Antigen binding molecules targeting il-12 and il-23

Abstract

In various embodiments, this disclosure provides polypeptides (e.g., antibodies and their antigen-binding fragments) that bind both interleukin-12 (IL-12) and IL-23. In various embodiments, this disclosure also provides fusion proteins comprising one or more of the said polypeptides, polynucleotides encoding the said polypeptides, vectors and host cells suitable for expressing the said polypeptides, and methods for treating IL-12 / IL-23 related diseases or disorders.

Description

[0001] Related applications

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 593,199, filed October 25, 2023. The entire teachings of the aforementioned application are incorporated herein by reference.

[0003] Materials incorporated into XML by reference

[0004] This application incorporates by reference the sequence lists contained in the following eXtensible Markup Language (XML) archives submitted concurrently with this document:

[0005] a) File name: 62311000001.xml; created on October 22, 2024, size is 325,178 bytes. Background Technology

[0006] The involvement of the interleukin (IL)-12 / 23 pathway is related to the pathogenesis of various diseases.

[0007] IL-12 plays a crucial role in the pathology of several diseases involving immune and inflammatory responses. A review of IL-12, its biological activity, and its role in disease can be found in Gately et al.1. Structurally, IL-12 is a heterodimeric protein containing a 35 kDa subunit (p35) and a 40 kDa subunit (p40) linked together by disulfide bridges (referred to as the "p70 subunit"). Functionally, IL-12 plays a central role in regulating the balance between antigen-specific T helper type 1 (Th1) and type 2 (Th2) lymphocytes. Consistent with the dominance of Th1 responses in autoimmune diseases and the pro-inflammatory activity of IFNγ, IL-12 plays a major role in the pathology of many autoimmune and inflammatory diseases. Attributing to the role of human IL-12 in various human diseases, therapeutic strategies have been designed to inhibit or counteract IL-12 activity. In particular, molecules that bind to and neutralize IL-12 have been sought as means of inhibiting IL-12 activity.

[0008] IL-23 is a heterodimeric cytokine composed of two subunits: p19 and p402. IL-23 has been reported to promote the proliferation of T cells, particularly memory T cells, and may contribute to the differentiation and / or maintenance of Th17 cells. IL-23 induces T cells to express numerous inflammatory genes, including IL-17A, IL-17A receptor, TNF-α, and GM-CSF. The main function of IL-23 is to drive the differentiation of T helper Th17 cells, as well as macrophages, natural killer (NK) cells, dendritic cells, and innate lymphoid cells, thereby leading to the upregulation of IL-17, IL-22, TNF-α, granulocyte-macrophage community-stimulating factor (GM-CSF), and interferon (IFN)-γ, and the downregulation of IL-10. IL-23 is involved in the pathogenesis of various inflammatory diseases, including but not limited to Crohn's disease, ulcerative colitis, psoriasis, psoriatic arthritis, rheumatoid arthritis, and ankylosing spondylitis.

[0009] The p40 subunit is shared by IL-12 and IL-23, and is targeted by inhibitors of IL-12 / 23. There is compelling evidence that therapeutics binding to the p40 subunit can inhibit IL-12 and IL-23-mediated cell signaling, activation, and cytokine production. Summary of the Invention

[0010] Ustekinumab (STELARA®) is a human IgG1 monoclonal antibody that binds to the p40 subunit shared by human IL-12 and IL-23. Binding prevents the interaction of IL-12 and IL-23 with their cell surface receptor IL-12Rβ1, subsequently inhibiting IL-12 and IL-23-mediated cell signaling, activation, and cytokine production, thereby modulating specific components of the immune system. Although ustekinumab has shown favorable target affinity, there is still a need to develop IL-12 / 23 inhibitors with improved target affinity, immunogenicity, stability, and / or serum half-life.4-7 Improved target affinity can enhance therapeutic efficacy and / or reduce the dosage. Increased stability and / or serum half-life can provide dosing advantages.

[0011] The disclosures herein are based in part on the finding that the antibodies and their antigen-binding fragments disclosed herein specifically bind to the p40 protein subunits of human IL-12 and IL-23 and exhibit one or more beneficial properties. Therefore, this disclosure generally relates to compositions (e.g., antibodies or their antigen-binding fragments, pharmaceutical compositions) and methods that can be used to regulate (e.g., antagonize) the function and / or activity (e.g., in vivo function and / or activity) of IL-12 and IL-23.

[0012] Furthermore, this disclosure provides an antibody or an antigen-binding fragment thereof, the antibody or antigen-binding fragment thereof comprising: a) An immunoglobulin heavy chain variable (VH) domain comprising heavy chain complementarity-determining regions (HCDRs) 1, HCDR2, and HCDR3 having 100% sequence identity with the amino acid sequences of any of the following: SEQ ID NO:3, SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:299, SEQ ID NO:300, SEQ ID NO:1, SEQ ID NO:5-11, and SEQ ID NO:19-21; and b) An immunoglobulin light chain variable (VL) domain, the VL domain comprising light chain complementarity-determining regions (LCDRs) 1, LCDR2, and LCDR3 having 100% sequence identity with the amino acid sequences of the VL domain comprising any one of SEQ ID NO:144, SEQ ID NO:142, SEQ ID NO:301, SEQ ID NO:302, and SEQ ID NO:140, respectively. The VH domain has less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1, and the VL domain has less than 100% sequence identity with the amino acid sequence of SEQ ID NO:140, or both.

[0013] In some embodiments, the antibody or its antigen-binding fragment comprises: a) A VH domain comprising HCDR1, HCDR2, and HCDR3 having 100% sequence identity with the VH domain containing the amino acid sequence of SEQ ID NO:3; and a VL domain comprising LCDR1, LCDR2, and LCDR3 having 100% sequence identity with the VL domain containing the amino acid sequence of SEQ ID NO:144; b) A VH domain comprising HCDR1, HCDR2, and HCDR3 having 100% sequence identity with the VH domain containing the amino acid sequence of SEQ ID NO:2; and a VL domain comprising LCDR1, LCDR2, and LCDR3 having 100% sequence identity with the VL domain containing the amino acid sequence of SEQ ID NO:144; c) A VH domain comprising HCDR1, HCDR2, and HCDR3 having 100% sequence identity with HCDR1, HCDR2, and HCDR3 containing the amino acid sequence of SEQ ID NO:4; and a VL domain comprising LCDR1, LCDR2, and LCDR3 having 100% sequence identity with LCDR1, LCDR2, and LCDR3 containing the amino acid sequence of SEQ ID NO:140; d) A VH domain comprising HCDR1, HCDR2, and HCDR3 having 100% sequence identity with HCDR1, HCDR2, and HCDR3 containing the amino acid sequence of SEQ ID NO:299, respectively; and a VL domain comprising LCDR1, LCDR2, and LCDR3 having 100% sequence identity with LCDR1, LCDR2, and LCDR3 containing the amino acid sequence of SEQ ID NO:140, respectively; e) A VH domain comprising HCDR1, HCDR2, and HCDR3 having 100% sequence identity with HCDR1, HCDR2, and HCDR3 having the amino acid sequence of SEQ ID NO:300; and a VL domain comprising LCDR1, LCDR2, and LCDR3 having 100% sequence identity with LCDR1, LCDR2, and LCDR3 having the amino acid sequence of SEQ ID NO:140; f) A VH domain comprising HCDR1, HCDR2, and HCDR3 having 100% sequence identity with HCDR1, HCDR2, and HCDR3 containing the amino acid sequence of SEQ ID NO:1; and a VL domain comprising LCDR1, LCDR2, and LCDR3 having 100% sequence identity with LCDR1, LCDR2, and LCDR3 containing the amino acid sequence of SEQ ID NO:144; g) A VH domain comprising HCDR1, HCDR2, and HCDR3 having 100% sequence identity with HCDR1, HCDR2, and HCDR3 containing the amino acid sequence of SEQ ID NO:1; and a VL domain comprising LCDR1, LCDR2, and LCDR3 having 100% sequence identity with LCDR1, LCDR2, and LCDR3 containing the amino acid sequence of SEQ ID NO:301; h) A VH domain comprising HCDR1, HCDR2, and HCDR3 having 100% sequence identity with HCDR1, HCDR2, and HCDR3 containing the amino acid sequence of SEQ ID NO:1; and a VL domain comprising LCDR1, LCDR2, and LCDR3 having 100% sequence identity with LCDR1, LCDR2, and LCDR3 containing the amino acid sequence of SEQ ID NO:302; or i) A VH domain comprising HCDR1, HCDR2, and HCDR3 having 100% sequence identity with the VH domain containing the amino acid sequence of SEQ ID NO:1; and a VL domain comprising LCDR1, LCDR2, and LCDR3 having 100% sequence identity with the VL domain containing the amino acid sequence of SEQ ID NO:142.

[0014] In some embodiments: a) HCDR1 contains the amino acid sequences of SEQ ID NO:45, SEQ ID NO:303, SEQ ID NO:304, SEQ ID NO:44 and SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:49, SEQ ID NO:50 or SEQ ID NO:51; b) HCDR2 contains the amino acid sequence of SEQ ID NO:72; c) HCDR3 contains the amino acid sequence of SEQ ID NO:79. d) LCDR1 contains the amino acid sequence of SEQ ID NO:146; e) LCDR2 contains the amino acid sequence AAS, IAS, or YAS; and f) LCDR3 contains the amino acid sequence of SEQ ID NO:150.

[0015] In some embodiments, the antibody or its antigen-binding fragment comprises: a) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, respectively, containing the amino acid sequences of SEQ ID NO:45, SEQ ID NO:72, SEQ ID NO:79, SEQ ID NO:146, AAS, and SEQ ID NO:150; b) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 respectively containing the amino acid sequences of SEQ ID NO:303, SEQ ID NO:72, SEQ ID NO:79, SEQ ID NO:146, AAS and SEQ ID NO:150; c) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, respectively containing the amino acid sequences of SEQ ID NO:304, SEQ ID NO:72, SEQ ID NO:79, SEQ ID NO:146, AAS, and SEQ ID NO:150; or d) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, respectively, containing the amino acid sequences of SEQ ID NO:44, SEQ ID NO:72, SEQ ID NO:79, SEQ ID NO:146, AAS and SEQ ID NO:150.

[0016] In some embodiments: a) HCDR1 contains the amino acid sequence of SEQ ID NO:80, SEQ ID NO:81, or SEQ ID NO:82; b) HCDR2 contains the amino acid sequence of SEQ ID NO:96; c) HCDR3 contains the amino acid sequence of SEQ ID NO:103. d) LCDR1 contains the amino acid sequence of SEQ ID NO:151; e) LCDR2 contains the amino acid sequence of SEQ ID NO:156, SEQ ID NO:154, SEQ ID NO:307, SEQ ID NO:308, or SEQ ID NO:152; and f) LCDR3 contains the amino acid sequence of SEQ ID NO:150.

[0017] In some embodiments, the antibody or its antigen-binding fragment comprises: a) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, respectively, containing the amino acid sequences of SEQ ID NO:80, SEQ ID NO:96, SEQ ID NO:103, SEQ ID NO:151, SEQ ID NO:156, and SEQ ID NO:150; b) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, respectively, containing the amino acid sequences of SEQ ID NO:80, SEQ ID NO:96, SEQ ID NO:103, SEQ ID NO:151, SEQ ID NO:152, and SEQ ID NO:150; c) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, respectively, containing the amino acid sequences of SEQ ID NO:80, SEQ ID NO:96, SEQ ID NO:103, SEQ ID NO:151, SEQ ID NO:307, and SEQ ID NO:150; d) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, respectively, containing the amino acid sequences of SEQ ID NO:80, SEQ ID NO:96, SEQ ID NO:103, SEQ ID NO:151, SEQ ID NO:308, and SEQ ID NO:150; or e) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 respectively containing the amino acid sequences of SEQ ID NO:80, SEQ ID NO:96, SEQ ID NO:103, SEQ ID NO:151, SEQ ID NO:154 and SEQ ID NO:150.

[0018] In some embodiments: a) HCDR1 contains the amino acid sequence of SEQ ID NO:105, SEQ ID NO:305, SEQ ID NO:306, SEQ ID NO:104, SEQ ID NO:106, SEQ ID NO:107, SEQ ID NO:109, SEQ ID NO:110 or SEQ ID NO:111; b) HCDR2 contains the amino acid sequence of SEQ ID NO:132; c) HCDR3 contains the amino acid sequence of SEQ ID NO:139. d) LCDR1 contains the amino acid sequence of SEQ ID NO:151; e) LCDR2 contains the amino acid sequence of SEQ ID NO:156, SEQ ID NO:154, SEQ ID NO:307, SEQ ID NO:308, or SEQ ID NO:152; and f) LCDR3 contains the amino acid sequence of SEQ ID NO:150.

[0019] In some embodiments, the antibody or its antigen-binding fragment comprises: a) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, respectively, containing the amino acid sequences of SEQ ID NO:105, SEQ ID NO:132, SEQ ID NO:139, SEQ ID NO:151, SEQ ID NO:156, and SEQ ID NO:150; b) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, respectively, containing the amino acid sequences of SEQ ID NO:105, SEQ ID NO:132, SEQ ID NO:139, SEQ ID NO:151, SEQ ID NO:152, and SEQ ID NO:150; c) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, respectively, containing the amino acid sequences of SEQ ID NO:305, SEQ ID NO:132, SEQ ID NO:139, SEQ ID NO:151, SEQ ID NO:152, and SEQ ID NO:150; d) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, respectively, containing the amino acid sequences of SEQ ID NO:306, SEQ ID NO:132, SEQ ID NO:139, SEQ ID NO:151, SEQ ID NO:152, and SEQ ID NO:150; e) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, respectively, containing the amino acid sequences of SEQ ID NO:104, SEQ ID NO:132, SEQ ID NO:139, SEQ ID NO:151, SEQ ID NO:156, and SEQ ID NO:150; f) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3, respectively, containing the amino acid sequences of SEQ ID NO:104, SEQ ID NO:132, SEQ ID NO:139, SEQ ID NO:151, SEQ ID NO:307, and SEQ ID NO:150; g) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 respectively containing the amino acid sequences of SEQ ID NO:104, SEQ ID NO:132, SEQ ID NO:139, SEQ ID NO:151, SEQ ID NO:308, and SEQ ID NO:150; or h) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 respectively containing the amino acid sequences of SEQ ID NO:104, SEQ ID NO:132, SEQ ID NO:139, SEQ ID NO:151, SEQ ID NO:154 and SEQ ID NO:150.

[0020] In some embodiments, the antibody or its antigen-binding fragment comprises: a) A VH domain containing the amino acid sequence of SEQ ID NO:3 and a VL domain containing the amino acid sequence of SEQ ID NO:144; b) A VH domain containing the amino acid sequence of SEQ ID NO:2 and a VL domain containing the amino acid sequence of SEQ ID NO:144; c) A VH domain containing the amino acid sequence of SEQ ID NO:4 and a VL domain containing the amino acid sequence of SEQ ID NO:144; d) A VH domain containing the amino acid sequence of SEQ ID NO:4 and a VL domain containing the amino acid sequence of SEQ ID NO:140; e) A VH domain comprising the amino acid sequence of SEQ ID NO:299 and a VL domain comprising the amino acid sequence of SEQ ID NO:140; f) A VH domain containing the amino acid sequence of SEQ ID NO:300 and a VL domain containing the amino acid sequence of SEQ ID NO:140; g) A VH domain containing the amino acid sequence of SEQ ID NO:1 and a VL domain containing the amino acid sequence of SEQ ID NO:144; h) A VH domain containing the amino acid sequence of SEQ ID NO:1 and a VL domain containing the amino acid sequence of SEQ ID NO:301; i) A VH domain comprising the amino acid sequence of SEQ ID NO:1 and a VL domain comprising the amino acid sequence of SEQ ID NO:302; or j) The VH domain containing the amino acid sequence of SEQ ID NO:1 and the VL domain containing the amino acid sequence of SEQ ID NO:142.

[0021] In some embodiments, the antibody or its antigen-binding fragment comprises an antibody heavy chain constant domain, an antibody light chain constant domain, or both.

[0022] In some embodiments, the antibody or its antigen-binding fragment includes an antibody heavy chain constant domain that contains one or more mutations that increase the serum half-life of the antibody or its antigen-binding fragment in humans.

[0023] In some embodiments, the antibody or its antigen-binding fragment comprises an antibody heavy chain constant domain, which comprises SEQ ID NO:280, YTE modification of SEQ ID NO:280, LS modification of SEQ ID NO:280, SEQ ID NO:279, YTE modification of SEQ ID NO:279, or LS modification of SEQ ID NO:279.

[0024] In addition, this disclosure also provides an antibody or an antigen-binding fragment thereof, the antibody or antigen-binding fragment thereof comprising: a) HCDR1 containing the amino acid sequence of SEQ ID NO:X1 (e.g., composed of it), b) HCDR2 containing the amino acid sequence of SEQ ID NO:X2 (e.g., composed of it), c) HCDR3 containing the amino acid sequence of SEQ ID NO:X3 (e.g., composed of it), d) LCDR1 containing the amino acid sequence of SEQ ID NO: Y1 (e.g., composed of it), e) LCDR2 containing the amino acid sequence of SEQ ID NO:Y2 (e.g., composed of it), and f) LCDR3 containing the amino acid sequence of SEQ ID NO:Y3 (e.g., composed of it).

[0025] Furthermore, this disclosure provides an antibody or an antigen-binding fragment thereof, the antibody or antigen-binding fragment thereof comprising: a) An immunoglobulin heavy chain variable (VH) domain comprising heavy chain complementarity-determining regions (HCDRs) 1, HCDR2, and HCDR3 having at least 80% sequence identity with the amino acid sequences of any of SEQ ID NO:2-11, 19-21, 299, and 300 (e.g., any of SEQ ID NO:2-11 and 19-21), and... b) An immunoglobulin light chain variable (VL) domain comprising light chain complementarity-determining regions (LCDRs) 1, 2, and 3 that have at least 80% sequence identity with the VL domain containing any of the amino acid sequences of SEQ ID NO: 144, 142, 301, and 302 (e.g., SEQ ID NO: 144 or 142). The VH domain has less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1, and the VL domain has less than 100% sequence identity with the amino acid sequence of SEQ ID NO:140, or both.

[0026] In addition, this disclosure also provides an antibody or an antigen-binding fragment thereof, the antibody or antigen-binding fragment thereof comprising: a) A VH domain comprising HCDR1, HCDR2, and HCDR3 having 100% sequence identity with the amino acid sequences of HCDR1, HCDR2, and HCDR3 containing any of the amino acid sequences of SEQ ID NO: 2-11, 19-21, 299, and 300 (e.g., any of SEQ ID NO: 2-11 and 19-21), and b) A VL domain comprising LCDR1, LCDR2, and LCDR3 having 100% sequence identity with an amino acid sequence comprising any one of SEQ ID NO: 144, 142, 301, and 302 (e.g., SEQ ID NO: 144 or 142), respectively. The VH domain has less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1, and the VL domain has less than 100% sequence identity with the amino acid sequence of SEQ ID NO:140, or both.

[0027] In some embodiments, the VH domain of the antibody or its antigen-binding fragment comprises four VH framework regions (VH FR1-4) and three heavy chain complementarity-determining regions (HCDR1-3) in the following order from N-terminus to C-terminus: VH FR1-HCDR1-VH FR2-HCDR2-VH FR3-HCDR3-VH FR4, wherein: a) The VH FR1-HCDR1 contains the amino acid sequence of any one of SEQ ID NO:309, 310, and 262-267 (e.g., SEQ ID NO:262-267). b) The VH FR2 contains the amino acid sequence GKGL, GDYL, or GYYL, or c) The VH FR3 contains an amino acid sequence of NSLK, PSLR, or NDLR, or Any combination of a) to c).

[0028] In addition, this disclosure also provides an antibody or an antigen-binding fragment thereof, the antibody or antigen-binding fragment thereof comprising: a) HCDR1 containing the amino acid sequence of SEQ ID NO:X (e.g., composed of it), b) HCDR2 containing the amino acid sequence of SEQ ID NO:72 (e.g., composed of it), c) HCDR3 containing the amino acid sequence of SEQ ID NO:79 (e.g., composed of it), d) LCDR1 containing the amino acid sequence of SEQ ID NO:146 (e.g., composed of it), e) LCDR2 containing the amino acid sequence of AAS (e.g., composed of it), and f) LCDR3 containing the amino acid sequence of SEQ ID NO:150 (e.g., composed of it).

[0029] In some embodiments, X is any one of 303, 304, 45-47, and 49-51. In some embodiments, X is any one of 45-47 and 49-51. In some embodiments, X is 303. In some embodiments, X is 304. In some embodiments, X is 45. In some embodiments, X is 46. In some embodiments, X is 47. In some embodiments, X is 49. In some embodiments, X is 50. In some embodiments, X is 51.

[0030] In addition, this disclosure also provides an antibody or an antigen-binding fragment thereof, the antibody or antigen-binding fragment thereof comprising: a) HCDR1 containing the amino acid sequence of SEQ ID NO:X1 (e.g., composed of it), b) HCDR2 containing the amino acid sequence of SEQ ID NO:X2 (e.g., composed of it), c) HCDR3 containing the amino acid sequence of SEQ ID NO:X3 (e.g., composed of it), d) LCDR1 containing the amino acid sequence of SEQ ID NO: Y1 (e.g., composed of it), e) LCDR2 containing the amino acid sequence of SEQ ID NO:Y2 (e.g., composed of it), and f) LCDR3 containing the amino acid sequence of SEQ ID NO:Y3 (e.g., composed of it).

[0031] In some embodiments, the antibody or its antigen-binding fragment does not contain a VH domain containing the amino acid sequence of SEQ ID NO: 1 and a VL domain containing the amino acid sequence of SEQ ID NO: 140.

[0032] In some embodiments, X1 is 80, 81, or 82, X2 is 96, X3 is 103, Y1 is 151, Y2 is any one of 156, 307, 308, and 154, and Y3 is 150. In some embodiments, X1 is 80, 81, or 82, X2 is 96, X3 is 103, Y1 is 151, Y2 is 156 or 154, and Y3 is 150. In some embodiments, X1 is 80, X2 is 96, X3 is 103, Y1 is 151, Y2 is 156, and Y3 is 150. In some embodiments, X1 is 80, X2 is 96, X3 is 103, Y1 is 151, Y2 is 307, and Y3 is 150. In some embodiments, X1 is 80, X2 is 96, X3 is 103, Y1 is 151, Y2 is 308, and Y3 is 150. In some embodiments, X1 is 80, X2 is 96, X3 is 103, Y1 is 151, Y2 is 154, and Y3 is 150. In some embodiments, X1 is 81, X2 is 96, X3 is 103, Y1 is 151, Y2 is 156, and Y3 is 150. In some embodiments, X1 is 81, X2 is 96, X3 is 103, Y1 is 151, Y2 is 307, and Y3 is 150. In some embodiments, X1 is 81, X2 is 96, X3 is 103, Y1 is 151, Y2 is 308, and Y3 is 150. In some embodiments, X1 is 81, X2 is 96, X3 is 103, Y1 is 151, Y2 is 154, and Y3 is 150. In some embodiments, X1 is 82, X2 is 96, X3 is 103, Y1 is 151, Y2 is 156, and Y3 is 150. In some embodiments, X1 is 82, X2 is 96, X3 is 103, Y1 is 151, Y2 is 307, and Y3 is 150. In some embodiments, X1 is 82, X2 is 96, X3 is 103, Y1 is 151, Y2 is 308, and Y3 is 150. In some embodiments, X1 is 82, X2 is 96, X3 is 103, Y1 is 151, Y2 is 154, and Y3 is 150.

[0033] In some embodiments, X1 is any one of 305, 306, 105-107, and 109-111, X2 is 132, X3 is 139, Y1 is 151, Y2 is any one of 307, 308, 156, and 154, and Y3 is 150. In some embodiments, X1 is any one of 305, 306, 105-107, and 109-111, X2 is 132, X3 is 139, Y1 is 151, Y2 is 307, and Y3 is 150. In some embodiments, X1 is any one of 305, 306, 105-107, and 109-111, X2 is 132, X3 is 139, Y1 is 151, Y2 is 308, and Y3 is 150. In some embodiments, X1 is any one of 305, 306, 105-107, and 109-111, X2 is 132, X3 is 139, Y1 is 151, Y2 is 156, and Y3 is 150. In some embodiments, X1 is any one of 305, 306, 105-107, and 109-111, X2 is 132, X3 is 139, Y1 is 151, Y2 is 154, and Y3 is 150. In some embodiments, X1 is any one of 105-107 and 109-111, X2 is 132, X3 is 139, Y1 is 151, Y2 is 156 or 154, and Y3 is 150. In some embodiments, X1 is any one of 105-107 and 109-111, X2 is 132, X3 is 139, Y1 is 151, Y2 is 307, and Y3 is 150. In some embodiments, X1 is any one of 105-107 and 109-111, X2 is 132, X3 is 139, Y1 is 151, Y2 is 308, and Y3 is 150. In some embodiments, X1 is any one of 105-107 and 109-111, X2 is 132, X3 is 139, Y1 is 151, Y2 is 156, and Y3 is 150. In some embodiments, X1 is any one of 105-107 and 109-111, X2 is 132, X3 is 139, Y1 is 151, Y2 is 154, and Y3 is 150.

[0034] In addition, this disclosure also provides an antibody or an antigen-binding fragment thereof, the antibody or the antigen-binding fragment thereof comprising a VH domain containing an amino acid sequence of SEQ ID NO:X and a VL domain containing an amino acid sequence of SEQ ID NO:Y.

[0035] In some embodiments, X is any one of 2-11, 19-21, 299, and 300, and Y is any one of 144, 142, 301, and 302. In some embodiments, X is any one of 2-11 and 19-21, and Y is 144 or 142.

[0036] In some embodiments, X is 2 and Y is 144. In some embodiments, X is 3 and Y is 144. In some embodiments, X is 4 and Y is 144. In some embodiments, X is 5 and Y is 144. In some embodiments, X is 6 and Y is 144. In some embodiments, X is 7 and Y is 144. In some embodiments, X is 8 and Y is 144. In some embodiments, X is 9 and Y is 144. In some embodiments, X is 10 and Y is 144. In some embodiments, X is 11 and Y is 144. In some embodiments, X is 19 and Y is 144. In some embodiments, X is 20 and Y is 144. In some embodiments, X is 21 and Y is 144. In some embodiments, X is 299 and Y is 144. In some embodiments, X is 300 and Y is 144.

[0037] In some embodiments, X is 2 and Y is 142. In some embodiments, X is 3 and Y is 142. In some embodiments, X is 4 and Y is 142. In some embodiments, X is 5 and Y is 142. In some embodiments, X is 6 and Y is 142. In some embodiments, X is 7 and Y is 142. In some embodiments, X is 8 and Y is 142. In some embodiments, X is 9 and Y is 142. In some embodiments, X is 10 and Y is 142. In some embodiments, X is 11 and Y is 142. In some embodiments, X is 19 and Y is 142. In some embodiments, X is 20 and Y is 142. In some embodiments, X is 21 and Y is 142. In some embodiments, X is 299 and Y is 142. In some embodiments, X is 300 and Y is 142.

[0038] In some embodiments, X is 2 and Y is 301. In some embodiments, X is 3 and Y is 301. In some embodiments, X is 4 and Y is 301. In some embodiments, X is 5 and Y is 301. In some embodiments, X is 6 and Y is 301. In some embodiments, X is 7 and Y is 301. In some embodiments, X is 8 and Y is 301. In some embodiments, X is 9 and Y is 301. In some embodiments, X is 10 and Y is 301. In some embodiments, X is 11 and Y is 301. In some embodiments, X is 19 and Y is 301. In some embodiments, X is 20 and Y is 301. In some embodiments, X is 21 and Y is 301. In some embodiments, X is 299 and Y is 301. In some embodiments, X is 300 and Y is 301.

[0039] In some embodiments, X is 2 and Y is 302. In some embodiments, X is 3 and Y is 302. In some embodiments, X is 4 and Y is 302. In some embodiments, X is 5 and Y is 302. In some embodiments, X is 6 and Y is 302. In some embodiments, X is 7 and Y is 302. In some embodiments, X is 8 and Y is 302. In some embodiments, X is 9 and Y is 302. In some embodiments, X is 10 and Y is 302. In some embodiments, X is 11 and Y is 302. In some embodiments, X is 19 and Y is 302. In some embodiments, X is 20 and Y is 302. In some embodiments, X is 21 and Y is 302. In some embodiments, X is 299 and Y is 302. In some embodiments, X is 300 and Y is 302.

[0040] In some embodiments, the antibodies disclosed herein or their antigen-binding fragments specifically bind to the p40 subunits of human interleukins 12 and 23 (e.g., the full-length human p40 subunit) or variants thereof. In some embodiments, the antibodies disclosed herein or their antigen-binding fragments bind to the D1 domain of the p40 subunit.

[0041] Furthermore, this disclosure also provides a polynucleotide encoding a VH domain, a VL domain, a light chain, or a heavy chain of the antibody or antigen-binding fragment thereof disclosed herein. In some embodiments, the polynucleotide is DNA. In some embodiments, the polynucleotide is RNA.

[0042] In addition, this disclosure also provides an expression vector comprising a polynucleotide disclosed herein.

[0043] In addition, this disclosure also provides a host cell comprising the polynucleotide or expression vector disclosed herein.

[0044] In addition, this disclosure also provides a method for generating the antibody or antigen-binding fragment thereof disclosed herein, the method comprising expressing the antibody or antigen-binding fragment thereof in a host cell and isolating the expressed antibody or antigen-binding fragment thereof.

[0045] In addition, this disclosure also provides a pharmaceutical composition comprising the antibody or antigen-binding fragment thereof disclosed herein, and a pharmaceutically acceptable carrier or diluent.

[0046] In addition, this disclosure also provides a kit comprising the pharmaceutical composition disclosed herein.

[0047] In addition, this disclosure also provides a method for blocking the binding of a ligand to a receptor expressed on a cell surface, the method comprising contacting the cell with an effective amount of an antibody or antigen-binding fragment thereof disclosed herein or a pharmaceutical composition thereof, thereby blocking the binding of the ligand to a receptor expressed on the cell surface, wherein the ligand comprises p40.

[0048] In addition, this disclosure also provides a method for treating IL-12 / IL-23-related disease in an individual in need, the method comprising administering to the individual an effective amount of the antibody or antigen-binding fragment thereof disclosed herein or a pharmaceutical composition thereof, thereby treating the IL-12 / IL-23-related disease. Attached Figure Description

[0049] The foregoing will become apparent from the following more detailed description of the exemplary embodiments, as illustrated in the accompanying drawings, in which similar reference characters refer to the same parts in different views. The drawings are not necessarily to scale, but are intended to emphasize the illustration of the embodiments.

[0050] Figure 1A-1C Describe the amino acid sequence of the heavy chain variable (VH) domain. The heavy chain complementarity-determining region (HCDR) amino acid sequence of ustekinumab, as determined by ImMunoGeneTics (IMGT), Kabat, or Chothia numbering, is indicated by boxes. Bold letters indicate... Figure 1G The ustekinumab shown is a variable residue in the example antibody.

[0051] Figure 1D-1F Describe the amino acid sequence of the light chain variable (VL) domain. The amino acid sequence of the light chain complementarity-determining region (LCDR) of ustekinumab, as determined by IMGT, Kabat, or Chothia numbering, is indicated by boxes. Bold letters indicate... Figure 1H The ustekinumab shown is a variable residue in the example antibody.

[0052] Figure 1G Alignment of amino acid sequences of the VH domain of ustekinumab and example variants.

[0053] Figure 1H Alignment of amino acid sequences of the VL domain of ustekinumab and example variants.

[0054] Figure 2A-2B The ELISA analysis of the indicated C and A variants is shown. Each variant contains the heavy chain of the indicated first-round VH variant and the light chain of ustekinumab. Compared with ustekinumab: (i) except for C2, most C variants showed similar protein expression (IgG yield), while A variants showed lower protein expression (IgG production). Figure 2A(ii) C38 showed a significantly higher IL-12 binding affinity, C7 and C11 showed slightly higher affinity, C3 showed a similar affinity, and the A variant showed a lower affinity. Figure 2B ).

[0055] Figure 3 The ELISA analysis of the indicated antibody variants is shown, each variant comprising: (i) a heavy chain containing the indicated second-round VH variant and a light chain of ustekinumab, or (ii) a heavy chain of ustekinumab and a light chain containing the indicated VL variant. Compared to antibody (C38) comprising a heavy chain containing C38 and a light chain of ustekinumab: (i) when paired with the light chain of ustekinumab, C41, C42, C61, C38xC81, C38xC82, C38xC91, and C38xC92 showed similar or higher IL-12 binding affinity, and (ii) when paired with the heavy chain of ustekinumab, C102, C103, C104, and C105 showed similar or higher IL-12 binding affinity. Among these, C42, C38xC81, C38xC82, C38xC91, C38xC92, and C104 are associated with higher IL-12 binding affinity.

[0056] Figure 4 The third-round ELISA analysis of the variants is shown. Compared with the antibody (C38) containing the heavy chain of C38 and the light chain of ustekinumab, the antibody variants C38xC104, C41xC104, C42xC104, C44xC104, C38xC82xC104, C38xC91xC104, C38xC92xC104, and C38x92xC102 showed similar or higher IL-12 binding affinity.

[0057] Figure 5A The fourth round of ELISA analysis of the variants is shown. Compared with the antibody (C38) containing the heavy chain of C38 and the light chain of ustekinumab, the antibody variant C38xC82xC92xC104 showed higher IL-12 binding affinity, while C42xC82xC92xC104, C42xC92xC104, and C38xC82xC92xC102 showed similar IL-12 binding affinity.

[0058] Figure 5B ELISA analysis showing the indicated antibody variants.

[0059] Figures 6A-6CELISA analysis of the indicated antibody variants is shown. IgG and IL-12 ELISA were performed to assess IL-12 binding affinity at the corresponding IgG concentrations. All ten antibody variants showed higher IL-12 binding affinity compared to ustekinumab. Compared to antibodies containing the heavy chain of C38 and the light chain of ustekinumab (C38), C38xC104, C38x82xC104, C38x91xC104, C38x92xC104, and C38x82x92xC104 showed higher IL-12 binding activity.

[0060] Figures 7A-7C ELISA analysis of the indicated antibody variants is shown. IL-12 binding affinity at corresponding IgG concentrations was assessed using IgG and IL-12 ELISA. Antibody concentrations were started at 600 ng / mL and serially diluted 3-fold. Ustekinumab and an antibody containing the heavy chain with C38 and the light chain of ustekinumab (C38) were used as internal references.

[0061] Figures 8A-8D The pharmacokinetic patterns of ustekinumab and the indicated antibody variants in mice following a single IV dose of 1 mg / kg are shown. Individual values ​​for each mouse are plotted, and the mean linear slope is calculated.

[0062] Figures 9A-9B This shows two types of ELISA analysis for ustekinumab-scFv-Fc.

[0063] Figure 10 To assess the effect of ustekinumab in IgG or scFv-Fc form on cell-based IL-12 activity.

[0064] Figure 11 The effects of (i) an antibody containing a heavy chain of C38 and a light chain of ustekinumab (C38) and (ii) an antibody containing a heavy chain of C11 and a light chain of ustekinumab (C11) on cell-based IL-12 activity were evaluated.

[0065] Figure 12 Assess the effect of the indicated antibody variant on cell-based IL-12 activity.

[0066] Figure 13A Assess the effect of the indicated antibody variant on cell-based IL-12 activity.

[0067] Figure 13BThe effects of indicated antibody variants on cell-based IL-12 activity were summarized. Compared with ustekinumab, antibodies containing the heavy chain of C38 and the light chain of ustekinumab (C38), C38C91C104, and C38C92C104 showed a statistically significant increase in the ability to reduce IL-12 activity (t-test; p<0.001).

[0068] Figure 13C Assess the effect of the indicated antibody variant on cell-based IL-23 activity.

[0069] Figure 14 Cell-based activity analysis of selected variants of scFv with superior mutations was performed. Purified variants of scFv form were assayed at doses ranging from 0.3 ng / mL to 1000 ng / mL to measure inhibition of IL-12 receptor binding and induced signaling. Data are from single-repeat examples from repeat plates. The variants showed equivalent potency compared to ustekinumab.

[0070] Figure 15A To evaluate the in vivo pharmacodynamic neutralization of IL-12 in C38C91C104.

[0071] Figure 15B To evaluate the in vivo pharmacodynamic neutralization of IL-12 in C38C92C104. Detailed Implementation

[0072] The example embodiment is described below.

[0073] The following description, by way of example only, is for illustrative purposes. Numerous specific details, relationships, and methods are set forth to provide a complete understanding of the disclosure. Those skilled in the art will readily recognize that the disclosure can be practiced and / or implemented with other materials (e.g., reagents, cells, animals), techniques, and / or procedures without one or more specific details. Many of the techniques and procedures described herein are fully understood and commonly employed by those skilled in the art using conventional methods.

[0074] definition

[0075] Unless otherwise defined, all technical terms, symbols, and other scientific terms or specialized terms used herein are intended to have the meaning commonly understood by one skilled in the art to which this disclosure pertains. In some cases, for clarity and / or ease of reference, terms are defined herein with the commonly understood meaning, and the inclusion of such definitions herein should not necessarily be construed as representing a material difference from the meaning generally understood in this art. It will be further understood that terms such as those defined in common dictionaries should be interpreted as having a meaning consistent with their meaning in the context of the relevant art and / or as otherwise defined herein.

[0076] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0077] When referring to the elements disclosed herein, the articles “a,” “an,” “the,” and “described” are intended to mean the presence of one or more of the elements. Furthermore, one or more elements may be the same or different. For example, unless the context clearly indicates otherwise, “polypeptide” includes a single polypeptide as well as two or more polypeptides.

[0078] Throughout this specification and in the following claims, unless the context otherwise requires, the term "comprise" and variations such as "comprises" and "comprising" will be understood to imply inclusion of, for example, the stated integers or steps or groups of integers or steps, but not to exclude any other integers or steps or groups of integers or steps. When used herein, the term "comprise" may be replaced by the terms "containing" or "including".

[0079] As used herein, the term “composed of” excludes any element, step or component not specified in the elements of the patent application scope.

[0080] When used herein, the term “consistently of” does not exclude materials or steps that do not substantially affect the essential and novel features of the claims.

[0081] This document also provides corresponding embodiments of each and every embodiment characterized by the terms “comprising,” “containing,” “including,” or “having,” wherein such terms are replaced by the terms “consisting of” or “substantially consisting of.”

[0082] As used herein, the connecting term "and / or" between multiple listed elements should be understood to encompass both individual options and combined options. For example, when two elements are connected by "and / or," the first option refers to the applicability of the first element in the absence of the second element. The second option refers to the applicability of the second element in the absence of the first element. The third option refers to the applicability of the first element together with the second element. Any of these options should be understood to fall within this meaning and therefore satisfy the requirement of the term "and / or" as used herein. The simultaneous applicability of more than one option should also be understood to fall within this meaning and therefore satisfy the requirement of the term "and / or".

[0083] It should be understood that for all numerical limits describing some parameters in this application, such as “about,” “at least,” “less than,” “less than,” and “greater than,” the description necessarily also covers any range defined by the listed values. Thus, for example, describing “at least 1, 2, 3, 4, or 5” also describes the ranges 1-2, 1-3, 1-4, 1-5, 2-3, 2-4, 2-5, 3-4, 3-5, and 4-5, etc.

[0084] When a list is presented, unless otherwise stated, it should be understood that each individual element of the list and each combination of the list is an independent embodiment. For example, a list of embodiments presented as "A, B, or C" should be interpreted as including embodiments "A", "B", "C", "A or B", "A or C", "B or C", or "A, B, or C".

[0085] As used herein, the term “about” means within an acceptable range of error for a particular value, as determined by someone generally skilled in the art. Typically, the acceptable range of error for a particular value depends at least in part on how the value is measured or determined, for example, limitations of the measurement system. For instance, “about” may mean within an acceptable standard deviation according to practice of the art. It should be understood that the term “about” may precede any particular value specified herein, except for the particular value used in the examples. When “about” precedes a range, as in “1-20”, the term “about” should be interpreted as applicable to two given values ​​in that range, such that “about 1-20” means about 1 to about 20.

[0086] As used herein, the term "peptide" refers to a polymer of at least two amino acids covalently linked by an amide bond, regardless of length or post-translational modifications (e.g., glycosylation or phosphorylation). Peptides may contain any suitable L-amino acids and / or D-amino acids, such as common α-amino acids (e.g., alanine, glycine, valine), non-α-amino acids (e.g., β-alanine, 4-aminobutyric acid, 6-aminohexanoic acid, sarcosine, statine), and uncommon amino acids (e.g., citrulline, homocitrulline, homoserine, orleucine, ornithine, ornithine). The amino, carboxyl, and / or other functional groups on the peptide may be free (e.g., unmodified) or protected with suitable protecting groups. Suitable protecting groups for amino and carboxyl groups and methods for adding or removing protecting groups are known in the art and disclosed, for example, in Green and Wuts, "Protecting Groups in Organic Synthesis", John Wiley and Sons, 1991. The functional groups of the peptide can also be derivatized (e.g., alkylated) or labeled (e.g., with detectable labels such as fluorophores or haptens) using methods known in this technology. Where desired, the peptide may contain one or more modifications (e.g., amino acid linkers, acylation, acetylation, amidation, methylation, terminal modifiers (e.g., cyclization), N-methyl-α-amino substitution). Additionally, the peptide may be an analogue of a known and / or naturally occurring peptide, such as a peptide analogue with conserved amino acid residue substitutions.

[0087] As used herein, a “polynucleotide” is defined as a plurality of nucleotides and / or nucleotide analogs linked together in a single molecule. In some embodiments, the polynucleotides disclosed herein comprise deoxyribonucleotides. In some embodiments, the polynucleotide comprises ribonucleotides. Non-limiting examples of polynucleotides include single-stranded, double-stranded, or multi-stranded DNA or RNA, DNA-RNA hybrids (e.g., where each “T” position may be independently substituted with a “U”, and vice versa), or polymers comprising purine and pyrimidine bases, or other natural, chemically or biochemically modified, non-natural, or derived nucleotide bases. The backbone of a polynucleotide may comprise a sugar and phosphate ester group, a modified or substituted sugar or phosphate ester group, a polymer of synthetic subunits (such as aminophosphates), or a combination thereof.

[0088] As used herein, the term "sequence identity" refers, expressed as a percentage, to the extent that two nucleotide sequences share identical residues at the same positions when sequences are aligned to achieve the maximum level of identity. For sequence alignment and comparison, typically one sequence is designated as the reference sequence, and the test sequence is compared to it. Sequence identity between the reference and test sequences is expressed as the percentage of identical nucleotide or amino acid positions across the entire length of the reference sequence when aligned to achieve the maximum level of identity. For example, if the test sequence shares identical nucleotide residues at 70% of the same positions across the entire length of the reference sequence after alignment to achieve the maximum level of identity, the two sequences should be considered to have 70% sequence identity.

[0089] Those familiar with this technique can easily align sequences for comparison to achieve the highest level of identity using appropriate alignment methods or algorithms. In some cases, alignment may include the introduction of gaps to provide the highest level of identity. Examples include the local homology algorithm of Smith and Waterman, Adv. Appl. Math. 2:482 (1981); the homology alignment algorithm of Needleman and Wunsch, J. Mol. Biol. 48:443 (1970); the similarity search method of Pearson and Lipman, Proc. Nat'l. Acad. Sci. USA 85:2444 (1988); computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics software package, Genetics Computer Group, 575 Science Dr., Madison, Wis.); and visual inspection (generally see Ausubel et al., Current Protocols in Molecular Biology).

[0090] When using sequence comparison algorithms, the test and reference sequences are input into the computer. If necessary, subsequent coordinates and sequence algorithm parameters are specified. The sequence comparison algorithm then calculates the percentage of sequence identity between the test sequence and the reference sequence based on the specified parameters. A commonly used tool for determining the percentage of sequence identity is the Protein Basic Local Alignment Search Tool (BLASTP), which is available from the National Center for Biotechnology Information and the National Library of Medicine of the National Institutes of Health (Altschul et al., 1990).

[0091] The term "expression vector" refers to a reproducible nucleic acid from which one or more proteins can be expressed when the expression vector is transformed into a suitable expression host cell (e.g., a recombinant cell).

[0092] As used in this article, the term "promoter" refers to the DNA region that RNA polymerase binds to and initiates gene transcription.

[0093] As used herein, the term “operably linked” means that a nucleic acid is located in a recombinant polynucleotide (e.g., a vector) such that the nucleic acid can be expressed under the control of the component it is linked to (e.g., a promoter).

[0094] As used herein, the term "selective biomarker component" refers to a component that imparts traits suitable for human selection. Selective biomarker components can be negative or positive selection biomarkers.

[0095] As used herein, the term "expression host cell" refers to a cell that can be used to receive, maintain, replicate, and / or amplify vectors.

[0096] As used herein, the term "antibody" refers to an immunoglobulin molecule capable of specifically binding to a target (such as carbohydrates, polynucleotides, lipids, peptides, etc.) via at least one antigen recognition site located in a variable domain of an immunoglobulin molecule. As used herein, the term "antibody" refers to a full-length antibody. In some embodiments, the antibody is a modified and / or engineered antibody; non-limiting examples of modified and / or engineered antibodies include chimeric antibodies, humanized antibodies, antibodies with multiple complementary sites, bispecific antibodies, and multispecific antibodies.

[0097] As used in this article, "humanized antibody" refers to an antibody whose antigen-binding site is derived from a non-human species and whose framework region is derived from a human immunoglobulin sequence.

[0098] As used in this article, "human antibody" refers to an antibody with variable regions of heavy and light chains, wherein the framework and antigen-binding sites are derived from human-origin sequences.

[0099] As used herein, the terms “single-domain antibody (sdAb)” or “nanobody” refer to an immunoglobulin molecule composed of a single monomeric variable antibody domain that can specifically bind to a target.

[0100] As used herein, the term "antigen-binding fragment" refers to a portion of an immunoglobulin molecule (e.g., an antibody) that retains antigen-binding properties (e.g., the antigen-binding properties of a corresponding full-length antibody). Non-limiting examples of antigen-binding fragments include VH regions, VL regions, Fab fragments, F(ab')2 fragments, Fd fragments, Fv fragments, and domain antibodies (dAbs) consisting of a VH domain or a VL domain, etc. VH and VL domains can be linked together via synthetic linkers to form various types of single-chain antibody designs, wherein the VH / VL domains pair intramolecularly or intermolecularly, where the VH and VL domains are expressed by separate chains, to form monovalent antigen-binding sites, such as single-chain Fv (scFv) or diabody antibodies. In some embodiments, the antigen-binding fragment is Fab, F(ab')2, Fab', scFv, or Fv. In some embodiments, the antigen-binding fragment is scFv.

[0101] As used herein, “complementarity-determining region (CDR)” encompasses any CDR defined by a technically recognized method for identifying CDR residues on an antibody. See, for example, Kabat, E.A. et al., (1991) Sequences of Proteins of Immunological Interest, 5th ed., US Department of Health and Human Services, NIH Publication No. 91-3242; Chothia et al., (1989) Nature 342:877; Chothia, C. et al., (1987) J. Mol. Biol. 196:901-917; Allazikani et al., (1997) J. Molec. Biol. 273:927-948; and Almagro, J. Mol. Recognit. 17:132-143 (2004). See also hgmp.mrc.ac.uk and bioinf.org.uk / abs. When the same method is used to determine the identity of the CDRs of two antibodies, it is determined that the two antibodies have the same CDRs for HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and / or LCDR3.

[0102] The scope of the antibody's framework region and CDR can be identified using one of several suitable methods well known in this art, for example, according to the Kabat definition, Chothia definition, AbM definition, and / or contact definition. Publicly available and / or commercially available tools for identifying architectures and / or CDR regions include IgBlast (available at www.ncbi.nlm.nih.gov / igblast / ), Scaligner (available at drugdesigntech at www.scaligner.com / ), IMGT rules and / or tools (see, for example, www.imgt.org / IMGTScientificChart / Nomenclature / IMGT-FRCDRdefinition.html, also available at www.imgt.org / ), Chothia specification assignment (available at www.bioinf.org.uk / abs / chothia.html), antigen receptor numbering and receptor classification (ANARCI, available at opig.stats.ox.ac.uk / webapps / newsabdab / sabpred / anarci / ), or Paratome web server (available at www.ofranlab.org / paratome / ), or Paratome web server (available at www.ofranlab.org / paratome / , see Vered Kunik et al., Nucleic Acids Research, Vol. 40, No. W1, July 1, 2012, pp. W521-W524.

[0103] For example, for AB-1, the amino acid sequences of HCDR1, HCDR2 and HCDR3: (1) contain SEQ ID NO:45, SEQ ID NO:72 and SEQ ID NO:79 respectively, as determined by the IMGT number; (2) contain SEQ ID NO:80, SEQ ID NO:96 and SEQ ID NO:103 respectively, as determined by the Kabat number; and (3) contain SEQ ID NO:105, SEQ ID NO:132 and SEQ ID NO:139 respectively, as determined by the Chothia number.

[0104] As used herein, the term "antibody mimic" refers to a polypeptide that mimics the ability of an antibody to bind to an antigen, but whose structure differs from that of a native antibody. Examples of antibody mimics include, but are not limited to, Adnectin, Affibody, Affilin, Affimer, Affitin, Alphabody, Antiticalin, Avimer, DARPin, Fynomer, Kunitz domain peptides, monobodies, nanobodies, nanoCLAMP, and Versabody.

[0105] As used herein, the term "KD," also known as "binding constant," "equilibrium dissociation constant," or "affinity constant," is a measure of the degree of reversible association between two molecular species (e.g., antibody and target protein) and includes both actual binding affinity and apparent binding affinity. Binding affinity can be determined using methods known in this art, including, for example, measurements based on surface plasma resonances, such as using the Octet (ForteBio) or Biacore systems and assays. A reference comparing various surface techniques used to measure binding affinity and kinetics is Yang, D., Singh, A., Wu, H., and Kroe-Barrett, R., Comparison of biosensor platforms in the evaluation of high affinity antibody-antigen bindingkinetics, Analytical Biochemistry 508: 78-96 (2016), the contents of which are incorporated herein by reference in their entirety.

[0106] As used herein, the term "fusion protein" refers to a single protein molecule that is synthetic, semi-synthetic, or recombinant. Fusion proteins may comprise all or part of two or more different proteins and / or polypeptides linked by covalent bonds (e.g., peptide bonds).

[0107] The terms "individual" or "patient" refer to an animal (e.g., a mammal, such as a human) diagnosed with or suspected of having an IL-12 / IL-23 related disease or disorder (e.g., Crohn's disease or ulcerative colitis), or an animal at risk of developing such a disease. Diagnosis can be made using any method or technique known in this art. Those skilled in the art will understand that an individual to be treated according to this disclosure may have already undergone standard testing or may have been identified without examination as being at risk due to the presence of one or more risk factors associated with the disease or disorder.

[0108] The phrase “pharmaceutically acceptable” means that the substance or composition modified by the phrase is suitable for use in contact with human and lower animal tissues without excessive toxicity, irritation, allergic reactions or similar reactions, within the scope of reasonable medical judgment, and is commensurate with a reasonable benefit / risk ratio.

[0109] As used herein, the term "pharmaceutically acceptable salt" means salts that, within the bounds of reasonable medical judgment, are suitable for use in contact with mammalian tissues without excessive toxicity, irritation, anaphylactic reactions, or similar reactions, and that are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in this art. For example, SM Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, the relevant teachings of which are incorporated herein by reference in their entirety. Pharmaceutically acceptable salts of agents / compounds described herein include salts derived from suitable inorganic and organic acids and suitable inorganic and organic bases.

[0110] Examples of salts derived from suitable acids include those formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid; or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid; or amino salts formed according to other methods used in this technique, such as ion exchange. Other pharmaceutically acceptable salts derived from suitable acids include adipates, alginates, ascorbic acid salts, aspartate salts, benzenesulfonates, benzoates, hydrogen sulfates, borates, butyrates, camphorates, camphorsulfonates, cinnamates, citrates, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, transbutenedioic acid, gluconate-heptate, glycerophosphates, gluconate, glutarate, glycolate, hemisulfate, heptahydrate, hexanoate, hydroiodate, hydroxybenzoate, and 2-hydroxy-ethanesulfonate. Hydroxybutenedioate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, dihydroxynaphthalate, pectate, persulfate, 2-phenoxybenzoate, phenylacetate, 3-phenylpropionate, phosphate, neopentanoate, propionate, pyruvate, salicylate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate and similar salts.

[0111] It can form monoacid salts, diacid salts, or triacid salts, and these salts can exist in hydrated, solvated, or substantially anhydrous forms.

[0112] Salts derived from suitable bases include those derived from inorganic bases, such as alkali metals, alkaline earth metals, and ammonium bases, and those derived from aliphatic, alicyclic, or aromatic organic amines, such as methylamine, trimethylamine, and methylpyridine, or N+((C1-C4)alkyl)4 salts. Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, barium, and similar salts. Where appropriate, other pharmaceutically acceptable salts include non-toxic ammonium salts, quaternary ammonium salts, and amine cations formed using counterions, such as halide, hydroxide, carboxyl, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate ions.

[0113] "Pharmaceutically acceptable carrier" refers to a non-toxic carrier or excipient that does not impair the pharmacological activity of the agent formulated together with it, and is non-toxic when administered at a dose sufficient to deliver a therapeutic amount of the agent. Pharmaceutically acceptable carriers that can be used in the compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffering substances (such as phosphates), glycine, sorbic acid, potassium sorbate, mixtures of saturated vegetable fatty acids in the form of glycerides, water, salts or electrolytes (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin.

[0114] As used herein, “treating” or “treatment” means taking steps to deliver a therapy to an individual in need, such as a mammal (e.g., by administering one or more therapeutic agents to a mammal). “Treating” or “treatment” includes suppressing a disease or ailment (e.g., by slowing or stopping the progression of a disease or ailment or causing the disease or ailment to regress) and relieving symptoms caused by a disease or ailment.

[0115] The term "treating" or "treatment" refers to the medical management of an individual with the aim of improving, ameliorhyming, stabilizing (i.e., preventing deterioration), preventing, or curing a disease, pathological condition, or symptom—such as the specific indications illustrated herein. This term includes active treatment (treatment aimed at improving a disease, pathological condition, or symptom), causal treatment (treatment addressing the cause of a related disease, pathological condition, or symptom), palliative treatment (treatment aimed at relieving symptoms), preventative treatment (treatment aimed at minimizing or partially or completely suppressing the development of a related disease, pathological condition, or symptom), and supportive treatment (treatment used to complement another therapy). Treatment also includes reducing the severity of a disease or symptom, preventing its spread, delaying or slowing its progression, improving or alleviating a disease or symptom, and resolving (whether partially or completely), whether detectable or undetectable. "Improvement" or "mitigation" of a disease or ailment means a reduction in the severity and / or undesirable clinical manifestations and / or a slowing or prolonging of its progression compared to the absence of treatment. "Treatment" can also mean an extension of life expectancy compared to the expected lifespan without treatment. Those requiring treatment include those already suffering from a disease or ailment, those susceptible to a disease or ailment, and those requiring prevention of a disease or ailment.

[0116] "Pharmaceutical composition" refers to one or more therapeutic agents and a generally accepted medium for delivering a bioactive agent to an individual (e.g., a human) in the art. In some embodiments, a pharmaceutical composition may comprise one or more pharmaceutically acceptable excipients, diluents, or carriers. In some embodiments, a pharmaceutical composition suitable for use in the methods disclosed herein further comprises one or more pharmaceutically acceptable carriers.

[0117] "Pharmaceutically acceptable carriers, diluents, or excipients" include any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier that has been approved by the U.S. Food and Drug Administration for use in humans or livestock.

[0118] "Pharmaceutically acceptable carrier" refers to a component of a pharmaceutical composition that is non-toxic to individuals, other than the active ingredient. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers, or preservatives. In some embodiments, the carrier may be a diluent, adjuvant, excipient, or solvent administered with an agent (e.g., a polynucleotide). Such solvents may be liquids, such as water and oils, including petroleum, animal, plant, or synthetic sources, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. For example, 0.4% saline and 0.3% glycine may be used. These solutions are sterile and generally free of particulate matter. They can be sterilized using known and familiar sterilization techniques (e.g., filtration). The composition may, as needed, contain pharmaceutically acceptable excipients that approximate physiological conditions, such as pH adjusters and buffers, stabilizers, thickeners, lubricants, and colorants. The concentration of the agent in such pharmaceutical preparations can vary widely, from less than about 0.5% to at least about 1%, or up to 15% or 20%, 25%, 30%, 35%, 40%, 45%, or 50% (by weight). The concentration is selected primarily based on the required dose, fluid volume, viscosity, etc., depending on the dosing method. Suitable solvents and preparations, including other human proteins such as human serum albumin, are described, for example, in Remington: The Science and Practice of Pharmacy, 21st edition, Troy, DB ed., Lipincott Williams and Wilkins, Philadelphia, PA 2006, Part 5, Pharmaceutical Manufacturing: 691-1092 (e.g., pp. 958-89).

[0119] Non-limiting examples of pharmaceutically acceptable carriers include physiologically compatible solvents, dispersion media, coating agents, antibacterial and antifungal agents, isotropic agents and absorption delay agents and the like, such as salts, buffers, antioxidants, sugars, aqueous or non-aqueous carriers, preservatives, wetting agents, surfactants or emulsifiers or combinations thereof.

[0120] Non-limiting examples of buffers include acetic acid, citric acid, formic acid, succinic acid, phosphoric acid, carbonic acid, malic acid, aspartic acid, histidine, boric acid, Tris buffer, HEPPSO, and HEPES.

[0121] Non-limiting examples of antioxidants include ascorbic acid, methionine, cysteine ​​hydrochloride, sodium bisulfate, sodium disulfite, sodium sulfite, lecithin, citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, and tartaric acid.

[0122] Non-limiting examples of amino acids include histidine, isoleucine, methionine, glycine, arginine, lysine, L-leucine, trileucine, alanine, glutamic acid, L-threonine, and 2-aniline.

[0123] Non-limiting examples of surfactants include polysorbates (e.g., polysorbate-20 or polysorbate-80); and polyoxamer. (e.g., poloxamer 188); Triton; sodium octyl glycoside; lauryl-, myristyl-, linoleyl-, or stearyl-sulfobetaine; lauryl-, myristyl-, linoleyl-, or stearyl-sarcosine; linoleyl-, myristyl-, or cetyl-betaine; lauramidopropyl-, cocamamidopropyl-, linoleamidopropyl-, myristamidopropyl-, palmitoamide-, or isostearamidopropyl-betaine (e.g., lauramidopropyl); myristamidopropyl-, palmitoamide-, or isostearamidopropyl-dimethylamine; sodium methylcocoyl taurate or disodium methyl oleyl taurate; and the MONAQUA™ series (MonaIndustries, Inc., Paterson, NJ), polyethylene glycol, polypropylene glycol, and copolymers of ethylene glycol and propylene glycol (e.g., PLURONICS™, PF68, etc.).

[0124] Non-limiting examples of preservatives include phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, phenylmercuric nitrite, phenoxyethanol, formaldehyde, chlorobutanol, magnesium chloride, alkyl p-hydroxybenzoate (methyl ester, ethyl ester, propyl ester, butyl ester and the like), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate and thimerosal, or mixtures thereof.

[0125] Non-limiting examples of sugars include monosaccharides, disaccharides, trisaccharides, polysaccharides, sugar alcohols, reducing sugars, non-reducing sugars (such as glucose), sucrose, trehalose, lactose, fructose, maltose, dextran, glycerol, glucan, erythritol, glycerol, arabinitol, xylitol, sorbitol, mannitol, melibiose, pinetriose, raffinose, manntriose, stachyose, maltose, lactulose, maltulose, glucol, maltitol, lactitol, or isomaltulose.

[0126] Non-limiting examples of salts are acid addition salts and base addition salts. Acid addition salts include salts derived from non-toxic inorganic acids, such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphorous acid, and similar acids, and salts derived from non-toxic organic acids, such as aliphatic monocarboxylic acids and dicarboxylic acids, phenyl-substituted phenylalkyl acids, hydroxyalkyl acids, aromatic acids, aliphatic and aromatic sulfonic acids, and similar acids. Base addition salts include salts derived from alkaline earth metals, such as sodium, potassium, magnesium, calcium, and the like, and salts derived from non-toxic organic amines, such as N,N'-diphenylmethylethylenediamine, N-methylreduced glucosamine, chloroprocaine, choline, diethanolamine, ethylenediamine, procaine, and the like. In some embodiments, the salt is sodium chloride (NaCl).

[0127] The agents described herein (e.g., polynucleotides) may be prepared according to standard procedures and administered at doses selected to reduce, prevent, or eliminate the disease being treated or to slow or stop its progression (for a general description of the methods of administering various agents for human therapeutic use, see, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA and Goodman and Gilman's The Pharmaceutical Basis of Therapeutics, McGraw-Hill, New York, NY, the contents of which are incorporated herein by reference).

[0128] As used herein, “administration” or “drug administration” refers to providing an individual with the compound, composition, or pharmaceutically acceptable salt thereof described herein for treatment or prevention. Administration may be performed, for example, once, multiple times, and / or over one or more extended periods. Administration includes direct administration (including self-administration) and indirect administration (including prescribing a drug or instructing an individual to consume the drug). For example, as used herein, instructing an individual (e.g., a human patient) to self-administer a drug (e.g., a medication) or having another person administer the drug and / or having a prescription for a drug given to a patient (e.g., a physician) administer the drug to the individual.

[0129] "Therapeutic effective dose," "effective dose," or "effective amount" refers to the amount effective at the dose and for the time period necessary to achieve the desired therapeutic outcome (e.g., treatment, cure, suppression, or improvement of a physiological response or disease). Complete therapeutic effect does not necessarily occur with a single dose and may only occur after a series of doses. Therefore, a therapeutic effective dose may be administered in one or more administrations. Therapeutic effective doses can vary depending on factors such as the disease state of the mammal (e.g., human patient), age, sex, and weight, administration pattern, and the ability of the therapeutic agent or combination of therapeutic agents to elicit the desired response.

[0130] The effective dose of the agent to be administered can be determined by a clinician of general skill using the guidelines provided herein and other methods known in this technique. Relevant factors include the given agent, pharmaceutical preparation, route of administration, type of disease or condition, the identity of the individual or host being treated (e.g., age, sex, weight), and similar factors. For example, suitable doses may be approximately 0.001 mg / kg to approximately 100 mg / kg per treatment, approximately 0.01 mg / kg to approximately 100 mg / kg, approximately 0.01 mg / kg to approximately 10 mg / kg, approximately 0.01 mg / kg to approximately 1 mg / kg body weight. Determining the dose for a specific agent, individual, and disease is entirely within the competence of a person skilled in this technique. Preferably, the dose will not cause adverse side effects or will produce minimal adverse side effects.

[0131] The desired response or outcome includes cellular, tissue-level effects, or clinical outcomes. Therefore, the term "therapeutic effective amount" or its synonyms depend on the context in which they are applied. For example, in some embodiments, the therapeutic effective amount is an amount of composition sufficient to achieve a therapeutic response compared to a response obtained without administration of the composition. In other embodiments, the therapeutic effective amount is an amount that produces a beneficial or desired outcome in an individual compared to a control. As defined herein, the therapeutic effective amount of the compositions disclosed herein (e.g., pharmaceutical compositions) can be readily determined by those skilled in the art using conventional methods known in the art. Dosing regimens and routes of administration can be adjusted to provide an optimal therapeutic response.

[0132] Antibody or its antigen-binding fragment

[0133] In some embodiments, the antibody or its antigen-binding fragment disclosed herein comprises an immunoglobulin heavy chain variable domain (VH), an immunoglobulin light chain variable domain (VL), or both.

[0134] Heavy-chain variable structural domain (VH)

[0135] In some embodiments, the antibody or its antigen-binding fragment comprises a VH domain (e.g., a mammalian VH domain, such as a rodent (e.g., mouse) VH domain, or a primate (e.g., human) VH domain). In some embodiments, the antibody or its antigen-binding fragment comprises a human VH domain. In some embodiments, the antibody or its antigen-binding fragment comprises a humanized (e.g., at least about: 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98%, or 99% humanized) VH domain containing a human framework region, or both.

[0136] In some embodiments, the antibody or its antigen-binding fragment includes a VH domain having less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1. In some embodiments, the antibody or its antigen-binding fragment does not include a VH domain containing the amino acid sequence of SEQ ID NO:1.

[0137] In some embodiments, the antibody or its antigen-binding fragment comprises the following VH domain: a) HCDR1, HCDR2, and HCDR3, which respectively contain heavy chain complementarity-determining regions (HCDRs) 1, HCDR2, and HCDR3 that have at least 80% sequence identity (e.g., at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity) with respect to the VH domain containing the amino acid sequence of SEQ ID NO:X. b) It has less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1.

[0138] In some embodiments, the antibody or its antigen-binding fragment comprises a VH domain, which includes HCDR1, HCDR2, and HCDR3 having 100% sequence identity with HCDR1, HCDR2, and HCDR3, respectively, that contain the amino acid sequence of SEQ ID NO: X.

[0139] In some embodiments, X is any one of 1-11, 19-21, 299, and 300. Table 1 shows sequences identified as SEQ ID NO: 1-11, 19-21, 299, and 300, which correspond to the human VH domain. In some embodiments, X is any one of 2-11, 19-21, 299, and 300. In some embodiments, X is any one of 2-11, 299, and 300. In some embodiments, X is any one of 2-4, 299, and 300. In some embodiments, X is 299. In some embodiments, X is 300. In some embodiments, X is any one of 1-11 and 19-21. In some embodiments, X is any one of 2-11 and 19-21. In some embodiments, X is any one of 1-11. In some embodiments, X is any one of 2-11. In some embodiments, X is any one of 1-4. In some embodiments, X is any one of 2-4. In some embodiments, X is 1. In some embodiments, X is 2. In some embodiments, X is 3. In some embodiments, X is 4. In some embodiments, X is 5. In some embodiments, X is 6. In some embodiments, X is 7. In some embodiments, X is 8. In some embodiments, X is 9. In some embodiments, X is 10. In some embodiments, X is 11. In some embodiments, X is 19. In some embodiments, X is 20. In some embodiments, X is 21. This paragraph applies to paragraph

[0110] and / or paragraph

[0111] .

[0140] HCDR sequences identified by ImMunoGeneTics (IMGT) numbers

[0141] In some embodiments, the antibody or its antigen-binding fragment comprises: a) HCDR1 having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:X (e.g., at least 85%, at least 90%, or at least 95% sequence identity). b) HCDR2 having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:72 (e.g., at least 85%, at least 90%, or at least 95% sequence identity), and c) HCDR3 having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:79 (e.g., at least 85%, at least 90%, or at least 95% sequence identity). The antibody or its antigen-binding fragment contains a VH domain that has less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1.

[0142] In addition, this disclosure also provides an antibody or an antigen-binding fragment thereof, the antibody or antigen-binding fragment thereof comprising: a) HCDR1 having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:X (e.g., at least 85%, at least 90%, or at least 95% sequence identity). b) HCDR2 having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:72 (e.g., at least 85%, at least 90%, or at least 95% sequence identity), and c) HCDR3 having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:79 (e.g., at least 85%, at least 90%, or at least 95% sequence identity). The antibody or its antigen-binding fragment contains a VH domain that has less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1.

[0143] In some embodiments, the antibody or its antigen-binding fragment comprises: a) HCDR1 containing the amino acid sequence of SEQ ID NO:X (e.g., composed of it), b) HCDR2 containing the amino acid sequence of SEQ ID NO:72 (e.g., composed of it), and c) HCDR3 containing the amino acid sequence of SEQ ID NO:79 (e.g., composed of it).

[0144] In some embodiments, X is any one of 303, 304, 45-47, and 49-51. In some embodiments, X is any one of 303, 304, and 45-47. In some embodiments, X is 303. In some embodiments, X is 304. In some embodiments, X is any one of 45-47 and 49-51. In some embodiments, X is any one of 45-47. In some embodiments, X is 45. In some embodiments, X is 46. In some embodiments, X is 47. In some embodiments, X is 49. In some embodiments, X is 50. In some embodiments, X is 51. This paragraph applies to any one or more of paragraphs

[0113] -

[0115] .

[0145] Table 2 shows the sequences identified as SEQ ID NO:45-47, 49-51, 72, 79, 303 and 304, which correspond to the human HCDR sequences determined according to the IMGT number.

[0146] In some embodiments, the antibody or its antigen-binding fragment comprises: a) HCDR1 containing the amino acid sequence of SEQ ID NO:45 (e.g., composed of it), b) HCDR2 containing the amino acid sequence of SEQ ID NO:72 (e.g., composed of it), and c) HCDR3 containing the amino acid sequence of SEQ ID NO:79 (e.g., composed of it).

[0147] In some embodiments, the antibody or its antigen-binding fragment comprises: a) HCDR1 containing the amino acid sequence of SEQ ID NO:303 (e.g., composed of it), b) HCDR2 containing the amino acid sequence of SEQ ID NO:72 (e.g., composed of it), and c) HCDR3 containing the amino acid sequence of SEQ ID NO:79 (e.g., composed of it).

[0148] In some embodiments, the antibody or its antigen-binding fragment comprises: a) HCDR1 containing the amino acid sequence of SEQ ID NO:304 (e.g., composed of it), b) HCDR2 containing the amino acid sequence of SEQ ID NO:72 (e.g., composed of it), and c) HCDR3 containing the amino acid sequence of SEQ ID NO:79 (e.g., composed of it).

[0149] HCDR sequence determined by Kabat number

[0150] In some embodiments, the antibody or its antigen-binding fragment comprises: a) HCDR1 having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:X (e.g., at least 85%, at least 90%, or at least 95% sequence identity). b) HCDR2 having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:96 (e.g., at least 85%, at least 90%, or at least 95% sequence identity), and c) HCDR3 having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:103 (e.g., at least 85%, at least 90%, or at least 95% sequence identity). The antibody or its antigen-binding fragment contains a VH domain that has less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1.

[0151] In addition, this disclosure also provides an antibody or an antigen-binding fragment thereof, the antibody or antigen-binding fragment thereof comprising: a) HCDR1 having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:X (e.g., at least 85%, at least 90%, or at least 95% sequence identity). b) HCDR2 having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:96 (e.g., at least 85%, at least 90%, or at least 95% sequence identity), and c) HCDR3 having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:103 (e.g., at least 85%, at least 90%, or at least 95% sequence identity). The antibody or its antigen-binding fragment contains a VH domain that has less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1.

[0152] In some embodiments, the antibody or its antigen-binding fragment comprises: a) HCDR1 containing the amino acid sequence of SEQ ID NO:X (e.g., composed of it), b) HCDR2 containing the amino acid sequence of SEQ ID NO:96 (e.g., composed of it), and c) HCDR3 containing the amino acid sequence of SEQ ID NO:103 (e.g., composed of it), The antibody or its antigen-binding fragment contains a VH domain that has less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1.

[0153] In some embodiments, X is 80, 81, or 82. In some embodiments, X is 80. In some embodiments, X is 81. In some embodiments, X is 82. This paragraph applies to any one or more of paragraphs

[0121] -

[0123] .

[0154] Table 2 shows the sequences identified as SEQ ID NO: 80-82, 96 and 103, which correspond to human HCDR sequences determined according to the Kabat number.

[0155] HCDR sequence determined according to Chothia number

[0156] In some embodiments, the antibody or its antigen-binding fragment comprises: a) HCDR1 having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:X (e.g., at least 85%, at least 90%, or at least 95% sequence identity). b) HCDR2 having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:132 (e.g., at least 85%, at least 90%, or at least 95%), and c) HCDR3 having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:139 (e.g., at least 85%, at least 90%, or at least 95% sequence identity). The antibody or its antigen-binding fragment contains a VH domain that has less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1.

[0157] In addition, this disclosure also provides an antibody or an antigen-binding fragment thereof, the antibody or antigen-binding fragment thereof comprising: a) HCDR1 having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:X (e.g., at least 85%, at least 90%, or at least 95% sequence identity). b) HCDR2 having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:132 (e.g., at least 85%, at least 90%, or at least 95%), and c) HCDR3 having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:139 (e.g., at least 85%, at least 90%, or at least 95% sequence identity). The antibody or its antigen-binding fragment contains a VH domain that has less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1.

[0158] In some embodiments, the antibody or its antigen-binding fragment comprises: a) HCDR1 containing the amino acid sequence of SEQ ID NO:X (e.g., composed of it), b) HCDR2 containing the amino acid sequence of SEQ ID NO:132 (e.g., composed of it), and c) HCDR3 containing the amino acid sequence of SEQ ID NO:139 (e.g., composed of it).

[0159] In some embodiments, X is any one of 305, 306, 105-107, and 109-111. In some embodiments, X is any one of 305, 306, and 105-107. In some embodiments, X is 305. In some embodiments, X is 306. In some embodiments, X is any one of 105-107 and 109-111. In some embodiments, X is any one of 105-107. In some embodiments, X is 105. In some embodiments, X is 106. In some embodiments, X is 107. In some embodiments, X is 109. In some embodiments, X is 110. In some embodiments, X is 111. This paragraph applies to any one or more of paragraphs

[0127] -

[0129] .

[0160] Table 2 shows the sequences identified as SEQ ID NO: 105-107, 109-111, 132, 139, 305 and 306, which correspond to the human HCDR sequences determined according to the Chothia number.

[0161] In some embodiments, the antibody or its antigen-binding fragment comprises: a) HCDR1 containing the amino acid sequence of SEQ ID NO:105 (e.g., composed of it), b) HCDR2 containing the amino acid sequence of SEQ ID NO:132 (e.g., composed of it), and c) HCDR3 containing the amino acid sequence of SEQ ID NO:139 (e.g., composed of it).

[0162] In some embodiments, the antibody or its antigen-binding fragment comprises: a) HCDR1 containing the amino acid sequence of SEQ ID NO:305 (e.g., composed of it), b) HCDR2 containing the amino acid sequence of SEQ ID NO:132 (e.g., composed of it), and c) HCDR3 containing the amino acid sequence of SEQ ID NO:139 (e.g., composed of it).

[0163] In some embodiments, the antibody or its antigen-binding fragment comprises: a) HCDR1 containing the amino acid sequence of SEQ ID NO:306 (e.g., composed of it), b) HCDR2 containing the amino acid sequence of SEQ ID NO:132 (e.g., composed of it), and c) HCDR3 containing the amino acid sequence of SEQ ID NO:139 (e.g., composed of it).

[0164] VH framework area (VH FR1-4)

[0165] In some embodiments, the VH domain of the antibody or its antigen-binding fragment comprises four VH framework regions (VH FR1-4) and three heavy chain complementarity-determining regions (HCDR1-3) in the following order from N-terminus to C-terminus: VH FR1-HCDR1-VH FR2-HCDR2-VH FR3-HCDR3-VH FR4, wherein: a) The VH FR1-HCDR1 contains the amino acid sequence of SEQ ID NO:X. b) The VH FR2 contains the amino acid sequence of GKGL (SEQ ID NO:268), GDYL (SEQ ID NO:269), or GYYL (SEQ ID NO:270), or c) The VH FR3 contains the amino acid sequence of NSLK (SEQ ID NO:271), PSLR (SEQ ID NO:272), or NDLR (SEQ ID NO:273), or Any combination of a) to c).

[0166] In some embodiments, the antibody or its antigen-binding fragment comprises: VH FR1-HCDR1 containing the amino acid sequence of SEQ ID NO:X, and

[0167] a) VH FR2 containing the amino acid sequence of GKGL (SEQ ID NO:268), GDYL (SEQ ID NO:269), or GYYL (SEQ ID NO:270), or

[0168] b) VH FR3 containing the amino acid sequence of NSLK (SEQ ID NO:271), PSLR (SEQ ID NO:272), or NDLR (SEQ ID NO:273), or

[0169] a) and b) both.

[0170] In some embodiments, the antibody or its antigen-binding fragment comprises: VH FR1-HCDR1 containing the amino acid sequence of SEQ ID NO:X, and

[0171] a) VH FR2 containing the amino acid sequence of GKGL (SEQ ID NO:268), GDYL (SEQ ID NO:269), or GYYL (SEQ ID NO:270), and

[0172] b) VH FR3 containing the amino acid sequence of NSLK (SEQ ID NO:271), PSLR (SEQ ID NO:272), or NDLR (SEQ ID NO:273).

[0173] In some embodiments, the antibody or its antigen-binding fragment comprises: VH FR2 containing the amino acid sequence of GKGL (SEQ ID NO:268), GDYL (SEQ ID NO:269), or GYYL (SEQ ID NO:270), and

[0174] a) VH FR1-HCDR1 containing the amino acid sequence of SEQ ID NO:X, or

[0175] b) VH FR3 containing the amino acid sequence of NSLK (SEQ ID NO:271), PSLR (SEQ ID NO:272), or NDLR (SEQ ID NO:273), or

[0176] a) and b) both.

[0177] In some embodiments, the antibody or its antigen-binding fragment comprises: VH FR2 containing the amino acid sequence of GKGL (SEQ ID NO:268), GDYL (SEQ ID NO:269), or GYYL (SEQ ID NO:270), and

[0178] a) VH FR1-HCDR1 containing the amino acid sequence of SEQ ID NO:X, and

[0179] b) VH FR3 containing the amino acid sequence of NSLK (SEQ ID NO:271), PSLR (SEQ ID NO:272), or NDLR (SEQ ID NO:273).

[0180] In some embodiments, the antibody or its antigen-binding fragment comprises: VH FR2 comprising the amino acid sequence GKGL (SEQ ID NO:268), and

[0181] a) VH FR1-HCDR1 containing the amino acid sequence of SEQ ID NO:X, or

[0182] b) VH FR3 containing the amino acid sequence of NSLK (SEQ ID NO:271), PSLR (SEQ ID NO:272), or NDLR (SEQ ID NO:273), or

[0183] a) and b) both.

[0184] In some embodiments, the antibody or its antigen-binding fragment comprises: VH FR2 comprising the amino acid sequence GKGL (SEQ ID NO:268), and

[0185] a) VH FR1-HCDR1 containing the amino acid sequence of SEQ ID NO:X, and

[0186] b) VH FR3 containing the amino acid sequence of NSLK (SEQ ID NO:271), PSLR (SEQ ID NO:272), or NDLR (SEQ ID NO:273).

[0187] In some embodiments, the antibody or its antigen-binding fragment comprises: VH FR2 comprising the amino acid sequence of GDYL (SEQ ID NO:269), and

[0188] a) VH FR1-HCDR1 containing the amino acid sequence of SEQ ID NO:X, or

[0189] b) VH FR3 containing the amino acid sequence of NSLK (SEQ ID NO:271), PSLR (SEQ ID NO:272), or NDLR (SEQ ID NO:273), or

[0190] a) and b) both.

[0191] In some embodiments, the antibody or its antigen-binding fragment comprises: VH FR2 comprising the amino acid sequence of GDYL (SEQ ID NO:269), and

[0192] a) VH FR1-HCDR1 containing the amino acid sequence of SEQ ID NO:X, and

[0193] b) VH FR3 containing the amino acid sequence of NSLK (SEQ ID NO:271), PSLR (SEQ ID NO:272), or NDLR (SEQ ID NO:273).

[0194] In some embodiments, the antibody or its antigen-binding fragment comprises: VH FR2 comprising the amino acid sequence GYYL (SEQ ID NO:270), and

[0195] a) VH FR1-HCDR1 containing the amino acid sequence of SEQ ID NO:X, or

[0196] b) VH FR3 containing the amino acid sequence of NSLK (SEQ ID NO:271), PSLR (SEQ ID NO:272), or NDLR (SEQ ID NO:273), or

[0197] a) and b) both.

[0198] In some embodiments, the antibody or its antigen-binding fragment comprises: VH FR2 comprising the amino acid sequence GYYL (SEQ ID NO:270), and

[0199] a) VH FR1-HCDR1 containing the amino acid sequence of SEQ ID NO:X, and

[0200] b) VH FR3 containing the amino acid sequence of NSLK (SEQ ID NO:271), PSLR (SEQ ID NO:272), or NDLR (SEQ ID NO:273).

[0201] In some embodiments, the antibody or its antigen-binding fragment comprises: VH FR3 containing an amino acid sequence comprising NSLK (SEQ ID NO:271), PSLR (SEQ ID NO:272), or NDLR (SEQ ID NO:273), and

[0202] a) VH FR1-HCDR1 containing the amino acid sequence of SEQ ID NO:X, or

[0203] b) VH FR2 containing the amino acid sequence of GKGL (SEQ ID NO:268), GDYL (SEQ ID NO:269), or GYYL (SEQ ID NO:270), or

[0204] a) and b) both.

[0205] In some embodiments, the antibody or its antigen-binding fragment comprises: VH FR3 containing an amino acid sequence comprising NSLK (SEQ ID NO:271), PSLR (SEQ ID NO:272), or NDLR (SEQ ID NO:273), and

[0206] a) VH FR1-HCDR1 containing the amino acid sequence of SEQ ID NO:X, and

[0207] b) VH FR2 containing the amino acid sequence of GKGL (SEQ ID NO:268), GDYL (SEQ ID NO:269), or GYYL (SEQ ID NO:270).

[0208] In some embodiments, the antibody or its antigen-binding fragment comprises: VH FR3 containing the amino acid sequence of NSLK (SEQ ID NO:271), and

[0209] a) VH FR1-HCDR1 containing the amino acid sequence of SEQ ID NO:X, or

[0210] b) VH FR2 containing the amino acid sequence of GKGL (SEQ ID NO:268), GDYL (SEQ ID NO:269), or GYYL (SEQ ID NO:270), or

[0211] a) and b) both.

[0212] In some embodiments, the antibody or its antigen-binding fragment comprises: VH FR3 containing the amino acid sequence of NSLK (SEQ ID NO:271), and

[0213] a) VH FR1-HCDR1 containing the amino acid sequence of SEQ ID NO:X, and

[0214] b) VH FR2 containing the amino acid sequence of GKGL (SEQ ID NO:268), GDYL (SEQ ID NO:269), or GYYL (SEQ ID NO:270).

[0215] In some embodiments, the antibody or its antigen-binding fragment comprises: VH FR3 comprising the amino acid sequence of PSLR (SEQ ID NO:272), and

[0216] a) VH FR1-HCDR1 containing the amino acid sequence of SEQ ID NO:X, or

[0217] b) VH FR2 containing the amino acid sequence of GKGL (SEQ ID NO:268), GDYL (SEQ ID NO:269), or GYYL (SEQ ID NO:270), or

[0218] a) and b) both.

[0219] In some embodiments, the antibody or its antigen-binding fragment comprises: VH FR3 comprising the amino acid sequence of PSLR (SEQ ID NO:272), and

[0220] a) VH FR1-HCDR1 containing the amino acid sequence of SEQ ID NO:X, and

[0221] b) VH FR2 containing the amino acid sequence of GKGL (SEQ ID NO:268), GDYL (SEQ ID NO:269), or GYYL (SEQ ID NO:270).

[0222] In some embodiments, the antibody or its antigen-binding fragment comprises: VH FR3 containing the amino acid sequence of NDLR (SEQ ID NO:273), and

[0223] a) VH FR1-HCDR1 containing the amino acid sequence of SEQ ID NO:X, or

[0224] b) VH FR2 containing the amino acid sequence of GKGL (SEQ ID NO:268), GDYL (SEQ ID NO:269), or GYYL (SEQ ID NO:270), or

[0225] a) and b) both.

[0226] In some embodiments, the antibody or its antigen-binding fragment comprises: VH FR3 containing the amino acid sequence of NDLR (SEQ ID NO:273), and

[0227] a) VH FR1-HCDR1 containing the amino acid sequence of SEQ ID NO:X, and

[0228] b) VH FR2 containing the amino acid sequence of GKGL (SEQ ID NO:268), GDYL (SEQ ID NO:269), or GYYL (SEQ ID NO:270).

[0229] In some embodiments, X is any one of 309, 310, and 262-267. In some embodiments, X is 309. In some embodiments, X is 310. In some embodiments, X is any one of 262-267. In some embodiments, X is 262. In some embodiments, X is 263. In some embodiments, X is 264. In some embodiments, X is 265. In some embodiments, X is 266. In some embodiments, X is 267. This paragraph applies to any one or more of paragraphs

[0134] -

[0152] .

[0230] In some embodiments, the antibody or its antigen-binding fragment comprises: a) VH FR1-HCDR1 containing the amino acid sequence of SEQ ID NO:262, b) VH FR2 containing the amino acid sequence GKGL (SEQ ID NO:268), and c) VH FR3 containing the amino acid sequence of PSLR (SEQ ID NO:272).

[0231] In some embodiments, the antibody or its antigen-binding fragment comprises: a) VH FR1-HCDR1 containing the amino acid sequence of SEQ ID NO:262, b) VH FR2 containing the amino acid sequence GKGL (SEQ ID NO:268), and c) VH FR3 containing the amino acid sequence of NDLR (SEQ ID NO:273).

[0232] In some embodiments, the antibody or its antigen-binding fragment comprises: a) VH FR1-HCDR1 containing the amino acid sequence of SEQ ID NO:262, b) VH FR2 containing the amino acid sequence GKGL (SEQ ID NO:268), and c) VH FR3 containing the amino acid sequence of NSLK (SEQ ID NO:271).

[0233] In some embodiments, the antibody or its antigen-binding fragment comprises: a) VH FR1-HCDR1 containing the amino acid sequence of SEQ ID NO:309, 310, or 262. b) VH FR2 containing the amino acid sequence GKGL (SEQ ID NO:268), and c) VH FR3 containing the amino acid sequence of NSLK (SEQ ID NO:271).

[0234] In paragraphs

[0121] -

[0144] , the HCDR1, HCDR2 and HCDR3 sequences can be any HCDR1, HCDR2 and HCDR3 sequences disclosed in any of paragraphs

[0097] -

[0144] .

[0235] VH

[0236] In some embodiments, the antibody or its antigen-binding fragment comprises a VH domain having at least 70% sequence identity with the amino acid sequence of SEQ ID NO:X (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity), wherein the VH domain has less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1.

[0237] In some embodiments, the antibody or its antigen-binding fragment comprises a VH containing at least one amino acid substitution relative to the amino acid sequence of SEQ ID NO:X, wherein the VH domain has less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1. For example, the number of amino acid substitutions may be at least about: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, or about: 1-20, 1-19, 2-19, 2-18, 2-17, 3-17, 3-16, 4-16, 4-15, 5-15, 5-14, 6-14, 6-13, 7-13, 7-12, 8-12, 8-11, or 9-11. In some embodiments, the antibody or its antigen-binding fragment comprises a VH containing about 1-10 amino acid substitutions relative to the amino acid sequence of SEQ ID NO:X.

[0238] In some embodiments, the amino acid substitution is a conservative substitution. The term "conservative amino acid substitution" or "conservative substitution" refers to an amino acid substitution having a value of 0 or greater in BLOSUM62.

[0239] In some embodiments, the amino acid substitution is a highly conserved substitution. The terms "highly conserved amino acid substitution" or "highly conserved substitution" refer to an amino acid substitution having a value of at least 1 (e.g., at least 2) in BLOSUM62.

[0240] In some embodiments, the antibody or its antigen-binding fragment comprises a VH having 100% sequence identity with the amino acid sequence of SEQ ID NO:X. In some embodiments, the antibody or its antigen-binding fragment comprises a VH containing (e.g., composed of) the amino acid sequence of SEQ ID NO:X.

[0241] In some embodiments, X is any one of 2-11, 19-21, 299, and 300. In some embodiments, X is any one of 2-11, 299, and 300. In some embodiments, X is any one of 2-4, 299, and 300. In some embodiments, X is 299. In some embodiments, X is 300. In some embodiments, X is any one of 2-11 and 19-21. In some embodiments, X is any one of 2-11. In some embodiments, X is any one of 2-4. In some embodiments, X is 2. In some embodiments, X is 3. In some embodiments, X is 4. In some embodiments, X is 5. In some embodiments, X is 6. In some embodiments, X is 7. In some embodiments, X is 8. In some embodiments, X is 9. In some embodiments, X is 10. In some embodiments, X is 11. In some embodiments, X is 19. In some embodiments, X is 20. In some embodiments, X is 21. This paragraph applies to any one or more of paragraphs

[0159] -

[0163] .

[0242] In some embodiments, the antibody or its antigen-binding fragment comprises a VH domain having at least 70% sequence identity with the amino acid sequence of SEQ ID NO:2 (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity), wherein the VH domain has less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1.

[0243] In some embodiments, the antibody or its antigen-binding fragment comprises a VH domain having at least 70% sequence identity with the amino acid sequence of SEQ ID NO:3 (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity), wherein the VH domain has less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1.

[0244] In some embodiments, the antibody or its antigen-binding fragment comprises a VH domain having at least 70% sequence identity with the amino acid sequence of SEQ ID NO:4 (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity), wherein the VH domain has less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1.

[0245] In some embodiments, the antibody or its antigen-binding fragment comprises a VH domain having at least 70% sequence identity with the amino acid sequence of SEQ ID NO:299 (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity), wherein the VH domain has less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1.

[0246] In some embodiments, the antibody or its antigen-binding fragment comprises a VH domain having at least 70% sequence identity with the amino acid sequence of SEQ ID NO:300 (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity), wherein the VH domain has less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1.

[0247] Light chain variable domain (VL)

[0248] In some embodiments, the antibody or its antigen-binding fragment comprises a VL domain (e.g., a mammalian VL domain, such as a rodent (e.g., mouse) VL domain, or a primate (e.g., human) VL domain). In some embodiments, the antibody or its antigen-binding fragment comprises a human VL domain. In some embodiments, the antibody or its antigen-binding fragment comprises a humanized (e.g., at least about: 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98%, or 99% humanized) VL domain containing a human framework region, or both.

[0249] In some embodiments, the antibody or its antigen-binding fragment includes a VL domain having less than 100% sequence identity with the amino acid sequence of SEQ ID NO:140. In some embodiments, the antibody or its antigen-binding fragment does not include a VL domain containing the amino acid sequence of SEQ ID NO:140.

[0250] In some embodiments, the antibody or its antigen-binding fragment comprises a VL domain, the VL domain comprising LCDR1, LCDR2, and LCDR3 having at least 80% sequence identity (e.g., at least 85%, at least 90%, or at least 95% sequence identity) with the light chain complementarity-determining regions (LCDRs) 1, LCDR2, and LCDR3 of the VL domain comprising the amino acid sequence of SEQ ID NO: Y. In some embodiments, the VL domain has less than 100% sequence identity with the amino acid sequence of SEQ ID NO: 140.

[0251] In some embodiments, the antibody or its antigen-binding fragment comprises a VL domain, the VL domain comprising LCDR1, LCDR2, and LCDR3 having 100% sequence identity with LCDR1, LCDR2, and LCDR3, respectively, which contain the amino acid sequence of SEQ ID NO: Y.

[0252] In some embodiments, Y is any one of 140-145, 301, and 302. Table 3 shows sequences identified as SEQ ID NO: 140-145, 301, and 302, which correspond to the human VL domain. In some embodiments, Y is any one of 141-145, 301, and 302. In some embodiments, Y is any one of 144, 142, 301, and 302. In some embodiments, Y is any one of 144, 301, and 302. In some embodiments, Y is 301. In some embodiments, Y is 302. In some embodiments, Y is any one of 140-145. In some embodiments, Y is any one of 141-145. In some embodiments, Y is 144 or 142. In some embodiments, Y is 140. In some embodiments, Y is 141. In some embodiments, Y is 142. In some embodiments, Y is 143. In some embodiments, Y is 144. In some embodiments, Y is 145. This paragraph applies to paragraph

[0172] and / or paragraph

[0173] .

[0253] For example, the LCDR sequence determined by the IMGT number.

[0254] In some embodiments, the antibody or its antigen-binding fragment comprises: a) LCDR1 with at least 80% sequence identity (e.g., at least 85%, at least 90%, or at least 95%) of the amino acid sequence of SEQ ID NO:146. b) LCDR2 containing an amino acid sequence of AAS, IAS, or YAS (e.g., composed of them), and c) LCDR3 having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:150 (e.g., at least 85%, at least 90%, or at least 95% sequence identity). The antibody or its antigen-binding fragment contains a VL domain that has less than 100% sequence identity with the amino acid sequence of SEQ ID NO:140.

[0255] Table 4 shows the sequences identified as SEQ ID NO: 146 and 150, which correspond to human LCDR sequences determined according to IMGT numbers.

[0256] In some embodiments, the antibody or its antigen-binding fragment comprises: a) LCDR1 containing the amino acid sequence of SEQ ID NO:146 (e.g., composed of it), b) LCDR2 containing an amino acid sequence of AAS, IAS, or YAS (e.g., composed of them), and c) LCDR3 containing the amino acid sequence of SEQ ID NO:150 (e.g., composed of it), The antibody or its antigen-binding fragment contains a VL domain that has less than 100% sequence identity with the amino acid sequence of SEQ ID NO:140.

[0257] In some embodiments, the antibody or its antigen-binding fragment comprises: a) LCDR1 with at least 80% sequence identity (e.g., at least 85%, at least 90%, or at least 95%) of the amino acid sequence of SEQ ID NO:146. b) LCDR2 containing the amino acid sequence of AAS (e.g., composed of it), and c) LCDR3 having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:150 (e.g., at least 85%, at least 90%, or at least 95% sequence identity). The antibody or its antigen-binding fragment contains a VL domain that has less than 100% sequence identity with the amino acid sequence of SEQ ID NO:140.

[0258] In some embodiments, the antibody or its antigen-binding fragment comprises: a) LCDR1 containing the amino acid sequence of SEQ ID NO:146 (e.g., composed of it), b) LCDR2 containing the amino acid sequence of AAS (e.g., composed of it), and c) LCDR3 containing the amino acid sequence of SEQ ID NO:150 (e.g., composed of it), The antibody or its antigen-binding fragment contains a VL domain that has less than 100% sequence identity with the amino acid sequence of SEQ ID NO:140.

[0259] In some embodiments, the antibody or its antigen-binding fragment comprises: a) LCDR1 with at least 80% sequence identity (e.g., at least 85%, at least 90%, or at least 95%) of the amino acid sequence of SEQ ID NO:146. b) LCDR2 containing the amino acid sequence of IAS (e.g., composed of it), and c) LCDR3 having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:150 (e.g., at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity).

[0260] In some embodiments, the antibody or its antigen-binding fragment comprises: a) LCDR1 containing the amino acid sequence of SEQ ID NO:146 (e.g., composed of it), b) LCDR2 containing the amino acid sequence of IAS (e.g., composed of it), and c) LCDR3 containing the amino acid sequence of SEQ ID NO:150 (e.g., composed of it).

[0261] In some embodiments, the antibody or its antigen-binding fragment comprises: a) LCDR1 with at least 80% sequence identity (e.g., at least 85%, at least 90%, or at least 95%) of the amino acid sequence of SEQ ID NO:146. b) LCDR2 containing the amino acid sequence of YAS (e.g., composed of it), and c) LCDR3 having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:150 (e.g., at least 85% sequence identity, at least 90% sequence identity, or at least 95% sequence identity).

[0262] In some embodiments, the antibody or its antigen-binding fragment comprises: a) LCDR1 containing the amino acid sequence of SEQ ID NO:146 (e.g., composed of it), b) LCDR2 containing the amino acid sequence of YAS (e.g., composed of it), and c) LCDR3 containing the amino acid sequence of SEQ ID NO:150 (e.g., composed of it).

[0263] LCDR sequences determined by Kabat or Chothia numbering, for example.

[0264] In some embodiments, the antibody or its antigen-binding fragment comprises: a) LCDR1 with at least 80% sequence identity to the amino acid sequence of SEQ ID NO:151 (e.g., at least 85%, at least 90%, or at least 95%). b) LCDR2 having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:Y (e.g., at least 85%, at least 90%, or at least 95% sequence identity), and c) LCDR3 having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:150 (e.g., at least 85%, at least 90%, or at least 95% sequence identity). The antibody or its antigen-binding fragment contains a VL domain that has less than 100% sequence identity with the amino acid sequence of SEQ ID NO:140.

[0265] In some embodiments, the antibody or its antigen-binding fragment comprises: a) LCDR1 containing the amino acid sequence of SEQ ID NO:151 (e.g., composed of it), b) LCDR2 containing the amino acid sequence of SEQ ID NO: Y (e.g., composed of it), and c) LCDR3 containing the amino acid sequence of SEQ ID NO:150 (e.g., composed of it), The antibody or its antigen-binding fragment contains a VL domain that has less than 100% sequence identity with the amino acid sequence of SEQ ID NO:140.

[0266] In some embodiments, Y is any one of 152-157, 307, and 308. Table 4 shows sequences identified as SEQ ID NO: 150-157, 307, and 308, which correspond to human LCDR sequences determined according to Kabat or Chothia numbers. In some embodiments, Y is any one of 153-157, 307, and 308. In some embodiments, Y is 156, 154, 307, or 308. In some embodiments, Y is 307. In some embodiments, Y is 308. In some embodiments, Y is any one of 152-157. In some embodiments, Y is any one of 153-157. In some embodiments, Y is 156 or 154. In some embodiments, Y is 152. In some embodiments, Y is 153. In some embodiments, Y is 154. In some embodiments, Y is 155. In some embodiments, Y is 156. In some embodiments, Y is 157. This paragraph applies to paragraph

[0184] and / or paragraph

[0185] .

[0267] VL

[0268] In some embodiments, the antibody or its antigen-binding fragment comprises a VL domain having at least 70% sequence identity with the amino acid sequence of SEQ ID NO: Y (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity), wherein the VL domain has less than 100% sequence identity with the amino acid sequence of SEQ ID NO: 140.

[0269] In some embodiments, the antibody or its antigen-binding fragment comprises a VL domain comprising at least one amino acid substitution relative to the amino acid sequence of SEQ ID NO:Y, wherein the VL domain has less than 100% sequence identity with the amino acid sequence of SEQ ID NO:140. For example, the number of amino acid substitutions may be at least about: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, or about: 1-20, 1-19, 2-19, 2-18, 2-17, 3-17, 3-16, 4-16, 4-15, 5-15, 5-14, 6-14, 6-13, 7-13, 7-12, 8-12, 8-11, or 9-11. In some embodiments, the antibody or its antigen-binding fragment comprises a VL comprising about 1-10 amino acid substitutions relative to the amino acid sequence of SEQ ID NO:Y. In some embodiments, the amino acid substitution is a conserved substitution. In some embodiments, the amino acid substitution is a highly conserved substitution.

[0270] In some embodiments, the antibody or its antigen-binding fragment comprises a VL having 100% sequence identity with the amino acid sequence of SEQ ID NO: Y. In some embodiments, the antibody or its antigen-binding fragment comprises a VL containing (e.g., composed of) the amino acid sequence of SEQ ID NO: Y.

[0271] In some embodiments, Y is any one of 140-145, 301, and 302. In some embodiments, Y is any one of 141-145, 301, and 302. In some embodiments, Y is any one of 144, 142, 140, 301, and 302. In some embodiments, Y is any one of 144, 142, 301, and 302. In some embodiments, Y is any one of 144, 301, and 302. In some embodiments, Y is 301. In some embodiments, Y is 302. In some embodiments, Y is any one of 140-145. In some embodiments, Y is any one of 141-145. In some embodiments, Y is any one of 144, 142, and 140. In some embodiments, Y is 144 or 142. In some embodiments, Y is 140. In some embodiments, Y is 141. In some embodiments, Y is 142. In some embodiments, Y is 143. In some embodiments, Y is 144. In some embodiments, Y is 145. This paragraph applies to any one or more of paragraphs

[0187] -

[0189] .

[0272] In some embodiments, the antibody or its antigen-binding fragment comprises a VL domain having at least 70% sequence identity with the amino acid sequence of SEQ ID NO:144 (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity), wherein the VL domain has less than 100% sequence identity with the amino acid sequence of SEQ ID NO:140.

[0273] In some embodiments, the antibody or its antigen-binding fragment comprises a VL having 100% sequence identity with the amino acid sequence of SEQ ID NO:144.

[0274] In some embodiments, the antibody or its antigen-binding fragment comprises a VL domain having at least 70% sequence identity with the amino acid sequence of SEQ ID NO:142 (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity), wherein the VL domain has less than 100% sequence identity with the amino acid sequence of SEQ ID NO:140.

[0275] In some embodiments, the antibody or its antigen-binding fragment comprises a VL having 100% sequence identity with the amino acid sequence of SEQ ID NO:142.

[0276] In some embodiments, the antibody or its antigen-binding fragment comprises a VL domain having at least 70% sequence identity with the amino acid sequence of SEQ ID NO:301 (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity), wherein the VL domain has less than 100% sequence identity with the amino acid sequence of SEQ ID NO:140.

[0277] In some embodiments, the antibody or its antigen-binding fragment comprises a VL having 100% sequence identity with the amino acid sequence of SEQ ID NO:301.

[0278] In some embodiments, the antibody or its antigen-binding fragment comprises a VL domain having at least 70% sequence identity with the amino acid sequence of SEQ ID NO:302 (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity), wherein the VL domain has less than 100% sequence identity with the amino acid sequence of SEQ ID NO:140.

[0279] In some embodiments, the antibody or its antigen-binding fragment comprises a VL having 100% sequence identity with the amino acid sequence of SEQ ID NO:302.

[0280] VH / VL

[0281] In some embodiments, the antibody or its antigen-binding fragment does not contain: a) A VH domain containing the amino acid sequence of SEQ ID NO:1. b) A VL domain containing the amino acid sequence of SEQ ID NO:140. Or both a) and b).

[0282] In some embodiments, the antibody or its antigen-binding fragment comprises: a) VH with less than 100% sequence identity to the amino acid sequence of SEQ ID NO:1. b) VLs with less than 100% sequence identity to the amino acid sequence of SEQ ID NO:140. Or both a) and b).

[0283] In some embodiments, the antibody or its antigen-binding fragment comprises: a) A VH domain comprising HCDR1, HCDR2, and HCDR3 having at least 80% sequence identity (e.g., at least 85%, at least 90%, or at least 95% sequence identity) with the VH domain containing the amino acid sequence of SEQ ID NO:X, respectively. b) A VL domain comprising LCDR1, LCDR2, and LCDR3 having at least 80% sequence identity (e.g., at least 85%, at least 90%, or at least 95% sequence identity) with respect to the VL domain containing the amino acid sequence SEQ ID NO: Y. in: i. The VH domain has less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1. ii. The VL domain has less than 100% sequence identity with the amino acid sequence of SEQ ID NO:140. Or both i and ii.

[0284] In some embodiments, the antibody or its antigen-binding fragment comprises: a) A VH domain, comprising HCDR1, HCDR2, and HCDR3 having 100% sequence identity with HCDR1, HCDR2, and HCDR3 containing the amino acid sequence of SEQ ID NO: X, respectively. b) A VL domain comprising LCDR1, LCDR2, and LCDR3, which are 100% sequence identical to the VL domains containing the amino acid sequence SEQ ID NO: Y. in: i. The VH domain has less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1. ii. The VL domain has less than 100% sequence identity with the amino acid sequence of SEQ ID NO:140. Or both i and ii.

[0285] In some embodiments, X is any one of 1-11, 19-21, 299, and 300, and Y is any one of 140-145, 301, and 302. In some embodiments, X is any one of 2-11, 19-21, 299, and 300, and Y is any one of 140-145, 301, and 302. In some embodiments, X is any one of 1-11, 19-21, 299, and 300, and Y is any one of 141-145, 301, and 302. In some embodiments, X is any one of 2-11, 19-21, 299, and 300, and Y is any one of 141-145, 301, and 302.

[0286] In some embodiments, X is any one of 1-11, 299, and 300, and Y is any one of 140-145, 301, and 302. In some embodiments, X is any one of 2-11, 299, and 300, and Y is any one of 140-145, 301, and 302. In some embodiments, X is any one of 1-11, 299, and 300, and Y is any one of 141-145, 301, and 302. In some embodiments, X is any one of 2-11, 299, and 300, and Y is any one of 141-145, 301, and 302.

[0287] In some embodiments, X is any one of 1-4, 299, and 300, and Y is any one of 144, 142, 140, 301, and 302. In some embodiments, X is any one of 1-4, 299, and 300, and Y is any one of 144, 142, 301, and 302. In some embodiments, X is any one of 2-4, 299, and 300, and Y is any one of 144, 142, 140, 301, and 302. In some embodiments, X is any one of 2-4, 299, and 300, and Y is any one of 144, 142, 301, and 302.

[0288] In some embodiments, X is any one of 2-4, 299, and 300, and Y is any one of 144, 301, and 302.

[0289] In some embodiments, X is any one of 1-11 and 19-21, and Y is any one of 140-145. In some embodiments, X is any one of 2-11 and 19-21, and Y is any one of 140-145. In some embodiments, X is any one of 1-11 and 19-21, and Y is any one of 141-145. In some embodiments, X is any one of 2-11 and 19-21, and Y is any one of 141-145.

[0290] In some embodiments, X is any one of 1-11, and Y is any one of 140-145. In some embodiments, X is any one of 2-11, and Y is any one of 140-145. In some embodiments, X is any one of 1-11, and Y is any one of 141-145. In some embodiments, X is any one of 2-11, and Y is any one of 141-145.

[0291] In some embodiments, X is any one of 1-4, and Y is any one of 144, 142, and 140. In some embodiments, X is any one of 1-4, and Y is 144 or 142. In some embodiments, X is any one of 2-4, and Y is any one of 144, 142, and 140. In some embodiments, X is any one of 2-4, and Y is 144 or 142.

[0292] In some embodiments, X is any one of 2-4, and Y is 144.

[0293] In some embodiments, X is 1, and Y is any one of 144, 142, 301, and 302. In some embodiments, X is 1, and Y is 142 or 144. In some embodiments, X is 1, and Y is 144. In some embodiments, X is 1, and Y is 142. In some embodiments, X is 1, and Y is 301. In some embodiments, X is 1, and Y is 302.

[0294] In some embodiments, X is 2, and Y is any one of 144, 142, 140, 301, and 302. In some embodiments, X is 2, and Y is any one of 144, 142, 301, and 302. In some embodiments, X is 2, and Y is any one of 144, 142, and 140. In some embodiments, X is 2, and Y is 142 or 144. In some embodiments, X is 2, and Y is 144. In some embodiments, X is 2, and Y is 142. In some embodiments, X is 2, and Y is 140. In some embodiments, X is 2, and Y is 301. In some embodiments, X is 2, and Y is 302.

[0295] In some embodiments, X is 3, and Y is any one of 144, 142, 140, 301, and 302. In some embodiments, X is 3, and Y is any one of 144, 142, 301, and 302. In some embodiments, X is 3, and Y is any one of 144, 142, and 140. In some embodiments, X is 3, and Y is 142 or 144. In some embodiments, X is 3, and Y is 144. In some embodiments, X is 3, and Y is 142. In some embodiments, X is 3, and Y is 140. In some embodiments, X is 3, and Y is 301. In some embodiments, X is 3, and Y is 302.

[0296] In some embodiments, X is 4, and Y is any one of 144, 142, 140, 301, and 302. In some embodiments, X is 4, and Y is any one of 144, 142, 301, and 302. In some embodiments, X is 4, and Y is any one of 144, 142, and 140. In some embodiments, X is 4, and Y is 142 or 144. In some embodiments, X is 4, and Y is 144. In some embodiments, X is 4, and Y is 142. In some embodiments, X is 4, and Y is 140. In some embodiments, X is 4, and Y is 301. In some embodiments, X is 4, and Y is 302.

[0297] In some embodiments, X is 299, and Y is any one of 144, 142, 140, 301, and 302. In some embodiments, X is 299, and Y is any one of 144, 142, 301, and 302. In some embodiments, X is 299, and Y is any one of 144, 142, and 140. In some embodiments, X is 299, and Y is 142 or 144. In some embodiments, X is 299, and Y is 144. In some embodiments, X is 299, and Y is 142. In some embodiments, X is 299, and Y is 140. In some embodiments, X is 299, and Y is 301. In some embodiments, X is 299, and Y is 302.

[0298] In some embodiments, X is 300, and Y is any one of 144, 142, 140, 301, and 302. In some embodiments, X is 300, and Y is any one of 144, 142, 301, and 302. In some embodiments, X is 300, and Y is any one of 144, 142, and 140. In some embodiments, X is 300, and Y is 142 or 144. In some embodiments, X is 300, and Y is 144. In some embodiments, X is 300, and Y is 142. In some embodiments, X is 300, and Y is 140. In some embodiments, X is 300, and Y is 301. In some embodiments, X is 300, and Y is 302.

[0299] In some embodiments, X is any one of 2-4, 299, and 300, and Y is 140. In some embodiments, X is any one of 4, 299, and 300, and Y is 140. In some embodiments, X is any one of 2-4, and Y is 140. In some embodiments, X is 2, and Y is 140. In some embodiments, X is 3, and Y is 140. In some embodiments, X is 4, and Y is 140. In some embodiments, X is 299, and Y is 140. In some embodiments, X is 300, and Y is 140.

[0300] In some embodiments, X is any one of 1-4, 299, and 300, and Y is 142. In some embodiments, X is any one of 2-4, 299, and 300, and Y is 142. In some embodiments, X is any one of 4, 299, and 300, and Y is 142. In some embodiments, X is any one of 1-4, and Y is 142. In some embodiments, X is any one of 2-4, and Y is 142. In some embodiments, X is 1, and Y is 142. In some embodiments, X is 2, and Y is 142. In some embodiments, X is 3, and Y is 142. In some embodiments, X is 4, and Y is 142. In some embodiments, X is 299, and Y is 142. In some embodiments, X is 300, and Y is 142.

[0301] In some embodiments, X is any one of 1-4, 299, and 300, and Y is 144. In some embodiments, X is any one of 2-4, 299, and 300, and Y is 144. In some embodiments, X is any one of 4, 299, and 300, and Y is 144. In some embodiments, X is any one of 1-4, and Y is 144. In some embodiments, X is any one of 2-4, and Y is 144. In some embodiments, X is 1, and Y is 144. In some embodiments, X is 2, and Y is 144. In some embodiments, X is 3, and Y is 144. In some embodiments, X is 4, and Y is 144. In some embodiments, X is 299, and Y is 144. In some embodiments, X is 300, and Y is 144.

[0302] In some embodiments, X is any one of 1-4, 299, and 300, and Y is 301. In some embodiments, X is any one of 2-4, 299, and 300, and Y is 301. In some embodiments, X is any one of 4, 299, and 300, and Y is 301. In some embodiments, X is any one of 1-4, and Y is 301. In some embodiments, X is any one of 2-4, and Y is 301. In some embodiments, X is 1, and Y is 301. In some embodiments, X is 2, and Y is 301. In some embodiments, X is 3, and Y is 301. In some embodiments, X is 4, and Y is 301. In some embodiments, X is 299, and Y is 301. In some embodiments, X is 300, and Y is 301.

[0303] In some embodiments, X is any one of 1-4, 299, and 300, and Y is 302. In some embodiments, X is any one of 2-4, 299, and 300, and Y is 302. In some embodiments, X is any one of 4, 299, and 300, and Y is 302. In some embodiments, X is any one of 1-4, and Y is 302. In some embodiments, X is any one of 2-4, and Y is 302. In some embodiments, X is 1, and Y is 302. In some embodiments, X is 2, and Y is 302. In some embodiments, X is 3, and Y is 302. In some embodiments, X is 4, and Y is 302. In some embodiments, X is 299, and Y is 302. In some embodiments, X is 300, and Y is 302.

[0304] Any of paragraphs

[0203] -

[0221] may apply to paragraph

[0201] and / or paragraph

[0202] .

[0305] In some embodiments, the antibody or its antigen-binding fragment comprises: a) A VH domain, comprising HCDR1, HCDR2, and HCDR3 having 100% sequence identity with HCDR1, HCDR2, and HCDR3 containing the amino acid sequence of SEQ ID NO:2, respectively. b) A VL domain comprising LCDR1, LCDR2, and LCDR3 having 100% sequence identity with LCDR1, LCDR2, and LCDR3, respectively, which contain the amino acid sequence of SEQ ID NO:144.

[0306] In some embodiments, the antibody or its antigen-binding fragment comprises: a) A VH domain, comprising HCDR1, HCDR2, and HCDR3 having 100% sequence identity with HCDR1, HCDR2, and HCDR3 containing the amino acid sequence of SEQ ID NO:3, respectively. b) A VL domain comprising LCDR1, LCDR2, and LCDR3 having 100% sequence identity with LCDR1, LCDR2, and LCDR3, respectively, which contain the amino acid sequence of SEQ ID NO:144.

[0307] In some embodiments, the antibody or its antigen-binding fragment comprises: a) A VH domain, comprising HCDR1, HCDR2, and HCDR3 having 100% sequence identity with HCDR1, HCDR2, and HCDR3 containing the amino acid sequence of SEQ ID NO:4, respectively. b) A VL domain comprising LCDR1, LCDR2, and LCDR3 having 100% sequence identity with LCDR1, LCDR2, and LCDR3, respectively, which contain the amino acid sequence of SEQ ID NO:140.

[0308] In some embodiments, the antibody or its antigen-binding fragment comprises: a) A VH domain, comprising HCDR1, HCDR2, and HCDR3 having 100% sequence identity with HCDR1, HCDR2, and HCDR3 containing the amino acid sequence of SEQ ID NO:299, respectively. b) A VL domain comprising LCDR1, LCDR2, and LCDR3 having 100% sequence identity with LCDR1, LCDR2, and LCDR3, respectively, which contain the amino acid sequence of SEQ ID NO:140.

[0309] In some embodiments, the antibody or its antigen-binding fragment comprises: a) A VH domain, comprising HCDR1, HCDR2, and HCDR3 having 100% sequence identity with HCDR1, HCDR2, and HCDR3 containing the amino acid sequence of SEQ ID NO:300, respectively. b) A VL domain comprising LCDR1, LCDR2, and LCDR3 having 100% sequence identity with LCDR1, LCDR2, and LCDR3, respectively, which contain the amino acid sequence of SEQ ID NO:140.

[0310] In some embodiments, the antibody or its antigen-binding fragment comprises: a) A VH domain, comprising HCDR1, HCDR2, and HCDR3 having 100% sequence identity with HCDR1, HCDR2, and HCDR3 containing the amino acid sequence of SEQ ID NO:1, respectively. b) A VL domain comprising LCDR1, LCDR2, and LCDR3 having 100% sequence identity with LCDR1, LCDR2, and LCDR3, respectively, which contain the amino acid sequence of SEQ ID NO:142.

[0311] In some embodiments, the antibody or its antigen-binding fragment comprises: a) A VH domain, comprising HCDR1, HCDR2, and HCDR3 having 100% sequence identity with HCDR1, HCDR2, and HCDR3 containing the amino acid sequence of SEQ ID NO:1, respectively. b) A VL domain comprising LCDR1, LCDR2, and LCDR3 having 100% sequence identity with LCDR1, LCDR2, and LCDR3, respectively, which contain the amino acid sequence of SEQ ID NO:144.

[0312] In some embodiments, the antibody or its antigen-binding fragment comprises: a) A VH domain, comprising HCDR1, HCDR2, and HCDR3 having 100% sequence identity with HCDR1, HCDR2, and HCDR3 containing the amino acid sequence of SEQ ID NO:1, respectively. b) A VL domain comprising LCDR1, LCDR2, and LCDR3 having 100% sequence identity with LCDR1, LCDR2, and LCDR3, respectively, which contain the amino acid sequence of SEQ ID NO:301.

[0313] In some embodiments, the antibody or its antigen-binding fragment comprises: a) A VH domain, comprising HCDR1, HCDR2, and HCDR3 having 100% sequence identity with HCDR1, HCDR2, and HCDR3 containing the amino acid sequence of SEQ ID NO:1, respectively. b) A VL domain comprising LCDR1, LCDR2, and LCDR3 having 100% sequence identity with LCDR1, LCDR2, and LCDR3, respectively, which contain the amino acid sequence of SEQ ID NO:302.

[0314] CDR sequence determined by IMGT number

[0315] In some embodiments, the antibody or its antigen-binding fragment comprises: a) VH, which contains: i. HCDR1 having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:X (e.g., at least 85%, at least 90%, or at least 95% sequence identity). ii. HCDR2 having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:72 (e.g., at least 85%, at least 90%, or at least 95%), and iii. HCDR3 having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:79 (e.g., at least 85%, at least 90%, or at least 95%), and b) VL, which includes: i. LCDR1 having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:146 (e.g., at least 85%, at least 90%, or at least 95% sequence identity). ii. LCDR2 containing an amino acid sequence of AAS, IAS, or YAS (e.g., composed of them), and iii. LCDR3 having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:150 (e.g., at least 85%, at least 90%, or at least 95%). The antibody or its antigen-binding fragment contains a VH domain having less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1 and / or a VL domain having less than 100% sequence identity with the amino acid sequence of SEQ ID NO:140.

[0316] In some embodiments, the antibody or its antigen-binding fragment comprises: a) VH, which contains: i. HCDR1 having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:X (e.g., at least 85%, at least 90%, or at least 95% sequence identity). ii. HCDR2 having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:72 (e.g., at least 85%, at least 90%, or at least 95%), and iii. HCDR3 having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:79 (e.g., at least 85%, at least 90%, or at least 95%), and b) VL, which includes: i. LCDR1 having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:146 (e.g., at least 85%, at least 90%, or at least 95% sequence identity). ii. LCDR2 containing the amino acid sequence of AAS (e.g., composed of it), and iii. LCDR3 having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:150 (e.g., at least 85%, at least 90%, or at least 95%). The antibody or its antigen-binding fragment contains a VH domain having less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1 and / or a VL domain having less than 100% sequence identity with the amino acid sequence of SEQ ID NO:140.

[0317] In some embodiments, the antibody or its antigen-binding fragment comprises: a) VH, which contains: i. HCDR1 containing the amino acid sequence of SEQ ID NO:X (e.g., composed of it), ii. HCDR2 containing the amino acid sequence of SEQ ID NO:72 (e.g., composed of it), and iii. HCDR3 containing the amino acid sequence of SEQ ID NO:79 (e.g., composed of it), and b) VL, which includes: i. LCDR1 containing the amino acid sequence of SEQ ID NO:146 (e.g., composed of it), ii. LCDR2 containing an amino acid sequence of AAS, IAS, or YAS (e.g., composed of them), and iii. LCDR3 containing the amino acid sequence of SEQ ID NO:150 (e.g., composed of it), The antibody or its antigen-binding fragment contains a VH domain having less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1 and / or a VL domain having less than 100% sequence identity with the amino acid sequence of SEQ ID NO:140.

[0318] In some embodiments, the antibody or its antigen-binding fragment comprises: a) VH, which contains: i. HCDR1 containing the amino acid sequence of SEQ ID NO:X (e.g., composed of it), ii. HCDR2 containing the amino acid sequence of SEQ ID NO:72 (e.g., composed of it), and iii. HCDR3 containing the amino acid sequence of SEQ ID NO:79 (e.g., composed of it), and b) VL, which includes: i. LCDR1 containing the amino acid sequence of SEQ ID NO:146 (e.g., composed of it), ii. LCDR2 containing the amino acid sequence of AAS (e.g., composed of it), and iii. LCDR3 containing the amino acid sequence of SEQ ID NO:150 (e.g., composed of it), The antibody or its antigen-binding fragment contains a VH domain having less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1 and / or a VL domain having less than 100% sequence identity with the amino acid sequence of SEQ ID NO:140.

[0319] In some embodiments, X is any one of 303, 304, 45-47, and 49-51. In some embodiments, X is any one of 303, 304, and 45-47. In some embodiments, X is 303. In some embodiments, X is 304. In some embodiments, X is any one of 45-47 and 49-51. In some embodiments, X is any one of 45-47. In some embodiments, X is 45. In some embodiments, X is 46. In some embodiments, X is 47. In some embodiments, X is 49. In some embodiments, X is 50. In some embodiments, X is 51. This paragraph applies to any one or more of paragraphs

[0232] -

[0235] .

[0320] In some embodiments, the antibody or its antigen-binding fragment comprises: a) VH, which contains the HCDR1, HCDR2, and HCDR3 amino acid sequences of SEQ ID NO:45, SEQ ID NO:72, and SEQ ID NO:79, respectively, and b) VL, which contains the amino acid sequences of LCDR1, LCDR2 and LCDR3 of SEQ ID NO:146, AAS and SEQ ID NO:150, respectively.

[0321] In some embodiments, the antibody or its antigen-binding fragment comprises: a) VH, which respectively contains the HCDR1, HCDR2, and HCDR3 amino acid sequences of SEQ ID NO:303, SEQ ID NO:72, and SEQ ID NO:79, and b) VL, which contains the amino acid sequences of LCDR1, LCDR2 and LCDR3 of SEQ ID NO:146, AAS and SEQ ID NO:150, respectively.

[0322] In some embodiments, the antibody or its antigen-binding fragment comprises: a) VH, which contains the HCDR1, HCDR2, and HCDR3 amino acid sequences of SEQ ID NO:304, SEQ ID NO:72, and SEQ ID NO:79, respectively, and b) VL, which contains the amino acid sequences of LCDR1, LCDR2 and LCDR3 of SEQ ID NO:146, AAS and SEQ ID NO:150, respectively.

[0323] For example, the CDR sequence determined by the Kabat number.

[0324] In some embodiments, the antibody or its antigen-binding fragment comprises: a) VH, which contains: i. HCDR1 having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:X (e.g., at least 85%, at least 90%, or at least 95% sequence identity). ii. HCDR2 having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:96 (e.g., at least 85%, at least 90%, or at least 95% sequence identity), and iii. HCDR3 having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:103 (e.g., at least 85%, at least 90%, or at least 95%), and b) VL, which includes: i. LCDR1 having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:151 (e.g., at least 85%, at least 90%, or at least 95% sequence identity). ii. LCDR2 having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:Y (e.g., at least 85%, at least 90%, or at least 95% sequence identity), and iii. LCDR3 having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:150 (e.g., at least 85%, at least 90%, or at least 95%). The antibody or its antigen-binding fragment contains a VH domain having less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1 and / or a VL domain having less than 100% sequence identity with the amino acid sequence of SEQ ID NO:140.

[0325] In some embodiments, the antibody or its antigen-binding fragment comprises: a) VH, which contains: i. HCDR1 containing the amino acid sequence of SEQ ID NO:X (e.g., composed of it), ii. HCDR2 containing the amino acid sequence of SEQ ID NO:96 (e.g., composed of it), and iii. HCDR3 containing the amino acid sequence of SEQ ID NO:103 (e.g., composed of it), and / or b) VL, which includes: i. LCDR1 containing the amino acid sequence of SEQ ID NO:151 (e.g., composed of it), ii. LCDR2 containing the amino acid sequence of SEQ ID NO: Y (e.g., composed of it), and iii. LCDR3 containing the amino acid sequence of SEQ ID NO:150 (e.g., composed of it), The antibody or its antigen-binding fragment contains a VH domain having less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1 and / or a VL domain having less than 100% sequence identity with the amino acid sequence of SEQ ID NO:140.

[0326] In some embodiments, X is any one of 80-82, and Y is any one of 307, 308, 156, 154, and 152. In some embodiments, X is any one of 80-82, and Y is any one of 307, 308, 156, and 154. In some embodiments, X is any one of 80-82, and Y is any one of 156, 154, and 152. In some embodiments, X is any one of 80-82, and Y is 156 or 154. In some embodiments, X is any one of 80-82, and Y is 307. In some embodiments, X is any one of 80-82, and Y is 308. In some embodiments, X is any one of 80-82, and Y is 156. In some embodiments, X is any one of 80-82, and Y is 154. In some embodiments, X is any one of 80-82, and Y is 152. In some embodiments, X is 80, and Y is any one of 307, 308, 156, and 154. In some embodiments, X is 80, and Y is 156 or 154. In some embodiments, X is 80, and Y is 307. In some embodiments, X is 80, and Y is 308. In some embodiments, X is 80, and Y is 156. In some embodiments, X is 80, and Y is 154. This paragraph applies to paragraph

[0240] or paragraph

[0241] .

[0327] In some embodiments, the antibody or its antigen-binding fragment comprises: a) VH, which contains the HCDR1, HCDR2, and HCDR3 amino acid sequences of SEQ ID NO:80, SEQ ID NO:96, and SEQ ID NO:103, respectively, and b) VL, which contains the amino acid sequences of LCDR1, LCDR2 and LCDR3 of SEQ ID NO:151, SEQ ID NO:154 and SEQ ID NO:150, respectively.

[0328] In some embodiments, the antibody or its antigen-binding fragment comprises: a) VH, which contains the HCDR1, HCDR2, and HCDR3 amino acid sequences of SEQ ID NO:80, SEQ ID NO:96, and SEQ ID NO:103, respectively, and b) VL, which contains the amino acid sequences of LCDR1, LCDR2 and LCDR3 of SEQ ID NO:151, SEQ ID NO:156 and SEQ ID NO:150, respectively.

[0329] In some embodiments, the antibody or its antigen-binding fragment comprises: a) VH, which contains the HCDR1, HCDR2, and HCDR3 amino acid sequences of SEQ ID NO:80, SEQ ID NO:96, and SEQ ID NO:103, respectively, and b) VL, which contains the amino acid sequences of LCDR1, LCDR2 and LCDR3 of SEQ ID NO:151, SEQ ID NO:307 and SEQ ID NO:150, respectively.

[0330] In some embodiments, the antibody or its antigen-binding fragment comprises: a) VH, which contains the HCDR1, HCDR2, and HCDR3 amino acid sequences of SEQ ID NO:80, SEQ ID NO:96, and SEQ ID NO:103, respectively, and b) VL, which contains the amino acid sequences of LCDR1, LCDR2 and LCDR3 of SEQ ID NO:151, SEQ ID NO:308 and SEQ ID NO:150, respectively.

[0331] For example, the CDR sequence determined according to the Chothia number.

[0332] In some embodiments, the antibody or its antigen-binding fragment comprises: a) VH, which contains: i. HCDR1 having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:X (e.g., at least 85%, at least 90%, or at least 95% sequence identity). ii. HCDR2 having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:132 (e.g., at least 85%, at least 90%, or at least 95%), and iii. HCDR3 having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:139 (e.g., at least 85%, at least 90%, or at least 95%), and b) VL, which includes: i. LCDR1 having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:151 (e.g., at least 85%, at least 90%, or at least 95% sequence identity). ii. LCDR2 having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:Y (e.g., at least 85%, at least 90%, or at least 95% sequence identity), and iii. LCDR3 having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:150 (e.g., at least 85%, at least 90%, or at least 95%). The antibody or its antigen-binding fragment contains a VH domain having less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1 and / or a VL domain having less than 100% sequence identity with the amino acid sequence of SEQ ID NO:140.

[0333] In some embodiments, the antibody or its antigen-binding fragment comprises: a) VH, which contains: i. HCDR1 containing the amino acid sequence of SEQ ID NO:X (e.g., composed of it), ii. HCDR2 containing the amino acid sequence of SEQ ID NO:132 (e.g., composed of it), and iii. HCDR3 containing the amino acid sequence of SEQ ID NO:139 (e.g., composed of it), and b) VL, which includes: i. LCDR1 containing the amino acid sequence of SEQ ID NO:151 (e.g., composed of it), ii. LCDR2 containing the amino acid sequence of SEQ ID NO: Y (e.g., composed of it), and iii. LCDR3 containing the amino acid sequence of SEQ ID NO:150 (e.g., composed of it), The antibody or its antigen-binding fragment contains a VH domain having less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1 and / or a VL domain having less than 100% sequence identity with the amino acid sequence of SEQ ID NO:140.

[0334] In some embodiments, X is any one of 305, 306, 104-107, and 109-111, and Y is any one of 156, 154, 152, 307, and 308. (This text is repeated four times in the original.) In some embodiments, X is any one of 305, 306, and 105, and Y is any one of 156, 154, 152, 307, and 308.

[0335] In some embodiments, X is any one of 104-107 and 109-111, and Y is any one of 156, 154, and 152. In some embodiments, X is any one of 105-107 and 109-111, and Y is 156 or 154. In some embodiments, X is any one of 104-107 and 109-111, and Y is 156 or 154. In some embodiments, X is 104 or 105, and Y is any one of 156, 154, and 152. In some embodiments, X is 105, and Y is any one of 156, 154, and 152. In some embodiments, X is 104 or 105, and Y is 156 or 154.

[0336] In some embodiments, X is any one of 105-107 and 109-111, and Y is any one of 156, 154, 307, and 308. In some embodiments, X is any one of 105-107 and 109-111, and Y is 156 or 154. In some embodiments, X is 305, and Y is 156. In some embodiments, X is 305, and Y is 154. In some embodiments, X is 305, and Y is 307. In some embodiments, X is 305, and Y is 308. In some embodiments, X is 306, and Y is 156. In some embodiments, X is 306, and Y is 154. In some embodiments, X is 306, and Y is 307. In some embodiments, X is 306, and Y is 308. In some embodiments, X is 105, and Y is 156. In some embodiments, X is 105, and Y is 154. In some embodiments, X is 105, and Y is 307. In some embodiments, X is 105 and Y is 308. In some embodiments, X is 106 and Y is 156. In some embodiments, X is 106 and Y is 154. In some embodiments, X is 106 and Y is 307. In some embodiments, X is 106 and Y is 308. In some embodiments, X is 107 and Y is 156. In some embodiments, X is 107 and Y is 154. In some embodiments, X is 107 and Y is 307. In some embodiments, X is 107 and Y is 308. In some embodiments, X is 109 and Y is 156. In some embodiments, X is 109 and Y is 154. In some embodiments, X is 109 and Y is 307. In some embodiments, X is 109 and Y is 308. In some embodiments, X is 110 and Y is 156. In some embodiments, X is 110 and Y is 154. In some embodiments, X is 110 and Y is 307. In some embodiments, X is 110 and Y is 308. In some embodiments, X is 111 and Y is 156. In some embodiments, X is 111 and Y is 154. In some embodiments, X is 111 and Y is 307. In some embodiments, X is 111 and Y is 308.

[0337] Each of paragraphs

[0249] -

[0251] applies to paragraph

[0247] or paragraph

[0248] .

[0338] In some embodiments, the antibody or its antigen-binding fragment comprises: a) VH, which contains the HCDR1, HCDR2, and HCDR3 amino acid sequences of SEQ ID NO:104, SEQ ID NO:132, and SEQ ID NO:139, respectively, and b) VL, which contains the amino acid sequences of LCDR1, LCDR2 and LCDR3 of SEQ ID NO:151, SEQ ID NO:154 and SEQ ID NO:150, respectively.

[0339] In some embodiments, the antibody or its antigen-binding fragment comprises: a) VH, which contains the HCDR1, HCDR2, and HCDR3 amino acid sequences of SEQ ID NO:104, SEQ ID NO:132, and SEQ ID NO:139, respectively, and b) VL, which contains the amino acid sequences of LCDR1, LCDR2 and LCDR3 of SEQ ID NO:151, SEQ ID NO:156 and SEQ ID NO:150, respectively.

[0340] In some embodiments, the antibody or its antigen-binding fragment comprises: a) VH, which contains the HCDR1, HCDR2, and HCDR3 amino acid sequences of SEQ ID NO:104, SEQ ID NO:132, and SEQ ID NO:139, respectively, and b) VL, which contains the amino acid sequences of LCDR1, LCDR2 and LCDR3 of SEQ ID NO:151, SEQ ID NO:307 and SEQ ID NO:150, respectively.

[0341] In some embodiments, the antibody or its antigen-binding fragment comprises: a) VH, which contains the HCDR1, HCDR2, and HCDR3 amino acid sequences of SEQ ID NO:104, SEQ ID NO:132, and SEQ ID NO:139, respectively, and b) VL, which contains the amino acid sequences of LCDR1, LCDR2 and LCDR3 of SEQ ID NO:151, SEQ ID NO:308 and SEQ ID NO:150, respectively.

[0342] In some embodiments, the antibody or its antigen-binding fragment comprises: a) VH, which contains the HCDR1, HCDR2, and HCDR3 amino acid sequences of SEQ ID NO:105, SEQ ID NO:132, and SEQ ID NO:139, respectively, and b) VL, which contains the amino acid sequences of LCDR1, LCDR2 and LCDR3 of SEQ ID NO:151, SEQ ID NO:152 and SEQ ID NO:150, respectively.

[0343] In some embodiments, the antibody or its antigen-binding fragment comprises: a) VH, which contains the HCDR1, HCDR2, and HCDR3 amino acid sequences of SEQ ID NO:305, SEQ ID NO:132, and SEQ ID NO:139, respectively, and b) VL, which contains the amino acid sequences of LCDR1, LCDR2 and LCDR3 of SEQ ID NO:151, SEQ ID NO:152 and SEQ ID NO:150, respectively.

[0344] In some embodiments, the antibody or its antigen-binding fragment comprises: a) VH, which contains the HCDR1, HCDR2, and HCDR3 amino acid sequences of SEQ ID NO:306, SEQ ID NO:132, and SEQ ID NO:139, respectively, and b) VL, which contains the amino acid sequences of LCDR1, LCDR2 and LCDR3 of SEQ ID NO:151, SEQ ID NO:152 and SEQ ID NO:150, respectively.

[0345] In some embodiments, the antibody or its antigen-binding fragment comprises: a) VH, which contains the HCDR1, HCDR2, and HCDR3 amino acid sequences of SEQ ID NO:105, SEQ ID NO:132, and SEQ ID NO:139, respectively, and b) VL, which contains the amino acid sequences of LCDR1, LCDR2 and LCDR3 of SEQ ID NO:151, SEQ ID NO:156 and SEQ ID NO:150, respectively.

[0346] VH / VL framework area

[0347] In some embodiments, the antibody or its antigen-binding fragment comprises: a) The VH structural domains of the four VH framework regions (VH FR1-4) and the three heavy chain complementarity determining regions (HCDR1-3) are arranged in the following order from N-terminus to C-terminus: VH FR1-HCDR1-VH FR2-HCDR2-VH FR3-HCDR3-VH FR4, where: i. The VH FR1-HCDR1 contains the amino acid sequence of SEQ ID NO:X. ii. The VH FR2 contains the amino acid sequence of GKGL (SEQ ID NO:268), GDYL (SEQ ID NO:269), or GYYL (SEQ ID NO:270), or iii. The VH FR3 contains the amino acid sequence of NSLK (SEQ ID NO:271), PSLR (SEQ ID NO:272), or NDLR (SEQ ID NO:273), or Any combination of i) to iii), and b) The VL domains of the four VL framework regions (VL FR1-4) and three heavy chain complementarity-determining regions (LCDR1-3) are arranged in the following N-terminal to C-terminal order: VL FR1-LCDR1-VL FR2-LCDR2-VL FR3-LCDR3-VL FR4, wherein VLFR2-HCDR2 contains the amino acid sequence of SLQS, SLQE, DLQR, SQQR, or SEQR. Depending on the circumstances, the VH domain may have less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1, and / or the VL domain may have less than 100% sequence identity with the amino acid sequence of SEQ ID NO:140.

[0348] In some embodiments, the antibody or its antigen-binding fragment comprises: a) VH FR1-HCDR1 containing the amino acid sequence of SEQ ID NO:X, and i. VH FR2 containing the amino acid sequence of GKGL (SEQ ID NO:268), GDYL (SEQ ID NO:269) or GYYL (SEQ ID NO:270), and / or ii. VH FR3 containing an amino acid sequence of NSLK (SEQ ID NO:271), PSLR (SEQ ID NO:272), or NDLR (SEQ ID NO:273), and / or b) VL FR2-HCDR2 contains the amino acid sequence of DLQR. Depending on the circumstances, the VH domain may have less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1, and / or the VL domain may have less than 100% sequence identity with the amino acid sequence of SEQ ID NO:140.

[0349] In some embodiments, the antibody or its antigen-binding fragment comprises: a) VH FR1-HCDR1 containing the amino acid sequence of SEQ ID NO:X, and i. VH FR2 containing the amino acid sequence of GKGL (SEQ ID NO:268), GDYL (SEQ ID NO:269) or GYYL (SEQ ID NO:270), and / or ii. VH FR3 containing an amino acid sequence of NSLK (SEQ ID NO:271), PSLR (SEQ ID NO:272), or NDLR (SEQ ID NO:273), and / or b) VL FR2-HCDR2 contains the amino acid sequence of SQQR. Depending on the circumstances, the VH domain may have less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1, and / or the VL domain may have less than 100% sequence identity with the amino acid sequence of SEQ ID NO:140.

[0350] In some embodiments, the antibody or its antigen-binding fragment comprises: a) VH FR2 containing the amino acid sequence of GKGL (SEQ ID NO:268), GDYL (SEQ ID NO:269), or GYYL (SEQ ID NO:270), and i. VH FR1-HCDR1 containing the amino acid sequence of SEQ ID NO:X, and / or ii. VH FR3 containing an amino acid sequence of NSLK (SEQ ID NO:271), PSLR (SEQ ID NO:272), or NDLR (SEQ ID NO:273), and / or b) VL FR2-HCDR2 contains the amino acid sequence of DLQR. Depending on the circumstances, the VH domain may have less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1, and / or the VL domain may have less than 100% sequence identity with the amino acid sequence of SEQ ID NO:140.

[0351] In some embodiments, the antibody or its antigen-binding fragment comprises: a) VH FR2 containing the amino acid sequence of GKGL (SEQ ID NO:268), GDYL (SEQ ID NO:269), or GYYL (SEQ ID NO:270), and i. VH FR1-HCDR1 containing the amino acid sequence of SEQ ID NO:X, and / or ii. VH FR3 containing an amino acid sequence of NSLK (SEQ ID NO:271), PSLR (SEQ ID NO:272), or NDLR (SEQ ID NO:273), and / or b) VL FR2-HCDR2 contains the amino acid sequence of SQQR. Depending on the circumstances, the VH domain may have less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1, and / or the VL domain may have less than 100% sequence identity with the amino acid sequence of SEQ ID NO:140.

[0352] In some embodiments, the antibody or its antigen-binding fragment comprises: a) VH FR2 containing the amino acid sequence GKGL (SEQ ID NO:268), and i. VH FR1-HCDR1 containing the amino acid sequence of SEQ ID NO:X, and / or ii. VH FR3 containing an amino acid sequence of NSLK (SEQ ID NO:271), PSLR (SEQ ID NO:272), or NDLR (SEQ ID NO:273), and / or b) VL FR2-HCDR2 contains the amino acid sequence of DLQR. Depending on the circumstances, the VH domain may have less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1, and / or the VL domain may have less than 100% sequence identity with the amino acid sequence of SEQ ID NO:140.

[0353] In some embodiments, the antibody or its antigen-binding fragment comprises: a) VH FR2 containing the amino acid sequence GKGL (SEQ ID NO:268), and i. VH FR1-HCDR1 containing the amino acid sequence of SEQ ID NO:X, and / or ii. VH FR3 containing an amino acid sequence of NSLK (SEQ ID NO:271), PSLR (SEQ ID NO:272), or NDLR (SEQ ID NO:273), and / or b) VL FR2-HCDR2 contains the amino acid sequence of SQQR. Depending on the circumstances, the VH domain may have less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1, and / or the VL domain may have less than 100% sequence identity with the amino acid sequence of SEQ ID NO:140.

[0354] In some embodiments, the antibody or its antigen-binding fragment comprises: a) VH FR2 containing the amino acid sequence of GDYL (SEQ ID NO:269), and i. VH FR1-HCDR1 containing the amino acid sequence of SEQ ID NO:X, and / or ii. VH FR3 containing an amino acid sequence of NSLK (SEQ ID NO:271), PSLR (SEQ ID NO:272), or NDLR (SEQ ID NO:273), and / or b) VL FR2-HCDR2 contains the amino acid sequence of DLQR. Depending on the circumstances, the VH domain may have less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1, and / or the VL domain may have less than 100% sequence identity with the amino acid sequence of SEQ ID NO:140.

[0355] In some embodiments, the antibody or its antigen-binding fragment comprises: a) VH FR2 containing the amino acid sequence of GDYL (SEQ ID NO:269), and i. VH FR1-HCDR1 containing the amino acid sequence of SEQ ID NO:X, and / or ii. VH FR3 containing an amino acid sequence of NSLK (SEQ ID NO:271), PSLR (SEQ ID NO:272), or NDLR (SEQ ID NO:273), and / or b) VL FR2-HCDR2 contains the amino acid sequence of SQQR. Depending on the circumstances, the VH domain may have less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1, and / or the VL domain may have less than 100% sequence identity with the amino acid sequence of SEQ ID NO:140.

[0356] In some embodiments, the antibody or its antigen-binding fragment comprises: a) VH FR2 containing the amino acid sequence of GYYL (SEQ ID NO:270), and i. VH FR1-HCDR1 containing the amino acid sequence of SEQ ID NO:X, and / or ii. VH FR3 containing an amino acid sequence of NSLK (SEQ ID NO:271), PSLR (SEQ ID NO:272), or NDLR (SEQ ID NO:273), and / or b) VL FR2-HCDR2 contains the amino acid sequence of DLQR. Depending on the circumstances, the VH domain may have less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1, and / or the VL domain may have less than 100% sequence identity with the amino acid sequence of SEQ ID NO:140.

[0357] In some embodiments, the antibody or its antigen-binding fragment comprises: a) VH FR2 containing the amino acid sequence of GYYL (SEQ ID NO:270), and i. VH FR1-HCDR1 containing the amino acid sequence of SEQ ID NO:X, and / or ii. VH FR3 containing an amino acid sequence of NSLK (SEQ ID NO:271), PSLR (SEQ ID NO:272), or NDLR (SEQ ID NO:273), and / or b) VL FR2-HCDR2 contains the amino acid sequence of SQQR. Depending on the circumstances, the VH domain may have less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1, and / or the VL domain may have less than 100% sequence identity with the amino acid sequence of SEQ ID NO:140.

[0358] In some embodiments, the antibody or its antigen-binding fragment comprises: a) VH FR3 containing the amino acid sequence of NSLK (SEQ ID NO:271), PSLR (SEQ ID NO:272), or NDLR (SEQ ID NO:273), and i. VH FR1-HCDR1 containing the amino acid sequence of SEQ ID NO:X, and / or ii. VH FR2 containing the amino acid sequence of GKGL (SEQ ID NO:268), GDYL (SEQ ID NO:269) or GYYL (SEQ ID NO:270), and / or b) VL FR2-HCDR2 contains the amino acid sequence of DLQR. Depending on the circumstances, the VH domain may have less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1, and / or the VL domain may have less than 100% sequence identity with the amino acid sequence of SEQ ID NO:140.

[0359] In some embodiments, the antibody or its antigen-binding fragment comprises: a) VH FR3 containing the amino acid sequence of NSLK (SEQ ID NO:271), PSLR (SEQ ID NO:272), or NDLR (SEQ ID NO:273), and i. VH FR1-HCDR1 containing the amino acid sequence of SEQ ID NO:X, and / or ii. VH FR2 containing the amino acid sequence of GKGL (SEQ ID NO:268), GDYL (SEQ ID NO:269) or GYYL (SEQ ID NO:270), and / or b) VL FR2-HCDR2 contains the amino acid sequence of SQQR. Depending on the circumstances, the VH domain may have less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1, and / or the VL domain may have less than 100% sequence identity with the amino acid sequence of SEQ ID NO:140.

[0360] In some embodiments, the antibody or its antigen-binding fragment comprises: a) VH FR3 containing the amino acid sequence of NSLK (SEQ ID NO:271), and i. VH FR1-HCDR1 containing the amino acid sequence of SEQ ID NO:X, and / or ii. VH FR2 containing the amino acid sequence of GKGL (SEQ ID NO:268), GDYL (SEQ ID NO:269) or GYYL (SEQ ID NO:270), and / or b) VL FR2-HCDR2 contains the amino acid sequence of DLQR. Depending on the circumstances, the VH domain may have less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1, and / or the VL domain may have less than 100% sequence identity with the amino acid sequence of SEQ ID NO:140.

[0361] In some embodiments, the antibody or its antigen-binding fragment comprises: a) VH FR3 containing the amino acid sequence of NSLK (SEQ ID NO:271), and i. VH FR1-HCDR1 containing the amino acid sequence of SEQ ID NO:X, and / or ii. VH FR2 containing the amino acid sequence of GKGL (SEQ ID NO:268), GDYL (SEQ ID NO:269) or GYYL (SEQ ID NO:270), and / or b) VL FR2-HCDR2 contains the amino acid sequence of SQQR. Depending on the circumstances, the VH domain may have less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1, and / or the VL domain may have less than 100% sequence identity with the amino acid sequence of SEQ ID NO:140.

[0362] In some embodiments, the antibody or its antigen-binding fragment comprises: a) VH FR3 containing the amino acid sequence of PSLR (SEQ ID NO:272), and i. VH FR1-HCDR1 containing the amino acid sequence of SEQ ID NO:X, and / or ii. VH FR2 containing the amino acid sequence of GKGL (SEQ ID NO:268), GDYL (SEQ ID NO:269) or GYYL (SEQ ID NO:270), and / or b) VL FR2-HCDR2 contains the amino acid sequence of DLQR. Depending on the circumstances, the VH domain may have less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1, and / or the VL domain may have less than 100% sequence identity with the amino acid sequence of SEQ ID NO:140.

[0363] In some embodiments, the antibody or its antigen-binding fragment comprises: a) VH FR3 containing the amino acid sequence of PSLR (SEQ ID NO:272), and i. VH FR1-HCDR1 containing the amino acid sequence of SEQ ID NO:X, and / or ii. VH FR2 containing the amino acid sequence of GKGL (SEQ ID NO:268), GDYL (SEQ ID NO:269) or GYYL (SEQ ID NO:270), and / or b) VL FR2-HCDR2 contains the amino acid sequence of SQQR. Depending on the circumstances, the VH domain may have less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1, and / or the VL domain may have less than 100% sequence identity with the amino acid sequence of SEQ ID NO:140.

[0364] In some embodiments, the antibody or its antigen-binding fragment comprises: a) VH FR3 containing the amino acid sequence of NDLR (SEQ ID NO:273), and i. VH FR1-HCDR1 containing the amino acid sequence of SEQ ID NO:X, and / or ii. VH FR2 containing the amino acid sequence of GKGL (SEQ ID NO:268), GDYL (SEQ ID NO:269) or GYYL (SEQ ID NO:270), and / or b) VL FR2-HCDR2 contains the amino acid sequence of DLQR. Depending on the circumstances, the VH domain may have less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1, and / or the VL domain may have less than 100% sequence identity with the amino acid sequence of SEQ ID NO:140.

[0365] In some embodiments, the antibody or its antigen-binding fragment comprises: a) VH FR3 containing the amino acid sequence of NDLR (SEQ ID NO:273), and i. VH FR1-HCDR1 containing the amino acid sequence of SEQ ID NO:X, and / or ii. VH FR2 containing the amino acid sequence of GKGL (SEQ ID NO:268), GDYL (SEQ ID NO:269) or GYYL (SEQ ID NO:270), and / or b) VL FR2-HCDR2 contains the amino acid sequence of SQQR. Depending on the circumstances, the VH domain may have less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1, and / or the VL domain may have less than 100% sequence identity with the amino acid sequence of SEQ ID NO:140.

[0366] In some embodiments, X is any one of 309, 310, and 262-267. In some embodiments, X is any one of 262-267. In some embodiments, X is 309. In some embodiments, X is 310. In some embodiments, X is 262. In some embodiments, X is 263. In some embodiments, X is 264. In some embodiments, X is 265. In some embodiments, X is 266. In some embodiments, X is 267.

[0367] VH / VL

[0368] In some embodiments, the antibody or its antigen-binding fragment comprises: a) A VH domain having at least 70% sequence identity with the amino acid sequence of SEQ ID NO:X (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity), and b) A VL domain having at least 70% sequence identity with the amino acid sequence of SEQ ID NO:Y (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity). The antibody or its antigen-binding fragment contains a VH domain having less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1 and / or a VL domain having less than 100% sequence identity with the amino acid sequence of SEQ ID NO:140.

[0369] In some embodiments, the antibody or its antigen-binding fragment comprises: a) The amino acid sequence relative to SEQ ID NO:X contains at least one amino acid-substituted VH, and b) The amino acid sequence relative to SEQ ID NO:Y contains a VL with at least one amino acid substitution. The antibody or its antigen-binding fragment contains a VH domain having less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1 and / or a VL domain having less than 100% sequence identity with the amino acid sequence of SEQ ID NO:140.

[0370] For example, the number of amino acid substitutions may be at least about: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, or about: 1-20, 1-19, 2-19, 2-18, 2-17, 3-17, 3-16, 4-16, 4-15, 5-15, 5-14, 6-14, 6-13, 7-13, 7-12, 8-12, 8-11 or 9-11.

[0371] In some embodiments, the antibody or its antigen-binding fragment comprises: a) The amino acid sequence relative to SEQ ID NO:X contains approximately 1-10 amino acid substitutions for VH, and b) The amino acid sequence relative to SEQ ID NO:Y contains a VL with approximately 1-10 amino acid substitutions.

[0372] In some embodiments, the amino acid substitution is a conservative substitution.

[0373] In some embodiments, the amino acid substitutions are highly conserved substitutions.

[0374] In some embodiments, the antibody or its antigen-binding fragment comprises: a) VH with 100% sequence identity to the amino acid sequence of SEQ ID NO:X, and / or b) A VL with 100% sequence identity to the amino acid sequence of SEQ ID NO:Y.

[0375] In some embodiments, X is any one of 1-11, 19-21, 299, and 300, and Y is any one of 144, 142, 301, and 302. In some embodiments, X is any one of 2-11, 19-21, 299, and 300, and Y is any one of 144, 142, 140, 301, and 302. In some embodiments, X is any one of 2-11, 19-21, 299, and 300, and Y is any one of 144, 142, 301, and 302. In some embodiments, X is any one of 1-4, 299, and 300, and Y is any one of 144, 142, 301, and 302. In some embodiments, X is any one of 2-4, 299, and 300, and Y is any one of 144, 142, 140, 301, and 302. In some embodiments, X is any one of 2-4, 299, and 300, and Y is any one of 144, 142, 301, and 302.

[0376] In some embodiments, X is any one of 1-11 and 19-21, and Y is 144 or 142. In some embodiments, X is any one of 2-11 and 19-21, and Y is any one of 144, 142, and 140. In some embodiments, X is any one of 2-11 and 19-21, and Y is 144 or 142. In some embodiments, X is any one of 1-4, and Y is 144 or 142. In some embodiments, X is any one of 2-4, and Y is any one of 144, 142, and 140. In some embodiments, X is any one of 2-4, and Y is 144 or 142.

[0377] In some embodiments, X is 2 and Y is 144. In some embodiments, X is 2 and Y is 142. In some embodiments, X is 2 and Y is 301. In some embodiments, X is 2 and Y is 302. In some embodiments, X is 3 and Y is 144. In some embodiments, X is 3 and Y is 142. In some embodiments, X is 3 and Y is 301. In some embodiments, X is 3 and Y is 302. In some embodiments, X is 4 and Y is 144. In some embodiments, X is 4 and Y is 142. In some embodiments, X is 4 and Y is 301. In some embodiments, X is 4 and Y is 302. In some embodiments, X is 5 and Y is 144. In some embodiments, X is 5 and Y is 142. In some embodiments, X is 5 and Y is 301. In some embodiments, X is 5 and Y is 302. In some embodiments, X is 6 and Y is 144. In some embodiments, X is 6 and Y is 142. In some embodiments, X is 6 and Y is 301. In some embodiments, X is 6 and Y is 302. In some embodiments, X is 7 and Y is 144. In some embodiments, X is 7 and Y is 142. In some embodiments, X is 7 and Y is 301. In some embodiments, X is 7 and Y is 302. In some embodiments, X is 8 and Y is 144. In some embodiments, X is 8 and Y is 142. In some embodiments, X is 8 and Y is 301. In some embodiments, X is 8 and Y is 302. In some embodiments, X is 9 and Y is 144. In some embodiments, X is 9 and Y is 142. In some embodiments, X is 9 and Y is 301. In some embodiments, X is 9 and Y is 302. In some embodiments, X is 10 and Y is 144. In some embodiments, X is 10 and Y is 142. In some embodiments, X is 10 and Y is 301. In some embodiments, X is 10 and Y is 302. In some embodiments, X is 11 and Y is 144. In some embodiments, X is 11 and Y is 142. In some embodiments, X is 11 and Y is 301. In some embodiments, X is 11 and Y is 302. In some embodiments, X is 19 and Y is 144. In some embodiments, X is 19 and Y is 142. In some embodiments, X is 19 and Y is 301. In some embodiments, X is 19 and Y is 302. In some embodiments, X is 20 and Y is 144. In some embodiments, X is 20 and Y is 142. In some embodiments, X is 20 and Y is 301. In some embodiments, X is 20 and Y is 302. In some embodiments, X is 21 and Y is 144. In some embodiments, X is 21 and Y is 142. In some embodiments, X is 21 and Y is 301.In some embodiments, X is 21 and Y is 302. In some embodiments, X is 299 and Y is 144. In some embodiments, X is 299 and Y is 142. In some embodiments, X is 299 and Y is 301. In some embodiments, X is 299 and Y is 302. In some embodiments, X is 300 and Y is 144. In some embodiments, X is 300 and Y is 142. In some embodiments, X is 300 and Y is 301. In some embodiments, X is 300 and Y is 302.

[0378] Each of paragraphs

[0288] -

[0290] applies to any one of paragraphs

[0281] -

[0287] .

[0379] In some embodiments, the antibody or its antigen-binding fragment comprises: a) VH, which has 100% sequence identity with the amino acid sequence of SEQ ID NO:4, and b) A VL with 100% sequence identity to the amino acid sequence of SEQ ID NO:140.

[0380] In some embodiments, the antibody or its antigen-binding fragment comprises: a) VH, which has 100% sequence identity with the amino acid sequence of SEQ ID NO:299, and b) A VL with 100% sequence identity to the amino acid sequence of SEQ ID NO:140.

[0381] In some embodiments, the antibody or its antigen-binding fragment comprises: a) VH, which has 100% sequence identity with the amino acid sequence of SEQ ID NO:300, and b) A VL with 100% sequence identity to the amino acid sequence of SEQ ID NO:140.

[0382] In some embodiments, the antibody or its antigen-binding fragment comprises: a) VH, which has 100% sequence identity with the amino acid sequence of SEQ ID NO:1, and b) A VL with 100% sequence identity to the amino acid sequence of SEQ ID NO:142.

[0383] In some embodiments, the antibody or its antigen-binding fragment comprises: a) VH, which has 100% sequence identity with the amino acid sequence of SEQ ID NO:1, and b) A VL with 100% sequence identity to the amino acid sequence of SEQ ID NO:144.

[0384] In some embodiments, the antibody or its antigen-binding fragment comprises: a) VH, which has 100% sequence identity with the amino acid sequence of SEQ ID NO:1, and b) A VL with 100% sequence identity to the amino acid sequence of SEQ ID NO:301.

[0385] In some embodiments, the antibody or its antigen-binding fragment comprises: a) VH, which has 100% sequence identity with the amino acid sequence of SEQ ID NO:1, and b) A VL with 100% sequence identity to the amino acid sequence of SEQ ID NO:302.

[0386] In some embodiments, the antibody or its antigen-binding fragment comprises: a) VH, which has 100% sequence identity with the amino acid sequence of SEQ ID NO:2, and b) A VL with 100% sequence identity to the amino acid sequence of SEQ ID NO:144.

[0387] In some embodiments, the antibody or its antigen-binding fragment comprises: a) VH, which has 100% sequence identity with the amino acid sequence of SEQ ID NO:3, and b) A VL with 100% sequence identity to the amino acid sequence of SEQ ID NO:144.

[0388] Heavy chain / light chain

[0389] In some embodiments, the antibody or its antigen-binding fragment comprises an antibody heavy chain constant domain sequence and / or an antibody light chain constant domain sequence.

[0390] Heavy chain constant structure domain

[0391] In some embodiments, the antibody or its antigen-binding fragment contains a constant domain sequence of the immunoglobulin heavy chain.

[0392] In some embodiments, the antibody or its antigen-binding fragment comprises a constant heavy chain domain of immunoglobulin IgA, IgD, IgE, IgG, or IgM.

[0393] In some embodiments, the antibody or its antigen-binding fragment comprises an immunoglobulin IgA heavy chain constant domain. In some embodiments, the antibody or its antigen-binding fragment comprises an immunoglobulin IgA1 heavy chain constant domain. In some embodiments, the antibody or its antigen-binding fragment comprises an immunoglobulin IgA2 heavy chain constant domain.

[0394] In some embodiments, the antibody or its antigen-binding fragment comprises an immunoglobulin IgG heavy chain constant domain. In some embodiments, the antibody or its antigen-binding fragment comprises an immunoglobulin IgG2 heavy chain constant domain (e.g., IgG2a, IgG2b, or IgG2c). In some embodiments, the antibody or its antigen-binding fragment comprises an immunoglobulin IgG3 heavy chain constant domain. In some embodiments, the antibody or its antigen-binding fragment comprises an immunoglobulin IgG1 heavy chain constant domain (e.g., SEQ ID NO:279 or SEQ ID NO:280).

[0395] In some embodiments, the antibody or its antigen-binding fragment comprises an immunoglobulin heavy chain constant domain sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO:279 and / or SEQ ID NO:280 (e.g., SEQ ID NO:279). For example, the antibody or its antigen-binding fragment may comprise an immunoglobulin heavy chain constant domain sequence having at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:279 and / or SEQ ID NO:280 (e.g., SEQ ID NO:279).

[0396] In some embodiments, the antibody or its antigen-binding fragment comprises an immunoglobulin heavy chain constant domain sequence comprising at least one amino acid substitution relative to the amino acid sequence of SEQ ID NO:279 and / or SEQ ID NO:280 (e.g., SEQ ID NO:279). For example, the number of amino acid substitutions may be at least 2, at least 5, at least 10, at least 15, at least 20, at least 25, or at least 30, or about: 1-30, 1-25, 2-25, 2-20, 5-20, 5-15, or 10-15.

[0397] In some embodiments, the antibody or its antigen-binding fragment comprises an immunoglobulin heavy chain constant domain sequence having 100% sequence identity with the amino acid sequence of SEQ ID NO:279.

[0398] In some embodiments, the antibody or its antigen-binding fragment comprises an immunoglobulin heavy chain constant domain sequence having 100% sequence identity with the amino acid sequence of SEQ ID NO:280.

[0399] In some embodiments, the antibody or its antigen-binding fragment is a heavy chain antibody or its antigen-binding fragment containing two or more heavy chains but lacking light chains. Non-limiting examples of heavy chain antibodies include Camelidae Vhh (also known as VHH or VHH) antibodies. Camelidae antibodies are antibodies derived from mammals of the Camelidae family, including llamas, camels, and alpacas.

[0400] Light chain constant structural domain

[0401] In some embodiments, the antibody or its antigen-binding fragment comprises a constant domain sequence of an immunoglobulin light chain.

[0402] In some embodiments, the antibody or its antigen-binding fragment comprises an immunoglobulin κ light chain constant domain (e.g., SEQ ID NO:281).

[0403] In some embodiments, the antibody or its antigen-binding fragment comprises an immunoglobulin λ light chain constant domain (e.g., SEQ ID NO:282).

[0404] In some embodiments, the antibody or its antigen-binding fragment comprises an immunoglobulin light chain constant domain sequence having at least 70% sequence identity with the amino acid sequence of SEQ ID NO:281 and / or SEQ ID NO:282 (e.g., SEQ ID NO:282). For example, the antibody or its antigen-binding fragment may comprise an immunoglobulin light chain constant domain sequence having at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity with the amino acid sequence of SEQ ID NO:281 and / or SEQ ID NO:282 (e.g., SEQ ID NO:282).

[0405] In some embodiments, the antibody or its antigen-binding fragment comprises an immunoglobulin light chain constant domain sequence comprising at least one amino acid substitution relative to the amino acid sequence of SEQ ID NO:281 and / or SEQ ID NO:282 (e.g., SEQ ID NO:282). For example, the number of amino acid substitutions may be at least 2, at least 5, at least 10, at least 15, at least 20, at least 25, or at least 30, or about: 1-30, 1-25, 2-25, 2-20, 5-20, 5-15, or 10-15.

[0406] In some embodiments, the antibody or its antigen-binding fragment comprises an immunoglobulin light chain constant domain sequence having 100% sequence identity with the amino acid sequence of SEQ ID NO:282.

[0407] In some embodiments, the antibody or its antigen-binding fragment comprises an immunoglobulin light chain constant domain sequence having 100% sequence identity with the amino acid sequence of SEQ ID NO:281.

[0408] Heavy / Light Chains

[0409] In some embodiments, the antibody or its antigen-binding fragment comprises: a) A heavy chain having at least 60% sequence identity (e.g., at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% sequence identity) with the amino acid sequence of SEQ ID NO:X, and / or b) A light chain having at least 60% sequence identity with the amino acid sequence of SEQ ID NO:Y (e.g., at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% sequence identity). The antibody or its antigen-binding fragment contains a VH domain having less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1 and / or a VL domain having less than 100% sequence identity with the amino acid sequence of SEQ ID NO:140.

[0410] In some embodiments, the antibody or its antigen-binding fragment comprises: a) The heavy chain containing at least one amino acid substitution relative to the amino acid sequence of SEQ ID NO:X, and / or b) The amino acid sequence relative to SEQ ID NO:Y contains a light chain with at least one amino acid substitution. The antibody or its antigen-binding fragment contains a VH domain having less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1 and / or a VL domain having less than 100% sequence identity with the amino acid sequence of SEQ ID NO:140.

[0411] For example, the number of amino acid substitutions may be at least about: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, or about: 1-20, 1-19, 2-19, 2-18, 2-17, 3-17, 3-16, 4-16, 4-15, 5-15, 5-14, 6-14, 6-13, 7-13, 7-12, 8-12, 8-11 or 9-11.

[0412] For example, the number of amino acid substitutions may be at least about: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, or about: 1-20, 1-19, 2-19, 2-18, 2-17, 3-17, 3-16, 4-16, 4-15, 5-15, 5-14, 6-14, 6-13, 7-13, 7-12, 8-12, 8-11 or 9-11.

[0413] In some embodiments, the antibody or its antigen-binding fragment comprises: a) The amino acid sequence relative to SEQ ID NO:X contains a heavy chain with approximately 1-10 substituted amino acids, and b) The amino acid sequence relative to SEQ ID NO:Y contains a light chain with approximately 1-10 amino acid substitutions.

[0414] In some embodiments, the amino acid substitution is a conservative substitution.

[0415] In some embodiments, the amino acid substitutions are highly conserved substitutions.

[0416] In some embodiments, the antibody or its antigen-binding fragment comprises: a) A heavy chain having 100% sequence identity with the amino acid sequence of SEQ ID NO:X, and / or b) A light chain that has 100% sequence identity with the amino acid sequence of SEQ ID NO:Y.

[0417] In some embodiments, the antibody or its antigen-binding fragment comprises: a) A heavy chain with 100% sequence identity to the amino acid sequence of SEQ ID NO:X, and b) A light chain that has 100% sequence identity with the amino acid sequence of SEQ ID NO:Y.

[0418] In some embodiments, X is any one of 160-170, 178-180, 311, and 312, and Y is any one of 207, 205, 313, and 314. In some embodiments, X is any one of 161-170, 178-180, 311, and 312, and Y is any one of 207, 205, 203, 313, and 314. In some embodiments, X is any one of 161-170, 178-180, 311, and 312, and Y is any one of 207, 205, 313, and 314. In some embodiments, X is any one of 160-163, 311, and 312, and Y is any one of 207, 205, 313, and 314. In some embodiments, X is any one of 161-163, 311, and 312, and Y is any one of 207, 205, 203, 313, and 314.

[0419] In some embodiments, X is any one of 160-170 and 178-180, and Y is 207 or 205. In some embodiments, X is any one of 161-170 and 178-180, and Y is any one of 207, 205, and 203. In some embodiments, X is any one of 161-170 and 178-180, and Y is 207 or 205. In some embodiments, X is any one of 160-163, and Y is 207 or 205. In some embodiments, X is any one of 161-163, and Y is any one of 207, 205, and 203. In some embodiments, X is any one of 161-163, and Y is 207 or 205.

[0420] In some embodiments, X is 161 and Y is 207. In some embodiments, X is 161 and Y is 205. In some embodiments, X is 161 and Y is 313. In some embodiments, X is 161 and Y is 314. In some embodiments, X is 162 and Y is 207. In some embodiments, X is 162 and Y is 205. In some embodiments, X is 162 and Y is 313. In some embodiments, X is 162 and Y is 314. In some embodiments, X is 163 and Y is 207. In some embodiments, X is 163 and Y is 205. In some embodiments, X is 163 and Y is 313. In some embodiments, X is 163 and Y is 314. In some embodiments, X is 164 and Y is 207. In some embodiments, X is 164 and Y is 205. In some embodiments, X is 164 and Y is 313. In some embodiments, X is 164 and Y is 314. In some embodiments, X is 165 and Y is 207. In some embodiments, X is 165 and Y is 205. In some embodiments, X is 165 and Y is 313. In some embodiments, X is 165 and Y is 314. In some embodiments, X is 166 and Y is 207. In some embodiments, X is 166 and Y is 205. In some embodiments, X is 166 and Y is 313. In some embodiments, X is 166 and Y is 314. In some embodiments, X is 167 and Y is 207. In some embodiments, X is 167 and Y is 205. In some embodiments, X is 167 and Y is 313. In some embodiments, X is 167 and Y is 314. In some embodiments, X is 168 and Y is 207. In some embodiments, X is 168 and Y is 205. In some embodiments, X is 168 and Y is 313. In some embodiments, X is 168 and Y is 314. In some embodiments, X is 169 and Y is 207. In some embodiments, X is 169 and Y is 205. In some embodiments, X is 169 and Y is 313. In some embodiments, X is 169 and Y is 314. In some embodiments, X is 170 and Y is 207. In some embodiments, X is 170 and Y is 205. In some embodiments, X is 170 and Y is 313. In some embodiments, X is 170 and Y is 314. In some embodiments, X is 178 and Y is 207. In some embodiments, X is 178 and Y is 205. In some embodiments, X is 178 and Y is 313. In some embodiments, X is 178 and Y is 314. In some embodiments, X is 179 and Y is 207. In some embodiments, X is 179 and Y is 205. In some embodiments, X is 179 and Y is 313.In some embodiments, X is 179 and Y is 314. In some embodiments, X is 180 and Y is 207. In some embodiments, X is 180 and Y is 205. In some embodiments, X is 180 and Y is 313. In some embodiments, X is 180 and Y is 314. In some embodiments, X is 311 and Y is 207. In some embodiments, X is 311 and Y is 205. In some embodiments, X is 311 and Y is 313. In some embodiments, X is 311 and Y is 314. In some embodiments, X is 312 and Y is 207. In some embodiments, X is 312 and Y is 205. In some embodiments, X is 312 and Y is 313. In some embodiments, X is 312 and Y is 314.

[0421] Each of paragraphs

[0327] -

[0329] applies to any one of paragraphs

[0318] -

[0326] .

[0422] In some embodiments, the antibody or its antigen-binding fragment comprises: a) A heavy chain with 100% sequence identity to the amino acid sequence of SEQ ID NO:163, and b) A light chain that has 100% sequence identity with the amino acid sequence of SEQ ID NO:203.

[0423] In some embodiments, the antibody or its antigen-binding fragment comprises: a) A heavy chain with 100% sequence identity to the amino acid sequence of SEQ ID NO:311, and b) A light chain that has 100% sequence identity with the amino acid sequence of SEQ ID NO:203.

[0424] In some embodiments, the antibody or its antigen-binding fragment comprises: a) A heavy chain with 100% sequence identity to the amino acid sequence of SEQ ID NO:312, and b) A light chain that has 100% sequence identity with the amino acid sequence of SEQ ID NO:203.

[0425] In some embodiments, the antibody or its antigen-binding fragment comprises: a) A heavy chain with 100% sequence identity to the amino acid sequence of SEQ ID NO:160, and b) A light chain that has 100% sequence identity with the amino acid sequence of SEQ ID NO:205.

[0426] In some embodiments, the antibody or its antigen-binding fragment comprises: a) A heavy chain with 100% sequence identity to the amino acid sequence of SEQ ID NO:160, and b) A light chain that has 100% sequence identity with the amino acid sequence of SEQ ID NO:207.

[0427] In some embodiments, the antibody or its antigen-binding fragment comprises: a) A heavy chain with 100% sequence identity to the amino acid sequence of SEQ ID NO:160, and b) A light chain that has 100% sequence identity with the amino acid sequence of SEQ ID NO:313.

[0428] In some embodiments, the antibody or its antigen-binding fragment comprises: a) A heavy chain with 100% sequence identity to the amino acid sequence of SEQ ID NO:160, and b) A light chain that has 100% sequence identity with the amino acid sequence of SEQ ID NO:314.

[0429] In some embodiments, the antibody or its antigen-binding fragment comprises: a) A heavy chain with 100% sequence identity to the amino acid sequence of SEQ ID NO:161, and b) A light chain that has 100% sequence identity with the amino acid sequence of SEQ ID NO:207.

[0430] In some embodiments, the antibody or its antigen-binding fragment comprises: a) A heavy chain with 100% sequence identity to the amino acid sequence of SEQ ID NO:162, and b) A light chain that has 100% sequence identity with the amino acid sequence of SEQ ID NO:207.

[0431] scFv

[0432] In some embodiments, the antibody or its antigen-binding fragment is a single-chain variable fragment (scFv), a heavy-chain variable restructure domain (VHH), an antigen-binding fragment (Fab), Fab', or F(ab')2.

[0433] In some embodiments, the antibody or its antigen-binding fragment is scFv.

[0434] In some embodiments, the antibody or its antigen-binding fragment comprises a VH domain disclosed herein, which is connected to the VL domain herein by an scFv connector.

[0435] In some embodiments, the antibody or its antigen-binding fragment comprises: a) A VH domain having at least 70% sequence identity with the amino acid sequence of SEQ ID NO:X (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity), and b) A VL domain having at least 70% sequence identity with the amino acid sequence of SEQ ID NO:Y (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity). The VH domain is connected to the VL domain by the scFv connector, and the VH domain has less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1 and / or the VL domain has less than 100% sequence identity with the amino acid sequence of SEQ ID NO:140.

[0436] In some embodiments, the antibody or its antigen-binding fragment comprises: a) The amino acid sequence relative to SEQ ID NO:X contains at least one amino acid-substituted VH, and b) The amino acid sequence relative to SEQ ID NO:Y contains a VL with at least one amino acid substitution. The VH domain is connected to the VL domain by the scFv connector, and the VH domain has less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1 and / or the VL domain has less than 100% sequence identity with the amino acid sequence of SEQ ID NO:140.

[0437] In some embodiments, the antibody or its antigen-binding fragment comprises: a) VH, which has 100% sequence identity with the amino acid sequence of SEQ ID NO:X, and b) VL with 100% sequence identity to the amino acid sequence of SEQ ID NO:Y. The VH structure field is connected to the VL structure field by the scFv connector.

[0438] In some embodiments, X is any one of 1-11, 19-21, 299, and 300, and Y is any one of 144, 142, 301, and 302. In some embodiments, X is any one of 2-11, 19-21, 299, and 300, and Y is any one of 144, 142, 140, 301, and 302. In some embodiments, X is any one of 2-11, 19-21, 299, and 300, and Y is any one of 144, 142, 301, and 302. In some embodiments, X is any one of 1-4, 299, and 300, and Y is any one of 144, 142, 301, and 302. In some embodiments, X is any one of 2-4, 299, and 300, and Y is any one of 144, 142, 140, 301, and 302. In some embodiments, X is any one of 2-4, 299, and 300, and Y is any one of 144, 142, 301, and 302.

[0439] In some embodiments, X is any one of 1-11 and 19-21, and Y is 144 or 142. In some embodiments, X is any one of 2-11 and 19-21, and Y is any one of 144, 142, and 140. In some embodiments, X is any one of 2-11 and 19-21, and Y is 144 or 142. In some embodiments, X is any one of 1-4, and Y is 144 or 142. In some embodiments, X is any one of 2-4, and Y is any one of 144, 142, and 140. In some embodiments, X is any one of 2-4, and Y is 144 or 142.

[0440] In some embodiments, X is 2 and Y is 144. In some embodiments, X is 2 and Y is 142. In some embodiments, X is 2 and Y is 301. In some embodiments, X is 2 and Y is 302. In some embodiments, X is 3 and Y is 144. In some embodiments, X is 3 and Y is 142. In some embodiments, X is 3 and Y is 301. In some embodiments, X is 3 and Y is 302. In some embodiments, X is 4 and Y is 144. In some embodiments, X is 4 and Y is 142. In some embodiments, X is 4 and Y is 301. In some embodiments, X is 4 and Y is 302. In some embodiments, X is 5 and Y is 144. In some embodiments, X is 5 and Y is 142. In some embodiments, X is 5 and Y is 301. In some embodiments, X is 5 and Y is 302. In some embodiments, X is 6 and Y is 144. In some embodiments, X is 6 and Y is 142. In some embodiments, X is 6 and Y is 301. In some embodiments, X is 6 and Y is 302. In some embodiments, X is 7 and Y is 144. In some embodiments, X is 7 and Y is 142. In some embodiments, X is 7 and Y is 301. In some embodiments, X is 7 and Y is 302. In some embodiments, X is 8 and Y is 144. In some embodiments, X is 8 and Y is 142. In some embodiments, X is 8 and Y is 301. In some embodiments, X is 8 and Y is 302. In some embodiments, X is 9 and Y is 144. In some embodiments, X is 9 and Y is 142. In some embodiments, X is 9 and Y is 301. In some embodiments, X is 9 and Y is 302. In some embodiments, X is 10 and Y is 144. In some embodiments, X is 10 and Y is 142. In some embodiments, X is 10 and Y is 301. In some embodiments, X is 10 and Y is 302. In some embodiments, X is 11 and Y is 144. In some embodiments, X is 11 and Y is 142. In some embodiments, X is 11 and Y is 301. In some embodiments, X is 11 and Y is 302. In some embodiments, X is 19 and Y is 144. In some embodiments, X is 19 and Y is 142. In some embodiments, X is 19 and Y is 301. In some embodiments, X is 19 and Y is 302. In some embodiments, X is 20 and Y is 144. In some embodiments, X is 20 and Y is 142. In some embodiments, X is 20 and Y is 301. In some embodiments, X is 20 and Y is 302. In some embodiments, X is 21 and Y is 144. In some embodiments, X is 21 and Y is 142. In some embodiments, X is 21 and Y is 301.In some embodiments, X is 21 and Y is 302. In some embodiments, X is 299 and Y is 144. In some embodiments, X is 299 and Y is 142. In some embodiments, X is 299 and Y is 301. In some embodiments, X is 299 and Y is 302. In some embodiments, X is 300 and Y is 144. In some embodiments, X is 300 and Y is 142. In some embodiments, X is 300 and Y is 301. In some embodiments, X is 300 and Y is 302.

[0441] Each of paragraphs

[0346] -

[0348] applies to any one of paragraphs

[0343] -

[0345] .

[0442] In some embodiments, the antibody or its antigen-binding fragment comprises: a) VH, which has 100% sequence identity with the amino acid sequence of SEQ ID NO:4, and b) VL with 100% sequence identity to the amino acid sequence of SEQ ID NO:140. The VH structure field is connected to the VL structure field by the scFv connector.

[0443] In some embodiments, the antibody or its antigen-binding fragment comprises: a) VH, which has 100% sequence identity with the amino acid sequence of SEQ ID NO:299, and b) VL with 100% sequence identity to the amino acid sequence of SEQ ID NO:140. The VH structure field is connected to the VL structure field by the scFv connector.

[0444] In some embodiments, the antibody or its antigen-binding fragment comprises: a) VH, which has 100% sequence identity with the amino acid sequence of SEQ ID NO:300, and b) VL with 100% sequence identity to the amino acid sequence of SEQ ID NO:140. The VH structure field is connected to the VL structure field by the scFv connector.

[0445] In some embodiments, the antibody or its antigen-binding fragment comprises: a) VH, which has 100% sequence identity with the amino acid sequence of SEQ ID NO:1, and b) VL with 100% sequence identity to the amino acid sequence of SEQ ID NO:142. The VH structure field is connected to the VL structure field by the scFv connector.

[0446] In some embodiments, the antibody or its antigen-binding fragment comprises: a) VH, which has 100% sequence identity with the amino acid sequence of SEQ ID NO:1, and b) VL with 100% sequence identity to the amino acid sequence of SEQ ID NO:144. The VH structure field is connected to the VL structure field by the scFv connector.

[0447] In some embodiments, the antibody or its antigen-binding fragment comprises: a) VH, which has 100% sequence identity with the amino acid sequence of SEQ ID NO:1, and b) VL with 100% sequence identity to the amino acid sequence of SEQ ID NO:301. The VH structure field is connected to the VL structure field by the scFv connector.

[0448] In some embodiments, the antibody or its antigen-binding fragment comprises: a) VH, which has 100% sequence identity with the amino acid sequence of SEQ ID NO:1, and b) VL with 100% sequence identity to the amino acid sequence of SEQ ID NO:302. The VH structure field is connected to the VL structure field by the scFv connector.

[0449] In some embodiments, the antibody or its antigen-binding fragment comprises: a) VH, which has 100% sequence identity with the amino acid sequence of SEQ ID NO:2, and b) VL with 100% sequence identity to the amino acid sequence of SEQ ID NO:144. The VH structure field is connected to the VL structure field by the scFv connector.

[0450] In some embodiments, the antibody or its antigen-binding fragment comprises: a) VH, which has 100% sequence identity with the amino acid sequence of SEQ ID NO:3, and b) VL with 100% sequence identity to the amino acid sequence of SEQ ID NO:144. The VH structure field is connected to the VL structure field by the scFv connector.

[0451] In some embodiments, the scFv linker comprises the amino acid sequence of SEQ ID NO:257 (e.g., constitutes thereof). In some embodiments, the scFv linker comprises the amino acid sequence of SEQ ID NO:258 (e.g., constitutes thereof). In some embodiments, the scFv linker comprises the amino acid sequence of any one of SEQ ID NO:257, SEQ ID NO:258, or SEQ ID NO:284-298 (e.g., constitutes thereof). See, for example, Tang et al., Selection of linkers for a catalytic single-chain antibody using phage display technology, J BiolChem. 271(26):15682-86 (1996), the contents of which are incorporated herein by reference in their entirety.

[0452] In some embodiments, the antibody or its antigen-binding fragment comprises, in the following N-terminal to C-terminal order: the VH domain disclosed herein (e.g., having the amino acid sequence of SEQ ID NO:2 or SEQ ID NO:3), the scFv connector (e.g., having the amino acid sequence of SEQ ID NO:257), and the VL domain disclosed herein (e.g., having the amino acid sequence of SEQ ID NO:144 or SEQ ID NO:142).

[0453] In some embodiments, the antibody or its antigen-binding fragment comprises, in the following N-terminal to C-terminal order: the VH domain disclosed herein (e.g., having the amino acid sequence of SEQ ID NO:2 or SEQ ID NO:3), the scFv linker (e.g., having the amino acid sequence of SEQ ID NO:257), the VL domain disclosed herein (e.g., having the amino acid sequence of SEQ ID NO:144 or SEQ ID NO:142), the Fc linker (e.g., having the amino acid sequence of SEQ ID NO:259), and the Fc domain (e.g., having the amino acid sequence of SEQ ID NO:283).

[0454] In some embodiments, the antibody or its antigen-binding fragment comprises an Fc domain containing one or more mutations (e.g., YTE modification) that, for example, increase the in vivo half-life of the antibody or its antigen-binding fragment, and / or increase the affinity of the constant domain for FcRn. See, for example, Grevys et al., Antibody variablesequences have a pronounced effect on cellular transport and plasma half-life, iScience 25(2):103746 (2022) and WO02060919, the contents of which are incorporated herein by reference in their entirety. In some embodiments, the Fc domain comprises a YTE modification. The YTE modification corresponding to M135Y / S137T / T139E of SEQ ID NO: 279 or SEQ ID NO: 280 has also been referred to as the M252Y / S254T / T256E substitution as determined according to the Kabat number. In some embodiments, the Fc domain comprises an LS modification. The LS modification corresponds to M311L / N317S of SEQ ID NO: 279 or SEQ ID NO: 280.

[0455] In some embodiments, the antibody or its antigen-binding fragment is a bispecific antibody or its antigen-binding fragment. In some embodiments, the bispecific antibody or its antigen-binding fragment contains an Fc. In some embodiments, the bispecific antibody or its antigen-binding fragment does not contain an Fc. Non-limiting example structures of bispecific antibodies or their antigen-binding fragments include bispecific IgG, monospecific IgG with an additional antigen-binding moiety, bispecific antibody fragments, bispecific fusion proteins, and bispecific antibody conjugates. See, for example, Spiess et al., Alternative molecular formats and therapeutic applications for bispecific antibodies, Mol Immunol. 67(2 Part A):95-106 (2015) and Velasquez et al., Redirecting T cells to hematological malignancies with bispecific antibodies, Blood 131(1):30-38 (2018), the contents of which are incorporated herein by reference.

[0456] In some embodiments, the antibody or its antigen-binding fragment is a multispecific antibody or its antigen-binding fragment.

[0457] In some embodiments, the antibody or its antigen-binding fragment is an isolated antibody. In some embodiments, the antibody or its antigen-binding fragment is an isolated antigen-binding fragment of an antibody.

[0458] In some embodiments, the antibody or its antigen-binding fragment is generated through recombinant processing. In some embodiments, the antibody or its antigen-binding fragment is generated through synthesis.

[0459] In some embodiments, the antibody or its antigen-binding fragment is an antibody mimic.

[0460] In some embodiments, the antibody or its antigen-binding fragment binds to human interleukin-12 (IL-12) and human interleukin-23 (IL-23) with a higher affinity than ustekinumab.

[0461] Fusion protein

[0462] In addition, this disclosure also provides fusion proteins comprising one or more of the polypeptides disclosed herein.

[0463] In some embodiments, fusion proteins are recombined or synthesized using conventional methods and reagents well known in the art. For example, fusion proteins can be recombined in suitable host cells (e.g., bacteria) according to methods known in the art. See, for example, Current Protocols in Molecular Biology, 2nd ed., Ausubel et al., John Wiley & Sons, 1992; and Molecular Cloning: a Laboratory Manual, 2nd ed., Sambrook et al., 1989, Cold Spring Harbor Laboratory Press. For example, nucleic acid molecules containing nucleotide sequences encoding fusion proteins can be introduced into suitable host cells (e.g., E. coli) and expressed, and the expressed fusion protein can be isolated / purified from the host cells (e.g., inclusion bodies) using conventional methods and readily available reagents. For example, DNA fragments encoding different protein sequences (e.g., light-responsive domains, heteropeptide components) can be concatenated together according to known techniques. In another embodiment, fusion genes can be synthesized according to known techniques including automated DNA synthesizers. Alternatively, PCR amplification of nucleic acid fragments can be performed using anchored primers that generate complementary overhangs between two consecutive nucleic acid fragments, which can then be fused and amplified to produce chimeric nucleic acid sequences (see, for example, Ausubel et al., Current Protocols in Molecular Biology, 1992).

[0464] Nucleic acid and vector

[0465] Furthermore, this disclosure also provides one or more polynucleotides (e.g., DNA, RNA, or analogues of either, e.g., including one or more modified nucleotides, as appropriate) encoding any one or more antibodies, antigen-binding fragments, or fusion proteins disclosed herein. In some embodiments, the polynucleotide is DNA. In some embodiments, the polynucleotide is RNA. In some embodiments, the polynucleotide is linear (e.g., linear RNA). In some embodiments, the polynucleotide is circular (e.g., circular RNA). In some embodiments, the polynucleotide comprises a nucleotide sequence codon-optimized for a selected cell (e.g., host cell).

[0466] In some embodiments, the antibody, antigen-binding fragment, or fusion protein is encoded by a single polynucleotide. In some embodiments, the antibody, antigen-binding fragment, or fusion protein is encoded by multiple polynucleotides.

[0467] In addition, this disclosure also provides a vector (e.g., an expression vector, including a viral delivery vector) comprising any one or more of the polynucleotides disclosed herein.

[0468] In some embodiments, the vector (e.g., an expression vector) further comprises an expression control polynucleotide sequence operatively linked to a polynucleotide, and / or a polynucleotide sequence encoding a selectability marker. In some embodiments, the expression control polynucleotide sequence comprises a promoter sequence and / or an enhancer sequence. In some embodiments, the expression control polynucleotide sequence comprises an inducible promoter sequence.

[0469] Host cells and their production methods

[0470] In addition, this disclosure also provides a host cell comprising any one or more of the polynucleotides or expression vectors disclosed herein.

[0471] Non-limiting examples of host cells (e.g., recombinant cells) include mammalian cells such as fusion tumor cells, Chinese hamster ovary (CHO) cells, COS cells, and human embryonic kidney (HEK); yeast cells such as Pichia pastoris cells; and bacterial cells such as Escherichia coli, including DH5α.

[0472] In addition, this disclosure also provides a method for generating the antibody or antigen-binding fragment thereof disclosed herein, the method comprising expressing the antibody or antigen-binding fragment thereof in a host cell (e.g., a recombinant cell) disclosed herein and isolating the expressed antibody or antigen-binding fragment thereof.

[0473] Compositions and kits

[0474] Furthermore, this disclosure also provides a composition comprising any one or more of the antibodies, antigen-binding fragments, fusion proteins, polynucleotides, or host cells disclosed herein. In some embodiments, the composition is a pharmaceutical composition.

[0475] In some embodiments, the composition (e.g., a pharmaceutical composition) further comprises a pharmaceutically acceptable carrier, excipient, stabilizer, diluent, or modifier (Remington's Pharmaceutical Sciences, 16th edition, Osol, A. ed. (1980)). Suitable pharmaceutically acceptable carriers, excipients, or stabilizers are non-toxic to the recipient at the doses and concentrations used. Non-limiting examples of pharmaceutically acceptable carriers, excipients, stabilizers, diluents, or modifiers include buffers (e.g., L-histidine), antioxidants (e.g., ascorbic acid or methionine), preservatives, proteins (e.g., serum albumin, gelatin, or immunoglobulins), hydrophilic polymers, amino acids, carbohydrates (e.g., monosaccharides, disaccharides, glucose, mannose, or dextrin), chelating agents (e.g., EDTA), sugars (e.g., sucrose), salt-forming antiions (e.g., sodium), metal complexes (e.g., Zn-protein complexes), nonionic surfactants (e.g., Tween), PLURONICS™, and polyethylene glycol (PEG).

[0476] In some embodiments, the composition comprises an antibody or an antigen-binding fragment thereof, L-histidine, L-histidine monohydrochloride monohydrate, polysorbate 80, and sucrose.

[0477] In some embodiments, the composition comprises an antibody or an antigen-binding fragment thereof, EDTA disodium dihydrate, L-histidine, L-histidine hydrochloride monohydrate, L-methionine, polysorbate 80, and sucrose.

[0478] In some embodiments, the composition (e.g., a pharmaceutical composition) is formulated for a suitable administration schedule and route. In some embodiments, the composition (e.g., a pharmaceutical composition) is formulated for administration by infusion (e.g., intravenous infusion). In some embodiments, the composition (e.g., a pharmaceutical composition) is formulated for administration by subcutaneous administration.

[0479] In some embodiments, the pharmaceutical composition comprises about 100 mg to about 600 mg of the antibody or antigen-binding fragment thereof disclosed herein, for example, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 100-550 mg, about 150-550 mg, about 150-520 mg, about 200-520 mg, about 200-500 mg, about 200-450 mg, about 200-400 mg, about 250-520 mg, about 250-500 mg, about 250-450 mg, or about 250-400 mg.

[0480] In some embodiments, the composition is formulated to be administered as a combination therapy with at least one additional therapeutic agent. In some embodiments, the at least one additional therapeutic agent includes vedolizumab, adalimumab, methotrexate, infliximab, tofacitinib, or any combination thereof.

[0481] In addition, this document also provides kits comprising containers and, where applicable, instructions for use, wherein the containers contain any one or more compositions disclosed herein (e.g., pharmaceutical compositions).

[0482] How to use

[0483] In addition, this disclosure also provides a method for blocking the binding of a ligand to a receptor expressed on a cell surface, the method comprising contacting the cell with an effective amount of at least one antibody disclosed herein or an antigen-binding fragment thereof or at least one composition (e.g., a pharmaceutical composition) to block the binding of the ligand to a receptor expressed on the cell surface, wherein the ligand comprises p40.

[0484] Furthermore, this disclosure also provides a method for blocking the binding of a ligand to its receptor in an individual, the method comprising administering to the individual an effective amount of at least one antibody or antigen-binding fragment thereof disclosed herein, thereby blocking the binding of the ligand to its receptor in the individual, wherein the ligand comprises p40.

[0485] Furthermore, this disclosure also provides a method for blocking the binding of a ligand to its receptor in an individual, the method comprising administering to the individual an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one antibody or antigen-binding fragment thereof disclosed herein, thereby blocking the binding of the ligand to its receptor in the individual, wherein the ligand comprises p40.

[0486] In addition, this disclosure also provides a method for treating IL-12 / IL-23-related diseases in individuals in need, the method comprising administering an effective amount of at least one antibody disclosed herein or an antigen-binding fragment thereof, thereby treating the IL-12 / IL-23-related disease.

[0487] In addition, this disclosure also provides a method for treating IL-12 / IL-23-related diseases in individuals of need, the method comprising administering an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one antibody or antigen-binding fragment thereof disclosed herein, thereby treating the IL-12 / IL-23-related disease.

[0488] In some embodiments, IL-12 / IL-23-related diseases include plaque psoriasis, psoriatic arthritis, Crohn's disease, ulcerative colitis, alopecia areata, alopecia totalis, alopecia universalis, hidradenitis suppurativa, pityriasis rubra pilaris, lichen planus, pemphigus, atopic dermatitis, pyoderma gangrenosa, or leukoderma.

[0489] In some embodiments, the individual is a mammal. In some embodiments, the individual is a mammal selected from a group consisting of dogs, cats, mice, rats, hamsters, guinea pigs, horses, pigs, sheep, dairy cows, chimpanzees, macaques, cynomolgus monkeys, and humans. In some embodiments, the individual is a primate. In some embodiments, the individual is a human.

[0490] In some embodiments, the individual is 6 years of age or older.

[0491] In some embodiments, the individual is an adult patient. In some embodiments, the individual is 18 years of age or older, for example, approximately: 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, or 80 years of age or older. In some embodiments, the individual is approximately: 18-80, 20-80, 20-75, 25-75, 25-70, 30-70, 30-65, 35-65, 35-60, 40-60, 40-55, or 45-55 years of age. In some embodiments, the individual is approximately 18-65 years of age. In some embodiments, the individual is 65 years of age or older.

[0492] In some embodiments, the individual is a pediatric human patient. In some embodiments, the individual is 6 to 17 years old. In some embodiments, the individual is 6 to 11 years old. In some embodiments, the individual is 12 to 17 years old. In some embodiments, the IL-12 / IL-23 related disease is plaque psoriasis.

[0493] In some embodiments, the individual is an adult with moderate or severe psoriasis or a child aged 6 years or older. In some embodiments, phototherapy is also used to treat the individual.

[0494] In some embodiments, the individual is an adult with active psoriatic arthritis or a child aged 6 years or older.

[0495] In some embodiments, the individual is 18 years of age or older and has moderate to severe active Crohn's disease.

[0496] In some embodiments, the individual is 18 years of age or older and has moderate to severe active ulcerative colitis.

[0497] In some embodiments, at least one antibody or its antigen-binding fragment comprises: VH domain, the VH domain comprising HCDR1, HCDR2, and HCDR3 having at least 80% sequence identity (e.g., at least 85%, at least 90%, or at least 95% sequence identity) with the VH domain comprising any of the amino acid sequences in SEQ ID NO: 2-11 and 19-21, and / or VL domain, wherein the VL domain comprises LCDR1, LCDR2, and LCDR3 having at least 80% sequence identity (e.g., at least 85%, at least 90%, or at least 95% sequence identity) with the VL domain comprising the amino acid sequence of SEQ ID NO:144, SEQ ID NO:142, or SEQ ID NO:140 (e.g., SEQ ID NO:144 or SEQ ID NO:142), respectively. Depending on the circumstances, the VH domain may have less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1, and / or the VL domain may have less than 100% sequence identity with the amino acid sequence of SEQ ID NO:140.

[0498] In some embodiments, at least one antibody or its antigen-binding fragment comprises: VH domain, the VH domain comprising HCDR1, HCDR2, and HCDR3 having 100% sequence identity with HCDR1, HCDR2, and HCDR3 containing the amino acid sequences of any of SEQ ID NO: 2-11 and 19-21, and / or VL domain, comprising LCDR1, LCDR2, and LCDR3 having 100% sequence identity with the VL domain of LCDR1, LCDR2, and LCDR3 respectively containing the amino acid sequence of SEQ ID NO:144, SEQ ID NO:142, or SEQ ID NO:140 (e.g., SEQ ID NO:144 or SEQ ID NO:142). Depending on the circumstances, the VH domain may have less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1, and / or the VL domain may have less than 100% sequence identity with the amino acid sequence of SEQ ID NO:140.

[0499] In some embodiments, at least one antibody or its antigen-binding fragment comprises: a) A VH domain having at least 70% sequence identity (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity) with the amino acid sequence of at least one of SEQ ID NO:2-11 and 19-21, and b) A VL domain having at least 70% sequence identity (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity) with the amino acid sequence of SEQ ID NO:144 or SEQ ID NO:142. The VH domain has less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1 and / or the VL domain has less than 100% sequence identity with the amino acid sequence of SEQ ID NO:140.

[0500] In some embodiments, at least one antibody or its antigen-binding fragment comprises: a) VH, which has 100% sequence identity with any of the amino acid sequences in SEQ ID NO:2-11 and 19-21, and b) A VL that has 100% sequence identity with the amino acid sequence of SEQ ID NO:144 or SEQ ID NO:142.

[0501] In some embodiments, at least one antibody or its antigen-binding fragment comprises: a) A VH domain having at least 70% sequence identity (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity) with an amino acid sequence that is at least one of those in SEQ ID NO:2-11, and b) A VL domain having at least 70% sequence identity (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity) with the amino acid sequence of SEQ ID NO:144 or SEQ ID NO:142. The VH domain has less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1 and / or the VL domain has less than 100% sequence identity with the amino acid sequence of SEQ ID NO:140.

[0502] In some embodiments, at least one antibody or its antigen-binding fragment comprises: a) VH, which has 100% sequence identity with any of the amino acid sequences in SEQ ID NO:2-11, and b) A VL that has 100% sequence identity with the amino acid sequence of SEQ ID NO:144 or SEQ ID NO:142.

[0503] In some embodiments, at least one antibody or its antigen-binding fragment comprises: a) A heavy chain having at least 60% sequence identity (e.g., at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% sequence identity) with an amino acid sequence of at least one of SEQ ID NO: 161-170 and 178-180, and / or b) A light chain having at least 60% sequence identity (e.g., at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% sequence identity) with the amino acid sequence of SEQ ID NO:207 or SEQ ID NO:205. Depending on the circumstances, the antibody or its antigen-binding fragment may contain a VH domain having less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1 and / or a VL domain having less than 100% sequence identity with the amino acid sequence of SEQ ID NO:140.

[0504] In some embodiments, at least one antibody or its antigen-binding fragment comprises: a) A heavy chain having 100% sequence identity with the amino acid sequences of any of SEQ ID NO:161-170 and 178-180, and / or b) A light chain having 100% sequence identity with the amino acid sequence of SEQ ID NO:207 or SEQ ID NO:205.

[0505] Table 1. VH and heavy chain amino acid sequences (SEQ ID NO)

[0506] Table 2. HCDR amino acid sequences as determined by ImMunoGeneTics (IMGT), Kabat, or Chothia numbers.

[0507] Table 3. VL and light chain amino acid sequences (SEQ) ID NO

[0508] Table 4. LCDR amino acid sequences as determined by IMGT number or Kabat or Chothia number.

[0509] Example

[0510] 1. An antibody or an antigen-binding fragment thereof, the antibody or antigen-binding fragment comprising: a) An immunoglobulin heavy chain variable (VH) domain comprising heavy chain complementarity-determining regions (HCDRs) 1, HCDR2, and HCDR3 having 100% sequence identity with the VH domain containing the amino acid sequences of any of SEQ ID NO: 2-11 and 19-21, respectively; and b) An immunoglobulin light chain variable (VL) domain comprising light chain complementarity-determining regions (LCDRs) 1, 2, and 3, respectively, having 100% sequence identity with the VL domain containing the amino acid sequence of SEQ ID NO: 144 or SEQ ID NO: 142. The VH domain has less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1, and the VL domain has less than 100% sequence identity with the amino acid sequence of SEQ ID NO:140, or both.

[0511] 2. The antibody or antigen-binding fragment thereof as described in Example 1, wherein the VH domain of the antibody or antigen-binding fragment comprises four VH framework regions (VH FR1-4) and three heavy chain complementarity-determining regions (HCDR1-3) in the following order from N-terminus to C-terminus: VH FR1-HCDR1-VH FR2-HCDR2-VH FR3-HCDR3-VH FR4, wherein: a) The VH FR1-HCDR1 contains the amino acid sequence of QFRTY (SEQ ID NO:262), HFDRY (SEQ ID NO:263), YFERY (SEQ ID NO:264), YFETR (SEQ ID NO:265), YFQTR (SEQ ID NO:266), or YFETY (SEQ ID NO:267); b) The VH FR2 contains the amino acid sequence of GKGL (SEQ ID NO:268), GDYL (SEQ ID NO:269), or GYYL (SEQ ID NO:270); or c) The VH FR3 contains the amino acid sequence of NSLK (SEQ ID NO:271), PSLR (SEQ ID NO:272), or NDLR (SEQ ID NO:273); or Any combination of a) to c).

[0512] 3. The antibody or its antigen-binding fragment as described in Example 1 or 2, wherein: The HCDR1 contains the amino acid sequence of SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:49, SEQ ID NO:50 or SEQ ID NO:51; The HCDR2 contains the amino acid sequence of SEQ ID NO:72; and The HCDR3 contains the amino acid sequence of SEQ ID NO:79.

[0513] 4. An antibody or antigen-binding fragment thereof as described in any of Examples 1 to 3, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 45.

[0514] 5. An antibody or antigen-binding fragment thereof as described in any of Examples 1 to 3, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:46.

[0515] 6. An antibody or antigen-binding fragment thereof as described in any of Examples 1 to 3, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:47.

[0516] 7. An antibody or antigen-binding fragment thereof as described in any of Examples 1 to 3, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 49.

[0517] 8. An antibody or antigen-binding fragment thereof as described in any of Examples 1 to 3, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 50.

[0518] 9. An antibody or antigen-binding fragment thereof as described in any of Examples 1 to 3, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 51.

[0519] 10. An antibody or antigen-binding fragment thereof as described in any one of Examples 1 to 9, wherein: The LCDR1 contains the amino acid sequence of SEQ ID NO:146; The LCDR2 contains the amino acid sequence of AAS; and The LCDR3 contains the amino acid sequence of SEQ ID NO:150.

[0520] 11. The antibody or antigen-binding fragment thereof as described in Example 1 or 2, wherein: The HCDR1 contains the amino acid sequence of SEQ ID NO:80, SEQ ID NO:81, or SEQ ID NO:82; The HCDR2 contains the amino acid sequence of SEQ ID NO:96; and The HCDR3 contains the amino acid sequence of SEQ ID NO:103.

[0521] 12. An antibody or antigen-binding fragment thereof as described in any of Examples 1, 2 and 11, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:80.

[0522] 13. An antibody or antigen-binding fragment thereof as described in any of Examples 1, 2 and 11, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:81.

[0523] 14. An antibody or antigen-binding fragment thereof as described in any of Examples 1, 2 and 11, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:82.

[0524] 15. An antibody or antigen-binding fragment thereof as described in any of Examples 1, 2 and 11 to 14, wherein: a) The LCDR1 contains the amino acid sequence of SEQ ID NO:151; b) The LCDR2 contains the amino acid sequence of SEQ ID NO:156; and c) The LCDR3 contains the amino acid sequence of SEQ ID NO:150.

[0525] 16. An antibody or antigen-binding fragment thereof as described in any of Examples 1, 2 and 11 to 14, wherein: a) The LCDR1 contains the amino acid sequence of SEQ ID NO:151; b) The LCDR2 contains the amino acid sequence of SEQ ID NO:154; and c) The LCDR3 contains the amino acid sequence of SEQ ID NO:150.

[0526] 17. The antibody or antigen-binding fragment thereof as described in Example 1 or 2, wherein: The HCDR1 contains the amino acid sequence of SEQ ID NO:105, SEQ ID NO:106, SEQ ID NO:107, SEQ ID NO:109, SEQ ID NO:110 or SEQ ID NO:111; The HCDR2 contains the amino acid sequence of SEQ ID NO:132; and The HCDR3 contains the amino acid sequence of SEQ ID NO:139.

[0527] 18. An antibody or antigen-binding fragment thereof as described in any of Examples 1, 2 and 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 105.

[0528] 19. An antibody or antigen-binding fragment thereof as described in any of Examples 1, 2 and 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 106.

[0529] 20. An antibody or antigen-binding fragment thereof as described in any of Examples 1, 2 and 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 107.

[0530] 21. An antibody or antigen-binding fragment thereof as described in any of Examples 1, 2 and 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 109.

[0531] 22. An antibody or antigen-binding fragment thereof as described in any of Examples 1, 2 and 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 110.

[0532] 23. An antibody or antigen-binding fragment thereof as described in any of Examples 1, 2 and 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 111.

[0533] 24. An antibody or antigen-binding fragment thereof as described in any of Examples 1, 2 and 17 to 23, wherein: a) The LCDR1 contains the amino acid sequence of SEQ ID NO:151; b) The LCDR2 contains the amino acid sequence of SEQ ID NO:156; and c) The LCDR3 contains the amino acid sequence of SEQ ID NO:150.

[0534] 25. An antibody or antigen-binding fragment thereof as described in any of Examples 1, 2 and 17 to 23, wherein: a) The LCDR1 contains the amino acid sequence of SEQ ID NO:151; b) The LCDR2 contains the amino acid sequence of SEQ ID NO:154; and c) The LCDR3 contains the amino acid sequence of SEQ ID NO:150.

[0535] 26. An antibody or antigen-binding fragment thereof as described in any of Examples 1 to 25, wherein the VH domain comprises the amino acid sequence of any one of SEQ ID NO: 2-11 and 19-21.

[0536] 27. An antibody or antigen-binding fragment thereof as described in any of Examples 1 to 25, wherein the VH domain comprises the amino acid sequence of SEQ ID NO:2.

[0537] 28. An antibody or antigen-binding fragment thereof as described in any of Examples 1 to 25, wherein the VH domain comprises the amino acid sequence of SEQ ID NO:3.

[0538] 29. An antibody or antigen-binding fragment thereof as described in any of Examples 1 to 25, wherein the VH domain comprises the amino acid sequence of SEQ ID NO:4.

[0539] 30. An antibody or antigen-binding fragment thereof as described in any of Examples 1 to 25, wherein the VH domain comprises the amino acid sequence of SEQ ID NO:5.

[0540] 31. An antibody or antigen-binding fragment thereof as described in any of Examples 1 to 25, wherein the VH domain comprises the amino acid sequence of SEQ ID NO:6.

[0541] 32. An antibody or antigen-binding fragment thereof as described in any of Examples 1 to 25, wherein the VH domain comprises the amino acid sequence of SEQ ID NO:7.

[0542] 33. An antibody or antigen-binding fragment thereof as described in any of Examples 1 to 25, wherein the VH domain comprises the amino acid sequence of SEQ ID NO:8.

[0543] 34. An antibody or antigen-binding fragment thereof as described in any of Examples 1 to 25, wherein the VH domain comprises the amino acid sequence of SEQ ID NO:9.

[0544] 35. An antibody or antigen-binding fragment thereof as described in any of Examples 1 to 25, wherein the VH domain comprises the amino acid sequence of SEQ ID NO: 10.

[0545] 36. An antibody or antigen-binding fragment thereof as described in any of Examples 1 to 25, wherein the VH domain comprises the amino acid sequence of SEQ ID NO:11.

[0546] 37. An antibody or antigen-binding fragment thereof as described in any of Examples 1 to 25, wherein the VH domain comprises the amino acid sequence of SEQ ID NO:19.

[0547] 38. An antibody or antigen-binding fragment thereof as described in any of Examples 1 to 25, wherein the VH domain comprises the amino acid sequence of SEQ ID NO:20.

[0548] 39. An antibody or antigen-binding fragment thereof as described in any of Examples 1 to 25, wherein the VH domain comprises the amino acid sequence of SEQ ID NO:21.

[0549] 40. An antibody or antigen-binding fragment thereof as described in any of Examples 2 to 39, wherein the VL domain comprises the amino acid sequence of SEQ ID NO:144 or SEQ ID NO:142.

[0550] 41. An antibody or antigen-binding fragment thereof as described in any of Examples 2 to 40, wherein the VL domain comprises the amino acid sequence of SEQ ID NO: 144.

[0551] 42. An antibody or antigen-binding fragment thereof as described in any of Examples 2 to 40, wherein the VL domain comprises the amino acid sequence of SEQ ID NO:142.

[0552] 43. An antibody or an antigen-binding fragment thereof, the antibody or antigen-binding fragment comprising a heavy chain variable (VH) domain containing the amino acid sequence of SEQ ID NO:2 and a light chain variable (VL) domain containing the amino acid sequence of SEQ ID NO:144.

[0553] 44. An antibody or an antigen-binding fragment thereof, the antibody or antigen-binding fragment comprising a heavy chain variable (VH) domain containing the amino acid sequence of SEQ ID NO:3 and a light chain variable (VL) domain containing the amino acid sequence of SEQ ID NO:144.

[0554] 45. An antibody or an antigen-binding fragment thereof as described in any of Examples 1 to 44, wherein the antigen-binding fragment comprises a single-chain variable fragment (scFv), a heavy-chain variable recombinant domain (VHH), an antigen-binding fragment (Fab), Fab', or F(ab')2.

[0555] 46. ​​An antibody or antigen-binding fragment thereof as described in any of Examples 1 to 44, wherein the antibody or antigen-binding fragment thereof comprises an antibody heavy chain constant domain, an antibody light chain constant domain, or both.

[0556] 47. An antibody or antigen-binding fragment thereof as described in Example 46, wherein the constant domain of the antibody heavy chain is an IgG1, IgG2, IgG3 or IgG4 constant domain.

[0557] 48. An antibody or antigen-binding fragment thereof as described in Example 47, wherein the constant domain of the antibody heavy chain contains one or more mutations that increase the serum half-life of the antibody or antigen-binding fragment thereof in humans.

[0558] 49. The antibody or antigen-binding fragment thereof as described in Example 47, wherein, relative to the constant domain of wild-type human IgG, the antibody heavy chain constant domain contains amino acid substitutions at amino acid residues 252, 254 and 256, respectively, with respect to amino acid residues tyrosine, threonine and glutamic acid, wherein the amino acid residues are numbered according to the EU index in Kabat.

[0559] 50. An antibody or antigen-binding fragment thereof as described in any of Examples 1 to 49, wherein the antibody or antigen-binding fragment comprises a heavy chain containing an amino acid sequence of any one of SEQ ID NO: 161-170 and SEQ ID NO: 178-180.

[0560] 51. An antibody or antigen-binding fragment thereof as described in any one of Examples 1 to 50, wherein the antibody or antigen-binding fragment comprises a light chain containing the amino acid sequence of SEQ ID NO:207 or SEQ ID NO:205.

[0561] 52. An antibody or antigen-binding fragment thereof as described in any of Examples 1 to 49, wherein the antibody is a multispecific antibody.

[0562] 53. An antibody or antigen-binding fragment thereof as described in any of Examples 1 to 52, wherein the antibody or antigen-binding fragment thereof binds both interleukin-12 (IL-12) and interleukin-23 (IL-23).

[0563] 54. A polynucleotide encoding a VH domain, VL domain, light chain, or heavy chain of an antibody or antigen-binding fragment thereof as described in any one of Examples 1 to 53.

[0564] 55. An expression vector comprising a polynucleotide as described in Example 54.

[0565] 56. An RNA that encodes a VH domain, VL domain, light chain, or heavy chain of an antibody or antigen-binding fragment thereof as described in any of Examples 1 to 53.

[0566] 57. A host cell comprising a polynucleotide as described in Example 54, an expression vector as described in Example 55, or RNA as described in Example 56.

[0567] 58. A method for producing an antibody or an antigen-binding fragment thereof as described in any one of Examples 1 to 53, the method comprising expressing the antibody or an antigen-binding fragment thereof in a host cell as described in Example 57 and isolating the expressed antibody or an antigen-binding fragment thereof.

[0568] 59. A pharmaceutical composition comprising an antibody or antigen-binding fragment thereof as in any one of Examples 1 to 53, a polynucleotide as in Example 54, an expression vector as in Example 55, RNA as in Example 56 or a host cell as in Example 57, and a pharmaceutically acceptable carrier or diluent.

[0569] 60. A kit comprising a pharmaceutical composition as described in Example 59.

[0570] 61. A method for blocking the binding of a ligand to a receptor expressed on a cell surface, the method comprising contacting the cell with an effective amount of an antibody or antigen-binding fragment thereof as described in any one of Examples 1 to 53, a polynucleotide as described in Example 54, an expression vector as described in Example 55, or RNA as described in Example 56, thereby blocking the binding of the ligand to a receptor expressed on the cell surface, wherein the ligand comprises p40.

[0571] 62. A method for blocking the binding of a ligand to its receptor in an individual, the method comprising administering to the individual an effective amount of an antibody or an antigen-binding fragment thereof as described in any one of Examples 1 to 53 or a pharmaceutical composition as described in Example 59, thereby blocking the binding of the ligand to its receptor in the individual, wherein the ligand comprises p40.

[0572] 63. A method for treating an individual with an IL-12 / IL-23-related disease, the method comprising administering to the individual an effective amount of an antibody or an antigen-binding fragment thereof as described in any one of Examples 1 to 53, or a pharmaceutical composition as described in Example 59, thereby treating the IL-12 / IL-23-related disease.

[0573] 64. The method of Example 63, wherein the IL-12 / IL-23 related disease is plaque psoriasis, psoriatic arthritis, Crohn's disease, ulcerative colitis, alopecia areata, alopecia totalis, alopecia universalis, hidradenitis suppurativa, pityriasis rubra pilaris, lichen planus pemphigus, atopic dermatitis, pyoderma gangrenosa, or vitiligo.

[0574] 65. The method of Example 63 or 64, wherein the IL-12 / IL-23 associated disease is plaque psoriasis, psoriatic arthritis, Crohn's disease, or ulcerative colitis.

[0575] 66. The method of any one of Examples 63 to 65, wherein the individual is an adult human patient.

[0576] 67. The method of any one of Examples 63 to 65, wherein the individual is a pediatric human patient.

[0577] 68. The method of Example 67, wherein the IL-12 / IL-23 associated disease is plaque psoriasis.

[0578] 69. The method of any one of Examples 63 to 68, further comprising administering at least one additional therapeutic agent.

[0579] 70. The method of Example 69, wherein the at least one additional therapeutic agent is vedolizumab, adalimumab, methotrexate, infliximab, tofacitinib, or any combination thereof.

[0580] Example

[0581] Example 1. Computer simulation of affinity maturation and computer simulation of deimmunization

[0582] Utekinumab (STELERA®) is a broadly designated, fully human monoclonal antibody for the treatment of psoriasis, psoriatic arthritis, Crohn's disease, and ulcerative colitis. Utekinumab targets the p40 subunit of IL-12 (p40 / p35) and IL-23 (p40 / p19), thereby preventing the binding of IL-12 and IL-23 to their respective receptors.

[0583] There is an opportunity to create “biomodified” molecules. For example, ustekinumab has been shown to induce antidrug-neutralizing antibodies in 5-12% of patients, so deimmunizing molecules may be more effective in the general population. Improved target affinity can enhance efficacy and / or reduce dosage. Increased stability and / or serum half-life provide dosing advantages.

[0584] Affinity maturation was simulated using a protein modeling application within the Molecular Operations Environment (MOE) (Chemical Computing Group ULC., Montreal, QC, Canada). The 3D coordinates of the X-ray crystal structure of the ustekinumab Fab / IL-12 complex (PDB ID: 3HMX) were obtained from the protein database at www.rcsb.org / structure / 3hmx and used as the starting template coordinates. Missing residues were computationally filled in, and the entire complex was computationally protonated and optimized before being used for computer-simulated mutagenesis.

[0585] Computer-simulated mutagenesis was performed using the residue scanning function in MOE to target residues involved in antigen-antibody interactions. One to ten point mutations were introduced into the Fab / IL-12 complex using alanine, arginine, asparagine, aspartic acid, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, serine, phenylalanine, proline, threonine, tyrosine, valine, or tryptophan. Approximately 200,000 mutants were sampled, and changes in affinity and stability were calculated. Variants to be constructed and further tested were preselected based on modified affinity and stability. Preselected variants were tested against reduced MHC II binding potential measured using IEDB (tools.iedb.org / mhcii / ) and / or the EpiVax interactive screening and protein reengineering interface (ISPRI) (epivax.com / immunogenicity-assessment / ispri-web-based-immunogenicity-screening). More than 500 variants were identified, which exhibited improved affinity, unaffected stability, and reduced MHC II binding potential. Of these 500 variants, VH variants A05, A08, A14, A24, A31, A39, CO2, CO3, C07, C11, C13, and C38 were initially selected for further downstream experimental testing to configure the desired molecular characteristics.

[0586] Example 2A. Construction of the insertion vector and DNA assembly of the first round of U variants.

[0587] Insertion-type VH and VL vectors were constructed using a modified pcDNA3.4 plastid backbone (Invitrogen, Waltham, MA). The selection strategy involved creating independent heavy and light chain plastids for ustekinumab, flanked by specific restriction enzyme sites for the VH and VL genes, which were then exchanged with the V gene fragment of the U variant. Restriction enzymes EcoRI / XhoI and BamHI / BsiwI were used for VH and VL selection, respectively. DNA fragments encoding the heavy and light chain genes for the U antibody were synthesized using gBlocks HiFi (Integrated DNA Technologies, Inc., Coralville, IA). A DNA fragment of the V gene variant, flanked by 20 nucleotide protrusions homologous to the insertion vector, was also synthesized using gBlocks. The heavy and light chain genes were selected and inserted into pcDNA3.4 vectors digested with SacI and EcoRV using DNA HiFi assembly (New England Biolabs, Ipswich, MA), followed by bacterial transformation and strain sequencing. Based on DNA HiFi assembly, the V gene fragment of the U variant was selected and inserted into heavy and light chain insert plastids linearized with specific restriction enzymes, followed by bacterial transformation and strain sequencing.

[0588] Utekinumab heavy chain fragment (SEQ ID NO:209). Utekinumab light chain fragment (SEQ ID NO:210). DNA sequences of the first-round VH variant: A05 (SEQ ID NO:211), A08 (SEQ ID NO:212), A14 (SEQ ID NO:213), A24 (SEQ ID NO:214), A31 (SEQ ID NO:215), A39 (SEQ ID NO:216), C02 (SEQ ID NO:217), C03 (SEQ ID NO:218), C07 (SEQ ID NO:219), C11 (SEQ ID NO:220), C13 (SEQ ID NO:221), and C38 (SEQ ID NO:222).

[0589] Example 2B. Cell transfection and ELISA of the first round of variants

[0590] The 24-well ExpiCHO-S cell expression system (Invitrogen) was used for antibody production according to the user manual. In short, DNA (with a 1:1 ratio of the heavy chain of the variant to the light chain of ustekinumab) was mixed with ExpiFectamine and added to the expiCHO-S cell culture, followed by transfection enhancer and ExpiCHO cell feed 20 hours later. The cell culture supernatant from day 5 post-transfection was diluted 1:500 in buffer for IgG and IL-12 ELISA, used to assess IgG yield (protein expression level) and IL-12 binding affinity, respectively. Utekinumab, starting at 300 ng / mL, was serially diluted 3-fold as a reference for IgG yield and IL-12 binding affinity.

[0591] For the IL-12 ELISA, 25 μL of IL-12 (PeproTech, RockyHill, NJ) diluted 1 μg / mL in PBS was added to each well of a 96-well half-zone microplate (Greiner AG, Kremsmünster, Austria) and incubated overnight at 4°C. The plate was washed with PBST (0.5% Tween) and then blocked with 120 µL of 1% BSA / PBS for 1 hour at room temperature. After three PBST washes, 25 μL of diluted supernatant of the antibody variant was added to each well and incubated for 2 hours at room temperature, followed by three PBST washes. The detection antibody (peroxidase AffiniPure F(ab')2 fragment goat anti-human IgG, Fcγ fragment specific; Jackson ImmunoResearch, West Grove, PA) was diluted 1:10,000 and added to each well, and incubated for 1 hour at room temperature. The plate was washed 6 times with PBST and then 25 μL of TMB receptor was added. The enzymatic reaction was carried out for 4–6 minutes, followed by the addition of 25 μL of sulfuric acid to terminate the reaction. The plate was read at OD 450 nm. For IgG ELISA, 25 μL of human IgG capture antibody (AffiniPure goat anti-human IgG, Fcγ fragment specific, Jackson ImmunoResearch) was diluted 2 μg / mL in PBS and added to each well of a 96-well half-zone microplate.

[0592] Figure 2A-2B The ELISA analysis of the indicated C and A variants is shown. Each variant contains the heavy chain of the indicated first-round VH variant and the light chain of ustekinumab. Compared with ustekinumab, most C variants, except for C2, showed similar protein expression (IgG yield), while A variants showed lower protein expression (IgG production). Figure 2ACompared to ustekinumab, C38 showed significantly higher IL-12 binding affinity, C7 and C11 showed slightly higher affinity, C3 showed similar affinity, and variant A showed lower affinity. Figure 2B ).

[0593] Example 3A. DNA assembly of the second-round U variant

[0594] The second-round U variant DNA fragment was synthesized by gBlocks, flanking a 20-nucleotide sequence homologous to the insert vector. Heavy and light chain variants were independently selected and colonized into insert plastids linearized with specific restriction enzymes using DNA HiFi assembly, followed by bacterial transformation and strain sequencing.

[0595] The sequences of the second round of VH variants are: C41 (SEQ ID NO:223), C42 (SEQ ID NO:224), C43 (SEQ ID NO:225), C44 (SEQ ID NO:226), C45 (SEQ ID NO:227), C46 (SEQ ID NO:228), C51 (SEQ ID NO:229), C52 (SEQ ID NO:230), C53 (SEQ ID NO:231), C54 (SEQ ID NO:232), C55 (SEQ ID NO:233), C56 (SEQ ID NO:234), C57 (SEQ ID NO:235), C58 (SEQ ID NO:236), C59 (SEQ ID NO:237), C61 (SEQ ID NO:238), C62 (SEQ ID NO:239), C71 (SEQ ID NO:240), C72 (SEQ ID NO:241), C73 (SEQ ID NO:229), C52 (SEQ ID NO:229), C53 (SEQ ID NO:231), C54 (SEQ ID NO:232), C55 (SEQ ID NO:233), C56 (SEQ ID NO:234), C57 (SEQ ID NO:235), C58 (SEQ ID NO:236), C59 (SEQ ID NO:237), C61 (SEQ ID NO:238), C62 (SEQ ID NO:239), C71 (SEQ ID NO:240), C72 (SEQ ID NO:241), C73 (SEQ ID NO:229), C52 (SEQ ID NO:239), C73 (SEQ ID NO:230), C54 (SEQ ID NO:225), C52 (SEQ ID NO:226), C73 (SEQ ID NO:227), C54 (SEQ ID NO:228), C55 (SEQ ID NO:229), C52 (SEQ ID NO:239), C53 (SEQ ID The sequences of the VL variants are: C101 (SEQ ID NO:242), C74 (SEQ ID NO:243), C38xC81 (SEQ ID NO:244), C38xC82 (SEQ ID NO:245), C38xC91 (SEQ ID NO:246), and C38xC92 (SEQ ID NO:247).

[0596] Example 3B. Second round of cell transfection and ELISA of VH and VL variants.

[0597] As described in Example 2B, the ExpiCHO cell transfection procedure for antibody variants in a 24-well configuration was followed. VH and VL variants were paired with ustekinumab VL and VH, respectively. C38 production was scaled up to a 25-mL transfection volume and subsequently purified using protein A resin. Three days post-transfection, the cell culture supernatant was diluted 1:300 in buffer for IgG and IL-12 ELISA. The C38 titration profile was used as a reference to assess the IL-12 binding affinity of the antibody variants at corresponding IgG concentrations.

[0598] ELISA analysis was performed on antibody variants, each comprising: (i) a heavy chain containing the indicated second-round VH variant and a light chain of ustekinumab, or (ii) a heavy chain of ustekinumab and a light chain containing the indicated VL variant. Compared to antibody (C38) comprising a heavy chain containing C38 and a light chain of ustekinumab: (i) when paired with the light chain of ustekinumab, C41, C42, C61, C38xC81, C38xC82, C38xC91, and C38xC92 showed similar or higher IL-12 binding affinity, and (ii) when paired with the heavy chain of ustekinumab, C102, C103, C104, and C105 showed similar or higher IL-12 binding affinity. Among these, C42, C38xC81, C38xC82, C38xC91, C38xC92, and C104 are associated with higher IL-12 binding affinity. Figure 3 ).

[0599] Example 4A. Third-round variant

[0600] Several mutations associated with modified IL-12 binding were identified. Twenty-four combined variants were generated from eight VH variants (C38, C41, C42, C44, C61, C38xC82, C38xC91, and C38xC92) and three VL variants (C102, C103, and C104).

[0601] Example 4B. Cell transfection and ELISA of the third-round variant

[0602] As described in Example 2B, the ExpiCHO cell transfection procedure for the antibody variant was followed in a 24-well configuration. Three days post-transfection, the cell culture supernatant of the antibody variant was diluted 1:200 in buffer for IgG and IL-12 ELISA. The titration profiles of antibodies containing the C38 heavy chain and the ustekinumab light chain were used as a reference to assess the IL-12 binding affinity of the antibody variant at the corresponding IgG concentrations.

[0603] Compared to antibodies containing a heavy chain with C38 and a light chain with ustekinumab, antibody variants C38xC104 (containing a heavy chain with C38 and a light chain with C104), C41xC104, C42xC104, C44xC104, C38xC82xC104, C38xC91xC104, C38xC92xC104, and C38x92xC102 exhibited higher IL-12 binding affinity. Figure 4 ).

[0604] Example 5A. DNA assembly of the fourth-round variant

[0605] Based on the results of the third round of variants, VH and VL mutations associated with modified IL-12 binding affinity were identified and merged to generate new antibody variants. Four VH variants (C38xC82xC92, C42xC82, C42xC92, and C42xC82xC92) were paired with two VL variants (C102 and C104) to assemble eight new variants. The selection strategy using DNA assembly with an insert vector, as described in Example 2A, was followed. The DNA sequences of the fourth round of VH variants are: C42xC82 (SEQ ID NO:253), C42xC92 (SEQ ID NO:254), C38xC82xC92 (SEQ ID NO:255), and C42xC82xC92 (SEQ ID NO:256).

[0606] Example 5B. Cell transfection and ELISA of the fourth-round variant

[0607] As described in Example 2B, the ExpiCHO cell transfection procedure for the combined variants in a 24-well configuration was followed. Three days post-transfection, the cell culture supernatant of the antibody variants was diluted 1:200 in buffer for IgG and IL-12 ELISA. Titration profiles of antibodies containing the heavy chain of C38 and the light chain of ustekinumab were used as a reference to assess the IL-12 binding affinity of the antibody variants at corresponding IgG concentrations. Compared to antibodies containing the heavy chain of C38 and the light chain of ustekinumab, C38xC82xC92xC104 showed better IL-12 binding affinity, while C42xC82xC92xC104, C42xC92xC104, and C38xC82xC92xC102 showed similar IL-12 binding affinity. Figure 5A ).

[0608] Example 5C. Single-mutant cell transfection and ELISA

[0609] As described in Example 2, four antibody variants were expressed in ExpiCHO: (i) an antibody containing a heavy chain with C38R and a light chain of ustekinumab (C38R), (ii) an antibody containing a heavy chain with C38Q and a light chain of ustekinumab (C38Q), (iii) an antibody containing a heavy chain of ustekinumab and a light chain of C104R (C104R), and (iv) an antibody containing a heavy chain of ustekinumab and a light chain of C104R (C104R). IL-12 binding and IgG levels in the cell culture supernatant were measured to control antibody concentration in the supernatant. C38R, C38Q, C104R, and C104Q showed slightly lower IL-12 binding affinity than the antibody containing a heavy chain with C38 and a light chain of ustekinumab (C38, which contains double mutations Q and R). Figure 5B ).

[0610] Example 5D. Characterization of the selected antibody variant

[0611] After four rounds of testing, antibody variants C38xC104, C41xC104, C42xC104, C44xC104, C38x82xC104, C38x91xC104, C38x92xC104, C38x82x92xC104, C42x82x92xC104, and C38x92xC102, which showed higher IL-12 binding affinity than antibodies containing the C38 heavy chain and the ustekinumab light chain, were selected for antibody production and purification. IgG and IL-12 ELISA and cell activation assays were performed for comparison with ustekinumab and antibodies containing the C38 heavy chain and the ustekinumab light chain (C38).

[0612] Figures 6A-6C Titration curves for IL-12 binding of ten selected antibody variants are shown. IgG and IL-12 ELISA were performed to assess IL-12 binding affinity at corresponding IgG concentrations. All ten antibody variants showed higher IL-12 binding affinity compared to ustekinumab. Compared to antibodies containing the heavy chain of C38 and the light chain of ustekinumab (C38), C38xC104, C38x82xC104, C38x91xC104, C38x92xC104, and C38x82x92xC104 showed higher IL-12 binding activity.

[0613] Six antibody variants, C38, C38xC104, C38xC82xC104, C38xC91xC104, C38xC92xC104, and C38xC82xC92xC104, were expressed in 25 mL expiCHO cell cultures and purified using Protein A resin. The recovered antibodies were quantified according to A280. Except for C38xC82xC92xC104, which had a lower yield than the others, the yields were similar (Table 5).

[0614] Table 5. Antibody yield and EC50 value

[0615] Titration curves for IL-12 binding of six antibody variants were generated. Antibody variants were expressed, purified, and quantified, and titrated in 3-fold serial dilutions from 600 ng / mL. IL-12 ELISA was performed to determine the EC50 value of IL-12 binding based on curve fitting to a 4-parameter sigmoid model in Prism. All six variants showed: (i) higher binding affinity compared to ustekinumab (Table 5, EC50 values ​​are averages of three experiments), and (ii) similar or higher binding affinity compared to antibodies containing the heavy chain of C38 and the light chain of ustekinumab (C38). Figures 7A-7C ).

[0616] Example 6. In vivo pharmacokinetic (PK) study of ustekinumab and its antibody variants

[0617] These experiments demonstrate the half-life of ustekinumab and three antibody variants in mice. For each antibody group, three C57BL / 6 mice were injected via the tail vein at a dose of 1 mg / kg. Blood was collected from the mice at 2, 24, 48, 96, 120, and 168 hours post-injection. Plasma samples were prepared and diluted in PBS / BSA. Serum concentrations of the antibody variants were measured using an IgG ELISA. Serial dilutions of ustekinumab were used as interpolated human IgG standards.

[0618] Serum concentrations of (i) ustekinumab and (ii) an antibody containing both the heavy chain of C38 and the light chain of ustekinumab (C38) remained at or near peak levels on day 5 (120 hours). The concentration of ustekinumab decreased on day 7 (168 hours), while the concentration of C38 remained stable. Figures 8A-8B C38xC91xC104 and C38xC92xC104 did not show a decrease in pharmacokinetic clearance or half-life, indicating similar pharmacokinetic properties compared to ustekinumab. Figure 8A , Figure 8C and Figure 8D ).

[0619] Example 7A. Construction of expression vectors and assembly of DNA for scFv generation

[0620] The effect of linker peptide sequences on the scFv form of ustekinumab was investigated. The human IgG Fc domain was tethered to the C-terminus of the scFv. Linker 1A (SEQ ID NO:257) or linker 1B (SEQ ID NO:258) was used to link the VH and VL domains, and a short peptide linker (SEQ ID NO:259) was used to link the scFv and Fc domains. To construct the expression vector, pcDNA3.4 plastids digested with SacI and EcoRV were used to assemble DNA with two scFv DNA fragments, U-scFv-Fc-linker 1A and U-scFv-Fc-linker 1B. DNA fragments containing a 25-nucleotide protrusion homologous to the vector were synthesized according to gBlocks HiFi (Integrated DNA Technologies) and selected into the vector according to DNA HiFi assembly (New England Biolabs), followed by bacterial transformation and strain sequencing. DNA sequence of U-scFv-Fc-connector 1A (SEQ ID NO:260), DNA sequence of U-scFv-Fc-connector 1B (SEQ ID NO:261).

[0621] Example 7B. Protein production and ELISA of ustekinumab ScFv with two different connectors.

[0622] Two forms of ustekinumab-scFv-Fc were expressed using the ExpiCHO cell system. Five days post-transfection, the cell culture supernatant was diluted 1:300 in PBS / BSA and subjected to IL-12 and IgG ELISA (as described in Example 2B). Both forms bound to IL-12 with similar affinity. Figure 9A However, the form containing the connector 1A shows a higher level of expression. Figure 9B ).

[0623] Example 8. Cell assay for measuring IL-12 and IL-23 activity

[0624] To measure IL-12 activity, HEK cells stably expressing an IL-12-sensitive alkaline phosphatase reporter gene were cultured in DMEM-based medium. Cells were passaged in CellStripper (Corning, Corning, NY) and seeded at a density of 50,000 cells per well in 96-well tissue culture plates. After 6 hours, cells were treated with an IL-12-antibody premix as follows: the antibody was titrated with 3-fold serial dilutions to obtain a final concentration twice that in DMEM growth medium (2,000 ng / mL to 0.6 ng / mL), and mixed 1:1 with an equal volume of 8 ng / mL recombinant human IL-12 (rhIL12) (R&D Systems, Inc., Minneapolis, MN) in DMEM growth medium to obtain (i) 4 ng / mL rhIL-12 and (ii) 1,000 ng / mL to 0.3 ng / mL antibody. Incubate this premix at 37°C for 30 minutes to allow antibody binding and rhIL-12 neutralization. Remove the culture medium from the HEK cells and replace it with 100 µL of the premixed medium, then incubate for 18 hours. Remove the medium and measure alkaline phosphatase activity based on tetramethylbenzidine-based acceptor transformation and absorbance at 450 nm or 650 nm.

[0625] To measure IL-23 activity, HEK cells stably expressing an IL-23-sensitive alkaline phosphatase reporter gene were cultured in DMEM-based medium. Cells were passaged in CellStripper (Corning) and seeded at a density of 20,000 cells per well in 96-well tissue culture plates. After 6 hours, cells were treated with an IL-23-antibody premix as follows: the antibody was titrated with 3-fold serial dilutions to obtain a final concentration twice that in DMEM growth medium (2,000 ng / mL to 0.6 ng / mL), and mixed 1:1 with an equal volume of 12 ng / mL recombinant human IL-23 (rhIL23) (R&DSystems, Inc.) in DMEM growth medium to obtain (i) 6 ng / mL rhIL-23 and (ii) 1,000 ng / mL to 0.3 ng / mL antibody. Incubate this premix at 37°C for 30 minutes to allow antibody binding and rhIL-23 neutralization. Remove the culture medium from the HEK cells and replace it with 100 µL of the premixed medium, then incubate for 18 hours. Remove the medium and measure alkaline phosphatase activity based on tetramethylbenzidine-based acceptor transformation and absorbance at 450 nm or 650 nm.

[0626] Figure 10The effects of ustekinumab in IgG or scFv-Fc form on cell-based IL-12 activity were evaluated. Utekinumab in both IgG and scFv-Fc forms were assayed at doses ranging from 0.3 ng / mL to 1,000 ng / mL to measure inhibition of IL-12 receptor binding and induced signaling. Data points are the mean of two replicates. Both scFv-Fc forms showed dose-dependent inhibition of IL-12 activity, but the ability to reduce IL-12 activity was decreased compared to the IgG form.

[0627] Figure 11 The effects of (i) antibodies containing the heavy chain of C38 and the light chain of ustekinumab (C38) and (ii) antibodies containing the heavy chain of C11 and the light chain of ustekinumab (C11) on cell-based IL-12 activity were evaluated. Purified C38 and C11 were assayed at doses ranging from 0.3 ng / mL to 1,000 ng / mL to measure inhibition of IL-12 receptor binding and induced signaling. Data points are the mean of two replicates. Compared to ustekinumab, C38 showed a more potent ability to reduce IL-12 activity, and C11 showed a similar ability.

[0628] Figure 12 The effect of the indicated antibody variants on cell-based IL-12 activity was assessed. Variants in purified IgG form were assayed at doses ranging from 0.3 ng / mL to 1,000 ng / mL to measure inhibition of IL-12 receptor binding and induced signaling. All tested antibody variants showed enhanced ability to reduce IL-12 activity compared to ustekinumab.

[0629] Figure 13A The effect of indicated antibody variants on cell-based IL-12 activity was evaluated. The purified IgG form of mAb was assayed at doses ranging from 0.3 ng / mL to 1,000 ng / mL to measure inhibition of IL-12 receptor binding and induced signaling. Data are the average of three independent experiments performed at monthly intervals using cells from different passages. Compared with ustekinumab, C38xC91xC104 and C38xC92xC104 showed enhanced ability to reduce IL-12 activity.

[0630] Figure 13BThe effects of indicated antibody variants on cell-based IL-12 activity were summarized. Inhibition of IL-12 receptor binding and induced signaling was measured by a single dose of 100 ng / mL of purified IgG mAbs in the presence of rhIL-12 treatment (5 ng / mL). Means and standard deviations of six replicates are shown. Antibodies containing the C38 heavy chain and the ustekinumab light chain (C38), C38C91C104, and C38C92C104 showed a statistically significant increase in the ability to reduce IL-12 activity compared to ustekinumab (t-test; p < 0.001).

[0631] Figure 13C The effect of indicated antibody variants on cell-based IL-23 activity was evaluated. The purified IgG form of mAb was assayed at doses ranging from 0.3 ng / mL to 1,000 ng / mL to measure inhibition of IL-23 receptor binding and induced signaling. Data points are the mean of three replicates. Compared with ustekinumab, C38xC91xC104 and C38xC92xC104 showed enhanced ability to reduce IL-23 activity.

[0632] Figure 14 Cell-based activity of two preferred variants of the scFv form was demonstrated. The variants of the purified scFv form were assayed at doses ranging from 0.3 ng / mL to 1,000 ng / mL to measure inhibition of IL-12 receptor binding and induced signaling. Data are from single-repeat examples from a repeat plate. The variants showed equivalent potency compared to ustekinumab.

[0633] Example 9. Combining Affinity

[0634] The binding affinity of ustekinumab and its variants was measured using a biolayer interferometry (BLI) instrument with an Octet instrument. The antibody was captured onto an Fc capture biosensor, immersed in a solution containing ligands (rhIL-12 or rhIL-23) for association, and then immersed in buffer to measure dissociation. The results are shown in Table 6.

[0635] Table 6. Binding Affinity

[0636] Example 10. In vivo pharmacodynamics

[0637] To determine the in vivo pharmacodynamic neutralization of IL-12 by ustekinumab and its selected variants.

[0638] Figure 15AComparison of in vivo pharmacodynamic neutralization of IL-12 between C38C91C104 and ustekinumab. Mice (n=3) were administered PBS solvent, ustekinumab (0.05 mg / kg), or C38C91C104 (0.05 mg / kg) intravenously at 0 (0) hour. rhIL-12 Fc was injected intravenously at 25 hours. Blood samples were collected at 27, 48, and 72 hours. Plasma rhIL-12 Fc was measured using a human IL-12 ELISA. Utekinumab neutralized approximately 50% of circulating rhIL-12 Fc. In contrast, C38C91C104 neutralized >80% of circulating rhIL-12 Fc to levels below the limit of quantitation (LOQ = 150 pg / mL).

[0639] Figure 15A Comparison of in vivo pharmacodynamic neutralization of IL-12 between C38C92C104 and ustekinumab. Mice (n=3) were intravenously administered PBS solvent, ustekinumab (0.05 mg / kg), 0.05 mg / kg C38C92C104, or 0.01 mg / kg C38C92C104 at 0 (0) hour. rhIL-12 Fc was intravenously injected at 25 hours. Blood was collected at 27, 48, and 72 hours. Plasma rhIL-12 Fc was measured using a human IL-12 ELISA. Utekinumab (0.05 mg / kg) and 0.01 mg / kg C38C92C104 neutralized circulating rhIL-12 Fc to similar levels. In comparison, 0.05 mg / kg C38C92C104 neutralized >80% of the circulating rhIL-12.Fc.

[0640] References

[0641] 1. Gately et al., The interleukin-12 / interleukin-12-receptor system: role in normal and pathologic immune responses, Annu Rev Immunol. 16:495-521 (1998).

[0642] 2. Oppmann et al., Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12, Immunity. 13(5):715-25 (2000).

[0643] 3. Frucht, IL-23: a cytokine that acts on memory T cells, Sci STKE. 2002(114):pe1 (2002).

[0644] 4. Roblin et al., Development of Antibodies to Ustekinumab Is Associated with Loss of Response in Patients with Inflammatory Bowel Disease, J Clin Med. 12(10):3395 (2023).

[0645] 5. Loeff et al., Clinical Impact of Antibodies against Ustekinumab in Psoriasis: An Observational, Cross-Sectional, Multicenter Study, J Invest Dermatol. 140(11):2129-37 (2020).

[0646] 6. Hsu and Armstrong, Anti-drug antibodies in psoriasis: a critical evaluation of clinical significance and impact on treatment response, Expert Rev Clin Immunol. 9(10):949-58 (2013).

[0647] 7. Bots et al., Anti-Drug Antibody Formation Against Biologic Agents in Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis, BioDrugs. 35(6):715-33 (2021).

[0648] All teachings of patents, publications, and references cited in this article are incorporated in full.

[0649] Although exemplary embodiments have been specifically shown and described, those skilled in the art will understand that various changes in form and detail may be made therein without departing from the scope of the embodiments covered by the appended claims.

Claims

1. An antibody or an antigen-binding fragment thereof, the antibody or antigen-binding fragment comprising: a) Variable immunoglobulin heavy chain (V H ) structural domain, the V H The domain contains V, which is respectively associated with an amino acid sequence containing any one of SEQ ID NO:3, SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:299, SEQ ID NO:300, SEQ ID NO:1, SEQ ID NO:5-11, and SEQ ID NO:19-21. H Heavy chain complementarity-determining regions (HCDRs) 1, HCDR2, and HCDR3 of the structural domains exhibit 100% sequence identity; and b) Variable immunoglobulin light chain (V L ) structural domain, the V L The domain contains V, which is respectively associated with an amino acid sequence containing any one of SEQ ID NO:144, SEQ ID NO:142, SEQ ID NO:301, SEQ ID NO:302, and SEQ ID NO:

140. L The light chain complementarity-determining regions (LCDRs) of the structural domains 1, 2, and 3 have 100% sequence identity. Among them, V H The domain has less than 100% sequence identity with the amino acid sequence of SEQ ID NO:

1. L The domain has less than 100% sequence identity with the amino acid sequence of SEQ ID NO: 140, or both.

2. The antibody or its antigen-binding fragment as claimed in claim 1, wherein: a) The V H The domain contains V, which is respectively associated with the amino acid sequence containing SEQ ID NO:

3. H The HCDR1, HCDR2, and HCDR3 domains have 100% sequence identity; and the V L The domain contains V, which is respectively associated with the amino acid sequence containing SEQ ID NO:

144. L The structural domains LCDR1, LCDR2, and LCDR3 have 100% sequence identity. b) The V H The domain contains V, which is respectively associated with the amino acid sequence containing SEQ ID NO:

2. H The HCDR1, HCDR2, and HCDR3 domains have 100% sequence identity; and the V L The domain contains V, which is respectively associated with the amino acid sequence containing SEQ ID NO:

144. L The structural domains LCDR1, LCDR2, and LCDR3 have 100% sequence identity. c) The V H The domain contains V, which is respectively associated with the amino acid sequence containing SEQ ID NO:

4. H The HCDR1, HCDR2, and HCDR3 domains have 100% sequence identity; and the V L The domain contains V, which is respectively associated with the amino acid sequence containing SEQ ID NO:

140. L The structural domains LCDR1, LCDR2, and LCDR3 have 100% sequence identity. d) The V H The domain contains V, which is respectively associated with the amino acid sequence containing SEQ ID NO:

299. H The HCDR1, HCDR2, and HCDR3 domains have 100% sequence identity; and the V L The domain contains V, which is respectively associated with the amino acid sequence containing SEQ ID NO:

140. L The structural domains LCDR1, LCDR2, and LCDR3 have 100% sequence identity. e) The V H The domain contains V, which is respectively associated with the amino acid sequence containing SEQ ID NO:

300. H The HCDR1, HCDR2, and HCDR3 domains have 100% sequence identity; and the V L The domain contains V, which is respectively associated with the amino acid sequence containing SEQ ID NO:

140. L The structural domains LCDR1, LCDR2, and LCDR3 have 100% sequence identity. f) The V H The domain contains V, which is respectively associated with the amino acid sequence containing SEQ ID NO:

1. H The HCDR1, HCDR2, and HCDR3 domains have 100% sequence identity; and the V L The domain contains V, which is respectively associated with the amino acid sequence containing SEQ ID NO:

144. L The structural domains LCDR1, LCDR2, and LCDR3 have 100% sequence identity. g) The V H The domain contains V, which is respectively associated with the amino acid sequence containing SEQ ID NO:

1. H The HCDR1, HCDR2, and HCDR3 domains have 100% sequence identity; and the V L The domain contains V, which is respectively associated with the amino acid sequence containing SEQ ID NO:

301. L The structural domains LCDR1, LCDR2, and LCDR3 have 100% sequence identity. h) The V H The domain contains V, which is respectively associated with the amino acid sequence containing SEQ ID NO:

1. H The HCDR1, HCDR2, and HCDR3 domains have 100% sequence identity; and the V L The domain contains V, which is respectively associated with the amino acid sequence containing SEQ ID NO:

302. L The LCDR1, LCDR2, and LCDR3 domains have 100% sequence identity; or i) The V H The domain contains V, which is respectively associated with the amino acid sequence containing SEQ ID NO:

1. H The HCDR1, HCDR2, and HCDR3 domains have 100% sequence identity; and the V L The domain contains V, which is respectively associated with the amino acid sequence containing SEQ ID NO:

142. L The structural domains LCDR1, LCDR2, and LCDR3 have 100% sequence identity.

3. The antibody or its antigen-binding fragment as claimed in claim 1, wherein: a) The HCDR1 contains the amino acid sequences of SEQ ID NO:45, SEQ ID NO:303, SEQ ID NO:304, SEQ ID NO:44 and SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:49, SEQ ID NO:50 or SEQ ID NO:51; b) The HCDR2 contains the amino acid sequence of SEQ ID NO:72; c) The HCDR3 contains the amino acid sequence of SEQ ID NO:

79. d) The LCDR1 contains the amino acid sequence of SEQ ID NO:146; e) The LCDR2 contains an amino acid sequence of AAS, IAS, or YAS; and f) The LCDR3 contains the amino acid sequence of SEQ ID NO:

150.

4. The antibody or antigen-binding fragment thereof as claimed in any one of claims 1 to 3, wherein: a) The HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 respectively contain the amino acid sequences of SEQ ID NO:45, SEQ ID NO:72, SEQ ID NO:79, SEQ ID NO:146, AAS and SEQ ID NO:150; b) The HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 respectively contain the amino acid sequences of SEQ ID NO:303, SEQ ID NO:72, SEQ ID NO:79, SEQ ID NO:146, AAS and SEQ ID NO:150; c) The HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 respectively contain the amino acid sequences SEQ ID NO:304, SEQ ID NO:72, SEQ ID NO:79, SEQ ID NO:146, AAS, and SEQ ID NO:150; or d) The HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 respectively contain the amino acid sequences of SEQ ID NO:44, SEQ ID NO:72, SEQ ID NO:79, SEQ ID NO:146, AAS and SEQ ID NO:

150.

5. The antibody or its antigen-binding fragment as claimed in claim 1, wherein: a) The HCDR1 contains the amino acid sequence of SEQ ID NO:80, SEQ ID NO:81 or SEQ ID NO:82; b) The HCDR2 contains the amino acid sequence of SEQ ID NO:96; c) The HCDR3 contains the amino acid sequence of SEQ ID NO:103; d) The LCDR1 contains the amino acid sequence of SEQ ID NO:151; e) The LCDR2 contains the amino acid sequence of SEQ ID NO:156, SEQ ID NO:154, SEQ ID NO:307, SEQ ID NO:308, or SEQ ID NO:152; and f) The LCDR3 contains the amino acid sequence of SEQ ID NO:

150.

6. The antibody or antigen-binding fragment thereof as claimed in any one of claims 1, 2, and 5, wherein: a) The HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 respectively contain the amino acid sequences of SEQ ID NO:80, SEQ ID NO:96, SEQ ID NO:103, SEQ ID NO:151, SEQ ID NO:156 and SEQ ID NO:150; b) The HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 respectively contain the amino acid sequences of SEQ ID NO:80, SEQ ID NO:96, SEQ ID NO:103, SEQ ID NO:151, SEQ ID NO:152 and SEQ ID NO:150; c) The HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 respectively contain the amino acid sequences of SEQ ID NO:80, SEQ ID NO:96, SEQ ID NO:103, SEQ ID NO:151, SEQ ID NO:307 and SEQ ID NO:150; d) The HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 respectively contain the amino acid sequences of SEQ ID NO:80, SEQ ID NO:96, SEQ ID NO:103, SEQ ID NO:151, SEQ ID NO:308, and SEQ ID NO:150; or e) The HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 respectively contain the amino acid sequences of SEQ ID NO:80, SEQ ID NO:96, SEQ ID NO:103, SEQ ID NO:151, SEQ ID NO:154 and SEQ ID NO:

150.

7. The antibody or antigen-binding fragment thereof as claimed in claim 1, wherein: a) The HCDR1 contains the amino acid sequence of SEQ ID NO:105, SEQ ID NO:305, SEQ ID NO:306, SEQ ID NO:104, SEQ ID NO:106, SEQ ID NO:107, SEQ ID NO:109, SEQ ID NO:110 or SEQ ID NO:111; b) The HCDR2 contains the amino acid sequence of SEQ ID NO:132; c) The HCDR3 contains the amino acid sequence of SEQ ID NO:139; d) The LCDR1 contains the amino acid sequence of SEQ ID NO:151; e) The LCDR2 contains the amino acid sequence of SEQ ID NO:156, SEQ ID NO:154, SEQ ID NO:307, SEQ ID NO:308, or SEQ ID NO:152; and f) The LCDR3 contains the amino acid sequence of SEQ ID NO:

150.

8. The antibody or antigen-binding fragment thereof as claimed in any one of claims 1, 2, and 7, wherein: a) The HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 respectively contain the amino acid sequences of SEQ ID NO:105, SEQ ID NO:132, SEQ ID NO:139, SEQ ID NO:151, SEQ ID NO:156 and SEQ ID NO:150; b) The HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 respectively contain the amino acid sequences of SEQ ID NO:105, SEQ ID NO:132, SEQ ID NO:139, SEQ ID NO:151, SEQ ID NO:152 and SEQ ID NO:150; c) The HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 respectively contain the amino acid sequences of SEQ ID NO:305, SEQ ID NO:132, SEQ ID NO:139, SEQ ID NO:151, SEQ ID NO:152 and SEQ ID NO:150; d) The HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 respectively contain the amino acid sequences of SEQ ID NO:306, SEQ ID NO:132, SEQ ID NO:139, SEQ ID NO:151, SEQ ID NO:152 and SEQ ID NO:150; e) The HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 respectively contain the amino acid sequences of SEQ ID NO:104, SEQ ID NO:132, SEQ ID NO:139, SEQ ID NO:151, SEQ ID NO:156 and SEQ ID NO:150; f) The HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 respectively contain the amino acid sequences of SEQ ID NO:104, SEQ ID NO:132, SEQ ID NO:139, SEQ ID NO:151, SEQ ID NO:307 and SEQ ID NO:150; g) The HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 respectively contain the amino acid sequences of SEQ ID NO:104, SEQ ID NO:132, SEQ ID NO:139, SEQ ID NO:151, SEQ ID NO:308, and SEQ ID NO:150; or h) The HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3 respectively contain the amino acid sequences of SEQ ID NO:104, SEQ ID NO:132, SEQ ID NO:139, SEQ ID NO:151, SEQ ID NO:154 and SEQ ID NO:

150.

9. The antibody or antigen-binding fragment thereof as claimed in any one of claims 1 to 8, wherein: a) The V H The domain contains the amino acid sequence of SEQ ID NO:3, and the V L The domain contains the amino acid sequence of SEQ ID NO:144; b) The V H The domain contains the amino acid sequence of SEQ ID NO:2, and the V L The domain contains the amino acid sequence of SEQ ID NO:144; c) The V H The domain contains the amino acid sequence of SEQ ID NO:4, and the V L The domain contains the amino acid sequence of SEQ ID NO:144; d) The V H The domain contains the amino acid sequence of SEQ ID NO:4, and the V L The domain contains the amino acid sequence of SEQ ID NO:140; e) The V H The domain contains the amino acid sequence of SEQ ID NO:299, and the V L The domain contains the amino acid sequence of SEQ ID NO:140; f) The V H The domain contains the amino acid sequence of SEQ ID NO:300, and the V L The domain contains the amino acid sequence of SEQ ID NO:140; g) The V H The domain contains the amino acid sequence of SEQ ID NO:1, and the V L The domain contains the amino acid sequence of SEQ ID NO:144; h) The V H The domain contains the amino acid sequence of SEQ ID NO:1, and the V L The domain contains the amino acid sequence of SEQ ID NO:301; i) The V H The domain contains the amino acid sequence of SEQ ID NO:1, and the V L The domain contains the amino acid sequence of SEQ ID NO:302; or j) The V H The domain contains the amino acid sequence of SEQ ID NO:1, and the V L The domain contains the amino acid sequence of SEQ ID NO:

142.

10. The antibody or antigen-binding fragment thereof as claimed in any one of claims 1 to 9, wherein the antigen-binding fragment comprises a single-chain variable fragment (scFv), an antigen-binding fragment (Fab), Fab', or F(ab')2.

11. The antibody or antigen-binding fragment thereof as claimed in any one of claims 1 to 9, wherein the antibody or antigen-binding fragment thereof comprises an antibody heavy chain constant domain, an antibody light chain constant domain, or both.

12. The antibody or antigen-binding fragment of claim 11, wherein the antibody or antigen-binding fragment comprises an antibody heavy chain constant domain, and wherein the antibody heavy chain constant domain comprises one or more mutations that increase the serum half-life of the antibody or antigen-binding fragment in humans.

13. The antibody or antigen-binding fragment thereof as claimed in claim 11, wherein the antibody or antigen-binding fragment thereof comprises an antibody heavy chain constant domain, and wherein the antibody heavy chain constant domain comprises SEQ ID NO:280, YTE modification of SEQ ID NO:280, LS modification of SEQ ID NO:280, YTE modification of SEQ ID NO:279, or LS modification of SEQ ID NO:

279.

14. A polynucleotide encoding an antibody or an antigen-binding fragment thereof as claimed in any one of claims 1 to 13.

15. A host cell comprising the polynucleotide of claim 14.

16. A method for producing an antibody or an antigen-binding fragment thereof as claimed in any one of claims 1 to 13, the method comprising expressing the antibody or an antigen-binding fragment thereof in a host cell as claimed in claim 15 and isolating the expressed antibody or an antigen-binding fragment thereof.

17. A pharmaceutical composition comprising an antibody or antigen-binding fragment thereof as claimed in any one of claims 1 to 13, a polynucleotide as claimed in claim 14 or a host cell as claimed in claim 15, and a pharmaceutically acceptable carrier or diluent.

18. A kit comprising an antibody or antigen-binding fragment thereof as claimed in any one of claims 1 to 13, a polynucleotide as claimed in claim 14, a host cell as claimed in claim 15, or a pharmaceutical composition as claimed in claim 17.

19. A method for blocking the binding of a ligand to a receptor expressed on a cell surface, the method comprising contacting the cell with an effective amount of an antibody or an antigen-binding fragment thereof as claimed in any one of claims 1 to 13, thereby blocking the binding of the ligand to a receptor expressed on the cell surface, wherein the ligand comprises p40.

20. A method for blocking the binding of a ligand to its receptor in an individual, the method comprising administering to the individual an effective amount of an antibody or an antigen-binding fragment thereof as claimed in any one of claims 1 to 13 or a pharmaceutical composition as claimed in claim 17, thereby blocking the binding of the ligand to its receptor in the individual, wherein the ligand comprises p40.

21. A method of treating an individual with an IL-12 / IL-23-related disease, the method comprising administering to the individual an effective amount of an antibody or an antigen-binding fragment thereof as claimed in any one of claims 1 to 13 or a pharmaceutical composition as claimed in claim 17, thereby treating the IL-12 / IL-23-related disease.

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