering of humanized anti-CD112R antibodies and the sources of their heavy and light chain variable regions

[0498]

[0499] The amino acid sequences of the light and heavy chains of antibodies Hu16, Hu52 and Hu59 are shown below. The sequences outside the variable regions of the remaining humanized antibodies LC and HC are identical to the corresponding sequences of Hu16, Hu52 and Hu59, among which the humanized antibodies subjected to biological tests were all IgG4 heavy chains.

[0500] Hu16-LC: SEQ ID NO: 133 (LCDR1-LCDR3 are SEQ ID NOs: 52, 53 and 54, respectively)

[0501] DIVMTQSPDSLAVSLGERATINC KASQSVSNDVA WYQQKPGQPPKLLIY YVSHRFT GVPDRFSGSGSGTDFTLTISSLQAEDVAVYFC HQAYRSPWT FGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0502] Hu16-HC-IgG4: SEQ ID NO:134 (HCDR1-HCDR3 are SEQ ID NO:40, 41, and 42 respectively)

[0503] EVQLVESGGGLVKPGGSLRLSCAASGFTFS SYHMS WVRQAPGKGLELVS AISRDGDSTYYPDTVKG RFTISRDNAKNSLYLQMNSLRAEDTAVYYCSR HEDYFGFAMDS WGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

[0504] Hu16-HC-IgG1: SEQ ID NO:135 (HCDR1-HCDR3 are SEQ ID NO:40, 41, and 42 respectively)

[0505] EVQLVESGGGLVKPGGSLRLSCAASGFTFS SYHMS WVRQAPGKGLELVS AISRDGDSTYYPDTVKG RFTISRDNAKNSLYLQMNSLRAEDTAVYYCSR HEDYFGFAMDSWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0506] Hu52-LC: SEQ ID NO:136 (LCDR1-LCDR3 are SEQ ID NO:52, 53 and 54 respectively)

[0507] DIVMTQSPDSLAVSLGERATINC KASQSVSNDVA WYQQKPGQPPKLLIY YVSHRFT GVPDRFSGSGSGTDFTLTISSLQAEDVAVYFC HQAYRSPWT FGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0508] Hu52-HC-IgG4: SEQ ID NO:137 (HCDR1-HCDR3 are SEQ ID NO:67, 68 and 69 respectively)

[0509] EVQLVESGGGLVKPGGSLRLSCAASGFTFS SYHMS WVRQAPGKGLELVS AINSNGINTYYLDTVKG RFTISRDNAKNSLYLQMNSLRAEDTAVYYCAR HEDYYGFAMDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

[0510] Hu52-HC-IgG1: SEQ ID NO:138 (HCDR1-HCDR3 are SEQ ID NO:67, 68, and 69 respectively)

[0511] EVQLVESGGGLVKPGGSLRLSCAASGFTFS SYHMS WVRQAPGKGLELVS AINSNGINTYYLDTVKG RFTISRDNAKNSLYLQMNSLRAEDTAVYYCAR HEDYYGFAMDY WGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0512] Hu59-LC: SEQ ID NO:139 (LCDR1-LCDR3 are SEQ ID NO:70, 71, and 72 respectively)

[0513] DIQMTQSPSSLSASVGDRVTITC KASQSVSNDVA WYQQKPGKAPKLLIY YVSNRFT GVPSRFSGSGSGTDFTLTISSLQPEDFATYFC QQAYRSPWT FGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

[0514] Hu59-HC-IgG4: SEQ ID NO:140 (HCDR1-HCDR3 are SEQ ID NO:67, 68, and 69 respectively)

[0515] EVQLVESGGGLVQPGGSLRLSCAASGFTFS SYHMS WIRQAPGKGLELVA AINSNGINTYYLDTVKG RFTISRDNAKNSLYLQMNSLRAEDTAVYYCAR HEDYYGFAMDY WGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK

[0516] Hu59-HC-IgG1: SEQ ID NO:141 (HCDR1-HCDR3 are SEQ ID NO:67, 68, and 69 respectively)

[0517] EVQLVESGGGLVQPGGSLRLSCAASGFTFS SYHMS WIRQAPGKGLELVA AINSNGINTYYLDTVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAR HEDYYGFAMDY WGQGTLVTVSSASTKGPSVFPLAPSSKSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFN WYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK

[0518] In some embodiments, amino acid changes include amino acid deletions, insertions or substitutions. In some embodiments, the anti-CD112R antibodies of the present invention or their antigen-binding fragments include those having been mutated by amino acid deletions, insertions or substitutions, but still having at least about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% identity with the above-mentioned antibodies (particularly in the CDR regions depicted in the above sequences). In some embodiments, when the antibodies of the present invention are compared with the CDR regions depicted in the specific sequences, the amino acid mutations by amino acid deletions, insertions or substitutions in the CDR regions are no more than 1, 2, 3, 4 or 5. In some embodiments, when the antibodies of the present invention are compared with the framework regions in the specific sequences, the amino acid mutations by amino acid deletions, insertions or substitutions in the framework regions are no more than 1, 2, 3, 4 or 5.

[0519] In some embodiments, the polynucleotide molecules encoding the antibodies of the present invention include polynucleotide molecules that have been mutated by nucleotide deletion, insertion or substitution, but still have at least about 60, 70, 80, 90, 95 or 100% identity with the CDR corresponding coding region depicted in the sequence described above.

[0520] In some embodiments, the CD112R antibody is an IgG antibody, such as an IgG1, IgG2, IgG3, or IgG4 antibody or a modified form thereof, as described in the following sections.

[0521] In some embodiments, one or more amino acid modifications can be introduced into the Fc region of an antibody provided herein to generate an Fc region variant. The Fc region variant can include a human Fc region sequence (e.g., a human IgG1, IgG2, IgG3, or IgG4 Fc region) comprising an amino acid modification (e.g., substitution) at one or more amino acid positions.

[0522] In some embodiments, it may be desirable to generate cysteine ​​engineered antibodies, such as "thioMAbs," in which one or more residues of an antibody are replaced with cysteine ​​residues.

[0523] In some embodiments, the antibodies provided herein can be further modified to contain other non-protein moieties known in the art and readily available. Suitable moieties for antibody derivatization include, but are not limited to, water-soluble polymers. Non-limiting examples of water-soluble polymers include, but are not limited to, polyethylene glycol (PEG), ethylene glycol / propylene glycol copolymers, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinyl pyrrolidone, poly-1,3-dioxane, poly-1,3,6-trioxane, ethylene / maleic anhydride copolymers, polyamino acids (homopolymers or random copolymers), and dextran or poly (n-vinyl pyrrolidone) polyethylene glycol, propylene glycol homopolymers, polypropylene oxide / ethylene oxide copolymers, polyoxyethylated polyols (e.g., glycerol), polyvinyl alcohol, and mixtures thereof.

[0524] Antibody expression

[0525] In yet another aspect, the invention provides a kind of polynucleotide molecule, it encodes anti-CD112R antibody or its antigen-binding fragment as described herein.Described polynucleotide molecule can comprise the polynucleotide molecule of the amino acid sequence of the light chain variable region and / or the heavy chain variable region of encoding antibody, or comprise the polynucleotide molecule of the amino acid sequence of the light chain and / or heavy chain of encoding antibody.

[0526] In yet another aspect, the present invention provides an expression vector comprising a polynucleotide molecule as described herein, preferably, the vector is a eukaryotic expression vector. In some embodiments, the polynucleotide molecule as described herein is contained in one or more expression vectors.

[0527] In yet another aspect, the present invention provides a host cell comprising the polynucleotide molecule as described herein or the expression vector as described herein, preferably, the host cell is a eukaryotic cell, more preferably a mammalian cell.

[0528] In yet another aspect, the present invention provides a method for preparing an anti-CD112R antibody or an antigen-binding fragment thereof as described herein, the method comprising expressing the antibody or antigen-binding fragment thereof in a host cell as described herein under conditions suitable for expression of the antibody or antigen-binding fragment thereof, and recovering the expressed antibody or antigen-binding fragment thereof from the host cell.

[0529] The present invention provides mammalian host cells for expressing the recombinant antibodies of the present invention, including many immortalized cell lines available from the American Type Culture Collection (ATCC). These include Chinese hamster ovary (CHO) cells, NS0, SP2 / 0 cells, HeLa cells, baby hamster kidney (BHK) cells, monkey kidney cells (COS), human hepatocellular carcinoma cells, A549 cells, 293T cells and many other cell lines. Mammalian host cells include humans, mice, rats, dogs, monkeys, pigs, goats, cattle, horses and hamster cells. Particularly preferred cell lines are selected by determining which cell line has a high expression level.

[0530] In one embodiment, the present invention provides a method for preparing an anti-CD112R antibody, wherein the method comprises, when an expression vector is introduced into a mammalian host cell, by culturing the host cell for a sufficient period of time to allow the antibody to be expressed in the host cell, or more preferably the antibody is secreted into a culture medium in which the host cell grows, to produce the antibody. Standard protein purification methods can be used to recover the antibody from the culture medium.

[0531] It is likely that antibodies expressed by different cell lines or expressed in transgenic animals have different glycosylation from one another. However, all antibodies encoded by the nucleic acid molecules provided herein or comprising the amino acid sequences provided herein are part of the present invention, regardless of the glycosylation of the antibodies. Likewise, in certain embodiments, non-fucosylated antibodies are advantageous because they generally have more potent efficacy in vitro and in vivo than their fucosylated counterparts and are unlikely to be immunogenic because their sugar structures are normal components of native human serum IgG.

[0532] Pharmaceutical compositions and pharmaceutical preparations

[0533] In another aspect, the present invention provides a pharmaceutical composition comprising an anti-CD112R antibody or an antigen-binding fragment thereof as described herein, a polynucleotide molecule as described herein, an expression vector as described herein, or a host cell as described herein, and a pharmaceutically acceptable carrier or excipient. It should be understood that the anti-CD112R antibody or its pharmaceutical composition provided by the present invention can be integrated with suitable carriers, excipients and other agents in the preparation for co-administration, thereby providing improved transfer, delivery, tolerance, etc.

[0534] The term "pharmaceutical composition" refers to a preparation which permits the active ingredient contained therein to exist in biologically effective form, and which contains no additional ingredients that are unacceptably toxic to a subject to which the preparation would be administered.

[0535] Pharmaceutical preparations containing the anti-CD112R antibodies described herein can be prepared by mixing the anti-CD112R antibodies of the present invention having the desired purity with one or more optional pharmaceutical excipients (Remington's Pharmaceutical Sciences, 16th edition, Osol, A. ed. (1980)), preferably in the form of aqueous solutions or lyophilized preparations.

[0536] The pharmaceutical composition or preparation of the present invention may also include one or more other active ingredients, which are required for the specific indications to be treated, preferably with those active ingredients that do not adversely affect the complementary activities of each other. In some embodiments, other active ingredients are chemotherapeutics, immune checkpoint inhibitors, growth inhibitors, antibiotics or various known anti-tumor or anticancer agents, and the active ingredients are suitably combined in an amount effective for the purpose. In some embodiments, the pharmaceutical composition of the present invention also includes a composition of a polynucleotide molecule encoding an anti-CD112R antibody.

[0537] In yet another aspect, the present invention provides a pharmaceutical combination comprising the antibody or antigen-binding fragment thereof described herein, the polynucleotide molecule described herein, the expression vector described herein, the host cell described herein, or the pharmaceutical composition described herein, and one or more additional therapeutic agents.

[0538] In one embodiment, the drug combination described in the present invention, wherein the additional therapeutic agent is selected from one or more of anti-PD-1 antibodies, anti-PD-L1 antibodies and anti-TIGIT antibodies; preferably, the additional therapeutic agent is an anti-TIGIT antibody, or a combination of an anti-TIGIT antibody and an anti-PD-1 antibody.

[0539] In one embodiment, the anti-PD-1 antibody of the present invention is selected from one or more of nivolumab, pembrolizumab, toripalimab, Sintilimab, Camrelizumab, Tislelizumab and Cemiplimab; preferably toripalimab.

[0540] In one embodiment, the anti-PD-L1 antibody of the present invention is selected from atezolizumab, avelumab and durvalumab.

[0541] In one embodiment, the embodiments of the anti-TIGIT antibodies of the present invention are described in PCT / CN2020 / 101883. The anti-TIGIT antibodies described in the present invention include any one of the anti-TIGIT antibodies described in PCT / CN2020 / 101883, preferably the humanized antibody hu20.

[0542] In yet another aspect, the present invention provides a kit comprising the antibody or antigen-binding fragment thereof described herein, the polynucleotide molecule described herein, the expression vector described herein, the host cell described herein, or the pharmaceutical composition described herein.

[0543] Medical uses and treatments

[0544] Any anti-CD112R antibody provided herein can be used in a therapeutic method. It should also be understood that when discussing "antibodies", compositions comprising antibodies are also included. The anti-CD112R antibodies of the present invention can be used in a therapeutic or preventive method described in any embodiment of the present invention in a therapeutically effective amount or a preventive effective amount.

[0545] In another aspect, the present invention provides an antibody or its antigen binding fragment as described herein, a polynucleotide molecule as described herein, an expression vector as described herein, a host cell as described herein, or a pharmaceutical composition as described herein for the preparation of a drug for treating and / or preventing a disease or condition mediated by CD112R, preferably the disease or condition is cancer, more preferably the cancer is selected from melanoma, renal cancer, prostate cancer, breast cancer, colon cancer, lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, uterine cancer, ovarian cancer and rectal cancer. In some embodiments, the drug is used to enhance, increase and / or maintain anti-tumor immune response in a subject with a tumor. In some embodiments, the drug is used to enhance the interaction with CD226 of CD112.

[0546] In another aspect, the present invention provides antibodies or antigen-binding fragments thereof as described herein, polynucleotide molecules as described herein, expression vectors as described herein, host cells as described herein, or pharmaceutical compositions as described herein, for treating and / or preventing CD112R-mediated diseases or conditions, preferably the disease or condition is cancer, more preferably the cancer is selected from melanoma, renal cancer, prostate cancer, breast cancer, colon cancer, lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, uterine cancer, ovarian cancer and rectal cancer. In some embodiments, the present invention provides anti-CD11R antibodies for enhancing, increasing and / or maintaining anti-tumor immune responses in subjects with tumors. In some embodiments, the present invention provides anti-CD112R antibodies for enhancing the interaction of CD226 with CD112.

[0547] In another aspect, the present invention provides a method for treating and / or preventing a disease or condition mediated by CD112R, comprising administering an antibody or antigen binding fragment thereof as described herein, a polynucleotide molecule as described herein, an expression vector as described herein, a host cell as described herein, or a pharmaceutical composition or drug combination as described herein to a subject in need, preferably the disease or condition is cancer, more preferably the cancer is selected from melanoma, renal cancer, prostate cancer, breast cancer, colon cancer, lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, uterine cancer, ovarian cancer and rectal cancer. In some embodiments, the present invention provides a method for treating a disease and / or condition requiring blocking CD112R, the method comprising administering an anti-CD112R antibody as described herein to a subject in need. In some embodiments, a method for enhancing, increasing and / or maintaining an anti-tumor immune response in a subject with a tumor is provided, the method comprising administering an anti-CD112R antibody as described herein to a subject in need.

[0548] In some embodiments, the cancer or tumor described herein can be selected from melanoma, renal cancer, prostate cancer, breast cancer, colon cancer, lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, uterine cancer, ovarian cancer and rectal cancer.

[0549] In some embodiments, the administration of the present invention includes, but is not limited to, oral, intravenous, subcutaneous, intramuscular, intraarterial, intraarticular (e.g., in arthritic joints), by inhalation, aerosol delivery, or intratumoral administration, etc.

[0550] The present invention also provides for co-administering a therapeutically effective amount of one or more therapies (e.g., treatment modalities and / or other therapeutic agents) to a subject. In some embodiments, the therapy includes surgical treatment and / or radiotherapy. The antibodies of the present invention can be used alone or in combination with other therapeutic agents in therapy. In some embodiments, the antibodies of the present invention are co-administered with at least one additional therapeutic agent. For example, one or more of anti-PD-1 antibodies, anti-PD-L1 antibodies, and anti-TIGIT antibodies. In some embodiments, the antibodies of the present invention are administered in combination with anti-TIGIT antibodies. In some embodiments, the antibodies of the present invention are administered in combination with anti-PD-1 antibodies and anti-TIGIT antibodies.

[0551] Methods for diagnosis and detection

[0552] In yet another aspect, the present invention provides a method for detecting the presence of CD112R in a sample using an antibody or its antigen-binding fragment as described herein. The term "detection" as used herein includes quantitative or qualitative detection. In some embodiments, the sample is a biological sample. In certain embodiments, the biological sample is blood, serum or other liquid samples of biological origin. In certain embodiments, the biological sample comprises cells or tissues. The method includes the step of contacting an antibody or its antigen-binding fragment as described herein or a detection composition containing the antibody or its antigen-binding fragment with a sample, and detecting whether there is a conjugate or a binding signal generated by the antibody or its antigen-binding fragment in combination with CD112R. When used for detection purposes, the antibody or its antigen-binding fragment as described herein may be labeled to indicate whether the conjugate has been formed.

[0553] The present invention includes all combinations of the specific embodiments described. Further embodiments of the present invention and the full scope of applicability will become apparent from the detailed description provided below. However, it should be understood that although the detailed description and specific examples indicate preferred embodiments of the present invention, these descriptions and examples are provided only by way of illustration, as various changes and modifications within the spirit and scope of the present invention will become apparent to those skilled in the art from this detailed description. For all purposes, all publications, patents and patent applications cited herein, including citations, will be incorporated herein by reference in their entirety.

[0554] The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present invention.

[0555] The present invention uses the following abbreviations:

[0556] his-tag stands for histidine tag;

[0557] Fc tag stands for fragment crystallizable tag;

[0558] ECD stands for extracellular domain;

[0559] PEI stands for polyethyleneimine;

[0560] BSA stands for bovine serum albumin;

[0561] PBS stands for phosphate-buffered saline;

[0562] FBS stands for fetal bovine serum;

[0563] CFSE stands for carboxyfluorescein diacetate succinimidyl ester;

[0564] APC stands for ectopic phycocyanin;

[0565] NA-PE represents phycoerythrin-labeled neutravidin;

[0566] PE stands for phycoerythrin;

[0567] TMB stands for 3,3',5,5'-tetramethylbenzidine;

[0568] HEPES: hydroxyethylpiperazineethanesulfonic acid buffer;

[0569] DTT: dithiothreitol.

[0570] Example

[0571] The present invention is illustrated by the following examples, but is not intended to limit the present invention in any way. The present invention has been described in detail herein, and specific embodiments thereof are disclosed therein. It will be apparent to those skilled in the art that various changes and modifications will be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention.

[0572] Example 1. Preparation of recombinant protein for anti-CD112R antibody activity detection

[0573] The cDNA sequence encoding the CD112R extracellular domain was amplified by conventional PCR technology, and the amplified fragment was cloned into a self-constructed eukaryotic expression plasmid system (MX2-mFc, containing the mouse IgG2a Fc domain) using conventional cloning technology, which contains a puromycin selection system, thereby generating a recombinant fusion protein expression plasmid hCD112R ECD mFC. The hCD112R mFC recombinant protein was expressed and purified using expression cells 293E.

[0574] The amino acid sequence of the human CD112R extracellular domain (hCD112R ECD) is the amino acid at position Met1-Ala160 of NCBI accession number NM_024070, which is used for the activity detection of the antibody of the present invention.

[0575] Example 2. Preparation of mouse hybridoma cells

[0576] 2.1. Immunization of animals

[0577] hCD112R-Fc (purchased from R&D Systems, catalog number 9365-PV) recombinant protein was used as an antigen to immunize 5 BALB / c mice (purchased from Simonsen Laboratories of Gilroy, female BALB / c, 8 weeks old). After the initial immunization (50ug / mouse), booster immunizations (25ug / mouse) were performed every 1 or 2 weeks for a total of 6 immunizations.

[0578] 2.2 Cell Fusion

[0579] On the fourth day after the last booster immunization, the inguinal lymph nodes, popliteal lymph nodes and spleen of the mice were taken, and the lymphocyte-rich suspension was obtained after grinding in physiological saline, and it was fused with mouse myeloma cells Sp2 / 0 by conventional electroporation method. The fusion product was cultured in DMEM complete medium containing 1:50 HAT (hypoxanthine, methotrexate and thymidine) for 5 days to screen the successfully fused cells (hybridoma cells). Then it was changed to DMEM complete medium containing 1:50 HT (hypoxanthine and thymidine) until the end of the screening.

[0580] The DMEM complete culture medium has a ratio of: 15% FBS (fetal bovine serum) + 1:50 L-glutamine + 100 U / mL penicillin-streptomycin + 1:100 OPI (oxaloacetate, pyruvate and insulin), and the incubator conditions are 8% CO2, 37°C.

[0581] Example 3 Screening of mouse hybridoma cells and performance testing of the resulting anti-CD112R mouse antibodies

[0582] Among 9600 different polyclonal hybridoma cells, 181 hybridoma cells were screened by combining ELISA, and the antibodies secreted by them can specifically bind to hCD112R. Among these 181 hybridoma cells with positive binding, 40 hybridoma cells expressed antibodies that could block the binding of hCD112R to hCD112 expressed on the cell surface in FACS. In the subsequent ELISA blocking experiment, 22 of the above 40 polyclonal cell lines were determined to be able to block the binding of hCD112R to hCD112. From these 22 hybridoma cell FACS and ELISA blocking double positive polyclonal clones, 15 strains were selected for subcloning.

[0583] 15 blocking monoclonal cell lines were obtained through subclone screening. The secreted antibodies were purified and analyzed. mRNA was extracted from monoclonal hybridoma cells, and the variable regions of the antibodies were sequenced. Through in vitro efficacy experiments and in combination with PD-1 monoclonal antibodies and TIGIT monoclonal antibodies, 8 candidate monoclonal hybridoma lines that can promote T cell activation were determined to finally enter recombinant expression. The serial numbers are 2G10.1, 3D2.1, 4E2, 4E5.1, 5B2.1, 5C10.1, 6A10.1 and 7C2.1. They are abbreviated as 2G10, 3D2, 4E2, 4E5, 5B2, 5C10, 6A10 and 7C2 in subsequent chimeric antibody construction.

[0584] The experimental method is as follows.

[0585] 3.1. ELISA method to detect the blocking effect of hybridoma antibodies on the binding of hCD112R and hCD112

[0586] 96-well MaxiSorp plates (Thermo Fisher Nunc) were coated with 2ug / mL hCD112 (mouse Fc tag, Junmeng) and blocked with 1% BSA. hCD112R with a final concentration of 0.5ug / ml was incubated with hybridoma culture supernatant on the microplate for 30 minutes. The mixture was then transferred to the MaxiSorp plate and incubated for 30 minutes. Detection was performed with horseradish peroxidase-labeled goat anti-human secondary antibody.

[0587] The results show that the hybridoma antibody of the present invention can effectively block the binding between hCD112R and hCD112.

[0588] 3.2. Biacore detection of affinity between anti-CD112R hybridoma antibodies and hCD112R mFc

[0589] Biacore T200 was used to detect the binding affinity of anti-CD112R hybridoma antibodies to recombinant hCD112R mFc proteins. Sheep anti-human Fc antibody fragments (Jackson ImmunoResearch) were coupled to the surface of the CM5 chip, and the chip was used to capture the anti-CD112R hybridoma antibodies, and then different concentrations of recombinant hCD112R mFc proteins were injected into the CM5 chip. As shown in Table 4, the affinity of the 15 anti-CD112R hybridoma antibodies to the recombinant hCD112R mF was high.

[0590] Table 4: Affinity of anti-CD112R hybridoma antibodies to recombinant hCD112R mFc

[0591] serial number Affinity KD(M) serial number Affinity KD(M) 1D11.1 2.36E-11 6A6.1 1.74E-11 2G10.1 3.02E-11 6A10.1 1.03E-11 3D2.1 3.36E-11 6C6.1 2.05E-11 4E2 2.37E-11 6D2.1 1.34E-11 4E5.1 9.26E-12 7C2.1 1.01E-11 5B1.1 1.63E-11 8D3.1 1.58E-11 5B2.1 2.32E-11 8H8.1 5.88E-11 5C10.1 8.55E-12

[0592] 3.3. FACS detection of hybridoma antibodies blocking the binding of hCD112R to cell surface hCD112

[0593] The self-constructed CHO CD112 cells overexpressing human CD112 were incubated with hCD112R mFc protein solution (0.5 μg / ml) prepared with staining buffer (PBS + 1% FBS), and different concentrations of anti-CD112R hybridoma antibodies or control antibodies (starting concentration of 100 μg / ml, 3-fold dilution, 10 concentration gradients) at 4°C for 30 minutes. The unbound antibodies were then washed away with staining buffer, and the cells were incubated with 1% (v / v) goat anti-mouse IgG Fc fluorescent secondary antibody (Jackson ImmunoResearch) prepared with staining buffer at 4°C in the dark for 30 minutes. Finally, the cells were collected by flow cytometry to detect fluorescent antibodies bound to the cell surface. The raw data were analyzed with FlowJo to obtain the MFI value, and the IC was obtained by four-parameter fitting curve using GraphPad Prism software. 50 value.

[0594] The results are shown in Table 5, which show that the hybridoma antibody of the present invention can effectively block the binding between hCD112R and hCD112.

[0595] Table 5: Anti-CD112R hybridoma antibodies block the binding of hCD112R to hCD112

[0596]

[0597] 3.4 Activity detection of hybridoma antibodies in CD112R / CD112 reporter gene assay system

[0598] The self-constructed target cells CHO CD112 (stable expression of human CD112 and CD3scFv) were plated in a 96-well white flat-bottom plate at a rate of 5 × 10 4 The number of cells was plated overnight; the next day, after the culture medium in the cell wells was aspirated, different concentrations of anti-CD112R hybridoma antibodies or control antibodies (starting concentration of 30 μg / ml, 3-fold dilution, a total of 8 concentration gradients) were added to the target cells with experimental buffer (RPMI 1640 (1X) (purchased from Gibco, Cat#22400-071) + 2% FBS) and incubated at 37°C for 30 minutes. Then, the self-constructed effector cells Jurkat CD112R (stable expression of human CD112R and luc2P / NFAT-RE) were added at 1×10 per well. 5The number of cells was added to the cell plate and incubated in a 37°C incubator for 6 hours; finally, ONE-Glo luciferase detection reagent (Promega) was added to the cell antibody mixture system, and the chemiluminescent signal was detected using a multifunctional microplate reader. The four-parameter regression curve was fitted using GraphPad prism software to calculate the EC 50 The positive control was Ref (anti-CD112R antibody from the University of Colorado, expressed and purified according to the sequence of US20170240613).

[0599] The results showed that the hybridoma antibodies of the present invention were able to effectively block the interaction between CD112R and CD112 in the CD112R / CD112 reporter gene system and promote the activation of T cells.

[0600] Among them, the EC of hybridoma antibodies 2G10.1, 5C10.1, 3D2.1, and 4E2 50 The EC values ​​of 7C2.1 and 6A10.1 were 72.91 ng / ml, 40.36 ng / ml, 49.28 ng / ml and 61.26 ng / ml, respectively, which were significantly better than the control antibody Ref (920.4 ng / ml); the EC values ​​of 7C2.1 and 6A10.1 were 50 The EC values ​​of 4E5.1 were 37.94 ng / ml and 50.73 ng / ml, respectively, which were significantly better than the control antibody Ref (870.9 ng / ml); 50 The concentration of 55.19 ng / ml was significantly better than that of the control antibody Ref (866.3 ng / ml).

[0601] 3.5 Activity detection of hybridoma antibodies combined with anti-TIGIT antibodies in a dual reporter gene system

[0602] Target CHO CD112 cells (stable expression of hCD112 and CD3 scFv) were plated in a 96-well white flat-bottom plate (Corning, cat#3917) at a rate of 5×10 4 After plating the cells overnight, a fixed concentration (0.3 μg / ml) of anti-CD112R hybridoma antibody and different concentrations (from 0.5 ng / ml to 30 μg / ml, 3-fold dilution) of anti-TIGIT antibody were added and incubated at 37°C for 30 minutes. Then, effector cells Jurkat PD-1TIGTI CD112R (stable expression of human PD-1, human TIGIT, human CD112R and luc2P / NFAT-RE) were added at 1×10 per well. 5 The number of cells was added to the target cells and incubated in a 37°C incubator for 4-6 hours; finally, ONE-Glo luciferase detection reagent (Promega, cat#E6120) was added to the cell-antibody mixture system and the chemiluminescent signal was detected using a multifunctional microplate reader.

[0603] Anti-TIGIT antibody (JS006): Derived from the anti-TIGIT humanized antibody hu20 in PCT application number PCT / CN2020 / 101883.

[0604] Hybridoma antibodies: 2G10.1, 3D2.1, 4E2, 4E5.1, 5B2.1, 5C10.1, 6A10.1 and 7C2.1.

[0605] like Figure 1 As shown in the dose-dependence curve, in the dual reporter gene system, after the hybridoma antibody of the present invention was used in combination with the anti-TIGIT antibody, the luciferase reporter gene NFAT signal was significantly higher than that of the anti-TIGIT antibody single-drug group, indicating that the combination of anti-CD112R antibody and anti-TIGIT antibody has a significant synergistic effect.

[0606] 3.6 Activity detection of hybridoma antibodies combined with anti-TIGIT antibodies and anti-PD-1 antibodies in a triple reporter gene system

[0607] Target cells CHO PD-L1 CD112 cells (stable expression of hPD-L1, hCD112 and CD3 scFv) were plated in 96-well white flat-bottom plates (Corning, cat#3917) at a rate of 5 × 10 4 After plating cells overnight, different concentrations (from 0.5 ng / ml to 10 μg / ml, 3-fold dilution) of anti-PD-1 antibody and fixed concentration (0.3 μg / ml) of anti-TIGIT antibody and fixed concentration (0.3 μg / ml) of anti-CD112R hybridoma antibody were added and incubated at 37°C for 30 minutes. Then, effector cells JurkatPD-1TIGTICD112R (stable expression of human PD-1, human TIGIT, human CD112R and luc2P / NFAT-RE) were added at 1×10 per well. 5 The number of cells was added to the target cells and incubated in a 37°C incubator for 4-6 hours; finally, ONE-Glo luciferase detection reagent (Promega, cat#E6120) was added to the cell-antibody mixture system and the chemiluminescent signal was detected using a multifunctional microplate reader.

[0608] Anti-TIGIT antibody (JS006): Derived from the anti-TIGIT humanized antibody hu20 in PCT application number PCT / CN2020 / 101883.

[0609] Anti-PD-1 antibody (JS001): Teplizumab derived from Junshi Biosciences.

[0610] Hybridoma antibodies: 2G10.1, 3D2.1, 4E2, 4E5.1, 5B2.1, 5C10.1, 6A10.1 and 7C2.1.

[0611] like Figure 2 As shown in (ah), the test results showed that the luciferase reporter gene NFAT signal in the combination group of anti-CD112R hybridoma monoclonal antibody with anti-TIGIT antibody and anti-PD-1 antibody was significantly higher than that in the anti-PD-1 antibody monotherapy group and the anti-PD-1 antibody with 0.3μg / ml anti-CD112R hybridoma monoclonal antibody combination group, indicating that the combination of anti-TIGIT antibody with anti-PD-1 antibody and anti-CD112R antibody has a significant synergistic effect.

[0612] Example 4. Determination of variable region sequences of anti-CD112R mouse antibodies (expressed according to Kabat or IMGT)

[0613] The DNA coding sequence corresponding to the variable region of the anti-CD112R mouse antibody was determined by a method based on degenerate primer PCR. Candidate hybridoma cells were cultured, the cells were collected by centrifugation at 1000rpm, and total RNA was extracted with Trizol. The first-chain cDNA was synthesized using this as a template, and then the first-chain cDNA was used as a subsequent template to PCR amplify the corresponding variable region DNA coding sequence. The primer sequence used in the amplification reaction is complementary to the first framework region and constant region of the variable region of the antibody (Larrick, JW, et al., 1990, Scand. J. Immunol., 32, 121-128 and Coloma, JJ, et al., (1991) BioTechniques, 11, 152-156). In a 50μl reaction system, add 1μl of cDNA, 5μl of 10×PCR buffer, 1μl of upstream and downstream primers (25pmol), 1μl of dNTP, 1μl of 25mmol PL MgCl2, 39μl of H2O, pre-denature at 95℃ for 10min, add 1μl of Taq enzyme, enter temperature cycle, and perform PCR amplification. The reaction conditions are 94℃ denaturation for 1min, 58℃ annealing for 1min, 72℃ extension for 15s, a total of 32 cycles, and then keep at 72℃ for 10min. Recover and purify the PCR product. Sequence the amplified product to obtain the amino acid sequence of the heavy chain variable region and light chain variable region of the anti-human CD112R mouse antibody.

[0614] Consensus sequences were searched in germline and rearranged Ig variable region sequence databases using NCBI Ig-Blast (http: / / www.ncbi.nlm.nih.gov / projects / igblast / ). Complementarity determining region (CDR) amino acid sequences were identified by sequence annotation based on the Kabat (Wu, TT and Kabat, EA 1970 J. Exp. Med., 132: 211-250) and IMGT systems (Lefranc M.-P. et al., 1999 Nucleic Acids Research, 27, 209-212) and by Internet-based sequence analysis (http: / / www.imgt.org / IMGT_vquest / vquest and http: / / www.ncbi.nlm.nih.gov / igblast / ).

[0615] The amino acid sequences of the light chain and heavy chain variable regions and CDRs of the selected anti-CD112R mouse antibodies are shown in Table 1. PCR sequencing analysis found that the hybridoma cell 4E2 contained two heavy chains, including heavy chain variable regions 4E2-VH1 and 4E2-VH2, respectively.

[0616] Example 5. Construction of anti-CD112R chimeric antibody

[0617] Considering the expression amount, activity, type, etc. of antibodies expressed by hybridoma cells, the light chain and heavy chain variable regions of anti-human CD112R mouse antibodies 2G10, 4E2HC1, 4E2HC2, 4E5HC, 5B2, 6A10, 7C2, 5C10, and 3D2 were selected to construct anti-CD112R chimeric antibodies.

[0618] The coding sequence of heavy chain constant region Fc and light chain constant region κ was cloned from human blood cells (from Beijing Institute of Hematology) and introduced into pCDNA3.1 plasmid. The heavy chain and light chain variable region coding sequences of the aforementioned anti-human CD112R mouse antibody were synthesized by Genscript. After Bspq I digestion, the heavy chain variable region coding sequence and light chain variable region coding sequence of various anti-human CD112R mouse antibodies were introduced into the pCDNA3.1 plasmid into which the constant region coding sequence had been introduced, and the correct clone was determined by sequencing. Various chimeric heavy chain and light chain expression plasmids were mixed and paired to transfect expression cells to obtain 72 anti-human CD112R chimeric antibodies, and their numbering and pairing methods were specifically shown in Table 2. Subsequent experimental materials were extracted and obtained after transfection of cells by this series of plasmids.

[0619] Example 6. Screening of chimeric antibodies

[0620] 6.1 Binding of anti-CD112R chimeric antibodies to human CHO-CD112R expressing cells

[0621] CHO-CD112R cells overexpressing human CD112R (Junshi independently constructed, the amino acid sequence of CD112R in the stable cell line overexpressing CD112R is the amino acid at Met1-Arg326 of NCBI accession number Q6DKI7) were incubated with different concentrations of anti-CD112R chimeric antibodies (starting concentration of 50μg / ml, 5-fold dilution, a total of 12 concentration gradients) at 4°C for 30min, then washed and incubated with fluorescently labeled secondary antibodies at 4°C in the dark for 30 minutes. Finally, the cells were collected by flow cytometry (BDCantoⅡ) to detect fluorescent antibodies bound to the cell surface. The raw data were analyzed by FlowJo to obtain the MFI value, and the antibody dose-dependent binding curve was fitted by GraphPad ( Figure 3 , a and b) and calculate EC 50 (Table 3), the positive control and negative control were Ref (anti-CD112R antibody from the University of Colorado, expressed and purified according to the sequence of US20170240613) and anti-KLH hu-IgG4 antibody, respectively.

[0622] like Figure 3 As shown in Table 6, most of the anti-CD112R chimeric antibodies of the present invention can bind to human CD112R highly expressed on the surface of CHO-CD112R cells with high affinity, and the binding activity is significantly better than that of the control antibody Ref.

[0623] Table 6: Cell-level affinity (EC 50 )

[0624] chimeric antibodies <![CDATA[EC 50 (ng / ml)]]> Relative activity (%)* chi-61 107.1 3993 chi-54 121.6 3516 chi-55 140 3054 chi-71 204.6 2090 chi-62 214.3 1995 chi-70 260 1645 chi-69 262.2 1631 chi-63 531.5 805 chi-47 279.9 600 chi-18 293.6 572 chi-36 351.5 478 chi-46 432.6 388 chi-53 626.9 268 chi-45 726.1 231 ref 4276 100 chi-72 12256 35 chi-10 NA NA chi-52 NA NA anti-KLH hIgG4 NA NA

[0625] Note: “*” indicates the EC of the control antibody Ref and the anti-CD112R chimeric antibody 50 ratio;

[0626] “NA” means not determined.

[0627] 6.2 Anti-CD112R chimeric antibody binds to cynomolgus monkey CD112R

[0628] The plate was coated with a fixed concentration of recombinant cynomolgus monkey CD112R antigen (Acrobiosystems, Cat# PVG-C5259), and a gradient dilution of anti-CD112R chimeric antibody (1 μg / ml starting, 2.5-fold gradient dilution, a total of 12 concentrations) was used to bind to it, and horseradish peroxidase (HRP)-coupled mouse anti-human IgG4 Fc (Southern Biotech, 9200-05) was diluted 5000 times as a detection antibody for detection, and then 0.1 mg / ml TMB was used for color development, and finally the reaction was terminated with 2M hydrochloric acid, and the plate was read at 420nm / 620nm. The EC was fitted using a four-parameter logarithmic regression (4PL) model 50 .

[0629] The positive control was Ref (anti-CD112R antibody from the University of Colorado, expressed and purified according to the sequence of US20170240613).

[0630] like Figure 4 As shown in (a and b) and Table 7, among the following 14 chimeric antibodies, except chi 18 which did not bind to cynomolgus monkey CD112R, the other 13 anti-CD112R chimeric antibodies all bound to cynomolgus monkey CD112R.

[0631] Table 7: Binding of anti-CD112R chimeric antibodies to cynomolgus monkey CD112R (EC50 ng / ml)

[0632] chimeric antibodies <![CDATA[EC 50 (ng / ml)]]> Relative activity (%)* chi 18 NA NA chi 36 3.906 89.6 chi 45 2.975 117.6 chi 46 3.263 107.2 chi 47 3.092 113.2 chi 53 3.296 106.2 chi 54 3.267 107.1 chi 55 4.187 100 chi 61 4.995 83.8 chi 62 3.714 112.8 chi 63 4.358 96.1 chi 69 4.739 88.4 chi 70 3.835 109.2 chi 71 4.418 94.8

[0633] Note: “*” indicates the EC of the control antibody Ref and the anti-CD112R chimeric antibody 50 ratio.

[0634] 6.3 Anti-CD112R chimeric antibody blocks binding of CD112R protein to human CHO-CD112 expressing cells

[0635] CHO CD112 cells overexpressing human CD112 were incubated with hCD112RmFc protein solution (5 μg / ml) prepared in staining buffer (PBS + 1% FBS), and different concentrations of anti-CD112R chimeric antibody or control antibody (starting concentration of 100 μg / ml, 3-fold dilution, 10 concentration gradients) at 4°C for 30 minutes. Unbound antibodies were then washed away with staining buffer, and the cells were incubated with 1% (v / v) goat anti-mouse IgG Fc fluorescent secondary antibody (Jackson ImmunoResearch) prepared in staining buffer at 4°C in the dark for 30 minutes. Finally, cells were collected using a flow cytometer (BD CantoⅡ) to detect fluorescent antibodies bound to the cell surface. The raw data were analyzed using FlowJo to obtain the MFI value, and the IC was obtained by performing a four-parameter fitting curve using GraphPadPrism software. 50 The positive control and negative control were Ref (anti-CD112R antibody from the University of Colorado, expressed and purified according to the sequence of US20170240613) and anti-KLH hu-IgG4 antibody, respectively.

[0636] like Figure 5 As shown in (a and b) and Table 8, the following 13 chimeric antibodies can effectively block the binding of CD112R protein to CHO-CD112 cells.

[0637] Table 8: Ability of anti-CD112R chimeric antibodies to block the binding of CD112R protein to CHO-CD112 cells (IC 50 )

[0638] chimeric antibodies <![CDATA[IC 50 (ng / ml)]]> Relative activity (%)* chi 70 0.7077 149.6 chi 71 0.7328 144.5 chi 46 0.7996 132.4 chi 63 0.8012 132.2 chi 47 0.8756 120.9 chi 54 0.9023 117.4 chi 36 0.9205 115.0 chi 45 0.9527 111.2 chi 69 0.9591 110.4 chi 62 0.9635 109.9 chi 61 0.9646 109.8 chi 53 0.9791 108.2 chi 55 1.017 104.1 Ref 1.059 100.0

[0639] Note: “*” indicates the EC of the control antibody Ref and the anti-CD112R chimeric antibody 50 ratio.

[0640] 6.4 Activity detection of anti-CD112R chimeric antibody in CD112R / CD112 reporter gene assay system

[0641] Target CHO CD112 cells (independently constructed by Junshi Biosciences, stably expressing human CD112 and CD3scFv) were plated in a 96-well white flat-bottom plate at a rate of 5 × 10 4The cells were plated overnight; the next day, the medium in the cell wells was aspirated, and different concentrations of anti-CD112R chimeric antibodies or control antibodies (starting concentration of 3 μg / ml, 3-fold dilution, a total of 10 concentration gradients) were added to the target cells with experimental buffer (RPMI 1640 (1X) (purchased from Gibco, Cat#22400-071) + 2% FBS) and incubated at 37°C for 30 minutes. Then, the self-constructed effector cells Jurkat CD112R (stable expression of human CD112R and luc2P / NFAT-RE) were added at 1×10 per well. 5 The cells were added to the cell plate and incubated in a 37°C incubator for 6 hours. Finally, ONE-Glo luciferase detection reagent (Promega) was added to the cell antibody mixture system, and the chemiluminescent signal was detected using a multifunctional microplate reader (TECANM1000 pro). The four-parameter regression curve was fitted using GraphPad prism software to calculate the EC 50 The positive control and negative control were Ref University of Colorado anti-CD112R antibody (expressed and purified according to the sequence of US20170240613) and anti-KLH hu-IgG4 antibody, respectively.

[0642] like Figure 6 As shown in (ae) and Table 9, the following 13 chimeric antibodies can effectively block the interaction between CD112R and CD112 in the CD112R / CD112 reporter gene system and promote the activation of T cells. Among them, the activities of 7 chimeric antibodies chi 46, chi 54, chi45, chi62, chi 53, chi 55 and chi 47 are more than 20 times as active as those of Ref.

[0643] The heavy and light chains of the above 7 chimeric antibodies were selected for humanized design and modification.

[0644] Table 9: Activity test data of anti-CD112R chimeric antibodies in CD112R / CD112 reporter gene assay system

[0645] chimeric antibodies <![CDATA[EC 50 (ng / ml)]]> Relative activity (%)* chi 46 7.01 4609.68 chi 54 7.46 4205.23 chi 45 11.94 2705.19 chi 62 12.88 2349.38 chi 53 12.9 2430.23 chi 55 13.12 2306.4 chi 47 14.04 2232.91 chi 70 13.86 1867.97 chi 63 17.41 1487.08 chi 69 18.66 1387.46 chi 61 19 1592.63 chi 71 19.45 1470.95 chi 36 30.57 1056.59

[0646] Note: “*” indicates the EC of the control antibody Ref and the anti-CD112R chimeric antibody 50 ratio.

[0647] Example 7: Humanization of antibody variable regions

[0648] For humanization of antibody variable regions, the human immunoglobulin gene database on the NCBI (http: / / www.ncbi.nlm.nih.gov / igblast / ) website is first searched for human germline IgG genes that are homologous to the cDNA sequence of mouse antibodies, and then the amino acid sequence and precise boundaries of the variable region CDR are defined using the Kabat numbering system or the IMGT numbering system. In principle, human IGHV with high homology to mouse antibodies is selected as a humanization template, and humanization of antibody variable regions is implemented by CDR grafting.

[0649] According to the sequence of the mouse antibody obtained above, humanization transformation is carried out. In short, the humanization transformation process involves the following steps: A. Compare the gene sequence of the mouse antibody with the gene sequence of the human embryonic system antibody to find out the sequence with high homology; B. Analyze and examine the HLA-DR affinity and select the human embryonic system framework sequence with low affinity; C. Use computer simulation technology to apply molecular docking to analyze the variable region and its surrounding framework amino acid sequence to examine its spatial three-dimensional binding mode. By calculating electrostatic force, van der Waals force, hydrophilicity and entropy value, analyze the key amino acid individuals in the mouse antibody gene sequence that can interact with human CD112R and maintain the spatial structure, graft it back to the selected human embryonic system gene framework, and on this basis, standardize the framework region amino acid sites that must be retained to synthesize humanized antibodies. On this basis, a variety of humanized antibody variable regions were obtained, and the designed humanized anti-CD112R antibody variable regions were combined in various ways to obtain 60 humanized anti-CD112R antibodies, whose numbers and amino acid sequences are specifically shown in Table 3.

[0650] Example 8. Screening of humanized anti-CD112R antibodies

[0651] 8.1 Binding of anti-CD112R humanized antibodies to human CD112R protein

[0652] The plate was coated with a fixed concentration of hCD112R-ECD-mFC protein (1.5 μg / mL), and a gradient-diluted humanized anti-CD112R antibody (1 μg / ml starting, 2.5-fold gradient dilution, a total of 12 concentrations) was used to bind to it, and the HRP-coupled goat anti-human antibody IgG (Fc specific) (Sigma, A0170) was diluted 5000 times as a detection antibody for detection, and then 0.1 mg / ml TMB was used for color development, and finally the reaction was terminated with 2M hydrochloric acid, and the plate was read at 420nm / 620nm. The EC50 was fitted using a four-parameter logarithmic regression (4PL) model. The positive controls were COM701 (Compugen's anti-CD112R antibody, expressed and purified according to the US20180280506A1 sequence) and anti-KLH hu-IgG4 antibody.

[0653] As shown in Table 10, all 60 anti-CD112R humanized antibodies were able to bind to the recombinant human CD112R protein with high affinity.

[0654] Table 10: Binding of anti-CD112R humanized antibodies to human CD112R protein (EC 50 )

[0655]

[0656]

[0657] Note: “*” indicates the EC of control antibody COM701 and anti-CD112R humanized antibody 50 Ratio; In this article, Hu and hu in the numbering of the anti-CD112R humanized antibody have the same meaning and can be used interchangeably, for example, Hu-01, Hu01, hu-01, hu01, hu-1, hu1 all represent the same humanized antibody.

[0658] 8.2 Anti-CD112 humanized antibody blocks the binding of CD112R protein to CHO-CD112 expressing cells

[0659] The cells overexpressing human CD112 were incubated with hCD112RmFc protein solution (5 μg / ml) prepared in staining buffer (PBS + 1% FBS), and different concentrations of anti-CD112R humanized antibody or control antibody (starting concentration of 100 μg / ml, 3-fold dilution, 10 concentration gradients) at 4°C for 30 minutes. The unbound antibodies were then washed away with staining buffer, and the cells were incubated with 1% (v / v) goat anti-mouse IgG Fc fluorescent secondary antibody (Jackson ImmunoResearch) prepared in staining buffer at 4°C in the dark for 30 minutes. Finally, the cells were collected by flow cytometry (BD CantoⅡ) to detect the fluorescent antibodies bound to the cell surface. The raw data were analyzed by FlowJo to obtain the MFI value, and the IC50 value was obtained by four-parameter fitting curve using GraphPadPrism software. The positive control and negative control were COM701 (Compugen's anti-CD112R antibody, expressed and purified according to the US20180280506A1 sequence) and anti-KLH hu-IgG4 antibody, respectively.

[0660] As shown in Table 11, the following 60 chimeric antibodies can effectively block the binding of CD112R protein to CHO-CD112 expressing cells.

[0661] Table 11: Ability of anti-CD112R humanized antibodies to block the binding of CD112R protein to CHO-CD112 cells (IC50)

[0662]

[0663]

[0664] Note: “*” indicates the IC of control antibody COM701 and anti-CD112R humanized antibody 50 ratio.

[0665] 8.3 Activity detection of anti-CD112 humanized antibody in CD112R / CD112 reporter gene assay system

[0666] Target CHO CD112 cells (stable expression of hCD112 and CD3scFv) were plated in a 96-well white flat-bottom plate at a rate of 5 × 10 cells per well. 4 The cells were plated overnight; the next day, the medium in the cell wells was aspirated, and different concentrations of anti-CD112R humanized antibodies or control antibodies (starting concentration of 3 μg / ml, 3-fold dilution, a total of 10 concentration gradients) were added to the target cells with experimental buffer (RPMI1640 (1X) + 2% FBS) and incubated at 37°C for 30 minutes. Then, effector cells JurkatCD112R (stable expression of human CD112R and luc2P / NFAT-RE) were plated at 1×10 per well. 5 The number of cells was added to the cell plate and incubated in a 37°C incubator for 6 hours; finally, ONE-Glo luciferase detection reagent (Promega) was added to the cell antibody mixture system and the chemiluminescent signal was detected by a multifunctional microplate reader (TECAN M1000 pro). The four-parameter regression curve was fitted by GraphPad prism software to calculate the EC50 value. The positive control and COM701 (Compugen's anti-CD112R antibody, expressed and purified according to the US20180280506A1 sequence) were used.

[0667] As shown in Table 12, except for hu-57, the other 59 anti-CD112R humanized antibodies among the following 60 humanized antibodies can effectively block the interaction between CD112R and CD112 in the CD112R / CD112 reporter gene system and promote the activation of T cells. Among them, the activities of the six humanized antibodies hu-52, hu-51, hu-53, hu-59, hu-54 and hu-55 are more than 3 times the relative activity compared with Ref (CGEN). The activities of the six humanized antibodies hu-16, hu-39, hu-45, hu-58, hu-56 and hu-60 are between 2.5 and 3 times the relative activity compared with Ref (CGEN).

[0668] Table 12: Activity test data of anti-CD112R humanized antibodies in CD112R / CD112 reporter gene assay system

[0669]

[0670]

[0671] Note: “*” indicates the EC of control antibody COM701 and anti-CD112R humanized antibody 50 8.4 Binding activity of anti-CD112R humanized antibody to cynomolgus monkey and mouse CD112R

[0672] The plates were coated with fixed concentrations of recombinant cynomolgus monkey CD112R antigen (purchased from Acrobiosystems, Cat#PVG-C5259) and mouse CD112R antigen (purchased from Acrobiosystems, Cat#PVG-M5257), respectively, and gradient dilutions of anti-CD112R humanized antibodies (1 μg / ml starting, 2.5-fold gradient dilution, 12 concentrations in total) were used to bind to them, and HRP-coupled mouse anti-human IgG4 Fc (Southern Biotech, 9200-05) was diluted 5000 times as a detection antibody for detection, and then 0.1 mg / ml TMB was used for color development, and finally the reaction was terminated with 2M hydrochloric acid, and the plate was read at 420nm / 620nm. The EC50 was fitted using a four-parameter logarithmic regression (4PL) model.

[0673] like Figure 7 As shown in (a and b), hu16, hu52, and hu59 can bind to cynomolgus monkey CD112R with high affinity, EC 50 They were 2.92ng / ml, 3.087ng / ml and 2.622ng / ml respectively, but all had no binding activity to mouse CD112R.

[0674] 8.5 Activity detection of anti-CD112R humanized antibody combined with anti-TIGIT antibody in dual reporter gene system

[0675] Target CHO CD112 cells (stable expression of hCD112 and CD3 scFv) were plated in a 96-well white flat-bottom plate (Corning, cat#3917) at a rate of 5×10 4After plating cells overnight, different concentrations (from 0.15 ng / ml to 3 μg / ml, 3-fold dilution) of anti-CD112R humanized antibody and fixed concentration (0.3 μg / ml) of anti-TIGIT antibody were added and incubated at 37°C for 30 minutes. Then, effector cells Jurkat PD-1TIGTI CD112R (stable expression of human PD-1, human TIGIT, human CD112R and luc2P / NFAT-RE) were added at 1×10 per well. 5 The number of cells was added to the target cells and incubated in a 37°C incubator for 4-6 hours; finally, ONE-Glo luciferase detection reagent (Promega, cat#E6120) was added to the cell-antibody mixture system and the chemiluminescent signal was detected using a multifunctional microplate reader (TECAN M1000 pro).

[0676] Anti-TIGIT antibody (JS006): Derived from the anti-TIGIT humanized antibody hu20 in PCT application number PCT / CN2020 / 101883.

[0677] The positive control was COM701 (Compugen's anti-CD112R antibody, expressed and purified according to the US20180280506A1 sequence).

[0678] like Figure 8 As shown in the dose-dependence curve, in the dual reporter gene system, after the anti-CD112R antibodies hu16, hu52 and hu59 were used in combination with the anti-TIGIT antibody, the luciferase reporter gene NFAT signal was significantly higher than that of the anti-CD112R antibody single-drug group, indicating that the combination of anti-CD112R antibody and anti-TIGIT antibody has a significant synergistic effect, and the efficacy of the combination group of three humanized anti-CD112R antibodies and anti-TIGIT antibody is significantly better than that of the COM701 combination group.

[0679] 8.6 Activity detection of anti-CD112R humanized antibody combined with anti-TIGIT antibody and anti-PD-1 antibody in a triple reporter gene system

[0680] Target cells CHO PD-L1 CD112 cells (stable expression of hPD-L1, hCD112 and CD3 scFv) were plated in 96-well white flat-bottom plates (Corning, cat#3917) at a rate of 5 × 10 4After plating the cells overnight, different concentrations (from 0.5 ng / ml to 10 μg / ml, 3-fold dilution) of anti-PD-1 antibody and fixed concentrations (0.3 μg / ml) of anti-TIGIT antibody and anti-CD112R antibody were added and incubated at 37°C for 30 minutes. Then, effector cells Jurkat PD-1TIGTI CD112R (stable expression of human PD-1, human TIGIT, human CD112R and luc2P / NFAT-RE) were added at 1×10 per well. 5 The number of cells was added to the target cells and incubated in a 37°C incubator for 4-6 hours; finally, ONE-Glo luciferase detection reagent (Promega, cat#E6120) was added to the cell-antibody mixture system and the chemiluminescent signal was detected using a multifunctional microplate reader (TECAN M1000 pro).

[0681] Anti-TIGIT antibody (JS006): derived from the anti-TIGIT humanized antibody hu20 in PCT application number PCT / CN2020 / 101883;

[0682] Anti-PD-1 antibody (JS001): Teplizumab from Junshi Biosciences;

[0683] The positive control was COM701 (Compugen's anti-CD112R antibody, expressed and purified according to the US20180280506A1 sequence).

[0684] like Fig. 9 As shown in the dose-dependence curve, in the three-reporter gene system, the luciferase reporter gene NFAT signal of the anti-CD112R antibody hu16, hu52 and hu59 combined with anti-TIGIT antibody and anti-PD-1 antibody was significantly higher than that of the anti-PD-1 antibody monotherapy group and the anti-PD-1 antibody combined with 0.3μg / ml anti-TIGIT antibody group, indicating that the combination of anti-TIGIT antibody with anti-PD-1 antibody and anti-CD112R antibody has a significant synergistic effect.

[0685] Example 9. Pharmacodynamic evaluation of anti-CD112R antibody, anti-TIGIT antibody and their combination in human melanoma A375 mixed PBMC subcutaneous transplant tumor model

[0686] Experimental animals: 48 NCG mice, female, 6-8 weeks old, weighing about 18-22 g, purchased from Jiangsu Jicui Yaokang Biotechnology Co., Ltd.

[0687] Anti-TIGIT antibody (JS006): Derived from the anti-TIGIT humanized antibody hu20 in PCT application number PCT / CN2020 / 101883.

[0688] The anti-CD112R antibody is the humanized antibody hu52 described herein.

[0689] A375 cells were cultured in DMEM medium containing 10% fetal bovine serum (FBS). A375 cells in the logarithmic growth phase were collected and resuspended in HBSS (Hank's balanced salt solution) to a suitable concentration for subcutaneous tumor inoculation in NCG mice. The A375 cells used in the co-culture experiment were treated with Mitomycin C for 2 hours and then washed three times with PBS. The frozen PBMCs were taken, resuscitated and counted, and the obtained PBMCs were added to the A375 cells treated with Mitomycin C. The PBMCs were co-cultured with A375 for 5 days in RPMI 1640 medium containing IL-2 and 10% FBS. After 5 days of co-culture of PBMCs with A375, the PBMCs and freshly digested A375 cells were collected. PBMC 4×10 5 A375 cells 4×10 6 0.2 ml / mouse (containing 50% Matrigel) was inoculated subcutaneously on the right side of NCG mice. The day of inoculation was day 0, and mice were randomly divided into groups and given medication according to their body weight. The detailed administration method, dosage and route of administration are shown in Table 13.

[0690] Table 13. Dosage regimen

[0691]

[0692]

[0693] Note: N: number of animals used; ip: intraperitoneal injection; Q3D: administration once every three days. Administration volume: the administration volume (0.1 mL / 10 g) was adjusted according to the weight of the tumor-bearing mice.

[0694] After the experiment started, the tumor volume and mouse body weight were measured twice a week. The experimental results are shown in Tables 14 and Fig.10 .

[0695] Table 14. Average tumor volume of mice in each group (Mean ± SEM)

[0696]

[0697] Note: p<0.05 is considered to be significantly different; T / C (%) is the relative tumor proliferation rate, that is, the percentage of the tumor volume of the drug-treated group relative to the control group at a certain time point, T and C are the tumor volumes (TV) of the drug-treated group and the control group at a specific time point, respectively; Tumor growth inhibition rate TGI (%) = (1-T / C) × 100%.

[0698] At the end of the experiment (25 days after administration), compared with the control group, the anti-CD112R antibody hu52 at a dose level of 30 mg / kg significantly inhibited tumor growth, with a tumor growth inhibition rate of 37.68% (p<0.05); 30 mg / kg of anti-CD112R antibody hu52 combined with 30 mg / kg of JS006 showed significant synergistic anti-tumor effect, with a tumor growth inhibition rate of 58.30% (p<0.01). Sequence Listing <110> Shanghai Junshi Biopharmaceuticals Co., Ltd. Suzhou Junmeng Biopharmaceutical Technology Co., Ltd. <120> Anti-CD112R antibodies and uses thereof <130> 220885 1CNCN <150> CN 202110178859.1 <151> 2021-02-09 <160> 150 <170> PatentIn version 3.5 <210> 1 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> HCDR1 <400> 1 Asn Tyr Asn Ile His 1 5 <210> 2 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> HCDR2 <400> 2 Tyr Val Tyr Pro Tyr Asn Gly Val Pro Gly Tyr Asn Gln Lys Phe Lys 1 5 10 15 Ser <210> 3 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> HCDR3 <400> 3 Glu Arg Gly Arg Asp Tyr Phe Asp Ser 1 5 <210> 4 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> LCDR1 <400> 4 Arg Val Ser Ala Asn Ile Tyr Ser Asn Leu Val 1 5 10 <210> 5 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> LCDR2 <400> 5 Gly Gly Thr Asn Leu Ala Asp 1 5 <210> 6 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> LCDR3 <400> 6 Gln His Phe Trp Ser Thr Pro Tyr Thr 1 5 <210> 7 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> HCDR1 <400> 7 Ser His Tyr Met Tyr 1 5 <210> 8 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> HCDR2 <400> 8 Glu Ile Asn Pro Ser Asn Gly Asp Thr Lys Phe Asn Glu Lys Phe Lys 1 5 10 15 Ser <210> 9 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> HCDR3 <400> 9 Glu Lys Asp Ala Phe Ser Ala Leu Asp Tyr 1 5 10 <210> 10 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> LCDR1 <400> 10 Arg Ala Ser Gln Gly Ile Arg Gly His Leu Asp 1 5 10 <210> 11 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> LCDR2 <400> 11 Ser Thr Ser Ile Leu Asn Phe 1 5 <210> 12 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> LCDR3 <400> 12 Leu Gln Arg Asn Ala Tyr Pro Leu Thr 1 5 <210> 13 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> HCDR1 <400> 13 Ser Tyr His Met Ser 1 5 <210> 14 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> HCDR2 <400> 14 Ala Ile Asn Ser Asn Asp Ile Asn Thr Tyr Tyr Leu Asp Thr Val Lys 1 5 10 15 Gly <210> 15 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> HCDR3 <400> 15 His Glu Asp Tyr Tyr Gly Phe Ala Met Asp Tyr 1 5 10 <210> 16 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> HCDR1 <400> 16 Asp Tyr Phe Ile His 1 5 <210> 17 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> HCDR2 <400> 17 Trp Ile Ile Pro Ala Ser Gly Asp Thr Asp Cys Ala Pro Ile Phe Gln 1 5 10 15 Gly <210> 18 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> HCDR3 <400> 18 Trp Val Trp Ser Pro Tyr Ala Val Asp Tyr 1 5 10 <210> 19 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> LCDR1 <400> 19 Ser Ala Thr Ser Ser Ile Asn Tyr Met His 1 5 10 <210> 20 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> LCDR2 <400> 20 Asp Thr Ser Lys Leu Ala Ser 1 5 <210> 21 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> LCDR3 <400> 21 Gln Gln Trp Thr Ser Asn Pro Leu Thr 1 5 <210> 22 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> HCDR1 <400> 22 Asn Tyr Ile Met Ser 1 5 <210> 23 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> HCDR2 <400> 23 Thr Ile Ser Ser Gly Gly Ser Ser Thr Tyr Tyr Val Asp Arg Val Lys 1 5 10 15 Gly <210> 24 <211> 14 <212> PRT <213> Artificial Sequence <220> <223> HCDR3 <400> 24 His Glu Asp Trp Asp Pro Leu Tyr Tyr Tyr Ser Met Asp Tyr 1 5 10 <210> 25 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> LCDR1 <400> 25 Ser Ala Ser Ser Ser Val Ser Tyr Met Tyr 1 5 10 <210> 26 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> LCDR2 <400> 26 Asp Thr Ser His Leu Ala Phe 1 5 <210> 27 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> LCDR3 <400> 27 Gln Gln Trp Thr Thr Tyr Pro Leu Thr 1 5 <210> 28 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> HCDR1 <400> 28 Asp Tyr Phe Ile His 1 5 <210> 29 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> HCDR2 <400> 29 Trp Ile Ile Pro Ala Ser Gly Asp Thr Asp Cys Ala Pro Ile Phe Gln 1 5 10 15 Gly <210> 30 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> HCDR3 <400> 30 Trp Val Trp Ser Pro Tyr Ala Val Asp Tyr 1 5 10 <210> 31 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> LCDR1 <400> 31 Lys Ser Ser Gln Ser Leu Leu Asn Ser Gly Asn Gln Lys Asn Phe Leu 1 5 10 15 Ala <210> 32 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> LCDR2 <400> 32 Gly Ala Ser Thr Arg Glu Ser 1 5 <210> 33 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> LCDR3 <400> 33 Gln Asn Asp His Ser Tyr Pro Trp Thr 1 5 <210> 34 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> HCDR1 <400> 34 Asp Tyr Asn Met His 1 5 <210> 35 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> HCDR2 <400> 35 Tyr Ile Tyr Pro Tyr Asn Gly Gly Thr Gly His Asn Gln Asn Phe Lys 1 5 10 15 Ser <210> 36 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> HCDR3 <400> 36 Glu Asp Phe Arg His Glu Lys Met Asp Tyr 1 5 10 <210> 37 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> LCDR1 <400> 37 Arg Thr Ser Asp Asn Ile Tyr Val Tyr Leu Ser 1 5 10 <210> 38 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> LCDR2 <400> 38 Asn Ala Lys Thr Leu Thr Glu 1 5 <210> 39 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> LCDR3 <400> 39 Gln His His Tyr Gly Thr Pro Tyr Thr 1 5 <210> 40 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> HCDR1 <400> 40 Ser Tyr His Met Ser 1 5 <210> 41 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> HCDR2 <400> 41 Ala Ile Ser Arg Asp Gly Asp Ser Thr Tyr Tyr Pro Asp Thr Val Lys 1 5 10 15 Gly <210> 42 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> HCDR3 <400> 42 His Glu Asp Tyr Phe Gly Phe Ala Met Asp Ser 1 5 10 <210> 43 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> LCDR1 <400> 43 Lys Ala Ser Gln Ser Val Thr Asn Asp Val Ala 1 5 10 <210> 44 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> LCDR2 <400> 44 Tyr Val Ser Asn His Tyr Thr 1 5 <210> 45 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> LCDR3 <400> 45 Gln Gln Ala Tyr Arg Ser Pro Trp Thr 1 5 <210> 46 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> LCDR1 <400> 46 Arg Ser Ser Gln Ser Ile Val His Ser Asn Gly Asn Thr Tyr Leu His 1 5 10 15 <210> 47 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> LCDR2 <400> 47 Lys Val Ser Asn Arg Phe Ser 1 5 <210> 48 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> LCDR3 <400> 48 Phe Gln Gly Ser His Val Pro Trp Thr 1 5 <210> 49 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> HCDR1 <400> 49 Ser Tyr His Met Ser 1 5 <210> 50 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> HCDR2 <400> 50 Ala Ile Asn Ser Asn Val Ile Ser Thr Tyr Tyr Leu Asp Thr Val Lys 1 5 10 15 Gly <210> 51 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> HCDR3 <400> 51 His Glu Asp Tyr Tyr Gly Phe Ala Met Asp Tyr 1 5 10 <210> 52 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> LCDR1 <400> 52 Lys Ala Ser Gln Ser Val Ser Asn Asp Val Ala 1 5 10 <210> 53 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> LCDR2 <400> 53 Tyr Val Ser His Arg Phe Thr 1 5 <210> 54 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> LCDR3 <400> 54 His Gln Ala Tyr Arg Ser Pro Trp Thr 1 5 <210> 55 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> HCDR1 <400> 55 Asp Tyr Asn Met Asn 1 5 <210> 56 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> HCDR2 <400> 56 Tyr Ile Tyr Pro Tyr Asn Gly Gly Ala Gly Tyr Asn Gln Asn Phe Lys 1 5 10 15 Asn <210> 57 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> HCDR3 <400> 57 Glu Arg Gly Met Gln Arg Asp Tyr Phe Asp Tyr 1 5 10 <210> 58 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> LCDR1 <400> 58 Arg Thr Ser Glu Asn Ile Tyr Ser Asn Leu Ala 1 5 10 <210> 59 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> LCDR2 <400> 59 Ala Ala Thr Asn Leu Ala Asp 1 5 <210> 60 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> LCDR3 <400> 60 Gln His Phe Trp Gly Thr Pro Tyr Thr 1 5 <210> 61 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> HCDR1 <400> 61 Asp Tyr Asn Ile His 1 5 <210> 62 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> HCDR2 <400> 62 Tyr Asn Tyr Pro Tyr Asn Gly Gly Ala Gly Tyr Asn Gln Asn Phe Arg 1 5 10 15 Ser <210> 63 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> HCDR3 <400> 63 Gly Glu Glu Val Arg Arg Gly Pro Phe Tyr Phe 1 5 10 <210> 64 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> LCDR1 <400> 64 Arg Thr Ser Glu Asn Ile Tyr Ser Phe Leu Val 1 5 10 <210> 65 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> LCDR2 <400> 65 Asn Ala Lys Thr Leu Ala Glu 1 5 <210> 66 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> LCDR3 <400> 66 Gln His Tyr Tyr Gly Thr Pro Tyr Thr 1 5 <210> 67 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> HCDR1 <400> 67 Ser Tyr His Met Ser 1 5 <210> 68 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> HCDR2 <400> 68 Ala Ile Asn Ser Asn Gly Ile Asn Thr Tyr Tyr Leu Asp Thr Val Lys 1 5 10 15 Gly <210> 69 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> HCDR3 <400> 69 His Glu Asp Tyr Tyr Gly Phe Ala Met Asp Tyr 1 5 10 <210> 70 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> LCDR1 <400> 70 Lys Ala Ser Gln Ser Val Ser Asn Asp Val Ala 1 5 10 <210> 71 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> LCDR2 <400> 71 Tyr Val Ser Asn Arg Phe Thr 1 5 <210> 72 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> LCDR3 <400> 72 Gln Gln Ala Tyr Arg Ser Pro Trp Thr 1 5 <210> 73 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> HCDR1 <400> 73 Asp Tyr Ser Met His 1 5 <210> 74 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> HCDR2 <400> 74 Trp Ile Ser Thr Glu Thr Ala Gln Pro Thr Tyr Ala Asp Asp Phe Arg 1 5 10 15 Gly <210> 75 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> HCDR3 <400> 75 Thr Gly Asn Tyr Gly Trp Tyr Phe Ser Val 1 5 10 <210> 76 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> LCDR1 <400> 76 Arg Ala Thr Ser Gly Val Ser Ser Ser Tyr Leu Phe 1 5 10 <210> 77 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> LCDR2 <400> 77 Ser Thr Ser Asn Leu Ala Ser 1 5 <210> 78 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> LCDR3 <400> 78 Gln Gln Tyr Ser Gly Tyr Pro Tyr Thr 1 5 <210> 79 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> HCDR1 <400> 79 Asp Tyr Pro Met Ser 1 5 <210> 80 <211> 16 <212> PRT <213> Artificial Sequence <220> <223> HCDR2 <400> 80 Cys Ile Asp Thr Asp Glu Asn Thr Tyr Tyr Pro Asp Ser Val Lys Gly 1 5 10 15 <210> 81 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> HCR3 <400> 81 Gly Trp Asp Asp Tyr Ala Ala Trp Phe Ala Tyr 1 5 10 <210> 82 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> LCDR1 <400> 82 Arg Ala Ser Ser Ser Val Asn Tyr Met Tyr 1 5 10 <210> 83 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> LCDR2 <400> 83 His Thr Ser Asn Leu Ala Pro 1 5 <210> 84 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> LCDR3 <400> 84 Gln Gln Phe Thr Ser Ser Pro Trp Thr 1 5 <210> 85 <211> 118 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 85 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Pro Phe Ile Asn Tyr 20 25 30 Asn Ile His Trp Leu Arg Gln Ser Arg Gly Lys Ser Leu Glu Trp Ile 35 40 45 Gly Tyr Val Tyr Pro Tyr Asn Gly Val Pro Gly Tyr Asn Gln Lys Phe 50 55 60 Lys Ser Lys Ala Thr Leu Thr Ala Asp Asn Ser Phe Ser Thr Ala Tyr 65 70 75 80 Met Glu Phe Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Phe Cys 85 90 95 Ala Arg Glu Arg Gly Arg Asp Tyr Phe Asp Ser Trp Gly Gln Gly Thr 100 105 110 Ser Leu Thr Val Ser Ser 115 <210> 86 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 86 Asp Ile Gln Leu Thr Gln Ser Pro Ala Ser Leu Ser Val Ser Val Gly 1 5 10 15 Glu Thr Val Thr Ile Thr Cys Arg Val Ser Ala Asn Ile Tyr Ser Asn 20 25 30 Leu Val Trp Tyr His Gln Arg Gln Gly Lys Ser Pro Gln Leu Leu Val 35 40 45 Tyr Gly Gly Thr Asn Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Gln Phe Ser Leu Lys Ile Asn Ser Leu Gln Ser 65 70 75 80 Glu Asp Phe Gly Ser Tyr His Cys Gln His Phe Trp Ser Thr Pro Tyr 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 87 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 87 Gln Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Leu Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser His 20 25 30 Tyr Met Tyr Trp Leu Lys Gln Arg Pro Gly Gln Gly Leu Glu Trp Ile 35 40 45 Gly Glu Ile Asn Pro Ser Asn Gly Asp Thr Lys Phe Asn Glu Lys Phe 50 55 60 Lys Ser Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Gln Leu Ser Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Thr Arg Glu Lys Asp Ala Phe Ser Ala Leu Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Ser Val Thr Asp Ser Ser 115 <210> 88 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 88 Asp Ile Gln Met Ile Gln Ser Pro Ser Ser Met Phe Ala Ser Leu Gly 1 5 10 15 Asp Arg Val Ser Leu Ser Cys Arg Ala Ser Gln Gly Ile Arg Gly His 20 25 30 Leu Asp Trp Tyr Gln Gln Lys Pro Gly Gly Thr Ile Lys Leu Leu Ile 35 40 45 Tyr Ser Thr Ser Ile Leu Asn Phe Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Ser Asp Tyr Ser Leu Thr Ile Ser Ser Leu Glu Ser 65 70 75 80 Glu Asp Phe Ala Asp Tyr Tyr Cys Leu Gln Arg Asn Ala Tyr Pro Leu 85 90 95 Thr Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys 100 105 <210> 89 <211> 120 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 89 Asp Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Leu Gly Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Val Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 His Met Ser Trp Ile Arg Gln Thr Pro Glu Lys Arg Leu Glu Leu Val 35 40 45 Ala Ala Ile Asn Ser Asn Asp Ile Asn Thr Tyr Tyr Leu Asp Thr Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Ile Ala Lys Asn Thr Leu His 65 70 75 80 Leu Gln Met Ser Ser Leu Lys Ser Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Arg His Glu Asp Tyr Tyr Gly Phe Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Ser Val Thr Val Ser Ser 115 120 <210> 90 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 90 Asp Ile Gln Leu Thr Gln Ser Pro Ala Ser Leu Ser Val Ser Val Gly 1 5 10 15 Glu Thr Val Thr Ile Thr Cys Arg Val Ser Ala Asn Ile Tyr Ser Asn 20 25 30 Leu Val Trp Tyr His Gln Arg Gln Gly Lys Ser Pro Gln Leu Leu Val 35 40 45 Tyr Gly Gly Thr Asn Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Gln Phe Ser Leu Lys Ile Asn Ser Leu Gln Ser 65 70 75 80 Glu Asp Phe Gly Ser Tyr His Cys Gln His Phe Trp Ser Thr Pro Tyr 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 91 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 91 Glu Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Ser Gly Thr 1 5 10 15 Ser Val Thr Leu Ser Cys Thr Ala Ser Gly Phe Asn Ile Arg Asp Tyr 20 25 30 Phe Ile His Trp Val Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile 35 40 45 Gly Trp Ile Ile Pro Ala Ser Gly Asp Thr Asp Cys Ala Pro Ile Phe 50 55 60 Gln Gly Lys Ala Thr Leu Thr Ala Asp Thr Phe Ser Asn Thr Ala Tyr 65 70 75 80 Leu His Leu Asn Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Asn Thr Trp Val Trp Ser Pro Tyr Ala Val Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Ser Val Thr Val Ser Ser 115 <210> 92 <211> 106 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 92 Gln Ile Val Leu Thr Gln Ser Pro Ala Ile Met Ser Val Ser Pro Gly 1 5 10 15 Glu Lys Val Thr Met Thr Cys Ser Ala Thr Ser Ser Ile Asn Tyr Met 20 25 30 His Trp Tyr Gln Gln Lys Ser Gly Thr Ser Pro Lys Arg Trp Ile Tyr 35 40 45 Asp Thr Ser Lys Leu Ala Ser Gly Val Pro Ala Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Asn Met Glu Ala Glu 65 70 75 80 Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Trp Thr Ser Asn Pro Leu Thr 85 90 95 Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys 100 105 <210> 93 <211> 123 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 93 Glu Val Met Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30 Ile Met Ser Trp Val Arg Gln Thr Pro Asp Met Arg Leu Glu Trp Val 35 40 45 Ala Thr Ile Ser Ser Gly Gly Ser Ser Thr Tyr Tyr Val Asp Arg Val 50 55 60 Lys Gly Gly Phe Pro Phe Ser Arg Asp Ser Val Lys Tyr Ile Leu Tyr 65 70 75 80 Val His Thr Ser Ser Leu Arg Ser Ala Asp Thr Ala Ile Tyr Tyr Cys 85 90 95 Ala Lys His Glu Asp Trp Asp Pro Leu Tyr Tyr Tyr Ser Met Asp Tyr 100 105 110 Trp Gly Gln Gly Thr Ser Val Thr Val Ser Ser 115 120 <210> 94 <211> 106 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 94 Gln Ile Val Leu Thr Gln Ser Pro Thr Val Met Ser Ala Ser Pro Gly 1 5 10 15 Asp Lys Val Thr Met Thr Cys Ser Ala Ser Ser Ser Val Ser Tyr Met 20 25 30 Tyr Trp Phe Gln Gln Lys Pro Gly Ser Ser Pro Arg Leu Leu Ile Tyr 35 40 45 Asp Thr Ser His Leu Ala Phe Gly Val Pro Ser Arg Phe Ser Gly Ser 50 55 60 Arg Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Arg Met Glu Ala Glu 65 70 75 80 Asp Thr Ala Thr Tyr Tyr Cys Gln Gln Trp Thr Thr Tyr Pro Leu Thr 85 90 95 Phe Gly Ala Gly Thr Lys Leu Glu Leu Lys 100 105 <210> 95 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 95 Glu Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Ser Gly Thr 1 5 10 15 Ser Val Thr Leu Ser Cys Thr Ala Ser Gly Phe Asn Ile Arg Asp Tyr 20 25 30 Phe Ile His Trp Val Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile 35 40 45 Gly Trp Ile Ile Pro Ala Ser Gly Asp Thr Asp Cys Ala Pro Ile Phe 50 55 60 Gln Gly Lys Ala Thr Leu Thr Ala Asp Thr Phe Ser Asn Thr Ala Tyr 65 70 75 80 Leu His Leu Asn Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Asn Thr Trp Val Trp Ser Pro Tyr Ala Val Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Ser Val Thr Val Ser Ser 115 <210> 96 <211> 113 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 96 Asp Ile Val Met Thr Gln Phe Pro Ser Ser Leu Ser Val Pro Val Gly 1 5 10 15 Glu Lys Val Thr Met Asn Cys Lys Ser Ser Gln Ser Leu Leu Asn Ser 20 25 30 Gly Asn Gln Lys Asn Phe Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu Ile Tyr Gly Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Tyr Arg Phe Thr Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Val Gln Ala Glu Asp Leu Ala Val Tyr Tyr Cys Gln Asn 85 90 95 Asp His Ser Tyr Pro Trp Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile 100 105 110 Lys <210> 97 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 97 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Arg Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Asn Met His Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile 35 40 45 Gly Tyr Ile Tyr Pro Tyr Asn Gly Gly Thr Gly His Asn Gln Asn Phe 50 55 60 Lys Ser Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Phe Arg Ser Leu Thr Ser Asp Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Asp Phe Arg His Glu Lys Met Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Ser Val Thr Val Ser Ser 115 <210> 98 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 98 Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Glu Thr Val Thr Ile Thr Cys Arg Thr Ser Asp Asn Ile Tyr Val Tyr 20 25 30 Leu Ser Trp Tyr Gln Gln Lys Gln Gly Lys Ser Pro Gln Leu Leu Val 35 40 45 Tyr Asn Ala Lys Thr Leu Thr Glu Asn Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Gln Phe Ser Leu Lys Ile Asn Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Gly Ser Tyr Tyr Cys Gln His His Tyr Gly Thr Pro Tyr 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 99 <211> 120 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 99 Asp Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Lys Leu Gly Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 His Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu Glu Leu Val 35 40 45 Ala Ala Ile Ser Arg Asp Gly Asp Ser Thr Tyr Tyr Pro Asp Thr Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ala Glu Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Ser Ser Leu Lys Ser Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ser Arg His Glu Asp Tyr Phe Gly Phe Ala Met Asp Ser Trp Gly Gln 100 105 110 Gly Thr Ser Val Thr Val Ser Ser 115 120 <210> 100 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 100 Ser Ile Val Met Thr Gln Thr Pro Lys Phe Leu Leu Val Ser Ala Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Ser Val Thr Asn Asp 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Met 35 40 45 Tyr Tyr Val Ser Asn His Tyr Thr Gly Val Pro Asp Arg Phe Ile Gly 50 55 60 Ser Gly Tyr Gly Thr Asp Phe Thr Phe Thr Ile Ser Thr Val Gln Ala 65 70 75 80 Glu Asp Leu Ala Val Tyr Phe Cys Gln Gln Ala Tyr Arg Ser Pro Trp 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 101 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 101 Glu Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Arg Ser Gly Thr 1 5 10 15 Ser Val Thr Leu Ser Cys Thr Ala Ser Gly Phe Asn Ile Arg Asp Tyr 20 25 30 Phe Ile His Trp Val Lys Gln Arg Pro Glu Gln Gly Leu Glu Trp Ile 35 40 45 Gly Trp Ile Ile Pro Ala Ser Gly Asp Thr Asp Cys Ala Pro Ile Phe 50 55 60 Gln Gly Lys Ala Thr Leu Thr Ala Asp Thr Phe Ser Asn Thr Ala Tyr 65 70 75 80 Leu His Leu Asn Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Asn Thr Trp Val Trp Ser Pro Tyr Ala Val Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Ser Val Thr Val Ser Ser 115 <210> 102 <211> 112 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 102 Asp Val Leu Met Thr Gln Thr Pro Leu Ser Leu Pro Val Ser Leu Gly 1 5 10 15 Asp Gln Thr Ser Ile Ser Cys Arg Ser Ser Gln Ser Ile Val His Ser 20 25 30 Asn Gly Asn Thr Tyr Leu His Trp Tyr Leu Gln Lys Pro Gly Gln Ser 35 40 45 Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro 50 55 60 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile 65 70 75 80 Ser Arg Val Glu Ala Glu Asp Leu Gly Val Tyr Tyr Cys Phe Gln Gly 85 90 95 Ser His Val Pro Trp Thr Phe Gly Gly Gly Thr Arg Leu Glu Ile Lys 100 105 110 <210> 103 <211> 120 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 103 Asp Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Lys Leu Gly Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 His Met Ser Trp Val Arg Gln Thr Pro Glu Lys Arg Leu Glu Leu Val 35 40 45 Ala Ala Ile Asn Ser Asn Val Ile Ser Thr Tyr Tyr Leu Asp Thr Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Ser Ser Leu Lys Ser Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Arg His Glu Asp Tyr Tyr Gly Phe Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Ser Val Thr Val Ser Ser 115 120 <210> 104 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 104 Ser Ile Val Met Thr Gln Thr Pro Lys Phe Leu Leu Val Ser Ala Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Ser Val Ser Asn Asp 20 25 30 Val Ala Trp Tyr Gln Glu Lys Pro Gly Gln Ser Pro Lys Leu Leu Met 35 40 45 Tyr Tyr Val Ser His Arg Phe Thr Gly Val Pro Asp Arg Phe Thr Gly 50 55 60 Ser Gly Tyr Gly Thr Asp Phe Thr Phe Thr Ile Asn Thr Val Gln Ala 65 70 75 80 Glu Asp Leu Ala Val Tyr Phe Cys His Gln Ala Tyr Arg Ser Pro Trp 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 105 <211> 120 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 105 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Arg Pro Gly Ala 1 5 10 15 Ser Val Arg Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Asn Met Asn Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile 35 40 45 Gly Tyr Ile Tyr Pro Tyr Asn Gly Gly Ala Gly Tyr Asn Gln Asn Phe 50 55 60 Lys Asn Lys Ala Thr Leu Thr Val Asp Thr Tyr Ser Arg Ala Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Glu Arg Gly Met Gln Arg Asp Tyr Phe Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Ile Leu Thr Val Ser Ser 115 120 <210> 106 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 106 Asp Ile Gln Met Thr Gln Ser Pro Ala Ser Leu Ser Val Ser Val Gly 1 5 10 15 Glu Thr Val Thr Ile Thr Cys Arg Thr Ser Glu Asn Ile Tyr Ser Asn 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Gln Gly Lys Ser Pro Gln Leu Leu Val 35 40 45 Tyr Ala Ala Thr Asn Leu Ala Asp Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Gln Phe Ser Leu Lys Ile Asn Ser Leu Gln Ser 65 70 75 80 Gly Asp Phe Gly Ser Tyr Phe Cys Gln His Phe Trp Gly Thr Pro Tyr 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 107 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 107 Glu Val Gln Leu Gln Gln Ser Gly Pro Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Asn Ile His Trp Val Lys Gln Ser His Gly Lys Arg Pro Asp Trp Ile 35 40 45 Gly Tyr Asn Tyr Pro Tyr Asn Gly Gly Ala Gly Tyr Asn Gln Asn Phe 50 55 60 Arg Ser Arg Ala Thr Leu Thr Val Asp Lys Phe Ser Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Ser Ala Val Tyr Tyr Cys 85 90 95 Ala Gly Glu Glu Val Arg Arg Gly Pro Phe Tyr Phe Trp Gly Gln Gly 100 105 110 Thr Ser Val Thr Val Ser Ser 115 <210> 108 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 108 Asp Ile Gln Met Thr Gln Ser Pro Asp Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Glu Thr Val Thr Ile Thr Cys Arg Thr Ser Glu Asn Ile Tyr Ser Phe 20 25 30 Leu Val Trp Tyr Gln Gln Lys Gln Gly Lys Ser Pro Gln Leu Leu Val 35 40 45 Tyr Asn Ala Lys Thr Leu Ala Glu Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Gln Phe Ser Leu Lys Ile Asn Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Gly Thr Tyr Tyr Cys Gln His Tyr Tyr Gly Thr Pro Tyr 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 109 <211> 120 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 109 Asp Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Lys Leu Gly Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 His Met Ser Trp Ile Arg Gln Thr Pro Glu Lys Arg Leu Glu Leu Val 35 40 45 Ala Ala Ile Asn Ser Asn Gly Ile Asn Thr Tyr Tyr Leu Asp Thr Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Ser Ser Leu Lys Ser Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Arg His Glu Asp Tyr Tyr Gly Phe Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Ser Val Thr Val Ser Ser 115 120 <210> 110 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 110 Ser Ile Val Met Thr Gln Thr Pro Lys Phe Leu Leu Val Ser Ala Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Ser Val Ser Asn Asp 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ser Pro Lys Leu Leu Met 35 40 45 Tyr Tyr Val Ser Asn Arg Phe Thr Gly Val Pro Asp Arg Phe Thr Gly 50 55 60 Ser Gly Tyr Gly Thr Asp Phe Thr Phe Thr Ile Asn Thr Val Gln Ala 65 70 75 80 Glu Asp Leu Ala Val Tyr Phe Cys Gln Gln Ala Tyr Arg Ser Pro Trp 85 90 95 Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 111 <211> 118 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 111 Gln Ile Gln Leu Val Gln Ser Gly Pro Glu Leu Lys Lys Pro Gly Glu 1 5 10 15 Thr Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Ser Met His Trp Val Lys Gln Ala Pro Gly Lys Gly Leu Lys Trp Val 35 40 45 Gly Trp Ile Ser Thr Glu Thr Ala Gln Pro Thr Tyr Ala Asp Asp Phe 50 55 60 Arg Gly Arg Phe Ala Phe Ser Leu Glu Thr Ser Ala Ser Thr Ala Tyr 65 70 75 80 Leu Gln Ile Asn Asn Leu Arg Asn Glu Asp Thr Ala Thr Tyr Phe Cys 85 90 95 Ala Thr Gly Asn Tyr Gly Trp Tyr Phe Ser Val Trp Gly Ala Gly Thr 100 105 110 Thr Val Thr Val Ser Ser 115 <210> 112 <211> 108 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 112 Glu Asn Val Leu Thr Gln Ser Pro Ala Ile Met Ser Ala Ser Pro Gly 1 5 10 15 Glu Lys Val Thr Met Thr Cys Arg Ala Thr Ser Gly Val Ser Ser Ser 20 25 30 Tyr Leu Phe Trp Tyr Gln Gln Lys Ser Gly Ala Ser Pro Lys Ile Trp 35 40 45 Ile Tyr Ser Thr Ser Asn Leu Ala Ser Gly Val Pro Thr Arg Phe Ser 50 55 60 Gly Ser Gly Ser Gly Thr Ser Tyr Ser Leu Thr Ile Ser Ser Val Glu 65 70 75 80 Ala Glu Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Tyr Ser Gly Tyr Pro 85 90 95 Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 113 <211> 119 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 113 Glu Val Lys Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Lys Val Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Pro Met Ser Trp Val Arg Gln Thr Pro Asp Lys Arg Leu Glu Trp Val 35 40 45 Ala Cys Ile Asp Thr Asp Glu Asn Thr Tyr Tyr Pro Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Gly Arg Asn Ile Val Asn Leu 65 70 75 80 Gln Met Ser Ser Leu Arg Ser Glu Asp Ala Ala Met Tyr Tyr Cys Ala 85 90 95 Arg Gly Trp Asp Asp Tyr Ala Ala Trp Phe Ala Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val Thr Val Ser Ala 115 <210> 114 <211> 106 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 114 Glu Asn Val Leu Thr Gln Phe Pro Ala Ile Met Ser Val Phe Leu Gly 1 5 10 15 Glu Arg Val Thr Met Ser Cys Arg Ala Ser Ser Ser Val Asn Tyr Met 20 25 30 Tyr Trp Tyr Gln Gln Lys Ser Asp Ala Ser Pro Lys Leu Trp Ile Tyr 35 40 45 His Thr Ser Asn Leu Ala Pro Gly Val Pro Ala Arg Phe Ser Gly Ser 50 55 60 Gly Ser Gly Asn Ser Tyr Ser Leu Thr Ile Ser Ser Met Glu Gly Glu 65 70 75 80 Asp Ala Ala Thr Tyr Tyr Cys Gln Gln Phe Thr Ser Ser Pro Trp Thr 85 90 95 Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 115 <211> 120 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 115 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 His Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Leu Val 35 40 45 Ala Ala Ile Asn Ser Asn Asp Ile Asn Thr Tyr Tyr Leu Asp Thr Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Ile Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg His Glu Asp Tyr Tyr Gly Phe Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 116 <211> 120 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 116 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 His Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Leu Val 35 40 45 Ser Ala Ile Asn Ser Asn Asp Ile Asn Thr Tyr Tyr Leu Asp Thr Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Ile Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg His Glu Asp Tyr Tyr Gly Phe Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 117 <211> 120 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 117 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 His Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Leu Val 35 40 45 Ser Ala Ile Asn Ser Asn Asp Ile Asn Thr Tyr Tyr Leu Asp Thr Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg His Glu Asp Tyr Tyr Gly Phe Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 118 <211> 120 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 118 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 His Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Leu Val 35 40 45 Ser Ala Ile Ser Arg Asp Gly Asp Ser Thr Tyr Tyr Pro Asp Thr Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg His Glu Asp Tyr Phe Gly Phe Ala Met Asp Ser Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 119 <211> 120 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 119 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 His Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Leu Val 35 40 45 Ser Ala Ile Ser Arg Asp Gly Asp Ser Thr Tyr Tyr Pro Asp Thr Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ala Glu Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg His Glu Asp Tyr Phe Gly Phe Ala Met Asp Ser Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 120 <211> 120 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 120 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 His Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Leu Val 35 40 45 Ala Ala Ile Ser Arg Asp Gly Asp Ser Thr Tyr Tyr Pro Asp Thr Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg His Glu Asp Tyr Phe Gly Phe Ala Met Asp Ser Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 121 <211> 120 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 121 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 His Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Leu Val 35 40 45 Ala Ala Ile Ser Arg Asp Gly Asp Ser Thr Tyr Tyr Pro Asp Thr Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ala Glu Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg His Glu Asp Tyr Phe Gly Phe Ala Met Asp Ser Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 122 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 122 Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Lys Ala Ser Gln Ser Val Thr Asn Asp 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile 35 40 45 Tyr Tyr Val Ser Asn His Tyr Thr Gly Val Pro Asp Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala 65 70 75 80 Glu Asp Val Ala Val Tyr Phe Cys Gln Gln Ala Tyr Arg Ser Pro Trp 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 123 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 123 Ala Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Ser Val Thr Asn Asp 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Tyr Val Ser Asn His Tyr Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Phe Cys Gln Gln Ala Tyr Arg Ser Pro Trp 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 124 <211> 120 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 124 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 His Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Leu Val 35 40 45 Ser Ala Ile Asn Ser Asn Val Ile Ser Thr Tyr Tyr Leu Asp Thr Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg His Glu Asp Tyr Tyr Gly Phe Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 125 <211> 120 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 125 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 His Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Leu Val 35 40 45 Ser Ala Ile Asn Ser Asn Val Ile Ser Thr Tyr Tyr Leu Asp Thr Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg His Glu Asp Tyr Tyr Gly Phe Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 126 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 126 Glu Ile Val Met Thr Gln Ser Pro Pro Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Val Thr Leu Ser Cys Lys Ala Ser Gln Ser Val Ser Asn Asp 20 25 30 Val Ala Trp Tyr Gln Glu Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Tyr Val Ser His Arg Phe Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Val Tyr Tyr Cys His Gln Ala Tyr Arg Ser Pro Trp 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 127 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 127 Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Lys Ala Ser Gln Ser Val Ser Asn Asp 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile 35 40 45 Tyr Tyr Val Ser His Arg Phe Thr Gly Val Pro Asp Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala 65 70 75 80 Glu Asp Val Ala Val Tyr Phe Cys His Gln Ala Tyr Arg Ser Pro Trp 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 128 <211> 120 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 128 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 His Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Leu Val 35 40 45 Ser Ala Ile Asn Ser Asn Gly Ile Asn Thr Tyr Tyr Leu Asp Thr Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg His Glu Asp Tyr Tyr Gly Phe Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 129 <211> 120 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 129 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 His Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Leu Val 35 40 45 Ala Ala Ile Asn Ser Asn Gly Ile Asn Thr Tyr Tyr Leu Asp Thr Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg His Glu Asp Tyr Tyr Gly Phe Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 130 <211> 120 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 130 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 His Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Leu Val 35 40 45 Ala Ala Ile Asn Ser Asn Asp Ile Asn Thr Tyr Tyr Leu Asp Thr Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg His Glu Asp Tyr Tyr Gly Phe Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser 115 120 <210> 131 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 131 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Ser Val Ser Asn Asp 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Tyr Val Ser Asn Arg Phe Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Phe Cys Gln Gln Ala Tyr Arg Ser Pro Trp 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 132 <211> 107 <212> PRT <213> Artificial Sequence <220> <223> VL <400> 132 Glu Ile Val Met Thr Gln Ser Pro Pro Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Val Thr Leu Ser Cys Lys Ala Ser Gln Ser Val Ser Asn Asp 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Tyr Val Ser Asn Arg Phe Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Val Tyr Phe Cys Gln Gln Ala Tyr Arg Ser Pro Trp 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys 100 105 <210> 133 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> LC <400> 133 Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Lys Ala Ser Gln Ser Val Ser Asn Asp 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile 35 40 45 Tyr Tyr Val Ser His Arg Phe Thr Gly Val Pro Asp Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala 65 70 75 80 Glu Asp Val Ala Val Tyr Phe Cys His Gln Ala Tyr Arg Ser Pro Trp 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 134 <211> 447 <212> PRT <213> Artificial Sequence <220> <223> HC <400> 134 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 His Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Leu Val 35 40 45 Ser Ala Ile Ser Arg Asp Gly Asp Ser Thr Tyr Tyr Pro Asp Thr Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg His Glu Asp Tyr Phe Gly Phe Ala Met Asp Ser Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro 210 215 220 Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser 290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys 435 440 445 <210> 135 <211> 450 <212> PRT <213> Artificial Sequence <220> <223> HC <400> 135 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 His Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Leu Val 35 40 45 Ser Ala Ile Ser Arg Asp Gly Asp Ser Thr Tyr Tyr Pro Asp Thr Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ser Arg His Glu Asp Tyr Phe Gly Phe Ala Met Asp Ser Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp 210 215 220 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 225 230 235 240 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 245 250 255 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 260 265 270 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 275 280 285 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 290 295 300 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 305 310 315 320 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 325 330 335 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 340 345 350 Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu 355 360 365 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 370 375 380 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 385 390 395 400 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 405 410 415 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 420 425 430 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 435 440 445 Gly Lys 450 <210> 136 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> LC <400> 136 Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Lys Ala Ser Gln Ser Val Ser Asn Asp 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro Lys Leu Leu Ile 35 40 45 Tyr Tyr Val Ser His Arg Phe Thr Gly Val Pro Asp Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala 65 70 75 80 Glu Asp Val Ala Val Tyr Phe Cys His Gln Ala Tyr Arg Ser Pro Trp 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 137 <211> 447 <212> PRT <213> Artificial Sequence <220> <223> HC <400> 137 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 His Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Leu Val 35 40 45 Ser Ala Ile Asn Ser Asn Gly Ile Asn Thr Tyr Tyr Leu Asp Thr Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg His Glu Asp Tyr Tyr Gly Phe Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro 210 215 220 Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser 290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys 435 440 445 <210> 138 <211> 450 <212> PRT <213> Artificial Sequence <220> <223> HC <400> 138 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 His Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Leu Val 35 40 45 Ser Ala Ile Asn Ser Asn Gly Ile Asn Thr Tyr Tyr Leu Asp Thr Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg His Glu Asp Tyr Tyr Gly Phe Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp 210 215 220 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 225 230 235 240 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 245 250 255 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 260 265 270 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 275 280 285 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 290 295 300 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 305 310 315 320 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 325 330 335 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 340 345 350 Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu 355 360 365 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 370 375 380 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 385 390 395 400 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 405 410 415 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 420 425 430 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 435 440 445 Gly Lys 450 <210> 139 <211> 214 <212> PRT <213> Artificial Sequence <220> <223> LC <400> 139 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Ser Val Ser Asn Asp 20 25 30 Val Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Tyr Val Ser Asn Arg Phe Thr Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Phe Cys Gln Gln Ala Tyr Arg Ser Pro Trp 85 90 95 Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala 100 105 110 Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly 115 120 125 Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala 130 135 140 Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln 145 150 155 160 Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser 165 170 175 Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr 180 185 190 Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser 195 200 205 Phe Asn Arg Gly Glu Cys 210 <210> 140 <211> 447 <212> PRT <213> Artificial Sequence <220> <223> HC <400> 140 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 His Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Leu Val 35 40 45 Ala Ala Ile Asn Ser Asn Gly Ile Asn Thr Tyr Tyr Leu Asp Thr Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg His Glu Asp Tyr Tyr Gly Phe Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro 210 215 220 Pro Cys Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val 225 230 235 240 Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 245 250 255 Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu 260 265 270 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 275 280 285 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser 290 295 300 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys 305 310 315 320 Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile 325 330 335 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 340 345 350 Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 355 360 365 Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 370 375 380 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 385 390 395 400 Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg 405 410 415 Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 420 425 430 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Leu Gly Lys 435 440 445 <210> 141 <211> 450 <212> PRT <213> Artificial Sequence <220> <223> HC <400> 141 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 His Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Leu Val 35 40 45 Ala Ala Ile Asn Ser Asn Gly Ile Asn Thr Tyr Tyr Leu Asp Thr Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg His Glu Asp Tyr Tyr Gly Phe Ala Met Asp Tyr Trp Gly Gln 100 105 110 Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 115 120 125 Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala 130 135 140 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 145 150 155 160 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 165 170 175 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro 180 185 190 Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys 195 200 205 Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp 210 215 220 Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly 225 230 235 240 Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 245 250 255 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 260 265 270 Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 275 280 285 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg 290 295 300 Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys 305 310 315 320 Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu 325 330 335 Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 340 345 350 Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser Leu 355 360 365 Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 370 375 380 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val 385 390 395 400 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 405 410 415 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His 420 425 430 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro 435 440 445 Gly Lys 450 <210> 142 <211> 121 <212> PRT <213> Artificial Sequence <220> <223> VH <400> 142 Glu Val Gln Leu Gln Gln Ser Gly Ala Glu Leu Val Lys Pro Gly Ala 1 5 10 15 Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Asp Tyr 20 25 30 Asn Met Asp Trp Val Lys Gln Ser His Gly Lys Ser Leu Glu Trp Ile 35 40 45 Gly Asp Ile His Pro Lys Tyr Asp Arg Thr Ser Tyr Asn Gln Asn Phe 50 55 60 Lys Gly Lys Ala Thr Leu Thr Val Asp Lys Ser Ser Arg Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Thr Ser Glu Asp Thr Ala Val Tyr Phe Cys 85 90 95 Val Arg Ile Asn Asp Phe Asp Glu Gly Phe Ala Met Asp Tyr Trp Gly 100 105 110 Gln Gly Thr Ser Val Thr Val Ser Ser 115 120 <210> 143 <211> 5 <212> PRT <213> Artificial Sequence <220> <223> HCDR1 <400> 143 Asp Tyr Asn Met Asp 1 5 <210> 144 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> HCDR2 <400> 144 Asp Ile His Pro Lys Tyr Asp Arg Thr Ser Tyr Asn Gln Asn Phe Lys 1 5 10 15 Gly <210> 145 <211> 12 <212> PRT <213> Artificial Sequence <220> <223> HCDR3 <400> 145 Ile Asn Asp Phe Asp Glu Gly Phe Ala Met Asp Tyr 1 5 10 <210> 146 <211> 17 <212> PRT <213> Artificial Sequence <220> <223> HCDR2 <220> <221> MUTAGEN <222> (3) <223> Xaa is N or S <220> <221> MUTAGEN <222> (4) <223> Xaa is S or R <220> <221> MUTAGEN <222> (5) <223> Xaa is N or D <220> <221> MUTAGEN <222> (6) <223> Xaa is D or G or V <220> <221> MUTAGEN <222> (7) <223> Xaa is I or D <220> <221> MUTAGEN <222> (8) <223> Xaa is N or S <220> <221> MUTAGEN <222> (12)..(12) <223> Xaa is L or P <400> 146 Ala Ile Xaa Xaa Xaa Xaa Xaa Xaa Thr Tyr Tyr Xaa Asp Thr Val Lys 1 5 10 15 Gly <210> 147 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> HCDR3 <220> <221> MUTAGEN <222> (5)..(5) <223> Xaa is Y or F <220> <221> MUTAGEN <222> (11)..(11) <223> Xaa is Y or S <400> 147 His Glu Asp Tyr Xaa Gly Phe Ala Met Asp Xaa 1 5 10 <210> 148 <211> 11 <212> PRT <213> Artificial Sequence <220> <223> LCDR1 <220> <221> MUTAGEN <222> (7)..(7) <223> Xaa is T or S <400> 148 Lys Ala Ser Gln Ser Val Xaa Asn Asp Val Ala 1 5 10 <210> 149 <211> 7 <212> PRT <213> Artificial Sequence <220> <223> LCDR2 <220> <221> MUTAGEN <222> (4) <223> Xaa is N or H <220> <221> MUTAGEN <222> (5) <223> Xaa is H or R <220> <221> MUTAGEN <222> (6) <223> Xaa is Y or F <400> 149 Tyr Val Ser Xaa Xaa Xaa Thr 1 5 <210> 150 <211> 9 <212> PRT <213> Artificial Sequence <220> <223> LCDR3 <220> <221> MUTAGEN <222> (1) <223> Xaa is Q or H <400> 150 Xaa Gln Ala Tyr Arg Ser Pro Trp Thr 1 5

Claims

1. An anti-CD112R antibody or an antigen-binding fragment thereof, wherein the antibody or the antigen-binding fragment thereof comprises: A heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO:67, SEQ ID NO:68 and SEQ ID NO:69, respectively; and a light chain variable region comprising LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO:70, SEQ ID NO:71 and SEQ ID NO:72, respectively; or A heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO:13, SEQ ID NO:14 and SEQ ID NO:15, respectively; and a light chain variable region comprising LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO:52, SEQ ID NO:53 and SEQ ID NO:54, respectively; or A heavy chain variable region comprising HCDR1, HCDR2 and HCDR3 as shown in SEQ ID NO: 13, SEQ ID NO: 14 and SEQ ID NO: 15, respectively; and a light chain variable region comprising LCDR1, LCDR2 and LCDR3 as shown in SEQ ID NO: 70, SEQ ID NO: 71 and SEQ ID NO: 72, respectively; or The heavy chain variable region comprises HCDR1, HCDR2 and HCDR3 whose amino acid sequences are shown in SEQ ID NO:67, SEQ ID NO:68 and SEQ ID NO:69, respectively; and the light chain variable region comprises LCDR1, LCDR2 and LCDR3 whose amino acid sequences are shown in SEQ ID NO:52, SEQ ID NO:53 and SEQ ID NO:54, respectively.

2. The anti-CD112R antibody or antigen-binding fragment thereof according to claim 1, wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region and a light chain variable region, wherein: The heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO: 109; and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO: 110; or The heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO: 89; and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO: 110; or The heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO: 109; and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO: 104; The heavy chain variable region comprises the amino acid sequence shown in SEQ ID NO:89; and the light chain variable region comprises the amino acid sequence shown in SEQ ID NO:

104.

3. The anti-CD112R antibody or antigen-binding fragment thereof according to claim 1, wherein the antibody or antigen-binding fragment thereof comprises: A heavy chain variable region with an amino acid sequence as shown in SEQ ID NO: 115 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO: 126, 127, 131 or 132; or A heavy chain variable region with an amino acid sequence as shown in SEQ ID NO: 116 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO: 126, 127, 131 or 132; or A heavy chain variable region with an amino acid sequence as shown in SEQ ID NO: 128 and a light chain variable region with an amino acid sequence as shown in SEQ ID NO: 126, 127, 131 or 132; or The heavy chain variable region has an amino acid sequence as shown in SEQ ID NO: 129 and the light chain variable region has an amino acid sequence as shown in SEQ ID NO: 126, 127, 131 or 132.

4. The anti-CD112R antibody or antigen-binding fragment thereof according to claim 3, wherein the antibody or antigen-binding fragment thereof comprises: The heavy chain variable region with the amino acid sequence shown in SEQ ID NO: 128 and the light chain variable region with the amino acid sequence shown in SEQ ID NO: 127; or The amino acid sequence of the heavy chain variable region is shown in SEQ ID NO:129 and the amino acid sequence of the light chain variable region is shown in SEQ ID NO:

131.

5. The anti-CD112R antibody or antigen-binding fragment thereof according to claim 1, wherein the antibody comprises: A heavy chain having an amino acid sequence as shown in SEQ ID NO: 137 or 138 and a light chain having an amino acid sequence as shown in SEQ ID NO: 136; or The heavy chain has an amino acid sequence as shown in SEQ ID NO: 140 or 141 and the light chain has an amino acid sequence as shown in SEQ ID NO:

139.

6. An anti-CD112R antibody or antigen-binding fragment thereof as described in any one of claims 1 to 5, wherein the antibody is selected from a murine antibody, a chimeric antibody or a humanized antibody, and the antigen-binding fragment is selected from Fab, Fab', F(ab')2, Fv, scFv or sdAb.

7. The anti-CD112R antibody or antigen-binding fragment thereof according to any one of claims 1 to 5, wherein the antibody or antigen-binding fragment thereof is of IgG4 subtype.

8. A polynucleotide molecule encoding an anti-CD112R antibody or an antigen-binding fragment thereof according to any one of claims 1 to 7.

9. An expression vector comprising the polynucleotide molecule according to claim 8.

10. The expression vector of claim 9, wherein the vector is a eukaryotic expression vector.

11. A host cell comprising the polynucleotide molecule of claim 8 or the expression vector of claim 9 or 10.

12. The host cell of claim 11, wherein the host cell is a eukaryotic cell.

13. The host cell of claim 11, wherein the host cell is a mammalian cell.

14. A method for preparing an anti-CD112R antibody or an antigen-binding fragment thereof as described in any one of claims 1 to 7, the method comprising expressing the antibody or its antigen-binding fragment in a host cell as described in any one of claims 11 to 13 under conditions suitable for expression of the antibody or its antigen-binding fragment, and recovering the expressed antibody or its antigen-binding fragment from the host cell.

15. A single-chain antibody comprising a light chain variable region and a heavy chain variable region of the antibody or antigen-binding fragment thereof according to any one of claims 1 to 7.

16. An immunoconjugate comprising the antibody or antigen-binding fragment thereof according to any one of claims 1 to 7 conjugated to a therapeutic agent or a diagnostic agent.

17. A pharmaceutical composition comprising an anti-CD112R antibody or antigen-binding fragment thereof as described in any one of claims 1 to 7, a polynucleotide molecule as described in claim 8, an expression vector as described in claim 9 or 10, or a host cell as described in any one of claims 11 to 13, and a pharmaceutically acceptable carrier or excipient.

18. A pharmaceutical combination comprising the antibody or antigen-binding fragment thereof according to any one of claims 1 to 7 or the pharmaceutical composition according to claim 17, and one or more additional therapeutic agents.

19. The pharmaceutical combination of claim 18, wherein the therapeutic agent is selected from one or more of an anti-PD-1 antibody, a PD-L1 antibody, and an anti-TIGIT antibody.

20. The pharmaceutical composition of claim 17, wherein the therapeutic agent is an anti-TIGIT antibody, or a combination of an anti-TIGIT antibody and a PD-1 antibody.

21. Use of the antibody or antigen-binding fragment thereof according to any one of claims 1 to 7, the polynucleotide molecule according to claim 8, the expression vector according to claim 9 or 10, the host cell according to any one of claims 11 to 13, the pharmaceutical composition according to claim 17 or the pharmaceutical combination according to claim 18 in the preparation of a medicament for treating and / or preventing a disease or condition mediated by CD112R, wherein the disease or condition is cancer.

22. The use of claim 21, wherein the cancer is selected from melanoma, renal cancer, prostate cancer, breast cancer, colon cancer, lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, uterine cancer, ovarian cancer and rectal cancer.

23. A kit comprising the antibody or antigen-binding fragment thereof according to any one of claims 1 to 7, the polynucleotide molecule according to claim 8, the expression vector according to claim 9 or 10, the host cell according to any one of claims 11 to 13, the pharmaceutical composition according to claim 17, or the pharmaceutical combination according to claim 18.

24. A method for detecting the presence of CD112R in a sample using an antibody or an antigen-binding fragment thereof as described in any one of claims 1 to 7, or a detection composition containing the antibody or its antigen-binding fragment, comprising the step of contacting the antibody or its antigen-binding fragment or a detection composition containing the antibody or its antigen-binding fragment with the sample; wherein, The method is for non-therapeutic and non-diagnostic purposes.

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