TW202535933A - Antigen binding molecules targeting il-12 and il-23 - Google Patents

Abstract

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

Description

Antigen-binding molecules targeting IL-12 and IL-23

This invention relates to antigen-binding molecules that target IL-12 and IL-23.

The involvement of interleukin (IL)-12/23 pathways is related to the pathogenesis of various diseases.

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 comprising 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 the Th1 response and the pro-inflammatory activity of IFNγ in autoimmune diseases, IL-12 plays a major role in the pathology of many autoimmune and inflammatory diseases. Due 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 a means of inhibiting IL-12 activity.

IL-23 is a heterodimeric intercytokine composed of two subunits: p19 and ^p40 . 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 many inflammatory genes, including IL-17A, IL-17A receptor, TNF-α, and GM-CSF. The primary 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 associated with the pathogenesis of various inflammatory diseases, including but not limited to Crohn's disease, ulcerative colitis, psoriasis, psoriatic arthritis, rheumatoid arthritis, and ankylosing spondylitis.

The p40 subunit is shared by IL-12 and IL-23, serving as a common subunit and targeted by IL-12/23 inhibitors. There is compelling evidence that therapies binding to the p40 subunit can inhibit IL-12 and IL-23-mediated cellular signaling, activation, and intercytokine production.

Ustekinumab ( ^STELARA® ) is a human IgG1 monoclonal antibody that binds to the p40 subunit shared by human IL-12 and IL-23. It prevents the interaction between IL-12 and IL-23 and their cell surface receptor IL-12Rβ1, subsequently inhibiting IL-12 and IL-23-mediated cellular signaling, activation, and intercytokine 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 therapeutic dosage. Increased stability and/or serum half-life can provide an advantage in drug administration.

The disclosures provided 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 combinations (e.g., antibodies or their antigen-binding fragments, pharmaceutical compounds) 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.

Furthermore, this disclosure provides an antibody or an antigen-binding fragment thereof, the antibody or antigen-binding fragment comprising: a) an immunoglobulin heavy chain variable ( _VH ) domain, the _VH domain comprising HCDR1, HCDR2, and HCDR3 having 100% sequence identity with the heavy chain complementarity determining regions (HCDRs) 1, HCDR2, and HCDR3 of the VH domain comprising any of the amino _acid sequences 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, respectively; and b) an immunoglobulin light chain variable ( _VL ) domain, the _VL domain comprising SEQ ID NO:144, SEQ ID NO:142, SEQ ID NO:301, SEQ ID NO:302, and SEQ ID NO:19-21, respectively. The light chain complementary determinant region (LCDR) of the V _L domain of any of the amino acid sequences in NO:140, LCDR1, LCDR2, and LCDR3 having 100% sequence identity, wherein the V _H domain has less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1, and the V _L domain has less than 100% sequence identity with the amino acid sequence of SEQ ID NO:140, or both.

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 of 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 LCDR1, LCDR2, and LCDR3 of 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 HCDR1, HCDR2, and HCDR3 of the VH domain containing the amino acid sequence of SEQ ID NO:2; and a _VL domain comprising LCDR1, LCDR2, and LCDR3 of the VH domain containing the _amino acid sequence of SEQ ID NO: ₂ ; and a _VL domain comprising LCDR1, LCDR2, and LCDR3 of the _VH domain containing the amino acid sequence of SEQ ID NO:144; c) A _VH domain comprising LCDR1, LCDR2, and LCDR3 having 100% sequence identity with the _VH domain of the amino acid sequence comprising SEQ ID NO:4; and a VL domain comprising LCDR1, LCDR2, and LCDR3 having 100% sequence identity with the _VH domain of the amino acid sequence comprising SEQ ID NO: ₄ ; and a _VL domain comprising LCDR1, LCDR2, and LCDR3 having 100% sequence identity with the _VL domain of the amino acid sequence comprising SEQ ID NO:4; d) A _VH domain comprising LCDR1, _LCDR2 , and LCDR3 having 100% sequence identity with the _VL domain of the amino acid sequence comprising SEQ ID NO:299; e) A _{V H domain} , comprising HCDR1, HCDR2, and HCDR3 having 100% sequence identity with HCDR1, HCDR2, and HCDR3 of the V _H domain containing the amino acid sequence of SEQ ID NO: 140; f) A V _H domain, comprising HCDR1, HCDR2 _, and HCDR3 having 100% sequence identity with HCDR1, HCDR2, and HCDR3 of the V _H domain containing the amino acid sequence of SEQ ID NO: 300; and a _{V L domain, comprising LCDR1, LCDR2, and LCDR3 having 100% sequence identity with LCDR1, LCDR2, and LCDR3 of the V L domain containing the} amino acid sequence of SEQ ID NO: 140; g) A _VH domain, wherein the _VH domain comprises HCDR1, HCDR2, and HCDR3 having 100% sequence identity with HCDR1, HCDR2, and HCDR3 of the _VH domain containing the amino acid sequence of SEQ ID NO:1; and a _VL domain, wherein the VL domain comprises LCDR1, LCDR2, and LCDR3 having 100% sequence identity with LCDR1, LCDR2, and LCDR3 of the _VL domain containing the amino acid sequence of SEQ ID NO:144; g) A VH domain, wherein the _VH domain comprises HCDR1, HCDR2, and HCDR3 having 100% sequence identity with HCDR1, HCDR2, and HCDR3 of the _VH domain containing the amino acid sequence of SEQ ID NO:1; and a _VL domain, wherein the _VL domain comprises LCDR1, LCDR2, and LCDR3 having 100% sequence identity with HCDR1, HCDR2, and HCDR3 of the _{VH domain} containing the amino acid sequence of SEQ ID NO:301; h) A _VH domain comprising LCDR1, LCDR2, and LCDR3 having 100% sequence identity with HCDR1, HCDR2, and HCDR3 of 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 HCDR1, HCDR2, and HCDR3 of 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 LCDR1, LCDR2, and LCDR3 of the _VL domain 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 HCDR1, HCDR2, and HCDR3 of the _VH domain containing the amino acid sequence of SEQ ID NO:1; and a _VL domain comprising LCDR1, HCDR2, and HCDR3 of the _VH domain containing the amino acid sequence of SEQ ID NO:1; and a VL domain containing LCDR1, LCDR2, and LCDR3 of the VL ... The V _L domain includes LCDR1, LCDR2, and LCDR3, which have 100% sequence identity with _LCDR1 , LCDR2 _, and LCDR3, which contain the amino acid sequence of SEQ ID NO:142.

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 of AAS, IAS, or YAS; and f) LCDR3 contains the amino acid sequence of SEQ ID NO:150.

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

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.

In some embodiments, the antibody or its antigen-binding fragment comprises: a) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of 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, respectively; b) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of 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, respectively; c) 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, respectively. d) Contains the amino acid sequences HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:150; e) Contains the amino acid sequences HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 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, respectively; f) Contains the amino acid sequences HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 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, respectively.

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.

In some embodiments, the antibody or its antigen-binding fragment comprises: a) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of 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, respectively; b) HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of 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, respectively; c) 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, respectively. d) Contains the amino acid sequences HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:150; d) Contains the amino acid sequences HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 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, respectively; e) Contains the amino acid sequences HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 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, respectively; f) Contains the amino acid sequences HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:104, SEQ ID NO:132, SEQ ID NO:139, SEQ ID NO:151, and SEQ ID NO:150, respectively; g) Contains the amino acid sequences HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 of SEQ ID NO:307 and SEQ ID NO:150, respectively; g) Contains the amino acid sequences HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 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, respectively; or h) Contains the amino acid sequences HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 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, respectively.

In some embodiments, the antibody or its antigen-binding fragment comprises: a) a _VH domain comprising the amino acid sequence of SEQ ID NO:3 and a _VL domain comprising the amino acid sequence of SEQ ID NO:144; b) a _VH domain comprising the amino acid sequence of SEQ ID NO:2 and a _VL domain comprising the amino acid sequence of SEQ ID NO:144; c) a _VH domain comprising the amino acid sequence of SEQ ID NO:4 and a _VL domain comprising the amino acid sequence of SEQ ID NO:144; d) a _VH domain comprising the amino acid sequence of SEQ ID NO:4 and a _VL domain comprising 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) comprising SEQ ID NO:3; g) The amino acid sequence NO:300 contains the V _H domain and the amino acid sequence NO:140 contains the V _L domain; g) The amino acid sequence NO:1 contains the V _H domain and the amino acid sequence NO:144 contains the V _L domain; h) The amino acid sequence NO:1 contains the V _H domain and the amino acid sequence NO:301 contains the V _L domain; i) The amino acid sequence NO:1 contains the V _H domain and the amino acid sequence NO:302 contains the V _L domain; or j) The amino acid sequence NO:1 contains the V _H domain and the amino acid sequence NO:142 contains the V _L domain.

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

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

In some embodiments, the antibody or its antigen-binding fragment includes an antibody heavy chain constant domain comprising SEQ ID NO:280, SEQ ID NO:280 with YTE modification, SEQ ID NO:280 with LS modification, SEQ ID NO:279, SEQ ID NO:279 with YTE modification, or SEQ ID NO:279 with LS modification.

Furthermore, this disclosure also provides an antibody or antigen-binding fragment thereof comprising: a) HCDR1 comprising the amino acid sequence of SEQ ID NO:X ₁ (e.g., composed thereof), b) HCDR2 comprising the amino acid sequence of SEQ ID NO:X ₂ (e.g., composed thereof), c) HCDR3 comprising the amino acid sequence of SEQ ID NO:X ₃ (e.g., composed thereof), d) LCDR1 comprising the amino acid sequence of SEQ ID NO:Y ₁ (e.g., composed thereof), e) LCDR2 comprising the amino acid sequence of SEQ ID NO:Y ₂ (e.g., composed thereof), and f) LCDR3 comprising the amino acid sequence of SEQ ID NO:Y ₃ (e.g., composed thereof).

Furthermore, this disclosure provides an antibody or an antigen-binding fragment thereof comprising: a) an immunoglobulin heavy chain variable ( _VH ) domain, the _VH domain comprising HCDR1, HCDR2, and HCDR3 having at least 80% sequence identity with the heavy chain complementarity determining regions (HCDRs) 1, HCDR2, and HCDR3 of the VH domain comprising an amino acid sequence comprising 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, the _VL domain comprising a _VH domain comprising an amino acid sequence comprising any of SEQ ID NO:144, 142, 301, and 302 (e.g., SEQ ID NO:144 or 142). The light chain complementary determinant regions (LCDRs) 1, 2, and 3 of the _L- domain have at least 80% sequence identity, wherein the V _H domain has less than 100% sequence identity with the amino acid sequence of SEQ ID NO: 1, and the V _L domain has less than 100% sequence identity with the amino acid sequence of SEQ ID NO: 140, or both.

Furthermore, this disclosure also provides an antibody or an antigen-binding fragment thereof, the antibody or antigen-binding fragment comprising: a) a _VH domain, the _VH domain comprising HCDR1, HCDR2, and HCDR3 having 100% sequence identity with HCDR1, HCDR2, and HCDR3 of the _VH domain containing an amino acid sequence comprising any one of SEQ ID NO:2-11, 19-21, 299, and 300 (e.g., any one of SEQ ID NO:2-11 and 19-21), and b) a _VL domain, the _VL domain comprising LCDR1, LCDR2, and LCDR3 having 100% sequence identity with LCDR1, LCDR2, and LCDR3 of the _VL domain containing an amino acid sequence comprising any one of SEQ ID NO:144, 142, 301, and 302 (e.g., SEQ ID NO:144 or 142), wherein the V... The _H domain has less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1, and the V _L domain has less than 100% sequence identity with the amino acid sequence of SEQ ID NO:140, or both.

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 N-terminal to C-terminal order: _VH FR1-HCDR1- _VH FR2-HCDR2- _VH FR3-HCDR3- _VH FR4, wherein: a) the _VH FR1-HCDR1 comprises an 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 comprises an amino acid sequence of GKGL, GDYL or GYYL, or c) the _VH FR3 comprises an amino acid sequence of NSLK, PSLR or NDLR, or any combination of a) to c).

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

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.

Furthermore, this disclosure also provides an antibody or antigen-binding fragment thereof comprising: a) HCDR1 comprising the amino acid sequence of SEQ ID NO:X ₁ (e.g., composed thereof), b) HCDR2 comprising the amino acid sequence of SEQ ID NO:X ₂ (e.g., composed thereof), c) HCDR3 comprising the amino acid sequence of SEQ ID NO:X ₃ (e.g., composed thereof), d) LCDR1 comprising the amino acid sequence of SEQ ID NO:Y ₁ (e.g., composed thereof), e) LCDR2 comprising the amino acid sequence of SEQ ID NO:Y ₂ (e.g., composed thereof), and f) LCDR3 comprising the amino acid sequence of SEQ ID NO:Y ₃ (e.g., composed thereof).

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.

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.

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.

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 the amino acid sequence of SEQ ID NO:X and a _VL domain containing the amino acid sequence of SEQ ID NO:Y.

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.

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.

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.

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.

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.

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

Furthermore, this disclosure also provides a polynucleotide that encodes the _VH domain, _VL domain, light chain, or heavy chain of the antibody or antigen-binding fragment disclosed herein. In some embodiments, the polynucleotide is DNA. In some embodiments, the polynucleotide is RNA.

In addition, this disclosure also provides an expression vector containing a polynucleotide disclosed herein.

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

Furthermore, 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 host cells and isolating the expressed antibody or antigen-binding fragment thereof.

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.

In addition, this disclosure also provides a kit containing the pharmaceutical composition disclosed herein.

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

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

Related Application This application claims a benefit in U.S. Provisional Application No. 63/593,199, filed October 25, 2023. The entire teaching content of the aforementioned application is incorporated herein by reference.

Material incorporated into XML by reference This application incorporates by reference the following sequence list contained in an eXtensible Markup Language (XML) file submitted concurrently with this document: a) File name: 62311000001.xml; created on October 22, 2024; size: 325,178 bytes.

The example implementation is described below.

The following examples, for illustrative purposes only, describe certain aspects of this disclosure. Numerous specific details, relationships, and methods are explained to provide a complete understanding of this disclosure. Those skilled in the art will readily recognize that this disclosure can be practiced without one or more specific details and/or with other materials (e.g., reagents, cells, animals), techniques, and/or procedures. Those skilled in the art will fully understand and commonly employ many of the techniques and procedures described herein using known methods.

Unless otherwise defined , all technical terms, symbols, and other scientific terms or proper nouns 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 convenience 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 substantial difference from the meaning generally understood in the art. It will be further understood that terms such as those defined in commonly used 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.

The terminology used in this article is for the purpose of describing specific embodiments only and is not intended to be restrictive.

When describing the elements disclosed herein, the articles “a,” “an,” “the,” and “the” 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.

Throughout this specification and the scope of the following claims, unless the context otherwise requires, the term "comprise" and variations thereof such as "comprises" and "comprising" shall be construed as implying inclusion of, for example, the integers or steps or groups of integers or steps stated, but not excluding 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".

As used herein, the term "composed of" excludes any element, step, or component not specified in the elements of the claims.

When used herein, the term "consistently made up of" does not exclude materials or steps that do not substantially affect the essential and novel features of the scope of the patent application.

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.”

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 one 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".

It should be understood that for all numerical limits describing certain 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 specifically 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.

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".

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

As used herein, the term "peptide" refers to a polymer of at least two amino acids covalently linked by amide bonds, regardless of length or post-translational modifications (e.g., glycosylation or phosphorylation). Peptides may contain any suitable L-amino acid and/or D-amino acid, such as common α-amino acids (e.g., alanine, glycine, volcanic acid), 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, leucine, orthovolcanic acid, guanine). 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 polypeptide can also be derivatized (e.g., alkylated) or labeled (e.g., with detectable labels, such as fluorescent groups or haptens) using methods known in the art. Where desired, the polypeptide may contain one or more modifications (e.g., amino acid linkers, acetylation, acetylation, amylation, methylation, terminal modifiers (e.g., cyclization), N -methyl-α-amino substitution). Additionally, the polypeptide may be an analogue of a known and/or naturally occurring peptide, such as a peptide analogue with conserved amino acid residue substitutions.

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 polynucleotides comprise 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 containing purine and pyrimidine bases, or other natural, chemically or biochemically modified, non-natural, or derived nucleotide bases. The backbone of a polynucleotide may comprise sugar and phosphate groups, modified or substituted sugar or phosphate groups, polymers of synthetic subunits (such as aminophosphates), or combinations thereof.

As used herein, the term "sequence identity" refers to the degree, expressed as a percentage, of the identical residues at the same positions when sequences are aligned to achieve the maximum level of identity. For sequence alignment and comparison, typically a sequence is designated as a reference sequence, and a 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 along the entire length of the reference sequence when aligned to achieve the maximum level of identity. For example, when the maximum level of identity is achieved, if the test sequence has identical nucleotide residues at 70% of the same positions along the entire length of the reference sequence, the two sequences should be considered to have 70% sequence identity.

Those familiar with this technique can easily perform alignments of the sequences to be compared to achieve the highest level of consistency using appropriate alignment methods or algorithms. In some cases, alignments may include the introduction of gaps to provide the highest level of consistency. Examples include the local homology algorithm of Smith and Waterman, Adv. Appl. Math . 2:482 (1981); the homology comparison 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); computer implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics software suite, Genetics Computer Group, 575 Science Dr., Madison, Wis.); and visual inspection (generally see Ausubel et al., Current Protocols in Molecular Biology ).

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 of the test sequence relative to 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 can be obtained from the National Center for Biotechnology Information and the National Library of Medicine of the National Institutes of Health (Altschul et al., 1990).

The term "expression vector" refers to a reproducible nucleic acid that can express one or more proteins when the expression vector is transformed into a suitable expression host cell (e.g., recombinant cell).

As used in this article, the term "initiator" refers to the DNA region where RNA polymerase binds and initiates gene transcription.

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 behave under the control of the element it is linked to (e.g., a promoter).

As used herein, the term "selective marker element" refers to an element endowed with characteristics suitable for human selection. Selective marker elements can be negative or positive selective markers.

As used herein, the term "expressing host cell" refers to a cell that can be used to receive, maintain, replicate, and/or amplify a vector.

As used herein, the term "antibody" refers to an immunoglobulin molecule that specifically binds to a target (such as a carbohydrate, polynucleotide, lipid, polypeptide, 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, multicomplementary antibodies, bispecific antibodies, and multispecific antibodies.

As used in this article, "humanized antibody" refers to an antibody in which the antigen-binding site is derived from a non-human species and the structural region is derived from a human immunoglobulin sequence.

As used in this article, "human antibody" is an antibody with variable regions of heavy and light chains, wherein the structure and antigen-binding sites are derived from human-origin sequences.

As used in this article, the term "single-domain antibody (sdAb)" or "nanoantibody" refers to an immunoglobulin molecule composed of a single monomeric variable antibody domain that can specifically bind to a target.

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 by synthetic linkers to form various types of monochain antibody designs, wherein the _VH / _VL domains pair intramolecularly or intermolecularly, in the case that the _VH and _VL domains are expressed as 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.

As used herein, “complementary determination region (CDR)” encompasses any CDR defined by a technically accepted method for identifying CDR residues on antibodies. See, for example, Kabat, E.A. et al., (1991) Sequences of Proteins of Immunological Interest, 5th ed., U.S. 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 consistency 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.

The structural region and CDR of an antibody can be identified using one of several suitable methods known in this art, such as by Kabat definition, Chothia definition, AbM definition and/or contact definition. Publicly available and/or commercially available tools for identifying scaffolds and/or CDR regions include IgBlast (available at www.ncbi.nlm.nih.gov/igblast/), Scaligner (available from 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 identification and receptor classification (ANARCI, available at opig.stats.ox.ac.uk/webapps/). (Available at newsabdab/sabpred/anarci/), or the Paratome website 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.

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

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, nanoantibodies, nanoCLAMP, and Versabody.

As used herein, the term " _KD ," also known as the "binding constant,""equilibrium dissociation constant," or "affinity constant," is a measure of the degree of reversible binding between two molecular classes (e.g., an antibody and a 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, measurement by surface plasma resonance, such as using the Octet (ForteBio) or Biacore systems and assays. References comparing various surface techniques used to measure binding affinity and kinetics include Yang, D., Singh, A., Wu, H. and Kroe-Barrett, R., Comparison of biosensor platforms in the evaluation of high affinity antibody-antigen binding kinetics , Analytical Biochemistry 508: 78-96 (2016), the contents of which are incorporated herein by reference in their entirety.

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).

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 by 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.

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

As used herein, the term "pharmaceutically acceptable salt" refers to salts suitable for use in tissue contact with mammals within the scope of reasonable medical judgment, without excessive toxicity, irritation, allergic reactions, or similar reactions, and in proportion to a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in this art. For example, S. M. 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.

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 amine salts formed by other methods used in this technique, such as ion exchange. Other pharmaceutically acceptable salts derived from suitable acids include adipic acid salts, alginates, ascorbic acid salts, aspartate salts, benzenesulfonate salts, benzoate salts, hydrogen sulfate salts, borate salts, butyrate salts, camphorate salts, camphorsulfonate salts, cinnamate salts, citrate salts, cyclopentanepropionate salts, and dioxins. Gluconate, Dodecyl Sulfate, Ethanesulfonate, Formate, Fumarate, Gluconium Heptate, Glyceryl Phosphate, Gluconate, Glutarate, Glycolate, Hemisulfate, Heptate, Hexanoate, Hydroiodate, Hydroxybenzoate, 2-Hydroxyl-Ethanesulfonate Hydroxycidomide, Lactobionate, Lactate, Laurate, Lauryl Sulfate, Macarate, Cisdomide, Malonate, Methanesulfonate, 2-Naphthalenesulfonate, Nicotinate, Nitrate, Oleate, Oxalate, Palmitate, Dihydroxynaphthalate, Pectate, Perylenesulfonate Sulfates, 2-phenoxybenzoates, phenylacetic acids, 3-phenylpropionates, phosphates, neopentanoates, propionates, pyruvates, salicates, stearates, succinates, sulfates, tartrates, thiocyanates, p-toluenesulfonates, undecanoates, valerates, and similar salts.

It can form monoacids, diacids, or triacids, and these salts can exist in hydrated, solvent-bound, or substantially anhydrous forms.

Salts derived from suitable bases include salts derived from inorganic bases, such as alkali metals, alkaline earth metals, and ammonium bases, and salts derived from aliphatic, alicyclic, or aromatic organic amines, such as methylamine, trimethylamine, and methylpyridine, or N ⁺ (( _C1 - _C4 )alkyl) ₄ salts. Representative alkali metal salts or alkaline earth metal salts include sodium salts, lithium salts, potassium salts, calcium salts, magnesium salts, barium salts, and similar salts. Where appropriate, other pharmaceutically acceptable salts include non-toxic ammonium salts, grade IV ammonium salts, and amine cation salts formed using counterions such as halogens, hydroxides, carboxyl groups, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

"Pharmaceutical acceptable carriers" refer to non-toxic carriers or excipients that do not impair the pharmacological activity of the formulations they are mixed with, and are non-toxic when administered in a dose sufficient to deliver a therapeutic dose. 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), buffers (such as phosphates), glycine, sorbic acid, potassium sorbate, mixtures of saturated vegetable fatty acid metaglycerides, water, salts or electrolytes (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, wax, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and lanolin.

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 medications 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 by causing the disease or ailment to regress) and relieving symptoms caused by a disease or ailment.

The term "treating" or "treatment" refers to the management of an individual's health with the aim of improving, ameliorhyming, stabilizing (i.e., preventing deterioration), preventing, or curing a disease, pathological condition, or symptom—as exemplified in this article for specific indications. 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 inhibiting the development of a related disease, pathological condition, or symptom), and supportive treatment (treatment used to supplement another therapy). Treatment also includes reducing the severity of a disease or ailment, preventing its spread, delaying or slowing its progression, improving or alleviating it, and resolving it (whether partially or completely), whether detectable or undetectable. "Improving" or "alleviating" a disease or ailment means a reduction in the severity and/or duration of undesirable clinical manifestations and/or progression of the disease, symptom, or illness compared to the absence of treatment. "Treatment" can also mean extending survival compared to the expected survival without treatment. Those requiring treatment include those already suffering from a disease or ailment, those susceptible to it, or those with a disease or ailment requiring prevention.

"Pharmaceutical composition" means a formulation of one or more therapeutic agents and a generally accepted medium for delivering a bioactive agent to an individual (e.g., a human). 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.

"Pharmaceutical-acceptable carriers, thinners, or excipients" include any adjuvant, carrier, excipient, glidant, sweetener, thinner, preservative, dye/coloring agent, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotoner, solvent, or emulsifier that has been approved by the U.S. Food and Drug Administration for use in humans or livestock.

"Pharmaceutically acceptable carriers" refer to components of a pharmaceutical composition that are non-toxic to individuals, excluding 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 mediator administered with the agent (e.g., a polynucleotide). Such mediators 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 similar substances. For example, 0.4% saline solution and 0.3% glycine may be used. These solutions are sterile and generally free of particulate matter. It can be sterilized using known and familiar sterilization techniques (e.g., filtration). The formulation may contain pharmaceutically acceptable adjuvants that approximate physiological conditions, such as pH adjusters and buffers, stabilizers, thickeners, lubricants, and colorants, as needed. The concentration of the agent in such pharmaceutical formulations can vary widely, from less than about 0.5% to at least about 1%, or up to 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% (by weight). The concentration is selected based primarily on the required dosage, fluid volume, viscosity, etc., depending on the dosing method. Suitable mediators and formulations, including other human proteins such as human serum albumin, are described, for example, in Remington: The Science and Practice of Pharmacy, 21st edition, Troy, D.B. ed., Lipincott Williams and Wilkins, Philadelphia, PA 2006, Part 5, Pharmaceutical Manufacturing: 691-1092 (e.g., pp. 958-89).

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

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.

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.

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

Non-limiting examples of surfactants include polysorbates (e.g., polysorbate-20 or polysorbate-80); polyoxamer (e.g., polyoxamer 188); Triton; sodium octyl glycoside; lauryl-, myristyl-, linoleyl-, or stearyl-sulfobetaine; lauryl-, myristyl-, linoleyl-, or stearyl-sarcosine; linoleyl-, myristyl-, linoleyl-, styrosine; linoleyl-, myristyl- Myristyl- or cetyl-betaine; laurylaminopropyl-, cocamylaminopropyl-, flaxylaminopropyl-, myristylaminopropyl-, palmylaminopropyl- or isostearylaminopropyl-betaine (e.g., laurylaminopropyl); myristylaminopropyl-, palmylaminopropyl- or isostearylaminopropyl-dimethylamine; sodium methylcocoyl taurate or disodium methyl oleyl taurate; and the MONAQUA™ series (Mona Industries, Inc., Paterson, N.J.), polyethylene glycol, polypropylene glycol, and copolymers of ethylene glycol and propylene glycol (e.g., PLURONICS™, PF68, etc.).

Non-limiting examples of preservatives include phenol, m-cresol, p-cresol, ortho-cresol, chlorocresol, benzyl alcohol, phenylmercuric nitrite, phenoxyethanol, formaldehyde, chlorobutanol, magnesium chloride, alkyl p-hydroxybenzoate (methyl, ethyl, propyl, butyl and similar), benzalkonium chloride, benzenethonium chloride, sodium dehydroacetate and thimerosal, or mixtures thereof.

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, erythritol, glycerol, arabinitol, xylitol, sorbitol, mannitol, melibiose, pinetriose, raffinose, manntriose, stachyose, maltose, lactulose, maltulose, glucol, maltitol, lactitol, or isomaltulose.

Non-limiting examples of salts are acid addition salts and alkali addition salts. Acid addition salts include those 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, as well as those 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. Alkali addition salts include salts derived from alkaline earth metals such as sodium, potassium, magnesium, calcium, and the like, as well as salts derived from non-toxic organic amines such as N,N'-diphenylmethylethylenediamine, N-methylreducing glucosamine, chloroprocaine, choline, diethanolamine, ethylenediamine, procaine, and the like. In some embodiments, the salt is sodium chloride (NaCl).

The agents described herein (e.g., polynucleotides) may be prepared according to standard procedures and administered in doses selected to reduce, prevent, or eliminate the treated disease or to slow or stop its progression (for a general description of methods for 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, N.Y., the contents of which are incorporated herein by reference).

As used herein, “administration” or “medication administration” refers to the provision of the compound, composition or its pharmaceutically acceptable salt described herein to an individual in need of treatment or prevention. Administration may, for example, be performed once, multiple times and/or over one or more extended periods of time. Administration includes direct administration (including self-administration) and indirect administration (including prescribing medication or instructing an individual to consume a consumable). For example, as used herein, instructing an individual (e.g., a human patient) to self-administer an agent (e.g., a drug) or to have another person administer an agent and/or a person who prescribes medication to a patient (e.g., a physician) administers the agent to the individual.

"Therapeutic effective dose," "effective dose," or "effective dosage" refers to the amount of medication necessary to achieve the desired therapeutic outcome (e.g., treatment, cure, suppression or improvement of a physiological response or disorder). Complete therapeutic effect does not necessarily occur with a single dose and may occur only after a series of doses. Therefore, a therapeutic effective dose can be administered in one or more administrations. Therapeutic effective doses can vary depending on factors such as the disease condition, age, sex, and weight of the mammal (e.g., human patient), the administration method, and the ability of the medication or combination of medications to elicit the desired response.

The effective dose of the administration can be determined by a clinician skilled in the art using the guidelines provided herein and other methods known in this art. Relevant factors include the dosage, the pharmaceutical preparation, the route of administration, the 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, or approximately 0.01 mg/kg to approximately 1 mg/kg of body weight. Determining the dosage for a specific dose, individual, and disease is entirely within the capabilities of a practitioner skilled in the art. Ideally, the dosage should not cause adverse side effects or should produce minimal adverse side effects.

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 the amount of the composition sufficient to achieve a therapeutic response compared to the response obtained without administration of the composition. In other embodiments, the therapeutic effective amount is the 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. Dosage regimens and routes of administration can be adjusted to provide the optimal therapeutic response.

In some embodiments, the antibodies or antigen-binding fragments thereof disclosed herein include an immunoglobulin heavy chain variable domain ( _VH ), an immunoglobulin light chain variable domain ( _VL ), or both.

In some embodiments, the antibody or its antigen-binding fragment contains a _VH domain (e.g., a mammalian _VH domain, such as a rodent (e.g., _a mouse) _VH domain, or a primate ( e.g. , a human) _VH domain). In some embodiments, the antibody or its antigen-binding fragment contains a human _VH domain. In some embodiments, the antibody or its antigen-binding fragment contains 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 structural region, or both.

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.

In some embodiments, the antibody or its antigen-binding fragment comprises the following _VH domains: a) HCDR1, HCDR2, and HCDR3 having at least 80% sequence identity (e.g., at least 85%, at least 90%, or at least 95%) with the _VH domain of the amino acid sequence comprising SEQ ID NO:X; b) 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 includes a _VH domain, which comprises HCDR1, HCDR2, and HCDR3 having 100% sequence identity with HCDR1, HCDR2, and HCDR3, respectively, of _{the VH} domain containing the amino acid sequence of SEQ ID NO:X.

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, corresponding to the human _VH structural 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].

In some embodiments, the antibody or its antigen-binding fragment, as identified by the ImMunoGeneTics (IMGT) code, 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%), 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%), 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%), wherein the antibody or its antigen-binding fragment comprises a _VH domain having less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1.

Furthermore, this disclosure also provides an 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%), 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%), 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%), wherein the antibody or antigen-binding fragment thereof comprises 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 comprises: a) HCDR1 comprising the amino acid sequence of SEQ ID NO:X (e.g., composed thereof), b) HCDR2 comprising the amino acid sequence of SEQ ID NO:72 (e.g., composed thereof), and c) HCDR3 comprising the amino acid sequence of SEQ ID NO:79 (e.g., composed thereof).

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].

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 identified by IMGT codes.

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

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

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

In some embodiments, the antibody or its antigen-binding fragment, as determined by the Kabat code, 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%), 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%), 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%), wherein the antibody or its antigen-binding fragment comprises a _VH domain having less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1.

Furthermore, this disclosure also provides an 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%), 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%), 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%), wherein the antibody or antigen-binding fragment thereof comprises 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 comprises: a) HCDR1 comprising the amino acid sequence of SEQ ID NO:X (e.g., composed thereof), b) HCDR2 comprising the amino acid sequence of SEQ ID NO:96 (e.g., composed thereof), and c) HCDR3 comprising the amino acid sequence of SEQ ID NO:103 (e.g., composed thereof), wherein the antibody or its antigen-binding fragment comprises a _VH domain having less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1.

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].

Table 2 shows the sequences identified as SEQ ID NO: 80-82, 96 and 103, which correspond to the human HCDR sequences identified by the Kabat code.

In some embodiments, the antibody or its antigen-binding fragment, as determined by the Chothia code, 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%), 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%), wherein the antibody or its antigen-binding fragment comprises a _VH domain having less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1.

Furthermore, this disclosure also provides an 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%), 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%), wherein the antibody or antigen-binding fragment thereof comprises 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 comprises: a) HCDR1 comprising the amino acid sequence of SEQ ID NO:X (e.g., composed thereof), b) HCDR2 comprising the amino acid sequence of SEQ ID NO:132 (e.g., composed thereof), and c) HCDR3 comprising the amino acid sequence of SEQ ID NO:139 (e.g., composed thereof).

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].

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 identified by the Chothia code.

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

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

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

In some embodiments, the _VH framework region ( _VH FR1-4) 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 N-terminal to C-terminal order: _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 NSLK (SEQ ID NO:271), PSLR (SEQ ID NO:272), or NDLR (SEQ ID NO:270). The amino acid sequence of NO:273, or any combination of a) to c).

In some embodiments, the antibody or its antigen-binding fragment comprises: V _H FR1-HCDR1 containing the amino acid sequence of SEQ ID NO:X, and a) V _H FR2 containing the amino acid sequence of GKGL (SEQ ID NO:268), GDYL (SEQ ID NO:269) or GYYL (SEQ ID NO:270), or b) V H _FR3 containing the amino acid sequence of NSLK (SEQ ID NO:271), PSLR (SEQ ID NO:272) or NDLR (SEQ ID NO:273), or both a) and b).

In some embodiments, the antibody or its antigen-binding fragment comprises: V _H FR1-HCDR1 containing the amino acid sequence of SEQ ID NO:X, and a) V _H FR2 containing the amino acid sequence of GKGL (SEQ ID NO:268), GDYL (SEQ ID NO:269) or GYYL (SEQ ID NO:270), and b) V H _FR3 containing the amino acid sequence of NSLK (SEQ ID NO:271), PSLR (SEQ ID NO:272) or NDLR (SEQ ID NO:273).

In some embodiments, the antibody or its antigen-binding fragment comprises: V _H FR2 containing the amino acid sequence of GKGL (SEQ ID NO:268), GDYL (SEQ ID NO:269), or GYYL (SEQ ID NO:270), and a) V _H FR1-HCDR1 containing the amino acid sequence of SEQ ID NO:X, or b) V _H FR3 containing the amino acid sequence of NSLK (SEQ ID NO:271), PSLR (SEQ ID NO:272), or NDLR (SEQ ID NO:273), or both a) and b).

In some embodiments, the antibody or its antigen-binding fragment comprises: V _H FR2 containing the amino acid sequence of GKGL (SEQ ID NO:268), GDYL (SEQ ID NO:269), or GYYL (SEQ ID NO:270); a) V _H FR1-HCDR1 containing the amino acid sequence of SEQ ID NO:X; and b) V H _FR3 containing the amino acid sequence of NSLK (SEQ ID NO:271), PSLR (SEQ ID NO:272), or NDLR (SEQ ID NO:273).

In some embodiments, the antibody or its antigen-binding fragment comprises: V _H FR2 containing the amino acid sequence GKGL (SEQ ID NO:268), and a) V _H FR1-HCDR1 containing the amino acid sequence SEQ ID NO:X, or b) V _H FR3 containing the amino acid sequence NSLK (SEQ ID NO:271), PSLR (SEQ ID NO:272), or NDLR (SEQ ID NO:273), or both a) and b).

In some embodiments, the antibody or its antigen-binding fragment comprises: V _H FR2 containing the amino acid sequence GKGL (SEQ ID NO:268), and a) V _H FR1-HCDR1 containing the amino acid sequence SEQ ID NO:X, and b) V _H FR3 containing the amino acid sequence NSLK (SEQ ID NO:271), PSLR (SEQ ID NO:272), or NDLR (SEQ ID NO:273).

In some embodiments, the antibody or its antigen-binding fragment comprises: V _H FR2 containing the amino acid sequence of GDYL (SEQ ID NO:269), and a) V _H FR1-HCDR1 containing the amino acid sequence of SEQ ID NO:X, or b) V _H FR3 containing the amino acid sequence of NSLK (SEQ ID NO:271), PSLR (SEQ ID NO:272), or NDLR (SEQ ID NO:273), or both a) and b).

In some embodiments, the antibody or its antigen-binding fragment comprises: V _H FR2 containing the amino acid sequence of GDYL (SEQ ID NO:269), and a) V _H FR1-HCDR1 containing the amino acid sequence of SEQ ID NO:X, and b) V _H FR3 containing the amino acid sequence of NSLK (SEQ ID NO:271), PSLR (SEQ ID NO:272), or NDLR (SEQ ID NO:273).

In some embodiments, the antibody or its antigen-binding fragment comprises: V _H FR2 containing the amino acid sequence GYYL (SEQ ID NO:270), and a) V _H FR1-HCDR1 containing the amino acid sequence SEQ ID NO:X, or b) V _H FR3 containing the amino acid sequence NSLK (SEQ ID NO:271), PSLR (SEQ ID NO:272), or NDLR (SEQ ID NO:273), or both a) and b).

In some embodiments, the antibody or its antigen-binding fragment comprises: V _H FR2 containing the amino acid sequence GYYL (SEQ ID NO:270), and a) V _H FR1-HCDR1 containing the amino acid sequence SEQ ID NO:X, and b) V _H FR3 containing the amino acid sequence NSLK (SEQ ID NO:271), PSLR (SEQ ID NO:272), or NDLR (SEQ ID NO:273).

In some embodiments, the antibody or its antigen-binding fragment comprises: V _H FR3 containing the amino acid sequence of NSLK (SEQ ID NO:271), PSLR (SEQ ID NO:272), or NDLR (SEQ ID NO:273), and a) V _H FR1-HCDR1 containing the amino acid sequence of SEQ ID NO:X, or b) V _H FR2 containing the amino acid sequence of GKGL (SEQ ID NO:268), GDYL (SEQ ID NO:269), or GYYL (SEQ ID NO:270), or both a) and b).

In some embodiments, the antibody or its antigen-binding fragment comprises: V _H FR3 containing an amino acid sequence of NSLK (SEQ ID NO:271), PSLR (SEQ ID NO:272), or NDLR (SEQ ID NO:273); a) V _H FR1-HCDR1 containing an amino acid sequence of SEQ ID NO:X; and b) V H _FR2 containing an amino acid sequence of GKGL (SEQ ID NO:268), GDYL (SEQ ID NO:269), or GYYL (SEQ ID NO:270).

In some embodiments, the antibody or its antigen-binding fragment comprises: V _H FR3 containing the amino acid sequence of NSLK (SEQ ID NO:271), and a) V _H FR1-HCDR1 containing the amino acid sequence of SEQ ID NO:X, or b) V _H FR2 containing the amino acid sequence of GKGL (SEQ ID NO:268), GDYL (SEQ ID NO:269), or GYYL (SEQ ID NO:270), or both a) and b).

In some embodiments, the antibody or its antigen-binding fragment comprises: V _H FR3 containing the amino acid sequence of NSLK (SEQ ID NO:271), and a) V _H FR1-HCDR1 containing the amino acid sequence of SEQ ID NO:X, and b) V _H FR2 containing the amino acid sequence of GKGL (SEQ ID NO:268), GDYL (SEQ ID NO:269), or GYYL (SEQ ID NO:270).

In some embodiments, the antibody or its antigen-binding fragment comprises: V _H FR3 containing the amino acid sequence of PSLR (SEQ ID NO:272), and a) V _H FR1-HCDR1 containing the amino acid sequence of SEQ ID NO:X, or b) V _H FR2 containing the amino acid sequence of GKGL (SEQ ID NO:268), GDYL (SEQ ID NO:269), or GYYL (SEQ ID NO:270), or both a) and b).

In some embodiments, the antibody or its antigen-binding fragment comprises: V _H FR3 containing the amino acid sequence of PSLR (SEQ ID NO:272), and a) V _H FR1-HCDR1 containing the amino acid sequence of SEQ ID NO:X, and b) V _H FR2 containing the amino acid sequence of GKGL (SEQ ID NO:268), GDYL (SEQ ID NO:269), or GYYL (SEQ ID NO:270).

In some embodiments, the antibody or its antigen-binding fragment comprises: V _H FR3 containing the amino acid sequence of NDLR (SEQ ID NO:273), and a) V _H FR1-HCDR1 containing the amino acid sequence of SEQ ID NO:X, or b) V _H FR2 containing the amino acid sequence of GKGL (SEQ ID NO:268), GDYL (SEQ ID NO:269), or GYYL (SEQ ID NO:270), or both a) and b).

In some embodiments, the antibody or its antigen-binding fragment comprises: V _H FR3 containing the amino acid sequence of NDLR (SEQ ID NO:273), and a) V _H FR1-HCDR1 containing the amino acid sequence of SEQ ID NO:X, and b) V _H FR2 containing the amino acid sequence of GKGL (SEQ ID NO:268), GDYL (SEQ ID NO:269), or GYYL (SEQ ID NO:270).

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].

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

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

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

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

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].

In some embodiments, the antibody or its antigen-binding fragment includes a _VH domain that has 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.

In some embodiments, the antibody or its antigen-binding fragment comprises a _VH domain 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 contains an amino acid sequence relative to SEQ ID NO:X containing about 1-10 amino acid substitutions of V _H.

In some embodiments, the amino acid substitution is 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.

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

In some embodiments, the antibody or its antigen-binding fragment comprises a _VH that has 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.

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].

In some embodiments, the antibody or its antigen-binding fragment includes a VH domain that has 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.

In some embodiments, the antibody or its antigen-binding fragment includes a VH domain that has 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.

In some embodiments, the antibody or its antigen-binding fragment includes a VH domain that has 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.

In some embodiments, the antibody or its antigen-binding fragment includes a VH domain that has 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.

In some embodiments, the antibody or its antigen-binding fragment includes a VH domain that has 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.

In some embodiments, the antibody or its antigen-binding fragment contains 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 contains a human _VL domain. In some embodiments, the antibody or its antigen-binding fragment contains 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 structural region, or both.

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.

In some embodiments, the antibody or its antigen _- binding fragment includes a _VL domain comprising LCDR1, LCDR2, and LCDR3, which have at least 80% sequence identity (e.g., at least 85%, at least 90%, or at least 95%) with light chain complementary determining regions (LCDRs) 1, LCDR2, and LCDR3, respectively, that contain the _VL domain of 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.

In some embodiments, the antibody or its antigen-binding fragment includes a _VL domain, which comprises LCDR1, LCDR2, and LCDR3 having 100% sequence identity with LCDR1, LCDR2, and LCDR3, respectively, that contain _{the VL} domain of the amino acid sequence of SEQ ID NO: Y.

In some embodiments, Y is any one of SEQ ID NOs: 140-145, 301, and 302. Table 3 shows sequences identified as SEQ ID NOs: 140-145, 301, and 302, corresponding to the human _VL structural domain. In some embodiments, Y is any one of SEQ ID NOs: 141-145, 301, and 302. In some embodiments, Y is any one of SEQ ID NOs: 144, 142, 301, and 302. In some embodiments, Y is any one of SEQ ID NOs: 144, 301, and 302. In some embodiments, Y is 301. In some embodiments, Y is 302. In some embodiments, Y is any one of SEQ ID NOs: 140-145. In some embodiments, Y is any one of SEQ ID NOs: 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].

In some embodiments, the LCDR sequence identified by the IMGT code may include: a) an 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%), b) an LCDR2 comprising an amino acid sequence of AAS, IAS, or YAS (e.g., composed of such sequences), and c) an 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%), wherein the antibody or its antigen-binding fragment includes a V _L domain having less than 100% sequence identity with the amino acid sequence of SEQ ID NO:140.

Table 4 shows the sequences identified as SEQ ID NO: 146 and 150, which correspond to the human LCDR sequences identified by IMGT codes.

In some embodiments, the antibody or its antigen-binding fragment comprises: a) an LCDR1 comprising (e.g., composed of) the amino acid sequence of SEQ ID NO:146, b) an LCDR2 comprising (e.g., composed of) the amino acid sequence of AAS, IAS, or YAS, and c) an LCDR3 comprising (e.g., composed of) the amino acid sequence of SEQ ID NO:150, wherein the antibody or its antigen-binding fragment comprises a V _L 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 comprises: a) an 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%), b) an LCDR2 comprising an amino acid sequence of AAS (e.g., composed of it), and c) an 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%), wherein the antibody or its antigen-binding fragment comprises a V _L 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 comprises: a) an LCDR1 comprising (e.g., composed of) the amino acid sequence of SEQ ID NO:146, b) an LCDR2 comprising (e.g., composed of) the amino acid sequence of AAS, and c) an LCDR3 comprising (e.g., composed of) the amino acid sequence of SEQ ID NO:150, wherein the antibody or its antigen-binding fragment comprises a V _L 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 comprises: a) an 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), b) an LCDR2 comprising (e.g., composed of) the amino acid sequence of IAS, and c) an 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).

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

In some embodiments, the antibody or its antigen-binding fragment comprises: a) an 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), b) an LCDR2 comprising (e.g., composed of) the amino acid sequence of YAS, and c) an 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).

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

In some embodiments, the LCDR sequence identified by the Kabat or Chothia code comprises an antibody or its antigen-binding fragment comprising: a) an 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%), b) an 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%), and c) an 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%), wherein the antibody or its antigen-binding fragment comprises a V _L 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 comprises: a) an LCDR1 comprising (e.g., composed of) the amino acid sequence of SEQ ID NO:151, b) an LCDR2 comprising (e.g., composed of) the amino acid sequence of SEQ ID NO:Y, and c) an LCDR3 comprising (e.g., composed of) the amino acid sequence of SEQ ID NO:150, wherein the antibody or its antigen-binding fragment comprises a V _L domain having less than 100% sequence identity with the amino acid sequence of SEQ ID NO:140.

In some embodiments, Y is any one of SEQ ID NOs 152-157, 307, and 308. Table 4 shows sequences identified as SEQ ID NOs 150-157, 307, and 308, corresponding to human LCDR sequences identified by Kabat or Chothia codes. In some embodiments, Y is any one of SEQ ID NOs 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 SEQ ID NOs 152-157. In some embodiments, Y is any one of SEQ ID NOs 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].

In some embodiments, the antibody or its antigen-binding fragment includes a _VL domain that has 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.

In some embodiments, the antibody or its antigen-binding fragment comprises at least one amino acid-substituted V- _L domain relative to the amino acid sequence of SEQ ID NO: Y, wherein the V _-L 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 V _L with approximately 1-10 amino acid substitutions relative to the amino acid sequence of SEQ ID NO: Y. In some embodiments, the amino acid substitutions are conservative substitutions. In some embodiments, the amino acid substitutions are highly conserved substitutions.

In some embodiments, the antibody or its antigen-binding fragment comprises a V _L that has 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 V _L containing (e.g., composed of) the amino acid sequence of SEQ ID NO: Y.

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].

In some embodiments, the antibody or its antigen-binding fragment includes a VL domain that has 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.

In some embodiments, the antibody or its antigen-binding fragment contains a V _L that has 100% sequence identity with the amino acid sequence of SEQ ID NO:144.

In some embodiments, the antibody or its antigen-binding fragment includes a VL domain that has 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.

In some embodiments, the antibody or its antigen-binding fragment contains a V _L that has 100% sequence identity with the amino acid sequence of SEQ ID NO:142.

In some embodiments, the antibody or its antigen-binding fragment includes a VL domain that has 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.

In some embodiments, the antibody or its antigen-binding fragment contains a V _L that has 100% sequence identity with the amino acid sequence of SEQ ID NO:301.

In some embodiments, the antibody or its antigen-binding fragment includes a VL domain that has 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.

In some embodiments, the antibody or its antigen-binding fragment contains a V _L that has 100% sequence identity with the amino acid sequence of SEQ ID NO:302.

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).

In some embodiments, the antibody or its antigen-binding fragment comprises: a) a V _H having less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1, b) a V _L having less than 100% sequence identity with the amino acid sequence of SEQ ID NO:140, or both a) and b).

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 comprising the amino acid sequence of SEQ ID NO:X; and 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 the _VL domain comprising the amino acid sequence of SEQ ID NO:Y, wherein: i. the _VH domain has less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1; ii. the _VH domain has at least 80% sequence identity with the amino acid sequence of SEQ ID NO:X; and 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 the _VL domain comprising the amino acid sequence of SEQ ID NO:Y. The _L domain has less than 100% sequence identity with the amino acid sequence of SEQ ID NO:140, or both i and ii.

_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 of the _VH domain containing the amino acid sequence of SEQ ID NO:X, and b) a _VL domain comprising LCDR1, LCDR2, and LCDR3 having 100% sequence identity with LCDR1, LCDR2, and LCDR3 of _{the VL} domain containing the amino acid sequence of SEQ ID NO:Y, wherein: 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.

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.

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.

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.

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

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.

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.

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.

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

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.

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.

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.

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.

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.

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 140. In some embodiments, X is 300, and Y is 301. In some embodiments, X is 300, and Y is 302.

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.

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.

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.

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.

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.

Any of paragraphs [0203]-[0221] may apply to paragraph [0201] and/or paragraph [0202].

_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 comprising the _VH domain of the amino acid sequence of SEQ ID NO:2, respectively _; and b) a _VL domain comprising LCDR1, LCDR2, and LCDR3 having 100% sequence identity with LCDR1, LCDR2, and LCDR3 comprising the _VL domain of the amino acid sequence of SEQ ID NO:144, respectively.

_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 of the _VH domain comprising the amino acid sequence of SEQ ID NO:3, and b) a _VL domain comprising LCDR1, LCDR2, and LCDR3 having 100% sequence identity with LCDR1, _LCDR2 , and LCDR3 of the _VL domain comprising the amino acid sequence of SEQ ID NO:144.

_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 comprising the _VH domain of the amino acid sequence of SEQ ID NO:4, respectively _; and b) a _VL domain comprising LCDR1, LCDR2, and LCDR3 having 100% sequence identity with LCDR1, LCDR2, and LCDR3 comprising the _VL domain of the amino acid sequence of SEQ ID NO:140, respectively.

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 comprising the _VH domain of the amino acid sequence of SEQ ID NO:299, respectively _; and b) a _VL domain comprising LCDR1, LCDR2, and LCDR3 having 100% sequence identity with LCDR1, LCDR2, and LCDR3 comprising the _VL domain of the amino acid sequence of SEQ ID NO:140, respectively.

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 comprising the _VH domain of the amino acid sequence of SEQ ID NO:300, respectively _; and b) a _VL domain comprising LCDR1, LCDR2, and LCDR3 having 100% sequence identity with LCDR1, LCDR2, and LCDR3 comprising the _VL domain of the amino acid sequence of SEQ ID NO:140, respectively.

_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 of the _VH domain comprising the amino acid sequence of SEQ ID NO:1, and b) a _VL domain comprising LCDR1, LCDR2, and LCDR3 having 100% sequence identity with LCDR1, _LCDR2 , and LCDR3 of the _VL domain comprising the amino acid sequence of SEQ ID NO:142.

_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 of the _VH domain comprising the amino acid sequence of SEQ ID NO:1, and b) a _VL domain comprising LCDR1, LCDR2, and LCDR3 having 100% sequence identity with LCDR1, _LCDR2 , and LCDR3 of the _VL domain comprising the amino acid sequence of SEQ ID NO:144.

_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 comprising the _VH domain of the amino acid sequence of SEQ ID NO:1, respectively _; and b) a _VL domain comprising LCDR1, LCDR2, and LCDR3 having 100% sequence identity with LCDR1, LCDR2, and LCDR3 comprising the _VL domain of the amino acid sequence of SEQ ID NO:301, respectively.

_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 of the _VH domain comprising the amino acid sequence of SEQ ID NO:1, and b) a _VL domain comprising LCDR1, LCDR2, and LCDR3 having 100% sequence identity with LCDR1, _LCDR2 , and LCDR3 of the _VL domain comprising the amino acid sequence of SEQ ID NO:302.

In some embodiments, the CDR sequence identified by the IMGT code may include: a) _VH , which includes: 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%), 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. HCDR1 having at least 80% sequence identity with the amino acid sequence of SEQ ID _NO :X ... ii. LCDR1 having at least 80% sequence identity (e.g., at least 85%, at least 90%, or at least 95%) with the amino acid sequence of NO:146; iii. LCDR2 comprising (e.g., composed of) an amino acid sequence of AAS, IAS, or YAS; and iii. LCDR3 having at least 80% sequence identity (e.g., at least 85%, at least 90%, or at least 95%) with the amino acid sequence of SEQ ID NO:150, wherein the antibody or its antigen-binding fragment comprises 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.

In some embodiments, the antibody or its antigen-binding fragment comprises: a) _VH , which comprises: 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%), 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 comprises: i. HCDR1 having at least 80% sequence identity with the amino acid sequence of SEQ ID NO:X ... 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 comprises: 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%), and b) HCDR3 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%), and b) HCDR3 having at least 80% sequence identity with the amino _acid sequence of SEQ ID NO:X ( ii. LCDR1 having at least 80% sequence identity (e.g., at least 85%, at least 90%, or at least 95%) with the amino acid sequence of NO:146; iii. LCDR2 containing an amino acid sequence of AAS (e.g., composed of it); and iii. LCDR3 having at least 80% sequence identity (e.g., at least 85%, at least 90%, or at least 95%) with the amino acid sequence of SEQ ID NO:150, wherein 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.

In some embodiments, the antibody or its antigen-binding fragment comprises: a) _VH , which comprises: i. _HCDR1 comprising (e.g., composed of) the amino acid sequence of SEQ ID NO:X, ii. HCDR2 comprising (e.g., composed of) the amino acid sequence of SEQ ID NO:72, and iii. HCDR3 comprising (e.g., composed of) the amino acid sequence of SEQ ID NO:79, and b) VL, which comprises: i. LCDR1 comprising (e.g., composed of) the amino acid sequence of SEQ ID NO:146, ii. LCDR2 comprising (e.g., composed of) the amino acid sequence of AAS, IAS, or YAS, and iii. _LCDR3 comprising (e.g., composed of) the amino acid sequence of SEQ ID NO:150, wherein the antibody or its antigen-binding fragment comprises the amino acid sequence of SEQ ID NO:X, and the amino acid sequence of SEQ ID NO:150, wherein the amino acid sequence of SEQ ID NO:X, and the amino acid sequence of SEQ ID NO:146, are: i. _HCDR1 comprising (e.g., composed of) the amino acid sequence of SEQ ID NO:X, and iii. HCDR3 comprising (e.g., composed of) the amino acid sequence of SEQ ID NO:150, and b) HCDR2 comprising (e.g., composed of) the amino acid sequence of SEQ ID NO:X, and iii. HCDR3 comprising (e.g., composed of) the amino acid sequence of SEQ ID NO:X, and b) HCDR3 ... b) HCDR3 comprising (e.g., composed of) the amino acid sequence of SEQ The amino acid sequence of NO:1 has a V _H domain with less than 100% sequence identity and/or a V _L domain with less than 100% sequence identity to the amino acid sequence of SEQ ID NO:140.

In some embodiments, the antibody or its antigen-binding fragment comprises: a) _VH , which comprises: i. _HCDR1 comprising (e.g., composed of) the amino acid sequence of SEQ ID NO:X, ii. HCDR2 comprising (e.g., composed of) the amino acid sequence of SEQ ID NO:72, and iii. HCDR3 comprising (e.g., composed of) the amino acid sequence of SEQ ID NO:79, and b) _VL , which comprises: i. _LCDR1 comprising (e.g., composed of) the amino acid sequence of SEQ ID NO:146, ii. LCDR2 comprising (e.g., composed of) the amino acid sequence of AAS, and iii. LCDR3 comprising (e.g., composed of) the amino acid sequence of SEQ ID NO:150, wherein the antibody or its antigen-binding fragment comprises VH having less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1. _H domain and/or V _L domain having less than 100% sequence identity with the amino acid sequence of SEQ ID NO:140.

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].

In some embodiments, the antibody or its antigen-binding fragment comprises: a) _VH , _which comprises 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 comprises the LCDR1, LCDR2 and LCDR3 amino acid sequences of SEQ ID NO:146, AAS and SEQ ID NO:150, respectively.

In some embodiments, the antibody or its antigen-binding fragment comprises: a) _VH , _which comprises the HCDR1, HCDR2 and HCDR3 amino acid sequences of SEQ ID NO:303, SEQ ID NO:72 and SEQ ID NO:79, respectively, and b) _VL , _which comprises the LCDR1, LCDR2 and LCDR3 amino acid sequences of SEQ ID NO:146, AAS and SEQ ID NO:150, respectively.

In some embodiments, the antibody or its antigen-binding fragment comprises: a) _VH , _which comprises 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 comprises the LCDR1, LCDR2 and LCDR3 amino acid sequences of SEQ ID NO:146, AAS and SEQ ID NO:150, respectively.

In some embodiments, the CDR sequence identified by the Kabat code may include: a) _VH , which includes: 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%), 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%), 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. HCDR1 having at least 80% sequence identity with the amino acid sequence of SEQ ID _NO :X ... The antibody or its antigen-binding fragment comprises an 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%), ii. an 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%), and iii. an 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%), wherein the antibody or its antigen-binding fragment comprises 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.

In some embodiments, the antibody or its antigen-binding fragment comprises: a) _VH , which comprises: i. _HCDR1 comprising (e.g., composed of) the amino acid sequence of SEQ ID NO:X, ii. HCDR2 comprising (e.g., composed of) the amino acid sequence of SEQ ID NO:96, and iii. HCDR3 comprising (e.g., composed of) the amino acid sequence of SEQ ID NO:103, and/or b) _VL , which comprises: i. LCDR1 comprising (e.g., composed of) the amino acid sequence of SEQ ID NO:151, ii. LCDR2 comprising (e.g., composed of) the amino acid sequence of SEQ ID NO:Y, and iii. LCDR3 comprising (e.g., composed of) the amino acid sequence of SEQ ID NO:150, wherein the antibody or its antigen-binding fragment comprises the amino acid sequence of SEQ ID NO:X, and/or b) _VL , which comprises: i. LCDR1 comprising (e.g., composed of) the amino acid sequence of SEQ ID NO:151, ii. LCDR2 comprising (e.g., composed of) the amino acid sequence of SEQ ID NO:Y, and iii. LCDR3 comprising (e.g., composed of) the amino acid sequence of SEQ ID NO:150, wherein the antibody or its antigen-binding fragment comprises the amino acid sequence of SEQ ID NO:X, and b) VL. The amino acid sequence of NO:1 has a V _H domain with less than 100% sequence identity and/or a V _L domain with less than 100% sequence identity to the amino acid sequence of SEQ ID NO:140.

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].

In some embodiments, the antibody or its antigen-binding fragment comprises: a) _VH , _which comprises 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 comprises the LCDR1, LCDR2 and LCDR3 amino acid sequences of SEQ ID NO:151, SEQ ID NO:154 and SEQ ID NO:150, respectively.

In some embodiments, the antibody or its antigen-binding fragment comprises: a) _VH , _which comprises 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 comprises the LCDR1, LCDR2 and LCDR3 amino acid sequences of SEQ ID NO:151, SEQ ID NO:156 and SEQ ID NO:150, respectively.

In some embodiments, the antibody or its antigen-binding fragment comprises: a) _VH , _which comprises 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 comprises the LCDR1, LCDR2 and LCDR3 amino acid sequences of SEQ ID NO:151, SEQ ID NO:307 and SEQ ID NO:150, respectively.

In some embodiments, the antibody or its antigen-binding fragment comprises: a) _VH , _which comprises 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 comprises the LCDR1, LCDR2 and LCDR3 amino acid sequences of SEQ ID NO:151, SEQ ID NO:308 and SEQ ID NO:150, respectively.

In some embodiments, the CDR sequence identified by the Chothia code may include: a) _VH , which includes: 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%), 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. HCDR1 having at least 80% sequence identity with the amino acid sequence of SEQ ID _NO :X ... The antibody or its antigen-binding fragment comprises an 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%), ii. an 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%), and iii. an 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%), wherein the antibody or its antigen-binding fragment comprises 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.

In some embodiments, the antibody or its antigen-binding fragment comprises: a) _VH , which comprises: i. _HCDR1 comprising (e.g., composed of) the amino acid sequence of SEQ ID NO:X, ii. HCDR2 comprising (e.g., composed of) the amino acid sequence of SEQ ID NO:132, and iii. HCDR3 comprising (e.g., composed of) the amino acid sequence of SEQ ID NO:139, and b) _VL , which comprises: i. _LCDR1 comprising (e.g., composed of) the amino acid sequence of SEQ ID NO:151, ii. LCDR2 comprising (e.g., composed of) the amino acid sequence of SEQ ID NO:Y, and iii. LCDR3 comprising (e.g., composed of) the amino acid sequence of SEQ ID NO:150, wherein the antibody or its antigen-binding fragment comprises VH having less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1. _H domain and/or V _L domain having less than 100% sequence identity with the amino acid sequence of SEQ ID NO:140.

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. In some embodiments, X is any one of 305, 306, and 105, and Y is any one of 156, 154, 152, 307, and 308.

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.

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.

Each of paragraphs [0249]-[0251] applies to paragraph [0247] or paragraph [0248].

In some embodiments, the antibody or its antigen-binding fragment comprises: a) _VH , _which comprises 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 comprises the LCDR1, LCDR2 and LCDR3 amino acid sequences of SEQ ID NO:151, SEQ ID NO:154 and SEQ ID NO:150, respectively.

In some embodiments, the antibody or its antigen-binding fragment comprises: a) _VH , _which comprises 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 comprises the LCDR1, LCDR2 and LCDR3 amino acid sequences of SEQ ID NO:151, SEQ ID NO:156 and SEQ ID NO:150, respectively.

In some embodiments, the antibody or its antigen-binding fragment comprises: a) _VH , _which comprises 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 comprises the LCDR1, LCDR2 and LCDR3 amino acid sequences of SEQ ID NO:151, SEQ ID NO:307 and SEQ ID NO:150, respectively.

In some embodiments, the antibody or its antigen-binding fragment comprises: a) _VH , _which comprises 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 comprises the LCDR1, LCDR2 and LCDR3 amino acid sequences of SEQ ID NO:151, SEQ ID NO:308 and SEQ ID NO:150, respectively.

In some embodiments, the antibody or its antigen-binding fragment comprises: a) _VH , _which comprises 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 comprises the LCDR1, LCDR2 and LCDR3 amino acid sequences of SEQ ID NO:151, SEQ ID NO:152 and SEQ ID NO:150, respectively.

In some embodiments, the antibody or its antigen-binding fragment comprises: a) _VH , _which comprises 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 comprises the LCDR1, LCDR2 and LCDR3 amino acid sequences of SEQ ID NO:151, SEQ ID NO:152 and SEQ ID NO:150, respectively.

In some embodiments, the antibody or its antigen-binding fragment comprises: a) _VH , _which comprises 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 comprises the LCDR1, LCDR2 and LCDR3 amino acid sequences of SEQ ID NO:151, SEQ ID NO:152 and SEQ ID NO:150, respectively.

In some embodiments, the antibody or its antigen-binding fragment comprises: a) _VH , _which comprises 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 comprises the LCDR1, LCDR2 and LCDR3 amino acid sequences of SEQ ID NO:151, SEQ ID NO:156 and SEQ ID NO:150, respectively.

In some embodiments, the _VH / _VL framework region comprises: a) four _VH framework regions ( _VH FR1-4) and three heavy chain complementarity-determining regions (HCDR1-3), in the following _N -terminal to C-terminal order: _VH FR1-HCDR1- _VH FR2-HCDR2- _VH FR3-HCDR3- _VH FR4, wherein: 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 NSLK (SEQ ID NO:271), PSLR (SEQ ID NO:272), or NDLR (SEQ ID NO:270). The amino acid sequence of NO:273), or any combination of i) to iii), and b) the _VL domains of the four _VL framework regions ( _VL FR1-4) and the three heavy chain complementarity determining regions (LCDR1-3), in the following N-terminal to C-terminal order: _VL FR1-LCDR1- _VL FR2-LCDR2- _VL FR3-LCDR3- _VL FR4, wherein the _VL FR2-HCDR2 contains the amino acid sequence of SLQS, SLQE, DLQR, SQQR or SEQR, wherein, where the _VL 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.

In some embodiments, the antibody or its antigen-binding fragment comprises: a) _VHFR1 -HCDR1 comprising the amino acid sequence of SEQ ID NO:X, and i. _VHFR2 comprising the amino acid sequence of GKGL (SEQ ID NO:268), GDYL (SEQ ID NO:269), or GYYL (SEQ ID NO:270), and/or ii. _VHFR3 comprising the amino acid sequence of NSLK (SEQ ID NO:271), PSLR (SEQ ID NO:272), or NDLR (SEQ ID NO:273), and/or b) _VLFR2 -HCDR2 comprising the amino acid sequence of DLQR, wherein 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.

In some embodiments, the antibody or its antigen-binding fragment comprises: a) _VHFR1 -HCDR1 comprising the amino acid sequence of SEQ ID NO:X, and i. _VHFR2 comprising the amino acid sequence of GKGL (SEQ ID NO:268), GDYL (SEQ ID NO:269), or GYYL (SEQ ID NO:270), and/or ii. _VHFR3 comprising the amino acid sequence of NSLK (SEQ ID NO:271), PSLR (SEQ ID NO:272), or NDLR (SEQ ID NO:273), and/or b) _VLFR2 -HCDR2 comprising the amino acid sequence of SQQR, wherein 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.

In some embodiments, the antibody or its antigen-binding fragment comprises: a) _VH FR2 comprising an 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 comprising an amino acid sequence of SEQ ID NO:X, and/or ii. _VH FR3 comprising 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 comprising an amino acid sequence of DLQR, wherein 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.

In some embodiments, the antibody or its antigen-binding fragment comprises: a) _VH FR2 comprising an 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 comprising an amino acid sequence of SEQ ID NO:X, and/or ii. _VH FR3 comprising 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 comprising an amino acid sequence of SQQR, wherein, where 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.

In some embodiments, the antibody or its antigen-binding fragment comprises: a) _VH FR2 comprising the amino acid sequence of GKGL (SEQ ID NO:268), and i. _VH FR1-HCDR1 comprising the amino acid sequence of SEQ ID NO:X, and/or ii. _VH FR3 comprising the 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 comprising the amino acid sequence of DLQR, wherein 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.

In some embodiments, the antibody or its antigen-binding fragment comprises: a) _VH FR2 comprising the amino acid sequence of GKGL (SEQ ID NO:268), and i. _VH FR1-HCDR1 comprising the amino acid sequence of SEQ ID NO:X, and/or ii. _VH FR3 comprising the 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 comprising the amino acid sequence of SQQR, wherein, where 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.

In some embodiments, the antibody or its antigen-binding fragment comprises: a) _VH FR2 comprising the amino acid sequence of GDYL (SEQ ID NO:269), and i. _VH FR1-HCDR1 comprising the amino acid sequence of SEQ ID NO:X, and/or ii. _VH FR3 comprising the 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 comprising the amino acid sequence of DLQR, wherein 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.

In some embodiments, the antibody or its antigen-binding fragment comprises: a) _VH FR2 comprising the amino acid sequence of GDYL (SEQ ID NO:269), and i. _VH FR1-HCDR1 comprising the amino acid sequence of SEQ ID NO:X, and/or ii. _VH FR3 comprising the 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 comprising the amino acid sequence of SQQR, wherein, where 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.

In some embodiments, the antibody or its antigen-binding fragment comprises: a) _VH FR2 comprising the amino acid sequence of GYYL (SEQ ID NO:270), and i. _VH FR1-HCDR1 comprising the amino acid sequence of SEQ ID NO:X, and/or ii. _VH FR3 comprising the 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 comprising the amino acid sequence of DLQR, wherein 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.

In some embodiments, the antibody or its antigen-binding fragment comprises: a) _VH FR2 comprising the amino acid sequence of GYYL (SEQ ID NO:270), and i. _VH FR1-HCDR1 comprising the amino acid sequence of SEQ ID NO:X, and/or ii. _VH FR3 comprising the 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 comprising the amino acid sequence of SQQR, wherein 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.

In some embodiments, the antibody or its antigen-binding fragment comprises: a) _VHFR3 comprising an amino acid sequence of NSLK (SEQ ID NO:271), PSLR (SEQ ID NO:272), or NDLR (SEQ ID NO:273), and i. _VHFR1 -HCDR1 comprising an amino acid sequence of SEQ ID NO:X, and/or ii. _VHFR2 comprising an amino acid sequence of GKGL (SEQ ID NO:268), GDYL (SEQ ID NO:269), or GYYL (SEQ ID NO:270), and/or b) _VLFR2 -HCDR2 comprising an amino acid sequence of DLQR, wherein 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.

In some embodiments, the antibody or its antigen-binding fragment comprises: a) _VHFR3 comprising an amino acid sequence of NSLK (SEQ ID NO:271), PSLR (SEQ ID NO:272), or NDLR (SEQ ID NO:273), and i. _VHFR1 -HCDR1 comprising an amino acid sequence of SEQ ID NO:X, and/or ii. _VHFR2 comprising an amino acid sequence of GKGL (SEQ ID NO:268), GDYL (SEQ ID NO:269), or GYYL (SEQ ID NO:270), and/or b) _VLFR2 -HCDR2 comprising an amino acid sequence of SQQR, wherein 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.

In some embodiments, the antibody or its antigen-binding fragment comprises: a) _VH FR3 comprising the amino acid sequence of NSLK (SEQ ID NO:271), and i. _VH FR1-HCDR1 comprising the amino acid sequence of SEQ ID NO:X, and/or ii. _VH FR2 comprising 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 comprising the amino acid sequence of DLQR, wherein 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.

In some embodiments, the antibody or its antigen-binding fragment comprises: a) _VH FR3 comprising the amino acid sequence of NSLK (SEQ ID NO:271), and i. _VH FR1-HCDR1 comprising the amino acid sequence of SEQ ID NO:X, and/or ii. _VH FR2 comprising 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 comprising the amino acid sequence of SQQR, wherein 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.

In some embodiments, the antibody or its antigen-binding fragment comprises: a) _VHFR3 comprising the amino acid sequence of PSLR (SEQ ID NO:272), and i. _VHFR1 -HCDR1 comprising the amino acid sequence of SEQ ID NO:X, and/or ii. _VHFR2 comprising the amino acid sequence of GKGL (SEQ ID NO:268), GDYL (SEQ ID NO:269) or GYYL (SEQ ID NO:270), and/or b) _VLFR2 -HCDR2 comprising the amino acid sequence of DLQR, wherein 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.

In some embodiments, the antibody or its antigen-binding fragment comprises: a) _VH FR3 comprising the amino acid sequence of PSLR (SEQ ID NO:272), and i. _VH FR1-HCDR1 comprising the amino acid sequence of SEQ ID NO:X, and/or ii. _VH FR2 comprising 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 comprising the amino acid sequence of SQQR, wherein 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.

In some embodiments, the antibody or its antigen-binding fragment comprises: a) _VH FR3 comprising the amino acid sequence of NDLR (SEQ ID NO:273), and i. _VH FR1-HCDR1 comprising the amino acid sequence of SEQ ID NO:X, and/or ii. _VH FR2 comprising 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 comprising the amino acid sequence of DLQR, wherein 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.

In some embodiments, the antibody or its antigen-binding fragment comprises: a) _VH FR3 comprising the amino acid sequence of NDLR (SEQ ID NO:273), and i. _VH FR1-HCDR1 comprising the amino acid sequence of SEQ ID NO:X, and/or ii. _VH FR2 comprising 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 comprising the amino acid sequence of SQQR, wherein 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.

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.

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), wherein the antibody or its antigen-binding fragment comprises 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.

In some embodiments, the antibody or its antigen-binding fragment comprises: a) a _VH domain with at least one amino acid substituted relative to the amino acid sequence of SEQ ID NO:X, and b) a _VL domain with at least one amino acid substituted relative to the amino acid sequence of SEQ ID NO:Y, wherein the antibody or its antigen-binding fragment comprises 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.

For example, the number of amino acid substitutions can 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) a V _H with about 1-10 amino acid substitutions relative to the amino acid sequence of SEQ ID NO:X, and b) a V _L with 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 conservative substitution.

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

In some embodiments, the antibody or its antigen-binding fragment comprises: a) a V _H having 100% sequence identity with the amino acid sequence of SEQ ID NO:X, and/or b) a V _L having 100% sequence identity with the amino acid sequence of SEQ ID NO:Y.

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 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.

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.

Each of paragraphs [0288]-[0290] applies to any of paragraphs [0281]-[0287].

In some embodiments, the antibody or its antigen-binding fragment comprises: a) a V _H having 100% sequence identity with the amino acid sequence of SEQ ID NO:4, and b) a V _L having 100% sequence identity with the amino acid sequence of SEQ ID NO:140.

In some embodiments, the antibody or its antigen-binding fragment comprises: a) a V _H having 100% sequence identity with the amino acid sequence of SEQ ID NO:299, and b) a V _L having 100% sequence identity with the amino acid sequence of SEQ ID NO:140.

In some embodiments, the antibody or its antigen-binding fragment comprises: a) a V _H having 100% sequence identity with the amino acid sequence of SEQ ID NO:300, and b) a V _L having 100% sequence identity with the amino acid sequence of SEQ ID NO:140.

In some embodiments, the antibody or its antigen-binding fragment comprises: a) a V _H having 100% sequence identity with the amino acid sequence of SEQ ID NO:1, and b) a V _L having 100% sequence identity with the amino acid sequence of SEQ ID NO:142.

In some embodiments, the antibody or its antigen-binding fragment comprises: a) a V _H having 100% sequence identity with the amino acid sequence of SEQ ID NO:1, and b) a V _L having 100% sequence identity with the amino acid sequence of SEQ ID NO:144.

In some embodiments, the antibody or its antigen-binding fragment comprises: a) a V _H having 100% sequence identity with the amino acid sequence of SEQ ID NO:1, and b) a V _L having 100% sequence identity with the amino acid sequence of SEQ ID NO:301.

In some embodiments, the antibody or its antigen-binding fragment comprises: a) a V _H having 100% sequence identity with the amino acid sequence of SEQ ID NO:1, and b) a V _L having 100% sequence identity with the amino acid sequence of SEQ ID NO:302.

In some embodiments, the antibody or its antigen-binding fragment comprises: a) a V _H having 100% sequence identity with the amino acid sequence of SEQ ID NO:2, and b) a V _L having 100% sequence identity with the amino acid sequence of SEQ ID NO:144.

In some embodiments, the antibody or its antigen-binding fragment comprises: a) a V _H having 100% sequence identity with the amino acid sequence of SEQ ID NO:3, and b) a V _L having 100% sequence identity with the amino acid sequence of SEQ ID NO:144.

In some embodiments, the heavy chain / light chain of an antibody or its antigen-binding fragment includes a constant domain sequence of the antibody heavy chain and/or a constant domain sequence of the antibody light chain.

Heavy Chain Constant Domain In some embodiments, the antibody or its antigen-binding fragment contains an immunoglobulin heavy chain constant domain sequence.

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

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

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

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).

In some embodiments, the antibody or its antigen-binding fragment comprises an amino acid sequence corresponding to SEQ ID NO:279 and/or SEQ ID NO:280 (e.g., SEQ ID NO:279) containing at least one amino acid-substituted immunoglobulin heavy chain constant domain sequence. 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.

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

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

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 a light chain. Non-limiting examples of heavy-chain antibodies include Camelidae Vhh (also known as VHH or V _HH ) antibodies. Camelidae antibodies are antibodies derived from the Camelidae family of mammals, including camels, alpacas, and camels.

Light Chain Constant Domain In some embodiments, the antibody or its antigen-binding fragment contains an immunoglobulin light chain constant domain sequence.

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

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

In some embodiments, the antibody or its antigen-binding fragment includes 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 include 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).

In some embodiments, the antibody or its antigen-binding fragment comprises an amino acid sequence corresponding to SEQ ID NO:281 and/or SEQ ID NO:282 (e.g., SEQ ID NO:282) containing at least one amino acid-substituted immunoglobulin light chain constant domain sequence. 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.

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

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

In some embodiments, the antibody or its antigen-binding fragment comprises: a) a heavy chain having at least 60% sequence identity with the amino acid sequence of SEQ ID NO:X (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), 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), wherein the antibody or its antigen-binding fragment comprises 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.

In some embodiments, the antibody or its antigen-binding fragment comprises: a) a heavy chain with at least one amino acid substituted relative to the amino acid sequence of SEQ ID NO:X, and/or b) a light chain with at least one amino acid substituted relative to the amino acid sequence of SEQ ID NO:Y, wherein the antibody or its antigen-binding fragment comprises 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.

For example, the number of amino acid substitutions can 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.

For example, the number of amino acid substitutions can 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) a heavy chain with about 1-10 amino acid substitutions relative to the amino acid sequence of SEQ ID NO:X, and b) a light chain with 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 conservative substitution.

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

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 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) a heavy chain having 100% sequence identity with the amino acid sequence of SEQ ID NO:X, and b) a light chain having 100% sequence identity with the amino acid sequence of SEQ ID NO:Y.

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.

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.

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.

Each of paragraphs [0327]-[0329] applies to any one of paragraphs [0318]-[0326].

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:163, and b) a light chain having 100% sequence identity with the amino acid sequence of SEQ ID NO:203.

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:311, and b) a light chain having 100% sequence identity with the amino acid sequence of SEQ ID NO:203.

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:312, and b) a light chain having 100% sequence identity with the amino acid sequence of SEQ ID NO:203.

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:160, and b) a light chain having 100% sequence identity with the amino acid sequence of SEQ ID NO:205.

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:160, and b) a light chain having 100% sequence identity with the amino acid sequence of SEQ ID NO:207.

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:160, and b) a light chain having 100% sequence identity with the amino acid sequence of SEQ ID NO:313.

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:160, and b) a light chain having 100% sequence identity with the amino acid sequence of SEQ ID NO:314.

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:161, and b) a light chain having 100% sequence identity with the amino acid sequence of SEQ ID NO:207.

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:162, and b) a light chain having 100% sequence identity with the amino acid sequence of SEQ ID NO:207.

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

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

In some embodiments, the antibody or its antigen-binding fragment includes a _VH domain disclosed herein, which is linked to the _VL domain herein by an scFv linker.

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), wherein the _VH domain is connected to the _VL domain by an scFv _linker , and wherein 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.

In some embodiments, the antibody or its antigen-binding fragment comprises: a) an amino acid sequence relative to SEQ ID NO:X comprising at least one amino acid-substituted _VH , and b) an amino acid sequence relative to SEQ ID NO:Y comprising at least one amino acid-substituted _VL , wherein the _VH domain is connected to the _VL domain by an scFv linker, and wherein 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.

In some embodiments, the antibody or its antigen-binding fragment comprises: a) a _VH having 100% sequence identity with the amino acid sequence of SEQ ID NO:X, and b) a _VL having 100% sequence identity with the amino acid sequence of SEQ ID NO:Y, wherein the _VH domain is connected to the _VL domain by an scFv linker.

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 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.

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.

Each of paragraphs [0346]-[0348] applies to any one of paragraphs [0343]-[0345].

In some embodiments, the antibody or its antigen-binding fragment comprises: a) a _VH having 100% sequence identity with the amino acid sequence of SEQ ID NO:4, and b) a _VL having 100% sequence identity with the amino acid sequence of SEQ ID NO:140, wherein the _VH domain is connected to the _VL domain by an scFv linker.

In some embodiments, the antibody or its antigen-binding fragment comprises: a) a _VH having 100% sequence identity with the amino acid sequence of SEQ ID NO:299, and b) a _VL having 100% sequence identity with the amino acid sequence of SEQ ID NO:140, wherein the _VH domain is connected to the _VL domain by an scFv linker.

In some embodiments, the antibody or its antigen-binding fragment comprises: a) a _VH having 100% sequence identity with the amino acid sequence of SEQ ID NO:300, and b) a _VL having 100% sequence identity with the amino acid sequence of SEQ ID NO:140, wherein the _VH domain is connected to the _VL domain by an scFv linker.

In some embodiments, the antibody or its antigen-binding fragment comprises: a) a _VH having 100% sequence identity with the amino acid sequence of SEQ ID NO:1, and b) a _VL having 100% sequence identity with the amino acid sequence of SEQ ID NO:142, wherein the _VH domain is connected to the _VL domain by an scFv linker.

In some embodiments, the antibody or its antigen-binding fragment comprises: a) a _VH having 100% sequence identity with the amino acid sequence of SEQ ID NO:1, and b) a _VL having 100% sequence identity with the amino acid sequence of SEQ ID NO:144, wherein the _VH domain is connected to the _VL domain by an scFv linker.

In some embodiments, the antibody or its antigen-binding fragment comprises: a) a _VH having 100% sequence identity with the amino acid sequence of SEQ ID NO:1, and b) a _VL having 100% sequence identity with the amino acid sequence of SEQ ID NO:301, wherein the _VH domain is connected to the _VL domain by an scFv linker.

In some embodiments, the antibody or its antigen-binding fragment comprises: a) a _VH having 100% sequence identity with the amino acid sequence of SEQ ID NO:1, and b) a _VL having 100% sequence identity with the amino acid sequence of SEQ ID NO:302, wherein the _VH domain is connected to the _VL domain by an scFv linker.

In some embodiments, the antibody or its antigen-binding fragment comprises: a) a _VH having 100% sequence identity with the amino acid sequence of SEQ ID NO:2, and b) a _VL having 100% sequence identity with the amino acid sequence of SEQ ID NO:144, wherein the _VH domain is connected to the _VL domain by an scFv linker.

In some embodiments, the antibody or its antigen-binding fragment comprises: a) a _VH having 100% sequence identity with the amino acid sequence of SEQ ID NO:3, and b) a _VL having 100% sequence identity with the amino acid sequence of SEQ ID NO:144, wherein the _VH domain is connected to the _VL domain by an scFv linker.

In some embodiments, the scFv linker comprises the amino acid sequence of SEQ ID NO:257 (e.g., composed of it). In some embodiments, the scFv linker comprises the amino acid sequence of SEQ ID NO:258 (e.g., composed of it). 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., composed of it). See, for example, Tang et al., Selection of linkers for a catalytic single-chain antibody using phage display technology , J Biol Chem. 271(26):15682-86 (1996), the contents of which are incorporated herein by reference in their entirety.

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), and the _VL domain disclosed herein (e.g., having the amino acid sequence of SEQ ID NO:144 or SEQ ID NO:142).

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).

In some embodiments, the antibody or its antigen-binding fragment includes 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 variable sequences 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 includes YTE modification. The YTE modification corresponding to M135Y/S137T/T139E of SEQ ID NO: 279 or SEQ ID NO: 280 has also been replaced by M252Y/S254T/T256E as determined by Kabat designation. In some embodiments, the Fc structural field includes the LS modification. The LS modification corresponds to M311L/N317S of SEQ ID NO: 279 or SEQ ID NO: 280.

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 includes an Fc. In some embodiments, the bispecific antibody or its antigen-binding fragment does not include an Fc. Non-limiting example structures of bispecific antibodies or their antigen-binding fragments include bispecific IgG, monospecific IgG with an additional antigen-binding portion, bispecific antibody fragments, bispecific fusion proteins, and bispecific antibody complexes. 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.

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

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.

In some embodiments, the antibody or its antigen-binding fragment is generated by recombination. In some embodiments, the antibody or its antigen-binding fragment is generated by synthesis.

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

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.

In addition, this disclosure also provides fusion proteins comprising one or more polypeptides disclosed herein.

In some embodiments, fusion proteins are recombinated or synthesized using conventional methods and reagents well known in this art. For example, fusion proteins can be recombinated in suitable host cells (e.g., bacteria) according to methods known in this 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 the nucleotide sequence encoding the fusion protein 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., photoresponsive domains, heteropeptide components) can be joined together in a frame using known techniques. In another embodiment, fusion genes can be synthesized using known techniques including automated DNA synthesizers. Alternatively, PCR amplification of nucleic acid fragments can be performed using anchoring primers that generate complementary overhangs between two consecutive nucleic acid fragments, which can then be joined and amplified to produce chimeric nucleic acid sequences (see, for example, Ausubel et al., Current Protocols in Molecular Biology, 1992).

In addition to nucleic acids and vectors , this disclosure also provides one or more polynucleotides (e.g., DNA, RNA, or analogs of either, including, for example, one or more modified nucleotides, as appropriate) encoding any one or more of the 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).

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.

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

In some embodiments, the vector (e.g., a performance vector) further includes a performance control polynucleotide sequence operatively linked to a polynucleotide, and/or a polynucleotide sequence encoding a selective marker. In some embodiments, the performance control polynucleotide sequence includes a promoter sequence and/or an enhancer sequence. In some embodiments, the performance control polynucleotide sequence includes an inducible promoter sequence.

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

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.

Furthermore, 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.

In addition, 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.

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 dosage and concentration used. Non-limiting examples of pharmaceutically acceptable carriers, excipients, stabilizers, diluents, or modifiers include buffers (e.g., L-histamine), 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 counterions (e.g., sodium), metal complexes (e.g., Zn-protein complexes), nonionic surfactants (e.g., Tween), PLURONICS™, and polyethylene glycol (PEG).

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

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

In some embodiments, the combination (e.g., a pharmaceutical combination) is formulated for a suitable timing and route of administration. In some embodiments, the combination (e.g., a pharmaceutical combination) is formulated for administration by infusion (e.g., intravenous infusion). In some embodiments, the combination (e.g., a pharmaceutical combination) is formulated for administration by subcutaneous administration.

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.

In some embodiments, the combination is formulated to be administered in combination therapy with at least one additional treatment agent. In some embodiments, the at least one additional treatment agent includes vedolizumab, adalimumab, methotrexate, infliximab, tofacitinib, or any combination thereof.

In addition, this document also provides a kit including a container and, if applicable, an instruction manual, wherein the container contains any one or more of the compositions disclosed herein (e.g., pharmaceutical compositions).

In addition, this disclosure also provides a method for blocking the binding of a ligand to a receptor expressed thereon on the 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 combination (e.g., a pharmaceutical composition) to block the binding of the ligand to the receptor expressed thereon on the cell surface, wherein the ligand comprises p40.

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 disclosed herein or an antigen-binding fragment thereof, thereby blocking the binding of the ligand to its receptor in the individual, wherein the ligand comprises p40.

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.

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 at least one antibody disclosed herein or an antigen-binding fragment thereof, thereby treating the IL-12/IL-23-related disease.

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.

In some embodiments, IL-12/IL-23-related diseases include plaque psoriasis, psoriatic arthritis, Crohn's disease, ulcerative colitis, alopecia areata, total alopecia, universal alopecia, hidradenitis suppurativa, pityriasis rubra pilaris, lichen planus, psoriatic arthritis, atopic dermatitis, pyoderma gangrenosa, or vitiligo.

In some embodiments, the individual is a mammal. In some embodiments, the individual is a group of mammals selected from 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.

In some implementations, the individual is 6 years of age or older.

In some embodiments, the individual is an adult human 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.

In some embodiments, the individuals were pediatric human patients. In some embodiments, the individuals were 6 to 17 years old. In some embodiments, the individuals were 6 to 11 years old. In some embodiments, the individuals were 12 to 17 years old. In some embodiments, the IL-12/IL-23 associated disease was plaque psoriasis.

In some implementations, the individuals are adults with moderate to severe psoriasis or children aged 6 or older. In some implementations, light therapy is also used to treat individuals.

In some implementations, the individual is an adult with active psoriasis arthritis or a child aged 6 years or older.

In some implementations, individuals are 18 years of age or older and have moderate to severe active Crohn's disease.

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

In some embodiments, at least one antibody or its antigen-binding fragment comprises: 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%) with an amino acid sequence comprising any of the amino acid sequences comprising SEQ ID NO:2-11 and 19-21; and/or a _VL domain comprising VH1, HCDR2, and HCDR3 having at least 80% sequence identity (e.g., at least 85%, at least 90%, or at least 95%) with an amino _acid sequence comprising any of the amino _acid sequences comprising SEQ ID NO:144, SEQ ID NO:142, or SEQ ID NO:140 (e.g., SEQ ID NO:144 or SEQ ID NO:142). LCDR1, LCDR2, and LCDR3 of _{the L-} domain have at least 80% sequence identity (e.g., at least 85%, at least 90%, or at least 95%), wherein the V _-H domain has less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1, and/or the V- _L domain has less than 100% sequence identity with the amino acid sequence of SEQ ID NO:140.

In some embodiments, at least one antibody or its antigen-binding fragment comprises: a _VH domain comprising _HCDR1 , HCDR2, and HCDR3 having 100% sequence identity with HCDR1, HCDR2, and HCDR3 of the _VH domain comprising any of the amino acid sequences comprising SEQ ID NO:2-11 and 19-21, respectively; and/or a _VL domain comprising LCDR1, LCDR2, and LCDR3 of the _VL domain comprising any of the amino acid sequences comprising 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; wherein, if the _VH domain has less than 100% sequence identity with the amino acid sequence of SEQ ID NO: ₁ , and/or the V... The _L -domain has less than 100% sequence identity with the amino acid sequence of SEQ ID NO:140.

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%) with an 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%) with an amino acid sequence of SEQ ID NO:144 or SEQ ID NO:142, wherein 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.

In some embodiments, at least one antibody or its antigen-binding fragment comprises: a) a V _H having 100% sequence identity with the amino acid sequence of any of SEQ ID NO:2-11 and 19-21, and b) a V _L having 100% sequence identity with the amino acid sequence of SEQ ID NO:144 or SEQ ID NO:142.

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%) with an amino acid sequence of at least one of 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%) with an amino acid sequence of SEQ ID NO: ₁₄₄ or SEQ ID NO:142, wherein the _VH domain has less than 100% sequence identity with an amino acid sequence of SEQ ID NO:1 and/or the _VL domain has less than 100% sequence identity with an amino acid sequence of SEQ ID NO:140.

In some embodiments, at least one antibody or its antigen-binding fragment comprises: a) a V _H having 100% sequence identity with the amino acid sequence of any of SEQ ID NO:2-11, and b) a V _L having 100% sequence identity with the amino acid sequence of SEQ ID NO:144 or SEQ ID NO:142.

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 the 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, wherein, whereby, the antibody or its antigen-binding fragment comprises a _VH domain having less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1 and/or a VH domain having less than 100% sequence identity with the amino acid sequence of SEQ ID NO:140. _L- structure domain.

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 sequence of any one 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.

Example 1. An antibody or an antigen-binding fragment thereof, the antibody or antigen-binding fragment comprising: a) an immunoglobulin heavy chain variable ( _VH ) domain, the _VH domain comprising HCDR1, HCDR2, and HCDR3 having 100% sequence identity with the heavy chain complementarity-determining regions (HCDRs) 1, HCDR2, and HCDR3 of the _VH domain comprising any of the amino acid sequences of SEQ ID NO:2-11 and 19-21; and b) an immunoglobulin light chain variable ( _VL ) domain, the VL domain comprising LCDR1, LCDR2, and LCDR3 having 100% sequence identity with the light chain complementarity-determining regions (LCDRs) 1, LCDR2, and LCDR3 of the _VL domain comprising any of the amino acid sequences of SEQ ID NO:144 or SEQ ID NO:142, wherein the VH domain comprises HCDR1, LCDR2, and LCDR3 having 100% sequence identity with the heavy chain complementarity-determining regions (LCDRs) 1, LCDR2, and LCDR3 of the _VL domain comprising any of the amino acid sequences of SEQ ID NO:144 or SEQ ID NO:142. The _H domain has less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1, and the V _L domain has less than 100% sequence identity with the amino acid sequence of SEQ ID NO:140, or both. 2. An antibody or antigen-binding fragment thereof as 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 comprises the amino acid sequence 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 comprises GKGL (SEQ ID NO:268), GDYL (SEQ ID NO:267), or GKGL (SEQ ID NO:268), or GDYL (SEQ ID NO:267), or GKGL (SEQ ID NO:268), or GKGL (SEQ ID NO:269), or GKGL (SEQ ID NO:260 ...0), or GKGL (SEQ ID NO:260), or GKGL (SEQ ID NO:260), or GKGL (SEQ ID NO:260), or GKGL (SEQ ID _NO :260), or GKGL (SEQ ID 3. An antibody or antigen-binding fragment thereof as described in Example 1 or 2, wherein: HCDR1 contains an amino acid sequence of SEQ ID NO:269 or GYYL (SEQ ID NO:270); or c) the V _H FR3 contains an amino acid sequence of NSLK (SEQ ID NO:271), PSLR (SEQ ID NO:272), or NDLR (SEQ ID NO:273); or any combination thereof. 4. An antibody or antigen-binding fragment thereof as described in any of Examples 1 to 3, wherein: HCDR1 contains an 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; HCDR2 contains an amino acid sequence of SEQ ID NO:72; and HCDR3 contains an amino acid sequence of SEQ ID NO:79. 5. An antibody or antigen-binding fragment thereof as described in any of Examples 1 to 3, wherein HCDR1 contains an amino acid sequence of SEQ ID NO:45. 5. An antibody or antigen-binding fragment thereof of any one of Examples 1 to 3, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:46. 6. An antibody or antigen-binding fragment thereof of any one of Examples 1 to 3, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:47. 7. An antibody or antigen-binding fragment thereof of any one of Examples 1 to 3, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:49. 8. An antibody or antigen-binding fragment thereof of any one of Examples 1 to 3, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:50. 9. An antibody or antigen-binding fragment thereof of any one of Examples 1 to 3, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:51. 10. An antibody or antigen-binding fragment thereof as described in any of Examples 1 to 9, wherein: LCDR1 contains the amino acid sequence of SEQ ID NO: 146; LCDR2 contains the amino acid sequence of AAS; and LCDR3 contains the amino acid sequence of SEQ ID NO: 150. 11. An antibody or antigen-binding fragment thereof as described in Example 1 or 2, wherein: HCDR1 contains the amino acid sequence of SEQ ID NO: 80, SEQ ID NO: 81, or SEQ ID NO: 82; HCDR2 contains the amino acid sequence of SEQ ID NO: 96; and HCDR3 contains the amino acid sequence of SEQ ID NO: 103. 12. An antibody or antigen-binding fragment thereof as described in any of Examples 1, 2, and 11, wherein HCDR1 contains the amino acid sequence of SEQ ID NO: 80. 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. 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. 15. An antibody or antigen-binding fragment thereof as described in any of Examples 1, 2, and 11 to 14, wherein: a) the LCDR1 comprises the amino acid sequence of SEQ ID NO: 151; b) the LCDR2 comprises the amino acid sequence of SEQ ID NO: 156; and c) the LCDR3 comprises the amino acid sequence of SEQ ID NO: 150. 16. An antibody or antigen-binding fragment thereof as described in 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. 17. An antibody or antigen-binding fragment thereof as described in Example 1 or 2, wherein: the HCDR1 contains the amino acid sequences 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. 18. An antibody or antigen-binding fragment thereof of any one of Examples 1, 2, and 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 105. 19. An antibody or antigen-binding fragment thereof of any one of Examples 1, 2, and 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 106. 20. An antibody or antigen-binding fragment thereof of any one of Examples 1, 2, and 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 107. 21. An antibody or antigen-binding fragment thereof of any one of Examples 1, 2, and 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 109. 22. An antibody or antigen-binding fragment thereof of any one of Examples 1, 2, and 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 110. 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. 24. An antibody or antigen-binding fragment thereof as described in any of Examples 1, 2, and 17 to 23, wherein: a) the LCDR1 comprises the amino acid sequence of SEQ ID NO: 151; b) the LCDR2 comprises the amino acid sequence of SEQ ID NO: 156; and c) the LCDR3 comprises the amino acid sequence of SEQ ID NO: 150. 25. An antibody or antigen-binding fragment thereof as described in any of Examples 1, 2, and 17 to 23, wherein: a) the LCDR1 comprises the amino acid sequence of SEQ ID NO: 151; b) the LCDR2 comprises the amino acid sequence of SEQ ID NO: 154; and c) the LCDR3 comprises the amino acid sequence of SEQ ID NO: 150. 26. An antibody or antigen-binding fragment thereof of any one 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. 27. An antibody or antigen-binding fragment thereof of any one of Examples 1 to 25, wherein the _VH domain comprises the amino acid sequence of SEQ ID NO:2. 28. An antibody or antigen-binding fragment thereof of any one of Examples 1 to 25, wherein the _VH domain comprises the amino acid sequence of SEQ ID NO:3. 29. An antibody or antigen-binding fragment thereof of any one of Examples 1 to 25, wherein the _VH domain comprises the amino acid sequence of SEQ ID NO:4. 30. An antibody or antigen-binding fragment thereof of any one of Examples 1 to 25, wherein the _VH domain comprises the amino acid sequence of SEQ ID NO:5. 31. An antibody or antigen-binding fragment thereof of any one of Embodiments 1 to 25, wherein the _VH domain comprises the amino acid sequence of SEQ ID NO:6. 32. An antibody or antigen-binding fragment thereof of any one of Embodiments 1 to 25, wherein the _VH domain comprises the amino acid sequence of SEQ ID NO:7. 33. An antibody or antigen-binding fragment thereof of any one of Embodiments 1 to 25, wherein the _VH domain comprises the amino acid sequence of SEQ ID NO:8. 34. An antibody or antigen-binding fragment thereof of any one of Embodiments 1 to 25, wherein the _VH domain comprises the amino acid sequence of SEQ ID NO:9. 35. An antibody or antigen-binding fragment thereof of any one of Embodiments 1 to 25, wherein the _VH domain comprises the amino acid sequence of SEQ ID NO:10. 36. An antibody or antigen-binding fragment thereof of any one of Examples 1 to 25, wherein the _VH domain comprises the amino acid sequence of SEQ ID NO:11. 37. An antibody or antigen-binding fragment thereof of any one of Examples 1 to 25, wherein the _VH domain comprises the amino acid sequence of SEQ ID NO:19. 38. An antibody or antigen-binding fragment thereof of any one of Examples 1 to 25, wherein the _VH domain comprises the amino acid sequence of SEQ ID NO:20. 39. An antibody or antigen-binding fragment thereof of any one of Examples 1 to 25, wherein the _VH domain comprises the amino acid sequence of SEQ ID NO:21. 40. An antibody or antigen-binding fragment thereof of any one of Examples 2 to 39, wherein the _VL domain comprises the amino acid sequence of SEQ ID NO:144 or SEQ ID NO:142. 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. 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. 43. An antibody or antigen-binding fragment thereof 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. 44. An antibody or antigen-binding fragment thereof 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. 45. An antibody or 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 heavy domain ( _VHH ), an antigen-binding fragment (Fab), Fab', or F(ab') ₂ . 46. An antibody or antigen-binding fragment thereof as described in any of Examples 1 to 44, comprising an antibody heavy chain constant domain, an antibody light chain constant domain, or both. 47. An antibody or antigen-binding fragment thereof as in Example 46, wherein the antibody heavy chain constant domain is a constant domain of IgG1, IgG2, IgG3, or IgG4. 48. An antibody or antigen-binding fragment thereof as in Example 47, wherein the antibody heavy chain constant domain includes one or more mutations that increase the serum half-life of the antibody or antigen-binding fragment thereof in humans. 49. An antibody or antigen-binding fragment thereof as in Example 47, wherein, relative to the wild-type human IgG constant domain, the antibody heavy chain constant domain includes amino acid substitutions at amino acid residues 252, 254, and 256, respectively, using tyrosine, threonine, and glutamic acid, wherein these amino acid residues are numbered according to the EU index in Kabat. 50. An antibody or antigen-binding fragment thereof of any one 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. 51. An antibody or antigen-binding fragment thereof of any one of Examples 1 to 50, wherein the antibody or antigen-binding fragment comprises a light chain containing an amino acid sequence of SEQ ID NO: 207 or SEQ ID NO: 205. 52. An antibody or antigen-binding fragment thereof of any one of Examples 1 to 49, wherein the antibody is a multispecific antibody. 53. An antibody or antigen-binding fragment thereof of any one of Examples 1 to 52, wherein the antibody or antigen-binding fragment thereof binds both interleukin-12 (IL-12) and interleukin-23 (IL-23). 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 of Examples 1 to 53. 55. A performance vector comprising a polynucleotide as described in Example 54. 56. An RNA encoding 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. 57. A host cell comprising a polynucleotide as described in Example 54, a performance vector as described in Example 55, or RNA as described in Example 56. 58. A method for generating an antibody or antigen-binding fragment thereof as described in any one of Examples 1 to 53, the method comprising expressing the antibody or antigen-binding fragment thereof in a host cell as described in Example 57 and isolating the expressed antibody or antigen-binding fragment thereof. 59. A pharmaceutical composition comprising 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, RNA as described in Example 56 or a host cell as described in Example 57, and a pharmaceutically acceptable loading agent or diluent. 60. A kit comprising the pharmaceutical composition as described in Example 59. 61. A method for blocking the binding of a ligand to its 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 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 its receptor expressed on the cell surface, wherein the ligand comprises p40. 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 antigen-binding fragment thereof as described in any 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. 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 antigen-binding fragment thereof as described in any of Examples 1 to 53, or a pharmaceutical composition as described in Example 59, thereby treating the IL-12/IL-23-related disease. 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, total alopecia, universal alopecia, hidradenitis suppurativa, pityriasis rubra pilaris, lichen planus, pemphigoid, atopic dermatitis, pustular dermatitis, or vitiligo. 65. The method of embodiment 63 or 64, wherein the IL-12/IL-23 related disease is plaque psoriasis, psoriatic arthritis, Crohn's disease, or ulcerative colitis. 66. The method of any one of embodiments 63 to 65, wherein the individual is an adult human patient. 67. The method of any one of embodiments 63 to 65, wherein the individual is a pediatric human patient. 68. The method of embodiment 67, wherein the IL-12/IL-23 related disease is plaque psoriasis. 69. The method of any one of embodiments 63 to 68, further comprising administering at least one additional treatment. 70. The method of embodiment 69, wherein the at least one additional treatment is vedolizumab, adalimumab, methotrexate, infliximab, tofacitinib, or any combination thereof.

Example 1. Computer-simulated affinity maturation and computer-simulated deimmunization. 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 IL-12 and IL-23 from binding to their respective receptors.

There is a possibility of creating "biomodified" molecules. For example, ustekinumab has been shown to induce drug-neutralizing antibodies in 5-12% of patients, therefore 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 a delivery advantage.

Computer-simulated affinity maturation was performed using a protein modeling application within the Molecular Manipulation 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. Deletion residues were computationally filled, and the entire complex was computationally protonated and optimized before being used as the structure for computer-simulated mutagenesis.

Computer-simulated mutagenesis was performed using the residue scanning function in the 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, aspartic acid, glutamic acid, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, serine, phenylalanine, proline, threonine, tyrosine, volamine, or tryptophan. Approximately 200,000 mutants were sampled, and changes in affinity and stability were calculated. Variants to be constructed and further tested were pre-selected based on the modified affinity and stability. We tested preselected variants for 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). Over 500 variants were identified with 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 experiments to configure desired molecular characteristics.

Example 2A. Construction of Insert Vectors and First-Round DNA Assembly of the U Variant . Insert vectors _VH and _VL were constructed by modifying the pcDNA3.4 plasmonic backbone (Invitrogen, Waltham, MA). The selection strategy involved creating independent heavy and light chain plasmonic structures of ustekinumab with specific restriction enzyme sites flanking 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 genes of the U antibody were synthesized by gBlocks HiFi (Integrated DNA Technologies, Inc., Coralville, IA). The V gene variant DNA fragment was also synthesized using gBlocks, containing 20 nucleotide protrusions on either side of the insertion vector. 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. The V gene fragment of the U variant was also selected and inserted into insertion plasmids containing linearized heavy and light chains using specific restriction enzymes using DNA HiFi assembly, followed by bacterial transformation and strain sequencing.

Ustekinumab heavy chain fragment (SEQ ID NO:209). Ustekinumab light chain fragment (SEQ ID NO:210). DNA sequence 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).

Example 2B. First-round variant cell transfection and ELISA: The Invitrogen ExpiCHO-S cell expression system (24-well configuration) was used for antibody production according to the user manual. In short, DNA (with a 1:1 ratio of the variant's heavy chain to the ustekinumab light chain) was mixed with ExpiFectamine and added to the expiCHO-S cell culture. Transfection enhancer and ExpiCHO cell feed were then added after 20 hours. The cell culture supernatant from 5 days post-transfection was diluted 1:500 in buffer for IgG and IL-12 ELISA, used to assess IgG production (protein expression level) and IL-12 binding affinity, respectively. Ustekinumab was initially diluted 3-fold at a concentration of 300 ng/mL and used as a reference for IgG production and IL-12 binding affinity.

For the IL-12 ELISA, 25 μL of IL-12 (PeproTech, Rocky Hill, NJ) diluted at 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 at room temperature for 1 hour. After three PBST washes, 25 μL of diluted supernatant of the antibody variant was added to the wells and incubated at room temperature for 2 hours, followed by three PBST washes. The detection antibody (AffiniPure goat anti-human IgG peroxidase F(ab') ₂ fragment, Fcγ fragment specific; Jackson Immuno Research, West Grove, PA) was diluted 1:10,000 and added to each well, and incubated at room temperature for 1 hour. 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, and then 25 μL of sulfuric acid was added 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 Immuno Research) was diluted 2 μg/mL in PBS and added to each well of a 96-well half-zone microplate.

Figures 2A-2B show the ELISA analysis of the indicated C and A variants. 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 production), while the A variant showed lower protein expression (Figure 2A). Compared with ustekinumab, C38 showed significantly higher IL-12 binding affinity, C7 and C11 showed slightly higher affinity, C3 showed similar affinity, and the A variant showed lower affinity (Figure 2B).

Example 3A. DNA Assembly of the Second Round U Variant : gBlocks synthesizes a DNA fragment of the second round U variant, which contains 20 nucleotide sequences homologous to the insert vector on both sides. Using DNA HiFi assembly, the heavy and light chain variants are independently colonized into insert plastids linearized with specific restriction enzymes, followed by bacterial transformation and strain sequencing.

The sequence of the second round of V _H variants is: 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), C42 (SEQ ID NO:229), 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: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:229), C54 (SEQ ID NO:225), C52 (SEQ ID NO:229), C53 (SEQ ID NO:229), C54 (SEQ ID NO:225), C55 (SEQ ID NO:226), C54 (SEQ ID NO:227), C55 (SEQ ID NO:228), C56 (SEQ ID NO:229), C57 (SEQ ID NO:239), C54 (SEQ ID The sequences of the V L 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).

Example 3B. Second round of cell transfection and ELISA for VH and _VL variants. As described in Example 2B, the ExpiCHO cell transfection procedure for the antibody variants was followed in a 24-well configuration. _{The VH} and _VL variants were paired with ustekinumab _VL and _VH , respectively. C38 production was scaled up to a 25-mL transfection volume, followed by purification 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 curve was used as a reference to evaluate the IL-12 binding affinity of the antibody variants at corresponding IgG concentrations.

ELISA analysis was performed on antibody variants, each variant comprising: (i) a heavy chain containing the indicated second-round _VH variant and a light chain containing ustekinumab, or (ii) a heavy chain containing ustekinumab and a light chain containing the indicated _VL variant. Compared to antibodies (C38) containing a heavy chain of 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. Of these, C42, C38xC81, C38xC82, C38xC91, C38xC92 and C104 are associated with higher IL-12 binding affinity (Figure 3).

Example 4A. The third round of variant identification identified several mutations associated with the modified IL-12. Twenty-four combined variants were generated by recombining eight _VH variants (C38, C41, C42, C44, C61, C38xC82, C38xC91 and C38xC92) and three _VL variants (C102, C103 and C104).

Example 4B. Cell transfection and ELISA of the third variant : 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 curve of the antibody containing the C38 heavy chain and the ustekinumab light chain was used as a reference to evaluate the IL-12 binding affinity of the antibody variant at the corresponding IgG concentration.

Compared to antibodies containing a heavy chain with C38 and a light chain with ustenumab, the 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).

Example 5A. DNA assembly of the fourth-round variants : Based on the results of the third-round 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 insert vectors, as described in Example 2A, was followed. The DNA sequences of the fourth round V _H variant are: C42xC82 (SEQ ID NO:253), C42xC92 (SEQ ID NO:254), C38xC82xC92 (SEQ ID NO:255) and C42xC82xC92 (SEQ ID NO:256).

Example 5B. Cell transfection and ELISA of the fourth variant : As described in Example 2B, the ExpiCHO cell transfection procedure for the combined variant in a 24-well configuration was followed. 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 curve of the antibody containing the C38 heavy chain and the ustekinumab light chain was used as a reference to evaluate the IL-12 binding affinity of the antibody variant at the corresponding IgG concentration. Compared with antibodies containing a heavy chain with C38 and a light chain with ustenumab, C38xC82xC92xC104 showed better IL-12 binding affinity, while C42xC82xC92xC104, C42xC92xC104 and C38xC82xC92xC102 showed similar IL-12 binding affinity (Figure 5A).

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

Example 5D. After four rounds of characterization tests on the selected antibody variants , the antibody variants C38xC104, C41xC104, C42xC104, C44xC104, C38x82xC104, C38x91xC104, C38x92xC104, C38x82x92xC104, C42x82x92xC104 and C38x92xC102 were selected for antibody production and purification. IgG and IL-12 ELISA and cell activation assays were performed to compare with ustekinumab and an antibody (C38) containing both the heavy chain of C38 and the light chain of ustekinumab.

Figures 6A-6C show the titration curves for IL-12 binding of the ten selected antibody variants. 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 the antibody (C38) containing both the C38 heavy chain and the ustekinumab light chain, C38xC104, C38x82xC104, C38x91xC104, C38x92xC104, and C38x82x92xC104 showed higher IL-12 binding activity.

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

Titration curves for IL-12 binding of six antibody variants were generated. The antibody variants were expressed, purified, and quantified, and titrated with 3-fold consecutive dilutions from 600 ng/mL. IL-12 ELISA was performed to determine the _EC50 value of IL-12 binding by 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 the average of three experiments), and (ii) similar or higher binding affinity compared to an antibody (C38) containing both the heavy chain of C38 and the light chain of ustekinumab (Figures 7A-7C).

Example 6. In vivo pharmacokinetic (PK) study of ustekinumab and its antibody variants . These experiments demonstrate the half-life of ustekinumab and three antibody variants in mice. For each antibody group, three C57BL/6 mice were injected intravenously 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. Continuously diluted ustekinumab was used as a concentration interpolation standard for human IgG.

Serum concentrations of (i) ustekinumab and (ii) the antibody (C38) comprising a heavy chain containing C38 and a light chain of ustekinumab 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 (Figures 8A, 8C, and 8D).

Example 7A. Construction of the expression vector and DNA assembly for scFv generation: Study on the effect of linker peptide sequences on the scFv form of ustekinumab. 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 domain. To construct the expression vector, pcDNA3.4 plastids digested with SacI and EcoRV were used to assemble two scFv DNA fragments, U-scFv-Fc-linker 1A and U-scFv-Fc-linker 1B. DNA fragments containing a prominent 25-nucleotide sequence homologous to the vector were synthesized using gBlocks HiFi (Integrated DNA Technologies) and then colonized into the vector using DNA HiFi assembly (New England Biolabs), followed by bacterial transformation and strain sequencing. The DNA sequences of U-scFv-Fc-linker 1A (SEQ ID NO:260) and U-scFv-Fc-linker 1B (SEQ ID NO:261) are shown.

Example 7B. Protein production and ELISA of ustekinumab scFv with two different linkers . Two forms of ustekinumab-scFv-Fc were expressed using the ExpiCHO cell system. Five days post-transfection, 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 (Fig. 9A), but the form containing linker 1A showed a higher level of expression (Fig. 9B).

Example 8. Cell assay for measuring IL-12 and IL-23 activity: To measure IL-12 activity, HEK cells stably expressing the 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. Six hours later, cells were treated with the IL-12 and antibody premix as follows: the antibody was titrated with a 3-fold serial dilution to obtain 2 times the final concentration 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 antibodies. This premix was incubated at 37°C for 30 minutes to allow for antibody binding and rhIL-12 neutralization. The culture medium was removed from HEK cells and replaced with 100 µL of premixed medium, and the cells were incubated for 18 hours. The culture medium was then removed, and alkaline phosphatase activity was measured by transconjugation of the tetramethylbenzidine-based receptor and absorption at 450 nm or 650 nm.

To measure IL-23 activity, HEK cells stably expressing the IL-23-sensitive alkaline phosphatase reporter gene were cultured in DMEM-based medium. Cells were passaged in CellStripper (Corning) and seeded in 96-well tissue plates at a density of 20,000 cells per well. Six hours later, cells were treated with the IL-23 and antibody premix as follows: the antibody was titrated with a 3-fold serial dilution to obtain 2 times the final concentration 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&D Systems, Inc.) in DMEM growth medium to obtain (i) 6 ng/mL rhIL-23 and (ii) 1,000 ng/mL to 0.3 ng/mL antibodies. This premix was incubated at 37°C for 30 minutes to allow for antibody binding and rhIL-23 neutralization. The culture medium was removed from HEK cells and replaced with 100 µL of premixed medium, and the cells were incubated for 18 hours. The culture medium was then removed, and alkaline phosphatase activity was measured by transconjugation of the tetramethylbenzidine-based receptor and absorption at 450 nm or 650 nm.

Figure 10 evaluates the effect of IgG or scFv-Fc form of ustekinumab on cell-based IL-12 activity. The inhibitory effects on IL-12 receptor binding and induction signaling were measured in both IgG and scFv-Fc forms at doses ranging from 0.3 ng/mL to 1,000 ng/mL. 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.

Figure 11 evaluates 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. 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 induction of signaling. Data points are the mean of two replicates. Compared to ustekinumab, C38 showed an enhanced ability to reduce IL-12 activity, and C11 showed a similar ability to reduce IL-12 activity.

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

Figure 13A assesses the effect of the indicated antibody variants on cell-based IL-12 activity. 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 induction of signaling. Data are the mean of three independent experiments performed monthly at time intervals using different cell passages. Compared to ustekinumab, C38xC91xC104 and C38xC92xC104 showed enhanced ability to reduce IL-12 activity.

Figure 13B summarizes the effects of the indicated antibody variants on cell-based IL-12 activity. In the presence of rhIL-12 treatment (5 ng/mL), a single dose of 100 ng/mL was used to measure the inhibition of IL-12 receptor binding and induction of signaling in purified IgG form of mAb. Mean and standard deviation of six replicates are shown. Compared to ustekinumab, antibodies containing the heavy chain of C38 and the light chain of ustekinumab (C38), C38C91C104, and C38C92C104 showed a statistically significant increase in their ability to reduce IL-12 activity (t-test; p < 0.001).

Figure 13C assesses the effect of the indicated antibody variants on cell-based IL-23 activity. 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 induction of signaling. Data points are the mean of three replicates. Compared to ustekinumab, C38xC91xC104 and C38xC92xC104 showed enhanced ability to reduce IL-23 activity.

Figure 14 shows the cell-based activity of two preferred variants of the scFv form. The variants of the purified scFv form were tested at doses ranging from 0.3 ng/mL to 1,000 ng/mL to measure inhibition of IL-12 receptor binding and induction of signaling. Data are from single replicates of a repeat plate. The variants showed equivalent potency compared to ustekinumab.

Example 9. Binding affinity was measured using biolayer interferometry (BLI) with an Octet instrument to measure the binding affinity of ustekinumab and its variants. The antibody was captured onto an Fc capture biosensor, immersed in a solution containing ligands (rhIL-12 or rhIL-23) for binding, and then immersed in a buffer to measure dissociation. The results are shown in Table 6.

Example 10. In Vivo Pharmacodynamics Determining the in vivo pharmacodynamic neutralization of IL-12 by ustekinumab and its selected variants.

Figure 15A compares the in vivo pharmacodynamic neutralization of IL-12 between C38C91C104 and ustekinumab. Mice (n=3) were administered PBS mordant, 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 was collected at 27, 48, and 72 hours. rhIL-12.Fc in plasma 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).

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

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

All doctrines of patents, public applications, and references cited in this article are incorporated herein by full quotation.

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 patent application.

The foregoing content will become apparent from the more detailed description of the exemplary embodiments below, as illustrated in the accompanying figures, where similar reference characters refer to the same parts in different views. The figures are not necessarily to scale, but are intended to emphasize the illustration of the embodiments.

[Figures 1A-1C] Depict the amino acid sequences of the heavy chain variable ( _VH ) domain. The heavy chain complementarity-determining region (HCDR) amino acid sequences of ustekinumab, as determined by ImMunoGeneTics (IMGT), Kabat, or Chothia designations, are indicated using boxes. Bold letters indicate variable residues in the ustekinumab and example antibodies shown in Figure 1G. [Figures 1D-1F] Depict the amino acid sequences of the light chain variable ( _VL ) domain. The light chain complementarity-determining region (LCDR) amino acid sequences of ustekinumab, as determined by IMGT, Kabat, or Chothia designations, are indicated using boxes. Bold letters indicate variable residues in the ustekinumab and example antibodies shown in Figure 1H. [Figure 1G] Comparison of the amino acid sequences of the _VH domain of ustekinumab and example variants. [Figure 1H] Comparison of the amino acid sequences of the _VL domain of ustekinumab and example variants. [Figures 2A-2B] ELISA analysis of the indicated C and A variants, each variant containing the heavy chain of the indicated first-round _VH variant and the light chain of ustekinumab. Compared to ustekinumab: (i) except for C2, most C variants showed similar protein expression (IgG production), while A variants showed lower protein expression (Fig. 2A); (ii) C38 showed significantly higher IL-12 binding affinity, C7 and C11 showed slightly higher affinity, C3 showed similar affinity, and A variants showed lower affinity (Fig. 2B). [Fig. 3] shows ELISA analysis of the indicated antibody variants, each variant comprising: (i) the heavy chain of the indicated second-round _VH variant and the light chain of ustekinumab, or (ii) the heavy chain of ustekinumab and the light chain of the indicated _VL variant. Compared to antibodies (C38) comprising a heavy chain containing C38 and a light chain containing ustekinumab: (i) when paired with the light chain of ustekinumab, C41, C42, C61, C38xC81, C38xC82, C38xC91, and C38xC92 exhibited similar or higher IL-12 binding affinity, and (ii) when paired with the heavy chain of ustekinumab, C102, C103, C104, and C105 exhibited similar or higher IL-12 binding affinity. Among these, C42, C38xC81, C38xC82, C38xC91, C38xC92, and C104 were associated with higher IL-12 binding affinity. [Figure 4] shows the ELISA analysis of the third-round variants. 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. [Figure 5A] shows the ELISA analysis of the fourth-round variants. Compared to the antibody (C38) containing a heavy chain with C38 and a light chain with ustekinumab, the antibody variant C38xC82xC92xC104 showed higher IL-12 binding affinity, while C42xC82xC92xC104, C42xC92xC104, and C38xC82xC92xC102 showed similar IL-12 binding affinity. [Figure 5B] shows the ELISA analysis of the indicated antibody variants. [Figures 6A-6C] show the ELISA analysis of the indicated antibody variants. 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. C38xC104, C38x82xC104, C38x91xC104, C38x92xC104, and C38x82x92xC104 showed higher IL-12 binding activity compared to the antibody (C38) containing both the heavy chain of C38 and the light chain of ustekinumab. [Figures 7A-7C] show the ELISA analysis of the indicated antibody variants. 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 continuously diluted 3-fold. Ustekinumab and an antibody containing a C38 heavy chain and a ustekinumab light chain (C38) were used as internal references. [Figures 8A-8D] show the pharmacokinetics of ustekinumab and the indicated antibody variant in mice after a single IV dose of 1 mg/kg. Individual values for each mouse were plotted, and the mean linear slope was calculated. [Figures 9A-9B] show the ELISA analysis of two forms of ustekinumab-scFv-Fc. [Figure 10] evaluate the effect of IgG or scFv-Fc form of ustekinumab on cell-based IL-12 activity. [Figure 11] Evaluation of the effects of (i) antibodies (C38) containing a heavy chain of C38 and a light chain of ustekinumab and (ii) antibodies (C11) containing a heavy chain of C11 and a light chain of ustekinumab on cell-based IL-12 activity. [Figure 12] Evaluation of the effects of the indicated antibody variants on cell-based IL-12 activity. [Figure 13A] Evaluation of the effects of the indicated antibody variants on cell-based IL-12 activity. [Figure 13B] Summary of the effects of the indicated antibody variants on cell-based IL-12 activity. 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 their ability to reduce IL-12 activity (t-test; p < 0.001). [Figure 13C] Evaluation of the effect of the indicated antibody variants on cell-based IL-23 activity. [Figure 14] Analysis of the cell-based activity of selected variants of scFv with better mutations. Purified variants of scFv were tested at doses ranging from 0.3 ng/mL to 1000 ng/mL to measure inhibition of IL-12 receptor binding and induction signaling. Data are from single replicates of the replicate plate. The variant showed equivalent potency compared to ustekinumab. [Figure 15A] Evaluation of in vivo pharmacodynamic neutralization of IL-12 in C38C91C104. [Figure 15B] Evaluation of in vivo pharmacodynamic neutralization of IL-12 in C38C92C104.

TW202535933A_113140866_SEQL.xml

Claims (21)

An antibody or antigen-binding fragment thereof, the antibody or antigen-binding fragment comprising: a) an immunoglobulin heavy chain variable ( _VH ) domain, the _VH domain comprising HCDR1, HCDR2, and HCDR3 having 100% sequence identity with the heavy chain complementarity-determining regions (HCDRs) 1, HCDR2, and HCDR3 of the _VH domain comprising any of the amino acid sequences 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, respectively; and b) an immunoglobulin light chain variable ( _VL ) domain, the _VL domain comprising SEQ ID NO:144, SEQ ID NO:142, SEQ ID NO:301, SEQ ID NO:302, and SEQ ID NO:19-21, respectively. The light chain complementary determinant region (LCDR) of the V _L domain of any of the amino acid sequences in NO:140, LCDR1, LCDR2, and LCDR3 having 100% sequence identity, wherein the V _H domain has less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1, and the V _L domain has less than 100% sequence identity with the amino acid sequence of SEQ ID NO:140, or both. The antibody or antigen-binding fragment thereof, as claimed in claim 1, wherein: a) the _VH domain comprises HCDR1, HCDR2, and HCDR3 having 100% sequence identity with HCDR1, HCDR2, and HCDR3 of the _VH domain containing the amino acid sequence of SEQ ID NO:3; and the _VL domain comprises LCDR1, LCDR2, and LCDR3 having 100% sequence identity with LCDR1, LCDR2, and LCDR3 of the _VL domain containing the amino acid sequence of SEQ ID NO:144; b) the _VH domain comprises HCDR1, HCDR2, and HCDR3 having 100% sequence identity with HCDR1, HCDR2, and HCDR3 of the _VH domain containing the amino acid sequence of SEQ ID NO:2; and the _VL domain comprises LCDR1, LCDR2, and LCDR3 of the VH domain containing the amino acid sequence of SEQ ID NO:144; c) The VH domain contains LCDR1, LCDR2, and LCDR3, which have 100% sequence identity with the _VH domain containing the amino acid sequence of SEQ ID NO:4; and the _VL domain contains LCDR1, LCDR2, and LCDR3, which have 100% sequence identity with the _VH domain containing the amino acid sequence of SEQ ID NO:4; and the _VL domain contains LCDR1, LCDR2, and LCDR3, which have 100% sequence identity with the _VL domain containing the amino acid sequence of SEQ ID NO:140; d) The _VH domain contains LCDR1, LCDR2, and LCDR3, which have 100% sequence identity with the _VH domain containing the amino acid sequence of SEQ ID NO:299; and the VL domain contains LCDR1, LCDR2, and LCDR3, which have 100% sequence identity with the _VH domain containing the amino acid sequence of SEQ ID NO:140; e) The V _H domain contains LCDR1, LCDR2, and LCDR3, which have 100% sequence identity with the V _H domain of the amino acid sequence containing SEQ ID NO:300; and the V _L domain contains LCDR1, LCDR2, and LCDR3, which have 100% sequence identity with the V _H domain of the amino acid sequence containing SEQ ID NO:140; f) The _{V H domain} contains HCDR1, HCDR2, and LCDR3, which have 100% sequence identity with the V _H domain of the amino acid sequence containing SEQ ID NO:140; and the ...4404444444454445444454444444444444444444444444444444444444444444 The _L -domain contains LCDR1, LCDR2, and LCDR3, which are 100% sequence identical to the V- _L -domain containing the amino acid sequence of SEQ ID NO:144; g) The V- _H -domain contains HCDR1, HCDR2, and HCDR3, which are 100% sequence identical to the V _-H -domain containing the amino acid sequence of SEQ ID NO:1; and the V- _L -domain contains LCDR1, LCDR2, and LCDR3, which are 100% sequence identical to the V _-L -domain containing the amino acid sequence of SEQ ID NO:301; h) The V-H-domain contains LCDR1, LCDR2, and LCDR3, which are 100% sequence identical to the V _-L -domain containing the amino acid sequence of SEQ ID NO:144; The _{V H} domain contains HCDR1, HCDR2, and HCDR3 with 100% sequence identity; and the V _L domain contains LCDR1, LCDR2, and LCDR3 with 100% sequence identity to the V _L domain containing the amino acid sequence of SEQ ID NO:302; or i) the V _H domain contains HCDR1, HCDR2, and HCDR3 with 100% sequence identity to the V _H domain containing the amino acid sequence of SEQ ID NO:1; and the V _L domain contains LCDR1, LCDR2, and LCDR3 with 100% sequence identity to the V _L domain containing the amino acid sequence of SEQ ID NO:142. The antibody or antigen-binding fragment thereof of claim 1, wherein: a) the HCDR1 comprises the amino acid sequence 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 comprises the amino acid sequence of SEQ ID NO:72; c) the HCDR3 comprises the amino acid sequence of SEQ ID NO:79; d) the LCDR1 comprises the amino acid sequence of SEQ ID NO:146; e) the LCDR2 comprises the amino acid sequence of AAS, IAS or YAS; and f) the LCDR3 comprises the amino acid sequence of SEQ ID NO:150. If the antibody or its antigen-binding fragment is any one of claims 1 to 3, wherein: a) the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 respectively contain the amino acid sequences 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 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; The amino acid sequences NO:146, AAS, and SEQ ID NO:150; or d) The HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 respectively contain the amino acid sequences SEQ ID NO:44, SEQ ID NO:72, SEQ ID NO:79, SEQ ID NO:146, AAS, and SEQ ID NO:150. The antibody or antigen-binding fragment thereof of claim 1, wherein: a) the HCDR1 comprises the amino acid sequence of SEQ ID NO:80, SEQ ID NO:81, or SEQ ID NO:82; b) the HCDR2 comprises the amino acid sequence of SEQ ID NO:96; c) the HCDR3 comprises the amino acid sequence of SEQ ID NO:103; d) the LCDR1 comprises the amino acid sequence of SEQ ID NO:151; e) the LCDR2 comprises 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 comprises the amino acid sequence of SEQ ID NO:150. If the antibody or its antigen-binding fragment is any one of claims 1, 2, and 5, wherein: a) the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 respectively contain the amino acid sequences 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 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 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; d) The HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 each contain the amino acid sequences SEQ ID NO:96, SEQ ID NO:103, SEQ ID NO:151, SEQ ID NO:307, and SEQ ID NO:150; or e) The HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 each contain the amino acid sequences 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. The antibody or antigen-binding fragment thereof of claim 1, wherein: a) the HCDR1 comprises 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 comprises the amino acid sequence of SEQ ID NO:132; c) the HCDR3 comprises the amino acid sequence of SEQ ID NO:139; d) the LCDR1 comprises the amino acid sequence of SEQ ID NO:151; e) the LCDR2 comprises 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 comprises the amino acid sequence of SEQ ID NO:150. If the antibody or antigen-binding fragment thereof is any one of claims 1, 2, and 7, wherein: a) the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 respectively contain the amino acid sequences 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 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 SEQ ID NO:305, SEQ ID NO:132, SEQ ID NO:139, SEQ ID NO:151, SEQ ID NO:156, and SEQ ID NO:150; d) The HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 each contain the amino acid sequences of 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 each 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 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 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; h) The HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 respectively contain the amino acid sequences 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; The amino acid sequences of NO:154 and SEQ ID NO:150. An antibody or antigen-binding fragment thereof for any of claims 1 to 8, wherein: a) the _VH domain contains the amino acid sequence of SEQ ID NO:3 and the _VL domain contains the amino acid sequence of SEQ ID NO:144; b) the _VH domain contains the amino acid sequence of SEQ ID NO:2 and the _VL domain contains the amino acid sequence of SEQ ID NO:144; c) the _VH domain contains the amino acid sequence of SEQ ID NO:4 and the _VL domain contains the amino acid sequence of SEQ ID NO:144; d) the _VH domain contains the amino acid sequence of SEQ ID NO:4 and the _VL domain contains the amino acid sequence of SEQ ID NO:140; e) the _VH domain contains the amino acid sequence of SEQ ID NO:299 and the _VL domain contains the amino acid sequence of SEQ ID NO:140; f) the _VH domain contains the amino acid sequence of SEQ ID NO:140. The following are possible interpretations of the following amino acid sequences: g) The V _H domain contains the amino acid sequence of SEQ ID NO:1 and the V _L domain contains the amino acid sequence of SEQ ID NO:140; h) The V _H domain contains the amino acid sequence of SEQ ID NO _{:1 and the V L domain contains the amino acid sequence of SEQ ID NO:301; i) The V H domain contains} the amino acid sequence of SEQ ID NO:1 and the V _L domain contains the amino acid sequence of SEQ ID NO:302; or j) The V _H domain contains the amino acid sequence of SEQ ID NO:1 and the V _L domain contains the amino acid sequence of SEQ ID NO:142. The antibody or antigen-binding fragment thereof, as claimed in any 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 . The antibody or antigen-binding fragment thereof, as claimed in any of claims 1 to 9, comprises an antibody heavy chain constant domain, an antibody light chain constant domain, or both. 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 one or more mutations that increase the serum half-life of the antibody or antigen-binding fragment thereof in humans. 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, SEQ ID NO: 280 with YTE modification, SEQ ID NO: 280 with LS modification, SEQ ID NO: 279, SEQ ID NO: 279 with YTE modification or SEQ ID NO: 279 with LS modification. A polynucleotide that encodes an antibody or antigen-binding fragment thereof as described in any of claims 1 to 13. A host cell containing the polynucleotides as claimed in claim 14. A method for generating 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. A pharmaceutical composition comprising an antibody or antigen-binding fragment thereof as claimed in any 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 delivery or diluent. A kit comprising an antibody or antigen-binding fragment thereof as claimed in any 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. A method for blocking the binding of a ligand to a receptor expressed thereon on the 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 the receptor expressed thereon on the cell surface, wherein the ligand comprises p40. 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 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. 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 antigen-binding fragment thereof as described in any one of claims 1 to 13 or a pharmaceutical composition as described in claim 17, thereby treating the IL-12/IL-23-related disease.