Antigen binding molecules targeting il-12 and il-23

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 isclosure 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-23RELATED APPLICATION

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 593,199, filed on October 25, 2023. The entire teachings of the above application are incorporated herein by reference.INCORPORATION BY REFERENCE OF MATERIAL IN XML

[0002] This application incorporates by reference the Sequence Listing contained in the following extensible Markup Language (XML) file being submitted concurrently herewith: a) File name: 62311000001. xml; created October 22, 2024, 325,178 Bytes in size.BACKGROUND

[0003] The involvement of the Interleukin (IL)- 12 / 23 pathway is implicated in the pathogenesis of various disorders.

[0004] IL-12 plays a critical role in the pathology associated with several diseases involving immune and inflammatory responses. A review of IL-12, its biological activities, and its role in disease can be found in Gately et al A Structurally, IL- 12 is a heterodimeric protein comprising a 35 kDa subunit (p35) and a 40 kDa subunit (p40) which are linked together by a disulfide bridge (referred to as the “p70 subunit”). Functionally, IL-12 plays a central role in regulating the balance between antigen specific T helper type 1 (Thl) and type 2 (Th2) lymphocytes.Consistent with the preponderance of Thl responses in autoimmune diseases and the proinflammatory activities of IFNy, IL- 12 plays a major role in the pathology associated with many autoimmune and inflammatory diseases. Due to the role of human IL- 12 in a variety of human diseases, therapeutic strategies have been designed to inhibit or counteract IL- 12 activities. In particular, molecules that bind and neutralize IL-12 have been sought as a means to inhibit IL- 12 activities.

[0005] IL-23 is a heterodimeric cytokine comprised of two subunits: pl9 and p402. IL-23 has been reported to promote the proliferation of T cells, in particular memory T cells and can contribute to the differentiation and / or maintenance of Thl7 cells3. IL-23 induces T-cells toexpress a number of inflammatory genes including IL- 17 A, IL-17A receptor, TNF-a, and GM- CSF. The main effects of IL -23 are to drive the differentiation of T helper Thl7 cells, as well as macrophages, natural killer (NK) cells, dendritic cells, and innate lymphoid cells leading to upregulation of IL-17, IL-22, TNF-a, granulocyte macrophage colony-stimulating factor (GM- CSF), and interferon (fFN)-y, and down-regulation of IL- 10. IL-23 is implicated in the pathogenesis of various inflammatory conditions including but not limited to Crohn’s disease, ulcerative colitis, psoriasis, psoriatic arthritis, rheumatoid arthritis, and ankylosing spondylitis.

[0006] The p40 subunit is shared by IL-12 and IL-23 as a common subunit and is targeted by inhibitors of IL- 12 / 23. There is compelling evidence that therapeutics that bind to the p40 subunit can be used to inhibit IL- 12- and IL -23 -mediated cell signaling, activation and cytokine production.SUMMARY

[0007] Ustekinumab (STELARA®) is a human IgGl class monoclonal antibody that binds to the shared p40 subunit of human IL- 12 and IL-23. The bindings prevent interactions of IL- 12 and IL-23 with their cell surface receptor IL-12R01, subsequently inhibiting IL-12- and IL-23- mediated cell signaling, activation and cytokine production which regulate specific components of the immune system. Although Ustekinumab has shown favorable target affinity, there is a need to develop inhibitors of IL-12 / 23 with improved target affinity, immunogenicity, stability, and / or serum half-life4-7. Improvements in target affinity can improve efficacy and / or lower dose of a therapeutic agent. Increased stability and / or serum half-life can provide dosing advantages.

[0008] The disclosure provided herein is based, in part, on the discovery that antibodies and antigen-binding fragments thereof disclosed herein specifically bind to the p40 protein subunit of human IL-12 and IL-23 and demonstrate one or more beneficial properties. Accordingly, the disclosure generally relates to compositions ( .g., antibodies or antigen-binding fragments thereof, pharmaceutical compositions) and methods that are useful for modulating (e.g., antagonizing) IL-12 and IL-23 function and / or activities e.g., in vivo function and / or activities).

[0009] The disclosure provides, among other things, an antibody or an antigen-binding fragment thereof, comprising:a) an immunoglobulin heavy chain variable (VH) domain comprising a heavy chain complementarity-determining region (HCDR) 1, a HCDR2, and a HCDR3 having 100% sequence identity to a HCDR1, a HCDR2, and a HCDR3, respectively, of a VHdomain comprising the amino acid sequence of any one of SEQ ID NO:3, SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:299, SEQ ID NO:300, SEQ ID NO: 1, SEQ ID NOs:5-ll, and SEQ ID NOs: 19-21; and b) an immunoglobulin light chain variable (VL) domain comprising a light chain complementarity-determining region (LCDR) 1, a LCDR2, and a LCDR3 having 100% sequence identity to a LCDR1, a LCDR2, and a LCDR3, respectively, of a VLdomain comprising the amino acid sequence of any one of SEQ ID NO: 144, SEQ ID NO: 142, SEQ ID NO:301, SEQ ID NO: 302, and SEQ ID NO: 140, wherein the VHdomain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 1, the VL domain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 140, or both.

[0010] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VHdomain comprising a HCDR1, a HCDR2, and a HCDR3 having 100% sequence identity to a HCDR1, a HCDR2, and a HCDR3, respectively, of a VHdomain comprising the amino acid sequence of SEQ ID NO:3, and a VLdomain comprising a LCDR1, a LCDR2, and a LCDR3 having 100% sequence identity to a LCDR1, a LCDR2, and a LCDR3, respectively, of a VLdomain comprising the amino acid sequence of SEQ ID NO: 144; b) a VHdomain comprising a HCDR1, a HCDR2, and a HCDR3 having 100% sequence identity to a HCDR1, a HCDR2, and a HCDR3, respectively, of a VHdomain comprising the amino acid sequence of SEQ ID NO:2, and a VLdomain comprising a LCDR1, a LCDR2, and a LCDR3 having 100% sequence identity to a LCDR1, a LCDR2, and a LCDR3, respectively, of a VLdomain comprising the amino acid sequence of SEQ ID NO: 144; c) a VHdomain comprising a HCDR1, a HCDR2, and a HCDR3 having 100% sequence identity to a HCDR1, a HCDR2, and a HCDR3, respectively, of a VHdomain comprising the amino acid sequence of SEQ ID NO:4, and a VLdomain comprising a LCDR1, aLCDR2, and a LCDR3 having 100% sequence identity to a LCDR1, a LCDR2, and a LCDR3, respectively, of a VLdomain comprising the amino acid sequence of SEQ ID NO: 140; d) a Vndomain comprising a HCDR1, a HCDR2, and a HCDR3 having 100% sequence identity to a HCDR1, a HCDR2, and a HCDR3, respectively, of a VH domain comprising the amino acid sequence of SEQ ID NO:299, and a VLdomain comprising a LCDR1, a LCDR2, and a LCDR3 having 100% sequence identity to a LCDR1, a LCDR2, and a LCDR3, respectively, of a VLdomain comprising the amino acid sequence of SEQ ID NO: 140; e) a VHdomain comprising a HCDR1, a HCDR2, and a HCDR3 having 100% sequence identity to a HCDR1, a HCDR2, and a HCDR3, respectively, of a VHdomain comprising the amino acid sequence of SEQ ID NO:300, and a VLdomain comprising a LCDR1, a LCDR2, and a LCDR3 having 100% sequence identity to a LCDR1, a LCDR2, and a LCDR3, respectively, of a VLdomain comprising the amino acid sequence of SEQ ID NO: 140; f) a VHdomain comprising a HCDR1, a HCDR2, and a HCDR3 having 100% sequence identity to a HCDR1, a HCDR2, and a HCDR3, respectively, of a VHdomain comprising the amino acid sequence of SEQ ID NO: 1, and a VLdomain comprising a LCDR1, a LCDR2, and a LCDR3 having 100% sequence identity to a LCDR1, a LCDR2, and a LCDR3, respectively, of a VLdomain comprising the amino acid sequence of SEQ ID NO: 144; g) a VHdomain comprising a HCDR1, a HCDR2, and a HCDR3 having 100% sequence identity to a HCDR1, a HCDR2, and a HCDR3, respectively, of a VHdomain comprising the amino acid sequence of SEQ ID NO: 1, and a VLdomain comprising a LCDR1, a LCDR2, and a LCDR3 having 100% sequence identity to a LCDR1, a LCDR2, and a LCDR3, respectively, of a VLdomain comprising the amino acid sequence of SEQ ID NO:301; h) a VHdomain comprising a HCDR1, a HCDR2, and a HCDR3 having 100% sequence identity to a HCDR1, a HCDR2, and a HCDR3, respectively, of a VHdomain comprising the amino acid sequence of SEQ ID NO: 1, and a VLdomain comprising a LCDR1, aLCDR2, and a LCDR3 having 100% sequence identity to a LCDR1, a LCDR2, and a LCDR3, respectively, of a VLdomain comprising the amino acid sequence of SEQ ID NO: 302; or i) a Vndomain c comprising a HCDR1, a HCDR2, and a HCDR3 having 100% sequence identity to a HCDR1, a HCDR2, and a HCDR3, respectively, of a VH domain comprising the amino acid sequence of SEQ ID NO: 1, and a VLdomain comprising a LCDR1, a LCDR2, and a LCDR3 having 100% sequence identity to a LCDR1, a LCDR2, and a LCDR3, respectively, of a VLdomain comprising the amino acid sequence of SEQ ID NO: 142.

[0011] In some embodiments: a) a 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) a HCDR2 comprises the amino acid sequence of SEQ ID NO:72; c) a HCDR3 comprises the amino acid sequence of SEQ ID NO:79, d) a LCDR1 comprises the amino acid sequence of SEQ ID NO: 146; e) a LCDR2 comprises the amino acid sequence of AAS, IAS, or YAS; and f) a LCDR3 comprises the amino acid sequence of SEQ ID NO: 150.

[0012] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2, and a LCDR3 comprising 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) a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2, and a LCDR3 comprising 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) a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2, and a LCDR3 comprising 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; ord) a HCDR1 , a HCDR2, a HCDR3, a LCDR1 , a LCDR2, and a LCDR3 comprising the amino acid sequences of SEQ ID NO:44, SEQ ID NO:72, SEQ ID NO:79, SEQ ID NO: 146, AAS, and SEQ ID NO: 150, respectively.

[0013] In some embodiments: a) a HCDR1 comprises the amino acid sequence of SEQ ID NO:80, SEQ ID NO:81 or SEQ ID NO 82; b) a HCDR2 comprises the amino acid sequence of SEQ ID NO:96; c) a HCDR3 comprises the amino acid sequence of SEQ ID NO: 103; d) a LCDR1 comprises the amino acid sequence of SEQ ID NO: 151; e) a 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) a LCDR3 comprises the amino acid sequence of SEQ ID NO: 150.

[0014] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2, and a LCDR3 comprising 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) a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2, and a LCDR3 comprising 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) a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2, and a LCDR3 comprising the amino acid sequences of SEQ ID NO:80, SEQ ID NO:96, SEQ ID NO:103, SEQ ID NO: 151, SEQ ID NO:307, and SEQ ID NO: 150, respectively; d) a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2, and a LCDR3 comprising the amino acid sequences of SEQ ID NO:80, SEQ ID NO:96, SEQ ID NO:103, SEQ ID NO: 151, SEQ ID NO:308, and SEQ ID NO: 150, respectively; or e) a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2, and a LCDR3 comprising the amino acid sequences of SEQ ID NO:80, SEQ ID NO:96, SEQ ID NO: 103, SEQ ID NO: 151, SEQ ID NO:154, and SEQ ID NO:150, respectively.

[0015] In some embodiments:a) a 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) a HCDR2 comprises the amino acid sequence of SEQ ID NO: 132; c) a HCDR3 comprises the amino acid sequence of SEQ ID NO: 139; d) a LCDR1 comprises the amino acid sequence of SEQ ID NO: 151; e) a 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) a LCDR3 comprises the amino acid sequence of SEQ ID NO: 150.

[0016] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2, and a LCDR3 comprising 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) a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2, and a LCDR3 comprising 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) a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2, and a LCDR3 comprising the amino acid sequences of SEQ ID NO:305, SEQ ID NO: 132, SEQ ID NO: 139, SEQ ID NO : 151 , SEQ ID NO : 152, and SEQ ID NO : 150, respectively; d) a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2, and a LCDR3 comprising the amino acid sequences of SEQ ID NO:306, SEQ ID NO: 132, SEQ ID NO: 139, SEQ ID NO: 151, SEQ ID NO:152, and SEQ ID NO: 150, respectively; e) a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2, and a LCDR3 comprising 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, respectively; f) a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2, and a LCDR3 comprising the amino acid sequences of SEQ ID NO: 104, SEQ ID NO: 132, SEQ ID NO: 139, SEQ ID NO: 151, SEQ ID NO:307, and SEQ ID NO: 150, respectively;g) a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2, and a LCDR3 comprising the amino acid sequences of SEQ ID NO: 104, SEQ ID NO: 132, SEQ ID NO: 139, SEQ ID NO: 151, SEQ ID NO:308, and SEQ ID NO: 150, respectively; or h) a HCDR1, a HCDR2, a HCDR3, a LCDR1, a LCDR2, and a LCDR3 comprising the amino acid sequences of SEQ ID NO: 104, SEQ ID NO: 132, SEQ ID NO: 139, SEQ ID NON51, SEQ ID NO:154, and SEQ ID NO: 150, respectively.

[0017] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VHdomain comprising the amino acid sequence of SEQ ID NO:3, and a VLdomain comprising the amino acid sequence of SEQ ID NO: 144; b) a VHdomain comprising the amino acid sequence of SEQ ID NO:2, and a VLdomain comprising the amino acid sequence of SEQ ID NO: 144; c) a VHdomain comprising the amino acid sequence of SEQ ID NON, and a VLdomain comprising the amino acid sequence of SEQ ID NO: 144; d) a VHdomain comprising the amino acid sequence of SEQ ID NON, and a VLdomain comprising the amino acid sequence of SEQ ID NO: 140; e) a VHdomain comprising the amino acid sequence of SEQ ID NO:299, and a VLdomain comprising the amino acid sequence of SEQ ID NO: 140; f) a VHdomain comprising the amino acid sequence of SEQ ID NO:300, and a VLdomain comprising the amino acid sequence of SEQ ID NO: 140; g) a VHdomain comprising the amino acid sequence of SEQ ID NO:1, and a VLdomain comprising the amino acid sequence of SEQ ID NO: 144; h) a VHdomain comprising the amino acid sequence of SEQ ID NON, and a VLdomain comprising the amino acid sequence of SEQ ID NO:301; i) a VHdomain comprising the amino acid sequence of SEQ ID NON, and a VLdomain comprising the amino acid sequence of SEQ ID NO:302; or j) a VHdomain comprising the amino acid sequence of SEQ ID NON, and a VLdomain comprising the amino acid sequence of SEQ ID NO: 142.

[0018] In some embodiments, an antibody or an antigen-binding fragment thereof comprises an antibody heavy chain constant domain, an antibody light chain constant domain, or both.

[0019] In some embodiments, an antibody or an antigen-binding fragment thereof comprises an antibody heavy chain constant domain comprising one or more mutations which increase serum half-life of the antibody or antigen-binding fragment thereof in humans.

[0020] In some embodiments, an antibody or an antigen-binding fragment thereof comprises an antibody heavy chain constant domain comprising SEQ ID NO:280, a YTE modification of SEQ ID NO: 280, a LS modification of SEQ ID NO: 280, SEQ ID NO: 279, a YTE modification of SEQ ID NO: 279, or a LS modification of SEQ ID NO: 279.

[0021] The disclosure also provides, among other things, an antibody or an antigen-binding fragment thereof, comprising: a) a HCDR1 comprising (e.g., consisting of) the amino acid sequence of SEQ ID N0:Xbb) a HCDR2 comprising (e. ., consisting of) the amino acid sequence of SEQ ID N0:X2, c) a HCDR3 comprising (e.g., consisting of) the amino acid sequence of SEQ ID N0:X3, d) a LCDR1 comprising (e.g., consisting of) the amino acid sequence of SEQ ID NO:Y e) a LCDR2 comprising (e.g., consisting of) the amino acid sequence of SEQ ID NO:Y2, and f) a LCDR3 comprising (e.g., consisting of) the amino acid sequence of SEQ ID NO:Y3.

[0022] The disclosure provides, among other things, an antibody or an antigen-binding fragment thereof, comprising: a) an immunoglobulin heavy chain variable (VH) domain comprising a heavy chain complementarity-determining region (HCDR) 1, a HCDR2, and a HCDR3 having at least 80% sequence identity to a HCDR1, a HCDR2, and a HCDR3, respectively, of a VHdomain comprising the amino acid sequence of any one of SEQ ID NOs:2-l 1, 19-21, 299, and 300 (e.g., any one of SEQ ID NOs:2-l 1 and 19-21), and b) an immunoglobulin light chain variable (VL) domain comprising a light chain complementarity-determining region (LCDR) 1, a LCDR2, and a LCDR3 having at least 80% sequence identity to a LCDR1, a LCDR2, and a LCDR3, respectively, of a VLdomain comprising the amino acid sequence of any one of SEQ ID NOs: 144, 142, 301, and 302 (e.g., SEQ ID NO: 144 or 142),wherein the VHdomain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 1, the VLdomain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 140, or both.

[0023] The disclosure also provides, among other things, an antibody or an antigen-binding fragment thereof, comprising: a) a VHdomain comprising a HCDR1, a HCDR2, and a EICDR3 having 100% sequence identity to a HCDR1, a HCDR2, and a HCDR3, respectively, of a VHdomain comprising the amino acid sequence of any one of SEQ ID NOs:2-l 1, 19-21, 299, and 300 (e.g., any one of SEQ ID NOs:2-l 1 and 19-21), and b) a VLdomain comprising a LCDR1, a LCDR2, and a LCDR3 having 100% sequence identity to a LCDR1, a LCDR2, and a LCDR3, respectively, of a VLdomain comprising the amino acid sequence of any one of SEQ ID NOs: 144, 142, 301, and 302 e.g., SEQ ID NO: 144 or 142), wherein the VHdomain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 1, the VLdomain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 140, or both.

[0024] In some embodiments, the VHdomain of an antibody or an antigen-binding fragment thereof comprises four VHframework regions (VHFR1-4) and three heavy chain complementarity determining regions (HCDR1-3) in the following N-terminal to C-terminal order: VHFR1-HCDR1-VHFR2-HCDR2-VHFR3-HCDR3-VHFR4, wherein: a) the VHFR1-HCDR1 comprises the amino acid sequence of any one of SEQ ID NOs:309, 310, and 262-267 e.g., SEQ ID NOs:262-267), b) the VHFR2 comprises the amino acid sequence of GKGL, GDYL, or GYYL, or c) the VHFR3 comprises the amino acid sequence of NSLK, PSLR, or NDLR, or any combination of a) to c).

[0025] The disclosure also provides, among other things, an antibody or an antigen-binding fragment thereof, comprising: a) a HCDR1 comprising (e.g., consisting of) the amino acid sequence of SEQ ID NO:X, b) a HCDR2 comprising (e.g., consisting of) the amino acid sequence of SEQ ID NO:72, c) a HCDR3 comprising (e.g., consisting of) the amino acid sequence of SEQ ID NO:79,d) a LCDR1 comprising (e.g., consisting of) the amino acid sequence of SEQ ID NO: 146, e) a LCDR2 comprising (e.g., consisting of) the amino acid sequence of AAS, and f) a LCDR3 comprising (e.g., consisting of) the amino acid sequence of SEQ ID NO: 150.

[0026] 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.

[0027] The disclosure also provides, among other things, an antibody or an antigen-binding fragment thereof, comprising: a) a HCDR1 comprising (e.g., consisting of) the amino acid sequence of SEQ ID NO:Xbb) a EICDR2 comprising (e.g., consisting of) the amino acid sequence of SEQ ID NO:X2, c) a HCDR3 comprising (e.g., consisting of) the amino acid sequence of SEQ ID NO:X3, d) a LCDR1 comprising (e.g., consisting of) the amino acid sequence of SEQ ID NO:Ybe) a LCDR2 comprising (e.g., consisting of) the amino acid sequence of SEQ ID NO:Y2, and f) a LCDR3 comprising (e.g., consisting of) the amino acid sequence of SEQ ID NO:Y3.

[0028] In some embodiments, an antibody or an antigen-binding fragment thereof does not comprise a VHdomain comprising the amino acid sequence of SEQ ID NO: 1 and a VLdomain comprising the amino acid sequence of SEQ ID NO: 140.

[0029] In some embodiments, X] is 80, 81 or 82, X2is 96, X3is 103, Yi is 151, Y2is any one of 156, 307, 308, and 154, and Y3is 150. In some embodiments, Xi is 80, 81 or 82, X2is 96, X3is 103, Yi is 151, Y2is 156 or 154, and Y3is 150. In some embodiments, Xi is 80, X2is 96, X3is 103, Yi is 151, Y2is 156, and Y3is 150. In some embodiments, X! is 80, X2is 96, X is 103, Y! is 151, Y2is 307, and Y3is 150. In some embodiments, Xi is 80, X2is 96, X3is 103, Yi is 151, Y2is 308, and Y3is 150. In some embodiments, Xi is 80, X2is 96, X3is 103, Yi is 151, Y2is 154, and Y3is 150. In some embodiments, Xi is 81, X2is 96, X3is 103, Yi is 151, Y2is 156, and Y3is 150. In some embodiments, Xi is 81, X2is 96, X3is 103, Yi is 151, Y2is 307, and Y3is 150. In some embodiments, Xxis 81, X2is 96, X3is 103, Yxis 151, Y2is 308, and Y3is 150. In some embodiments, Xi is 81, X2is 96, X3is 103, Yi is 151, Y2is 154, and Y3is 150. In someembodiments, Xi is 82, X2is 96, X is 103, Yi is 151 , Y2is 156, and Y3is 150. In some embodiments, Xi is 82, X2is 96, X3is 103, Yi is 151, Y2is 307, and Y3is 150. In some embodiments, X! is 82, X2is 96, X3is 103, Ytis 151, Y2is 308, and Y3is 150. In some embodiments, Xtis 82, X2is 96, X is 103, Ytis 151, Y2is 154, and Y3is 150.

[0030] In some embodiments, Xi is any one of 305, 306, 105-107, and 109-111, X2is 132, X3is 139, Yi is 151, Y2is any one of 307, 308, 156, and 154, and Y3is 150. In some embodiments, Xtis any one of 305, 306, 105-107, and 109-111, X2is 132, X3is 139, Ytis 151, Y2is 307, and Y3is 150. In some embodiments, X] is any one of 305, 306, 105-107, and 109- 111, X2is 132, X3is 139, Yi is 151, Y2is 308, and Y3is 150. In some embodiments, Xi is any one of 305, 306, 105-107, and 109-111, X2is 132, X3is 139, Yi is 151, Y2is 156, and Y3is 150. In some embodiments, Xi is any one of 305, 306, 105-107, and 109-111, X2is 132, X3is 139, Y] is 151, Y2is 154, and Y3is 150. In some embodiments, Xi is any one of 105-107 and 109-111, X2is 132, X3is 139, Yi is 151, Y2is 156 or 154, and Y3is 150. In some embodiments, Xi is any one of 105-107 and 109-111, X2is 132, X3is 139, Yi is 151, Y2is 307, and Y3is 150. In some embodiments, Xtis any one of 105-107 and 109-111, X2is 132, X3is 139, Yxis 151, Y2is 308, and Y3is 150. In some embodiments, X] is any one of 105-107 and 109-111, X2is 132, X3is 139, Yi is 151, Y2is 156, and Y3is 150. In some embodiments, Xi is any one of 105-107 and 109-111, X2is 132, X3is 139, Yi is 151, Y2is 154, and Y3is 150.

[0031] The disclosure also provides, among other things, an antibody or an antigen-binding fragment thereof, comprising a VHdomain comprising the amino acid sequence of SEQ ID NO:X and a VLdomain comprising the amino acid sequence of SEQ ID NO:Y.

[0032] 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.

[0033] 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 someembodiments, 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.

[0034] 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.

[0035] In some embodiments, X is 2, and Y is 301. In some embodiments, X is 3, and Y is301. 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.

[0036] In some embodiments, X is 2, and Y is 302. In some embodiments, X is 3, and Y is302. 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.

[0037] In some embodiments, an antibody or an antigen binding fragment thereof disclosed herein specifically binds the p40 subunit of the human interleukins 12 and 23 (e.g., a full-length human p40 subunit) or a variant thereof. In some embodiments, an antibody or an antigen binding fragment thereof disclosed herein binds the DI domain of the p40 subunit.

[0038] The disclosure also provides, among other things, a polynucleotide encoding a VHdomain, a VLdomain, a light chain, or a heavy chain of an antibody or an antigen binding fragment thereof disclosed herein. In some embodiments, a polynucleotide is a DNA. In some embodiments, a polynucleotide is an RNA.

[0039] The disclosure also provides, among other things, an expression vector comprising a polynucleotide disclosed herein.

[0040] The disclosure also provides, among other things, a host cell comprising a polynucleotide or an expression vector disclosed herein.

[0041] The disclosure also provides, among other things, a method of producing an antibody or an antigen binding fragment thereof disclosed herein, comprising expressing the antibody or the antigen binding fragment thereof, in a host cell and isolating the expressed antibody or the antigen binding fragment thereof.

[0042] The disclosure also provides, among other things, a pharmaceutical composition comprising an antibody or an antigen binding fragment thereof disclosed herein, and a pharmaceutically acceptable carrier or diluent.

[0043] The disclosure also provides, among other things, a kit comprising a pharmaceutical composition disclosed herein.

[0044] The disclosure also provides, among other things, a method of blocking 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 an antigen binding fragment thereof or a pharmaceutical composition disclosed herein, thereby blocking the binding of the ligand to its receptor expressed on the cell surface, wherein the ligand comprises p40.

[0045] The disclosure also provides, among other things, a method of treating an IL-12 / IL- 23-associated disease in a subject in need thereof, comprising administering an effective amount of an antibody or an antigen binding fragment thereof or a pharmaceutical composition disclosed herein to the subject, thereby treating the IL- 12 / IL-23 -associated disease.BRIEF DESCRIPTION OF THE DRAWINGS

[0046] The foregoing will be apparent from the following more particular description of example embodiments, as illustrated in the accompanying drawings in which like referencecharacters refer to the same parts throughout the different views. The drawings are not necessarily to scale, emphasis instead being placed upon illustrating embodiments.

[0047] FIGs. 1 A-1C depict heavy chain variable (VH) domain amino acid sequences. Heavy chain complementarity determining region (HCDR) amino acid sequences of Ustekinumab as determined by ImMunoGeneTics (IMGT), Kabat, or Chothia numbering are indicated using Boxes. The bold letters indicate variable residues in Ustekinumab and example antibodies shown in FIG. 1G.

[0048] FIGs. ID- IF depict light chain variable (VL) domain amino acid sequences. Light chain complementarity determining region (LCDR) amino acid sequences of Ustekinumab as determined by IMGT, Kabat, or Chothia numbering are indicated using Boxes. The bold letters indicate variable residues in Ustekinumab and example antibodies shown in FIG. 1H.

[0049] FIG. 1G depicts an alignment of the amino acid sequences of the VHdomains of Ustekinumab and example variants.

[0050] FIG. 1H depicts an alignment of the amino acid sequences of the VLdomains of Ustekinumab and example variants.

[0051] FIGs. 2A-2B show ELISA analysis of indicated C and A variants, each comprising a heavy chain comprising an indicated first round VHvariant, and the light chain of Ustekinumab. Compared to Ustekinumab: (i) most C variants showed similar protein expression (IgG yields) except for C2, while the A variants showed lower protein expression (FIG. 2A); (ii) C38 showed significantly higher IL- 12 binding affinity, C7 and Cl 1 showed slightly higher affinities, C3 showed a similar affinity, and the A variants showed lower affinities (FIG. 2B).

[0052] FIG. 3 shows ELISA analysis of indicated antibody variants, each comprising: (i) a heavy chain comprising an indicated second round VHvariant and the light chain of Ustekinumab or (ii) the heavy chain of Ustekinumab and a light chain comprising an indicated VLvariant. Compared to the antibody comprising a heavy chain comprising C38 and the light chain of Ustekinumab (C38): (i) C41, C42, C61, C38xC81, C38xC82, C38xC91, and C38xC92 showed similar or higher IL- 12 binding affinities, when paired with the light chain of Ustekinumab, and (ii) C102, C103, C104, and C105, showed similar or higher IL-12 binding affinities, when paired with the heavy chain of Ustekinumab. Among these, C42, C38xC81, C38xC82, C38xC91, C38xC92, and C104 were associated with higher IL-12 binding affinities.

[0053] FIG. 4 shows ELISA analysis of third-round variants. Antibody variants C38xC104, C41xC104, C42xC104, C44xC104, C38xC82xC104, C38xC91xC104, C38xC92xC104, and C38x92xC102 showed similar or higher IL- 12 binding affinities compared to the antibody comprising a heavy chain comprising C38 and the light chain of Ustekinumab (C38).

[0054] FIG. 5A shows ELISA analysis of fourth-round variants. Antibody variants C38xC82xC92xC104 showed higher IL-12 binding affinity, and C42xC82xC92xC104, C42xC92xC104, and C38xC82xC92xC102 showed similar IL- 12 binding affinities, compared to the antibody comprising a heavy chain comprising C38 and the light chain of Ustekinumab (C38).

[0055] FIG. 5B shows ELISA analysis of indicated antibody variants.

[0056] FIGs. 6A-6C show ELISA analysis of indicated antibody variants. IgG and IL-12 ELISAs were performed to evaluate IL-12 binding affinities at corresponding IgG concentrations. Compared to Ustekinumab, all ten antibody variants showed higher IL-12 binding affinities. Comparing to the antibody comprising a heavy chain comprising C38 and the light chain of Ustekinumab (C38), C38xC104, C38x82xC104, C38x91xC104, C38x92xC104, and C38x82x92xC104 showed higher IL- 12 binding activities.

[0057] FIGs. 7A-7C show ELISA analysis of indicated antibody variants. IL-12 binding affinities at corresponding IgG concentrations were evaluated using IgG and IL- 12 ELISAs. Antibody concentrations started at 600 ng / mL, with 3-fold serial dilutions. Ustekinumab and the antibody comprising a heavy chain comprising C38 and the light chain of Ustekinumab (C38) were used as internal references.

[0058] FIGs. 8A-8D show pharmacokinetic profiles of Ustekinumab and indicated antibody variants in mice following a single IV dose of 1 mg / kg. Individual values were plotted for each mouse, and an average linear slope was calculated.

[0059] FIGs. 9A-9B show ELISA analysis of two versions of Ustekinumab-scFv-Fc.

[0060] FIG. 10 evaluates effects of Ustekinumab, in IgG or scFv-Fc format, on cell-based IL- 12 activities.

[0061] FIG. 11 evaluates effects of (i) the antibody comprising a heavy chain comprising C38 and the light chain of Ustekinumab (C38) and (ii) the antibody comprising a heavy chain comprising Cl 1 and the light chain of Ustekinumab (Cl 1) on cell-based IL-12 activities.

[0062] FIG. 12 evaluates effects of indicated antibody variants on cell-based IL-12 activities.

[0063] FIG. 13A evaluates effects of indicated antibody variants on cell-based IL-12 activities.

[0064] FIG. 13B summarizes effects of indicated antibody variants on cell-based IL- 12 activities. Compared to Ustekinumab, the antibody comprising a heavy chain comprising C38 and the light chain of Ustekinumab (C38), C38C91C104, and C38C92C104 showed statistically significantly increased ability in reducing IL-12 activities (t-test; p<0.001).

[0065] FIG. 13C evaluates effects of indicated antibody variants on cell-based IL-23 activities.

[0066] FIG. 14 shows analysis of the cell-based activity of scFv versions of selected variants incorporating preferred mutations. Purified variants in scFv format were assayed at a dose range of 0.3 ng / mL to 1000 ng / mL to measure inhibition of IL- 12 receptor binding and induced signaling. Data is an example of a single replicate from duplicate plates. Variants showed equivalent potency compared to Ustekinumab.

[0067] FIG. 15A evaluates in vivo pharmacodynamic neutralization of IL-12 of C38C91C104.

[0068] FIG. 15B evaluates in vivo pharmacodynamic neutralization of IL- 12 of C38C92C104.DETAILED DESCRIPTION

[0069] A description of example embodiments follows.

[0070] Several aspects of the disclosure are described below, with reference to examples for illustrative purposes only. Numerous specific details, relationships, and methods are set forth to provide a full understanding of the disclosure. One having ordinary skill in the relevant art will readily recognize that the disclosure can be practiced without one or more of the specific details and / or practiced with other materials (e.g. reagents, cells, animals), techniques, and / or procedures. Many techniques and procedures described herein are well understood and commonly employed by those skilled in the art using conventional methodology.Definitions

[0071] Unless otherwise defined, all terms of art, notations and other scientific terms or terminology used herein are intended to have the meanings commonly understood by those of skill in the art to which this disclosure pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and / or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a substantial difference over what is 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 that is consistent with their meaning in the context of the relevant art and / or as otherwise defined herein.

[0072] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0073] When introducing elements disclosed herein, the articles “a,” “an,” “the,” and “said” are intended to mean that there are one or more of the elements. Further, the one or more elements may be the same or different. For example, unless the context clearly indicates otherwise, “a polypeptide” includes a single polypeptide, and two or more polypeptides.

[0074] Throughout this specification and the claims which follow, unless the context requires otherwise, the term “comprise,” and variations such as “comprises” and “comprising”, will be understood to imply the inclusion of, e.g., a stated integer or step or group of integers or steps, but not the exclusion of any other integer or step or group of integer or step. When used herein, the term “comprising” can be substituted with the term “containing” or “including.”

[0075] As used herein, the term “consisting of’ excludes any element, step, or ingredient not specified in the claim element.

[0076] When used herein, the term “consisting essentially of’ does not exclude materials or steps that do not materially affect the basic and novel characteristics of the claim.

[0077] Also provided herein are corresponding embodiments for each and every embodiment featuring the term “comprising,” “containing,” “including,” or “having,” wherein those terms are replaced by the term “consisting of’ or “consisting essentially of.”

[0078] As used herein, the conjunctive term “and / or” between multiple recited elements is understood as encompassing both individual and combined options. For instance, where twoelements are conjoined by “and / or,” a first option refers to the applicability of the first element without the second. A second option refers to the applicability of the second element without the first. A third option refers to the applicability of the first and second elements together. Any one of these options is understood to fall within the meaning, and, therefore, satisfy the requirement of the term “and / or” as used herein. Concurrent applicability of more than one of the options is also understood to fall within the meaning, and, therefore, satisfy the requirement of the term “and / or.”

[0079] It should be understood that for all numerical bounds describing some parameter in this application, such as “about,” “at least,” “less than,” “fewer than,” and “more than,” the description also necessarily encompasses any range bounded by the recited values. Accordingly, for example, the description “at least 1, 2, 3, 4, or 5” also describes, inter alia, the ranges 1-2, 1- 3, 1-4, 1-5, 2-3, 2-4, 2-5, 3-4, 3-5, and 4-5, etcetera.

[0080] When a list is presented, unless stated otherwise, it is to be understood that each individual element of that list, and every combination of that list, is a separate embodiment. For example, a list of embodiments presented as “A, B, or C” is to be interpreted as including the embodiments, “A,” “B,” “C,” “A or B ,” “A or C,” “B or C,” or “A, B, or C.”

[0081] As used herein, the term “about” means within an acceptable error range for a particular value, as determined by one of ordinary skill in the art. Typically, an acceptable error range for a particular value depends, at least in part, on how the value is measured or determined, e.g., the limitations of the measurement system. For example, “about” can mean within an acceptable standard deviation, per the practice in the art. It is to be understood that the term “about” can precede any particular value specified herein, except for particular values used in the Exemplification. When “about” precedes a range, as in “1-20”, the term “about” should be read as applying to both given values of the range, such that “about 1-20” means about 1 to about 20.

[0082] As used herein, the term “polypeptide” refers to a polymer of at least two amino acids covalently linked by an amide bond, regardless of length or post-translational modification (e.g., glycosylation or phosphorylation). A polypeptide can comprise any suitable L-and / or D-amino acid, for example, common ot-amino acids (e.g., alanine, glycine, valine), non-a-amino acids (e.g., 0-alanine, 4-aminobutyric acid, 6-aminocaproic acid, sarcosine, statine), and unusual amino acids (e.g., citrulline, homocitruline, homoserine, norleucine, norvaline, ornithine). Theamino, carboxyl, and / or other functional groups on a polypeptide can be free (e.g, unmodified) or protected with a suitable protecting group. Suitable protecting groups for amino and carboxyl groups, and methods for adding or removing protecting groups are known in the art and are disclosed in, for example, Green and Wuts, “Protecting Groups in Organic Synthesis, ” John Wiley and Sons, 1991. The functional groups of a polypeptide can also be derivatized (e.g., alkylated) or labeled (e.g., with a detectable label, such as a fluorogen or a hapten) using methods known in the art. A polypeptide can comprise one or more modifications e.g., amino acid linkers, acylation, acetylation, amidation, methylation, terminal modifiers (e.g., cyclizing modifications), A-methyl-oc-amino group substitution), if desired. In addition, a polypeptide can be an analog of a known and / or naturally-occurring peptide, for example, a peptide analog having conservative amino acid residue substitution(s).

[0083] 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, a polynucleotide disclosed herein comprises deoxyribonucleotides. In some embodiments, the polynucleotide comprises ribonucleotides. Non-limiting examples of polynucleotides include single-, double- or multi-stranded DNA or RNA, DNA-RNA hybrids (e.g., each “T” position may be independently substituted by a “U” or vice versa), or a polymer comprising purine and pyrimidine bases, or other natural, chemically, or biochemically modified, non-natural, or derivatized nucleotide bases. The backbone of the polynucleotide can comprise sugars and phosphate groups, modified or substituted sugar or phosphate groups, a polymer of synthetic subunits such as phosphoramidates, or a combination thereof.

[0084] As used herein, the term “sequence identity” refers to the extent to which two nucleotide sequences have the same residues at the same positions when the sequences are aligned to achieve a maximal level of identity, expressed as a percentage. For sequence alignment and comparison, typically one sequence is designated as a reference sequence, to which test sequences are compared. Sequence identity between reference and test sequences is expressed as a percentage of positions across the entire length of the reference sequence where the reference and test sequences share the same nucleotide or amino acid upon alignment of the reference and test sequences to achieve a maximal level of identity. As an example, two sequences are considered to have 70% sequence identity when, upon alignment to achieve amaximal level of identity, the test sequence has the same nucleotide residue at 70% of the same positions over the entire length of the reference sequence.

[0085] Alignment of sequences for comparison to achieve maximal levels of identity can be readily performed by a person of ordinary skill in the art using an appropriate alignment method or algorithm. In some instances, alignment can include introduced gaps to provide for the maximal level of identity. Examples include the local homology algorithm of Smith & Waterman, Adv. AppL Math. 2:482 (1981), the homology alignment algorithm of Needleman & Wunsch, J. Mol. Biol. 48:443 (1970), the search for similarity method of Pearson & Lipman, Proc. Nat’l. Acad. Sci. USA 85:2444 (1988), computerized implementations of these algorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Dr., Madison, Wis.), and visual inspection (see generally Ausubel et al., Current Protocols in Molecular Biology)' .

[0086] When using a sequence comparison algorithm, test and reference sequences are input into a computer, subsequent coordinates are designated, if necessary, and sequence algorithm program parameters are designated. The sequence comparison algorithm then calculates the percent sequence identity for the test sequence(s) relative to the reference sequence, based on the designated program parameters. A commonly used tool for determining percent sequence identity is Protein Basic Local Alignment Search Tool (BLASTP) available through National Center for Biotechnology Information, National Library of Medicine, of the United States National Institutes of Health. (Altschul et al., 1990).

[0087] The term “expression vector” refers to a replicable nucleic acid from which one or more proteins can be expressed when the expression vector is transformed into a suitable expression host cell e.g., a recombinant cell).

[0088] As used herein, the term “promoter” refers to a region of DNA to which RNA polymerase binds and initiates the transcription of a gene.

[0089] As used herein, the term “operably linked” means that the nucleic acid is positioned in the recombinant polynucleotide, e.g., vector, in such a way that enables expression of the nucleic acid under control of the element {e.g., promoter) to which it is linked.

[0090] As used herein, the term “selectable marker element” is an element that confers a trait suitable for artificial selection. Selectable marker elements can be negative or positive selection markers.

[0091] As used herein, the term “expression host cell” refers to a cell useful for receiving, maintaining, reproducing and / or amplifying a vector.

[0092] As used herein, the term “antibody” refers to an immunoglobulin molecule capable of specific binding to a target, such as a carbohydrate, polynucleotide, lipid, polypeptide, etc., through at least one antigen recognition site, located in the variable domain of the immunoglobulin molecule. As used herein, the term “antibody” refers to a full-length antibody. In some embodiments, an antibody is a modified and / or engineered antibody; non-limiting examples of modified and / or engineered antibodies include chimeric antibodies, humanized antibodies, multiparatopic antibodies, bispecific antibodies, and multispecific antibodies.

[0093] As used herein, a “humanized antibody” is an antibody in which the antigen binding sites are derived from non-human species and the framework regions are derived from human immunoglobulin sequences.

[0094] As used herein, a “human antibody” is an antibody having heavy and light chain variable regions in which the framework and the antigen binding sites are derived from sequences of human origin.

[0095] As used herein, the term “single-domain antibody (sdAb)” or “nanobody” refers to an immunoglobulin molecule consisting of a single monomeric variable antibody domain and capable of specific binding to a target.

[0096] As used herein, the term “antigen-binding fragment” refers to a portion of an immunoglobulin molecule (e.g., antibody) that retains the antigen binding properties (e.g., of a corresponding full-length antibody). Non-limiting examples of antigen-binding fragments include a VHregion, a VLregion, a Fab fragment, a F(ab’)2fragment, a Fd fragment, a Fv fragment, and a domain antibody (dAb) consisting of one VHdomain or one VLdomain, etc. VHand VL domains may be linked together via a synthetic linker to form various types of singlechain antibody designs in which the VH / VLdomains pair intramolecularly, or intermolecularly in those cases when the VHand VLdomains are expressed by separate chains, to form a monovalent antigen binding site, such as single chain Fv (scFv) or diabody. In some embodiments, anantigen-binding fragment is Fab, F(ab’)2, Fab’, scFv, or Fv. In some embodiments, antigenbinding fragment is a scFv.

[0097] As used herein, a “complementarity determining region (CDR)” encompasses any CDR defined by an art-recognized method for identifying the CDR residues on an antibody. See, e.g., Kabat, E.A., et al., (1991) Sequences of Proteins of Immunological Interest, Fifth Edition, 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, Al-lazikani 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. Two antibodies are determined to have the same CDR as one another with respect to a HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and / or LCDR3, when the identity of that CDR is determined for both antibodies using the same method.

[0098] The extent of the framework region and the CDRs of an antibody can be identified using one of several suitable methodologies that are well known in the art, for example, by the Kabat definition, the Chothia definition, the AbM definition, and / or the contact definition. Publicly and / or commercially available tools for identifying framework and / or CDR regions include, IgBlast (accessible 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 accessible at www.imgt.org / ), Chothia Canonical Assignment (accessible at www.bioinf.org.uk / abs / chothia.html), Antigen receptor Numbering And Receptor Calssificatilon (ANARCI, accessible at opig.stats.ox.ac.uk / webapps / newsabdab / sabpred / anarci / ), or the Paratome web server (accessible at www.ofranlab.org / paratome / , or the Paratome web server (accessible at www.ofranlab.org / paratome / see Vered Kunik, et al, Nucleic Acids Research, Volume 40, Issue Wl, 1 July 2012, Pages W521-W524).

[0099] For example, for AB-1, the HCDR1, HCDR2, and HCDR3 amino acid sequences: (1) comprise SEQ ID NO:45, SEQ ID NO:72, and SEQ ID NO:79, respectively, as determined by IMGT numbering, (2) comprise SEQ ID NO:80, SEQ ID NO:96, and SEQ ID NO: 103, respectively, as determined by Kabat numbering, and (3) comprise SEQ ID NO: 105, SEQ ID NO: 132, and SEQ ID NO: 139, respectively, as determined by Chothia numbering.

[0100] As used herein, the term “antibody mimetic” refers to polypeptides capable of mimicking an antibody’s ability to bind an antigen, but structurally differ from native antibody structures. Examples of antibody mimetics include, but not limited to, Adnectins, Affibodies, Affilins, Affimers, Affitins, Alphabodies, Anticalins, Avimers, DARPins, Fynomers, Kunitz domain peptides, monobodies, nanobodies, nanoCLAMPs, and Versabodies.

[0101] As used herein, the term “KD,” also referred to as “binding constant,” “equilibrium dissociation constant” or “affinity constant,” is a measure of the extent of a reversible association between two molecular species (e.g., antibody and target protein) and includes both the actual binding affinity as well as the apparent binding affinity. Binding affinity can be determined using methods known in the art including, for example, by measurement of surface plasmon resonance, e.g., using a Biolayer interferometry (Octet, ForteBio) or a surface plasmon resonance (Biacore) system and assay. A reference that compares various surface technologies for measuring binding affinity and kinetics is Yang, D., Singh, A., Wu, H., & 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 by reference herein in their entirety.

[0102] As used herein, the term “fusion protein” refers to a synthetic, semi -synthetic or recombinant single protein molecule. A fusion protein can comprise all or a portion of two or more different proteins and / or polypeptides that are attached by covalent bonds (e.g., peptide bonds).

[0103] The term “subject” or “patient” refers to an animal (e.g., a mammal such as a human), diagnosed with or suspected of having an IL- 12 / IL-23 -associated disease or condition (e.g., Crohn’s disease or ulcerative colitis), or one at risk of developing such conditions. Diagnosis may be performed by any method or technique known in the art. One skilled in the art will understand that a subject to be treated according to the present disclosure may have been subjected to standard tests or may have been identified, without examination, as one at risk due to the presence of one or more risk factors associated with the disease or condition.

[0104] The phrase “pharmaceutically acceptable” means that the substance or composition the phrase modifies is, within the scope of sound medical judgment, suitable for use in contactwith the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit / risk ratio.

[0105] As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of mammals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge etal., 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 the agents / compounds described herein include salts derived from suitable inorganic and organic acids, and suitable inorganic and organic bases.

[0106] Examples of salts derived from suitable acids include salts of an amino group 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 by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts derived from suitable acids include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cinnamate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, glutarate, glycolate, hemisulfate, heptanoate, hexanoate, hydroiodide, hydroxybenzoate, 2-hydroxy-ethanesulfonate, hydroxymaleate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 2-phenoxybenzoate, phenyl acetate, 3 -phenylpropionate, phosphate, pivalate, propionate, pyruvate, salicylate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.

[0107] Either the mono-, di- or tri-acid salts can be formed, and such salts can exist in either a hydrated, solvated or substantially anhydrous form.

[0108] Salts derived from appropriate bases include salts derived from inorganic bases, such as alkali metal, alkaline earth metal, and ammonium bases, and salts derived from aliphatic,alicyclic or aromatic organic amines, such as methylamine, tri methyl amine and picoline, or N+((Ci-C4)alkyl)4salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, barium and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxyl, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.

[0109] “Pharmaceutically acceptable carrier” refers to a non-toxic carrier or excipient that does not destroy the pharmacological activity of the agent with which it is formulated and is nontoxic when administered in doses sufficient to deliver a therapeutic amount of the agent. Pharmaceutically acceptable carriers that may 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, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium tri silicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, poly acrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0110] “Treating” or “treatment,” as used herein, refers to taking steps to deliver a therapy to a subject, such as a mammal, in need thereof (e.g, as by administering to a mammal one or more therapeutic agents). “Treating” or “treatment” includes inhibiting the disease or condition (c'.g, as by slowing or stopping its progression or causing regression of the disease or condition) and relieving the symptoms resulting from the disease or condition.

[0111] The term “treating,” or “treatment” refers to the medical management of a subject with the intent to improve, ameliorate, stabilize (z.e., not worsen), prevent, or cure a disease, pathological condition, or disorder — such as the particular indications exemplified herein. This term includes active treatment (treatment directed to improve the disease, pathological condition, or disorder), causal treatment (treatment directed to the cause of the associated disease, pathological condition, or disorder), palliative treatment (treatment designed for the relief of symptoms), preventative treatment (treatment directed to minimizing or partially or completelyinhibiting the development of the associated disease, pathological condition, or disorder), and supportive treatment (treatment employed to supplement another therapy). Treatment also includes diminishment of the extent of the disease or condition, preventing spread of the disease or condition, delay or slowing the progress of the disease or condition, amelioration or palliation of the disease or condition, and remission (whether partial or total), whether detectable or undetectable. “Ameliorating” or “palliating” a disease or condition means that the extent and / or undesirable clinical manifestations of the disease, disorder, or condition are lessened and / or time course of the progression is slowed or lengthened, as compared to the extent or time course in the absence of treatment. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those already with the condition or disorder, as well as those prone to have the condition or disorder or those in which the condition or disorder is to be prevented.

[0112] A “pharmaceutical composition” refers to a formulation of one or more therapeutic agents and a medium generally accepted in the art for delivery of a biologically active agent to subjects, e.g., humans. In some embodiments, a pharmaceutical composition may include one or more pharmaceutically acceptable excipients, diluents, or carriers. In some embodiments, a pharmaceutical composition suitable for use in methods disclosed herein further comprises one or more pharmaceutically acceptable carriers.

[0113] “Pharmaceutically acceptable carrier, diluent, or excipient” includes any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.

[0114] “Pharmaceutically acceptable carrier” refers to an ingredient in a pharmaceutical composition, other than an active ingredient, which is nontoxic to a subject. A pharmaceutically acceptable carrier includes, but is not limited to, a buffer, excipient, stabilizer, or preservative. In some embodiments, the carrier may be a diluent, adjuvant, excipient, or vehicle with which the agent (e.g., polynucleotide) is administered. Such vehicles may be liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and the like. For example, 0.4% saline and 0.3% glycine can be used.These solutions are sterile and generally free of particulate matter. They may be sterilized by conventional, well-known sterilization techniques (e.g., filtration). The compositions may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pH adjusting and buffering agents, stabilizing, thickening, lubricating, and coloring agents, etc. The concentration of the agent in such pharmaceutical formulation may vary widely, i.e., from less than about 0.5%, to at least about 1%, or to as much as 15% or 20%, 25%, 30%, 35%, 40%, 45% or 50% by weight. The concentration will be selected primarily based on required dose, fluid volumes, viscosities, etc., according to the mode of administration. Suitable vehicles and formulations, inclusive of other human proteins, e.g., human serum albumin, are described, for example, in Remington: The Science and Practice of Pharmacy, 21stEdition, Troy, D.B. ed., Lipincott Williams and Wilkins, Philadelphia, PA 2006, Part 5, Pharmaceutical Manufacturing: 691-1092 (e.g., pages 958-89).

[0115] Non-limiting examples of pharmaceutically acceptable carriers are solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible, such as salts, buffers, antioxidants, saccharides, aqueous or non-aqueous carriers, preservatives, wetting agents, surfactants or emulsifying agents, or combinations thereof.

[0116] Non-limiting examples of buffers are acetic acid, citric acid, formic acid, succinic acid, phosphoric acid, carbonic acid, malic acid, aspartic acid, histidine, boric acid, Tris buffers, HEPPSO, and HEPES.

[0117] Non-limiting examples of antioxidants are ascorbic acid, methionine, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, lecithin, citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, and tartaric acid.

[0118] Non-limiting examples of amino acids are histidine, isoleucine, methionine, glycine, arginine, lysine, L-leucine, tri-leucine, alanine, glutamic acid, L-threonine, and 2-phenylamine.

[0119] Non-limiting examples of surfactants are polysorbates (e.g., polysorbate-20 or polysorbate-80), polyoxamers (e.g., poloxamer 188), Triton, sodium octyl glycoside, lauryl-, myristyl-, linoleyl-, or stearyl-sulfobetaine, lauryl-, myristyl-, linoleyl- or stearyl-sarcosine, linoleyl-, myristyl-, or cetyl -betaine, lauroamidopropyl-, cocamidopropyl-, linoleamidopropyl-, myristamidopropyl-, palmidopropyl-, or isostearamidopropyl-betaine (e.g., lauroamidopropyl),myristamidopropyl-, palmidopropyl-, or isostearamidopropyl-dimethylamine, sodium methyl cocoyl-, or disodium methyl oleyl-taurate, and the MONAQUA™ series (Mona Industries, Inc., Paterson, N.J.), polyethyl glycol, polypropyl glycol, and copolymers of ethylene and propylene glycol (e.g, PLURONICS™, PF68, etc.).

[0120] Non-limiting examples of preservatives are phenol, m-cresol, p-cresol, o-cresol, chlorocresol, benzyl alcohol, phenylmercuric nitrite, phenoxyethanol, formaldehyde, chlorobutanol, magnesium chloride, alkylparaben (methyl, ethyl, propyl, butyl, and the like), benzalkonium chloride, benzethonium chloride, sodium dehydroacetate, and thimerosal, or mixtures thereof.

[0121] Non-limiting examples of saccharides are monosaccharides, disaccharides, trisaccharides, polysaccharides, sugar alcohols, reducing sugars, nonreducing sugars such as glucose, sucrose, trehalose, lactose, fructose, maltose, dextran, glycerin, dextran, erythritol, glycerol, arabitol, sylitol, sorbitol, mannitol, mellibiose, melezitose, raffinose, mannotriose, stachyose, maltose, lactulose, maltulose, glucitol, maltitol, lactitol, or iso-maltulose.

[0122] Non-limiting examples of salts are acid addition salts and base addition salts. Acid addition salts include those derived from nontoxic inorganic acids, such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, phosphorous, and the like, as well as from nontoxic organic acids such as aliphatic mono- and dicarboxylic acids, phenyl -substituted alkanoic acids, hydroxy alkanoic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like. Base addition salts include those derived from alkaline earth metals, such as sodium, potassium, magnesium, calcium, and the like, as well as from nontoxic organic amines, such as N,N’ -dibenzylethylenediamine, N-methylglucamine, chloroprocaine, choline, diethanolamine, ethylenediamine, procaine, and the like. In some embodiments, the salt is sodium chloride (NaCl).

[0123] Agents (e.g., polynucleotides) described herein may be prepared in accordance with standard procedures and are administered at dosages that are selected to reduce, prevent, or eliminate, or to slow or halt progression of, a condition being treated (see, e.g., 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 ofwhich are incorporated herein by reference, for a general description of methods for administering various agents for human therapy).

[0124] “Administering” or “administration,” as used herein, refers to providing a compound, composition, or pharmaceutically acceptable salt thereof described herein to a subject in need of treatment or prevention. Administering can be performed, for example, once, a plurality of times, and / or over one or more extended periods. Administration includes both direct administration (including self-administration), and indirect administration (including an act of prescribing a drug or directing a subject to consume an agent). For example, as used herein, one (e.g., a physician) who instructs a subject (e.g., a human patient) to self-administer an agent (e.g., a drug), or to have an agent administered by another and / or who provides a patient with a prescription for a drug is administering an agent to a subject.

[0125] ‘ ‘A therapeutically effective amount,” “an effective amount” or “an effective dosage” refers to an amount effective, at dosages and for periods of time necessary, to achieve a desired therapeutic result (e.g., treatment, healing, inhibition or amelioration of physiological response or condition, etc.). A full therapeutic effect does not necessarily occur by administration of one dose and may occur only after administration of a series of doses. Thus, a therapeutically effective amount may be administered in one or more administrations. A therapeutically effective amount may vary according to factors such as the disease state, age, sex, and weight of a mammal (e.g., a human patient), mode of administration, and the ability of a therapeutic or a combination of therapeutics to elicit a desired response.

[0126] An effective amount of an agent to be administered can be determined by a clinician of ordinary skill using the guidance provided herein and other methods known in the art.Relevant factors include the given agent, the pharmaceutical formulation, the route of administration, the type of disease or disorder, the identity of the subject (e.g., age, sex, weight) or host being treated, and the like. For example, suitable dosages can be from about 0.001 mg / kg to about 100 mg / kg, from about 0.01 mg / kg to about 100 mg / kg, from about 0.01 mg / kg to about 10 mg / kg, from about 0.01 mg / kg to about 1 mg / kg body weight per treatment. Determining the dosage for a particular agent, subject and disease is well within the abilities of one of skill in the art. Preferably, the dosage does not cause or produces minimal adverse side effects.

[0127] Desired response or desired results include effects at the cellular level, tissue level, or clinical results. As such, “a therapeutically effective amount” or synonym thereto depends upon the context in which it is being applied. For example, in some embodiments it is an amount of the composition sufficient to achieve a treatment response as compared to the response obtained without administration of the composition. In other embodiments, it is an amount that results in a beneficial or desired result in a subject as compared to a control. As defined herein, a therapeutically effective amount of a composition (e.g., a pharmaceutical composition) disclosed herein may be readily determined by one of ordinary skill by routine methods known in the art. Dosage regimen and route of administration may be adjusted to provide the optimum therapeutic response.Antibodies or Antigen-Binding Fragments Thereof

[0128] In some embodiments, an antibody or an antigen-binding fragment thereof disclosed herein comprises an immunoglobulin heavy chain variable domain (VH), an immunoglobulin light chain variable domain (VL), or both.Heavy Chain Variable Domain (VH)

[0129] In some embodiments, an antibody or an antigen-binding fragment thereof comprises a VHdomain e.g., a mammalian VHdomain such as a rodent (e.g., mouse) VHdomain, a primate (e.g., human) VHdomain). In some embodiments, an antibody or an antigen-binding fragment thereof comprises a human VHdomain. In some embodiments, an antibody or an antigen-binding fragment thereof comprises a VHdomain that is humanized (e.g., at least about: 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98% or 99% humanized), contains human framework regions, or both.

[0130] In some embodiments, an antibody or an antigen-binding fragment thereof comprises a VHdomain having less than 100% sequence identity to the amino acid sequence of SEQ ID NO:1. In some embodiments, an antibody or an antigen-binding fragment thereof does not comprise a VHdomain comprising the amino acid sequence of SEQ ID NO: 1.

[0131] In some embodiments, an antibody or an antigen-binding fragment thereof comprises a VHdomain that:a) comprises a heavy chain complementarity-determining region (HCDR) 1, a HCDR2, and a HCDR3 having at least 80% sequence identity (e.g., having at least 85% sequence identity, having at least 90% sequence identity, or having at least 95% sequence identity) to a HCDR1, a HCDR2, and a HCDR3, respectively, of a Vndomain comprising the amino acid sequence of SEQ ID N0:X; b) has less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 1.

[0132] In some embodiments, an antibody or an antigen-binding fragment thereof comprises a VHdomain comprising a HCDR1, a HCDR2, and a HCDR3 having 100% sequence identity to a HCDR1, a HCDR2, and a HCDR3, respectively, of a VHdomain comprising the amino acid sequence of SEQ ID NO:X.

[0133] In some embodiments, X is any one of 1-11, 19-21, 299, and 300. The sequences identified as SEQ ID NOs: l-l l, 19-21, 299, and 300 are shown in Table 1, which correspond to human VH domains. 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 is applicable to paragraph

[0130] and / or paragraph

[0131] ,HCDRs Sequences as Determined by ImMunoGeneTics (TMGT) Numbering

[0134] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a HCDR1 having at least 80% sequence identity (e.g, having at least 85% sequence identity, having at least 90% sequence identity, or having at least 95% sequence identity) to the amino acid sequence of SEQ ID NO:X,b) a HCDR2 having at least 80% sequence identity (e.g., having at least 85% sequence identity, having at least 90% sequence identity, or having at least 95% sequence identity) to the amino acid sequence of SEQ ID NO:72, and c) a HCDR3 having at least 80% sequence identity (e.g., having at least 85% sequence identity, having at least 90% sequence identity, or having at least 95% sequence identity) to the amino acid sequence of SEQ ID NO:79, wherein the antibody or the antigen-binding fragment thereof comprises a VHdomain having less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 1.

[0135] The disclosure also provides, among other things, an antibody or an antigen-binding fragment thereof comprising: a) a HCDR1 having at least 80% sequence identity (e.g., having at least 85% sequence identity, having at least 90% sequence identity, or having at least 95% sequence identity) to the amino acid sequence of SEQ ID N0:X, b) a HCDR2 having at least 80% sequence identity (e.g., having at least 85% sequence identity, having at least 90% sequence identity, or having at least 95% sequence identity) to the amino acid sequence of SEQ ID NO:72, and c) a HCDR3 having at least 80% sequence identity (e.g., having at least 85% sequence identity, having at least 90% sequence identity, or having at least 95% sequence identity) to the amino acid sequence of SEQ ID NO:79, wherein the antibody or the antigen-binding fragment thereof comprises a VHdomain having less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 1.

[0136] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a HCDR1 comprising (e.g., consisting of) the amino acid sequence of SEQ ID N0:X, b) a HCDR2 comprising (e.g., consisting of) the amino acid sequence of SEQ ID NO:72, and c) a HCDR3 comprising (e.g., consisting of) the amino acid sequence of SEQ ID NO:79.

[0137] 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 is46. 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 is applicable to any one or more of paragraphs

[0133] -

[0135] ,

[0138] The sequences identified as SEQ ID NOs:45-47, 49-51, 72, 79, 303, and 304 are shown in Table 2, which correspond to human HCDR sequences determined by IMGT numbering.

[0139] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a HCDR1 comprising (e.g., consisting of) the amino acid sequence of SEQ ID NO:45, b) a HCDR2 comprising (e.g., consisting of) the amino acid sequence of SEQ ID NO:72, and c) a HCDR3 comprising (e.g., consisting of) the amino acid sequence of SEQ ID NO:79.

[0140] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a HCDR1 comprising (e.g., consisting of) the amino acid sequence of SEQ ID NO:303, b) a HCDR2 comprising (e.g., consisting of) the amino acid sequence of SEQ ID NO:72, and c) a HCDR3 comprising (e.g., consisting of) the amino acid sequence of SEQ ID NO:79.

[0141] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a HCDR1 comprising (e.g., consisting of) the amino acid sequence of SEQ ID NO:304, b) a HCDR2 comprising (e.g., consisting of) the amino acid sequence of SEQ ID NO:72, and c) a HCDR3 comprising (e.g., consisting of) the amino acid sequence of SEQ ID NO:79.HCDR Sequences as Determined by Kabat Numbering

[0142] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a HCDR1 having at least 80% sequence identity (e.g., having at least 85% sequence identity, having at least 90% sequence identity, or having at least 95% sequence identity) to the amino acid sequence of SEQ ID N0:X, b) a HCDR2 having at least 80% sequence identity (e.g., having at least 85% sequence identity, having at least 90% sequence identity, or having at least 95% sequence identity) to the amino acid sequence of SEQ ID NO:96, andc) a HCDR3 having at least 80% sequence identity (e.g., having at least 85% sequence identity, having at least 90% sequence identity, or having at least 95% sequence identity) to the amino acid sequence of SEQ ID NO: 103, wherein the antibody or the antigen-binding fragment thereof comprises a Vndomain having less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 1.

[0143] The disclosure also provides, among other things, an antibody or an antigen-binding fragment thereof comprising: a) a HCDR1 having at least 80% sequence identity (e.g., having at least 85% sequence identity, having at least 90% sequence identity, or having at least 95% sequence identity) to the amino acid sequence of SEQ ID N0:X, b) a HCDR2 having at least 80% sequence identity (e.g., having at least 85% sequence identity, having at least 90% sequence identity, or having at least 95% sequence identity) to the amino acid sequence of SEQ ID NO:96, and c) a HCDR3 having at least 80% sequence identity (e.g., having at least 85% sequence identity, having at least 90% sequence identity, or having at least 95% sequence identity) to the amino acid sequence of SEQ ID NO: 103, wherein the antibody or the antigen-binding fragment thereof comprises a VHdomain having less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 1.

[0144] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a HCDR1 comprising (e.g., consisting of) the amino acid sequence of SEQ ID N0:X, b) a HCDR2 comprising (e.g., consisting of) the amino acid sequence of SEQ ID NO:96, and c) a HCDR3 comprising (e.g., consisting of) the amino acid sequence of SEQ ID NO: 103, wherein the antibody or the antigen-binding fragment thereof comprises a VHdomain having less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 1.

[0145] 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 is applicable to any one or more of paragraphs

[0141] -

[0143] ,

[0146] The sequences identified as SEQ ID NOs:80-82, 96 and 103 are shown in Table 2, which correspond to human HCDR sequences determined by Kabat numbering.HCDR Sequences as Determined by Chothia Numbering

[0147] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a HCDR1 having at least 80% sequence identity (e.g., having at least 85% sequence identity, having at least 90% sequence identity, or having at least 95% sequence identity) to the amino acid sequence of SEQ ID N0:X, b) a HCDR2 having at least 80% sequence identity (e.g., having at least 85% sequence identity, having at least 90% sequence identity, or having at least 95% sequence identity) to the amino acid sequence of SEQ ID NO: 132, and c) a HCDR3 having at least 80% sequence identity (e.g., having at least 85% sequence identity, having at least 90% sequence identity, or having at least 95% sequence identity) to the amino acid sequence of SEQ ID NO: 139, wherein the antibody or the antigen-binding fragment thereof comprises a VHdomain having less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 1.

[0148] The disclosure also provides, among other things, an antibody or an antigen-binding fragment thereof comprising: a) a HCDR1 having at least 80% sequence identity (e.g., having at least 85% sequence identity, having at least 90% sequence identity, or having at least 95% sequence identity) to the amino acid sequence of SEQ ID N0:X, b) a HCDR2 having at least 80% sequence identity (e.g., having at least 85% sequence identity, having at least 90% sequence identity, or having at least 95% sequence identity) to the amino acid sequence of SEQ ID NO: 132, and c) a HCDR3 having at least 80% sequence identity (e.g., having at least 85% sequence identity, having at least 90% sequence identity, or having at least 95% sequence identity) to the amino acid sequence of SEQ ID NO: 139, wherein the antibody or the antigen-binding fragment thereof comprises a VHdomain having less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 1.

[0149] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a HCDR1 comprising (e.g., consisting of) the amino acid sequence of SEQ ID NO:X, b) a HCDR2 comprising (e.g., consisting of) the amino acid sequence of SEQ ID NO: 132, andc) a HCDR3 comprising (e.g., consisting of) the amino acid sequence of SEQ ID NO: 139.

[0150] 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 is applicable to any one or more of paragraphs

[0147] -

[0149] ,

[0151] The sequences identified as SEQ ID NOs: 105-107, 109-111, 132, 139, 305, and 306 are shown in Table 2, which correspond to human HCDR sequences determined by Chothia numbering.

[0152] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a HCDR1 comprising (e.g., consisting of) the amino acid sequence of SEQ ID NO: 105, b) a HCDR2 comprising (e.g., consisting of) the amino acid sequence of SEQ ID NO: 132, and c) a HCDR3 comprising (e.g., consisting of) the amino acid sequence of SEQ ID NO: 139.

[0153] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a HCDR1 comprising (e.g., consisting of) the amino acid sequence of SEQ ID NO:305, b) a HCDR2 comprising (e.g., consisting of) the amino acid sequence of SEQ ID NO: 132, and c) a HCDR3 comprising (e.g., consisting of) the amino acid sequence of SEQ ID NO: 139.

[0154] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a HCDR1 comprising (e.g., consisting of) the amino acid sequence of SEQ ID NO:306, b) a HCDR2 comprising (e.g., consisting of) the amino acid sequence of SEQ ID NO: 132, and c) a HCDR3 comprising (e.g., consisting of) the amino acid sequence of SEQ ID NO: 139.Vn framework regions (VH FR1-4)

[0155] In some embodiments, a VHdomain of an antibody or an antigen-binding fragment thereof comprises four VHframework regions (VHFR1-4) and three heavy chaincomplementarity determining regions (HCDR1-3) in the following N-terminal to C-terminal order: VHFR1-HCDR1-VHFR2-HCDR2-VHFR3-HCDR3-VHFR4, wherein: a) the VHFR1-HCDR1 comprises the amino acid sequence of SEQ ID NO:X, b) the VnFR2 comprises the amino acid sequence of GKGL (SEQ ID NO:268), GDYL (SEQ ID NO:269), or GYYL (SEQ ID NO:270), or c) the VHFR3 comprises the amino acid sequence of NSLK (SEQ ID NO:271), PSLR (SEQ ID NO: 272), or NDLR (SEQ ID NO: 273), or any combination of a) to c).

[0156] In some embodiments, an antibody or an antigen-binding fragment thereof comprises a VHFR1-HCDR1 comprising the amino acid sequence of SEQ ID NO:X, and a) a VHFR2 comprising the amino acid sequence of GKGL (SEQ ID NO:268), GDYL (SEQ ID NO:269), or GYYL (SEQ ID NO:270), or b) a VH FR3 comprising 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).

[0157] In some embodiments, an antibody or an antigen-binding fragment thereof comprises a VHFR1-HCDR1 comprising the amino acid sequence of SEQ ID NO:X, and a) a VHFR2 comprising the amino acid sequence of GKGL (SEQ ID NO:268), GDYL (SEQ ID NO: 269), or GYYL (SEQ ID NO: 270), and b) a VHFR3 comprising the amino acid sequence of NSLK (SEQ ID NO:271), PSLR (SEQ ID NO:272), or NDLR (SEQ ID NO:273).

[0158] In some embodiments, an antibody or an antigen-binding fragment thereof comprises a VHFR2 comprising the amino acid sequence of GKGL (SEQ ID NO:268), GDYL (SEQ ID NO:269), or GYYL (SEQ ID NO:270), and a) a VHFR1-HCDR1 comprising the amino acid sequence of SEQ ID NO:X, or b) a VHFR3 comprising 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).

[0159] In some embodiments, an antibody or an antigen-binding fragment thereof comprises a VHFR2 comprising the amino acid sequence of GKGL (SEQ ID NO:268), GDYL (SEQ ID NO:269), or GYYL (SEQ ID NO:270), and a) a VnFR1-HCDR1 comprising the amino acid sequence of SEQ ID NO:X, and b) a VH FR3 comprising the amino acid sequence of NSLK (SEQ ID NO:271), PSLR (SEQ ID NO:272), or NDLR (SEQ ID NO:273).

[0160] In some embodiments, an antibody or an antigen-binding fragment thereof comprises a VHFR2 comprising the amino acid sequence of GKGL (SEQ ID NO:268), and a) a VHFR1-HCDR1 comprising the amino acid sequence of SEQ ID NO:X, or b) a VHFR3 comprising 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).

[0161] In some embodiments, an antibody or an antigen-binding fragment thereof comprises a VHFR2 comprising the amino acid sequence of GKGL (SEQ ID NO:268), and a) a VHFR1-HCDR1 comprising the amino acid sequence of SEQ ID NO:X, and b) a VHFR3 comprising the amino acid sequence of NSLK (SEQ ID NO:271), PSLR (SEQ ID NO:272), or NDLR (SEQ ID NO:273).

[0162] In some embodiments, an antibody or an antigen-binding fragment thereof comprises a VHFR2 comprising the amino acid sequence of GDYL (SEQ ID NO:269), and a) a VHFR1-HCDR1 comprising the amino acid sequence of SEQ ID NO:X, or b) a VHFR3 comprising 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).

[0163] In some embodiments, an antibody or an antigen-binding fragment thereof comprises a VHFR2 comprising the amino acid sequence of GDYL (SEQ ID NO:269), and a) a VHFR1-HCDR1 comprising the amino acid sequence of SEQ ID NO:X, and b) a VH FR3 comprising the amino acid sequence of NSLK (SEQ ID NO:271), PSLR (SEQ ID NO:272), or NDLR (SEQ ID NO:273).

[0164] In some embodiments, an antibody or an antigen-binding fragment thereof comprises a VHFR2 comprising the amino acid sequence of GYYL (SEQ ID NO:270), anda) a VHFR1 -HCDR1 comprising the amino acid sequence of SEQ ID NO:X, or b) a VHFR3 comprising 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).

[0165] In some embodiments, an antibody or an antigen-binding fragment thereof comprises a VHFR2 comprising the amino acid sequence of GYYL (SEQ ID NO:270), and a) a VHFR1-HCDR1 comprising the amino acid sequence of SEQ ID NO:X, and b) a VHFR3 comprising the amino acid sequence of NSLK (SEQ ID NO:271), PSLR (SEQ ID NO:272), or NDLR (SEQ ID NO:273).

[0166] In some embodiments, an antibody or an antigen-binding fragment thereof comprises a VHFR3 comprising the amino acid sequence of NSLK (SEQ ID NO:271), PSLR (SEQ ID NO:272), or NDLR (SEQ ID NO:273), and a) a VH FR1-HCDR1 comprising the amino acid sequence of SEQ ID NO:X, or b) a VHFR2 comprising 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).

[0167] In some embodiments, an antibody or an antigen-binding fragment thereof comprises a VHFR3 comprising the amino acid sequence of NSLK (SEQ ID NO:271), PSLR (SEQ ID NO:272), or NDLR (SEQ ID NO:273), and a) a VHFR1-HCDR1 comprising the amino acid sequence of SEQ ID NO:X, and b) a VHFR2 comprising the amino acid sequence of GKGL (SEQ ID NO:268), GDYL (SEQ ID NO:269), or GYYL (SEQ ID NO:270).

[0168] In some embodiments, an antibody or an antigen-binding fragment thereof comprises a VHFR3 comprising the amino acid sequence of NSLK (SEQ ID NO:271), and a) a VHFR1-HCDR1 comprising the amino acid sequence of SEQ ID NO:X, or b) a VHFR2 comprising 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).

[0169] In some embodiments, an antibody or an antigen-binding fragment thereof comprises a VHFR3 comprising the amino acid sequence of NSLK (SEQ ID NO:271), anda) a VHFR1 -HCDR1 comprising the amino acid sequence of SEQ ID NO:X, and b) a VHFR2 comprising the amino acid sequence of GKGL (SEQ ID NO:268), GDYL (SEQ ID NO:269), or GYYL (SEQ ID NO:270).

[0170] In some embodiments, an antibody or an antigen-binding fragment thereof comprises a VH FR3 comprising the amino acid sequence of PSLR (SEQ ID NO:272), and a) a VHFR1-HCDR1 comprising the amino acid sequence of SEQ ID NO:X, or b) a VHFR2 comprising 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).

[0171] In some embodiments, an antibody or an antigen-binding fragment thereof comprises a VHFR3 comprising the amino acid sequence of PSLR (SEQ ID NO:272), and a) a VHFR1-HCDR1 comprising the amino acid sequence of SEQ ID NO:X, and b) a VH FR2 comprising the amino acid sequence of GKGL (SEQ ID NO:268), GDYL (SEQ ID NO:269), or GYYL (SEQ ID NO:270).

[0172] In some embodiments, an antibody or an antigen-binding fragment thereof comprises a VHFR3 comprising the amino acid sequence of NDLR (SEQ ID NO:273), and a) a VHFR1-HCDR1 comprising the amino acid sequence of SEQ ID NO:X, or b) a VHFR2 comprising 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).

[0173] In some embodiments, an antibody or an antigen-binding fragment thereof comprises a VHFR3 comprising the amino acid sequence of NDLR (SEQ ID NO:273), and a) a VHFR1-HCDR1 comprising the amino acid sequence of SEQ ID NO:X, and b) a VHFR2 comprising the amino acid sequence of GKGL (SEQ ID NO:268), GDYL (SEQ ID NO:269), or GYYL (SEQ ID NO:270).

[0174] 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 is applicable to any one or more of paragraphs

[0154] -

[0172] ,

[0175] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VHFR1-HCDR1 comprising the amino acid sequence of SEQ ID NO:262, b) a VHFR2 comprising the amino acid sequence of GKGL (SEQ ID NO:268), and c) a VnFR3 comprising the amino acid sequence of PSLR (SEQ ID NO:272).

[0176] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VHFR1-HCDR1 comprising the amino acid sequence of SEQ ID NO:262, b) a VHFR2 comprising the amino acid sequence of GKGL (SEQ ID NO:268), and c) a VHFR3 comprising the amino acid sequence of NDLR (SEQ ID NO:273).

[0177] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VHFR1-HCDR1 comprising the amino acid sequence of SEQ ID NO:262, b) a VHFR2 comprising the amino acid sequence of GKGL (SEQ ID NO:268), and c) a VHFR3 comprising the amino acid sequence of NSLK (SEQ ID NO:271).

[0178] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VH FR1-HCDR1 comprising the amino acid sequence of SEQ ID NO:309, 310, or 262, b) a VHFR2 comprising the amino acid sequence of GKGL (SEQ ID NO:268), and c) a VHFR3 comprising the amino acid sequence of NSLK (SEQ ID NO:271).

[0179] In paragraphs

[0141] -

[0164] , the HCDR1, HCDR2, and HCDR3 sequences can be any HCDR1, HCDR2, and HCDR3 sequences disclosed in any one of paragraphs

[0117] -

[0164] ,VH

[0180] In some embodiments, an antibody or an antigen-binding fragment thereof comprises a Vndomain having at least 70% sequence identity (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity) to the amino acid sequence of SEQ ID NO:X, wherein the VHdomain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO:1.

[0181] In some embodiments, an antibody or an antigen-binding fragment thereof comprises a VHcomprising at least one amino acid substitution relative to the amino acid sequence of SEQ ID NO:X, wherein the VHdomain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 1. 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, an antibody or an antigen-binding fragment thereof comprises a VHthat comprises about 1-10 amino acid substitutions, relative to the amino acid sequence of SEQ ID N0:X.

[0182] In some embodiments, an amino acid substitution is a conservative substitution. The term “a conservative amino acid substitution” or “a conservative substitution” refers to an amino acid substitution having a value of 0 or greater in BLOSUM62.

[0183] In some embodiments, an amino acid substitution is a highly conservative substitution. The term “a highly conservative amino acid substitution” or “a highly conservative substitution” refers to an amino acid substitution having a value of at least 1 (e.g., at least 2) in BLOSUM62.

[0184] In some embodiments, an antibody or an antigen-binding fragment thereof comprises a VH having 100% sequence identity to the amino acid sequence of SEQ ID N0:X. In some embodiments, an antibody or an antigen-binding fragment thereof comprises a VHcomprising (e.g, consisting of) the amino acid sequence of SEQ ID N0:X.

[0185] 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 is applicable to any one or more of paragraphs

[0179] -

[0183] ,

[0186] In some embodiments, an antibody or an antigen-binding fragment thereof comprises a VH domain having at least 70% sequence identity (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity) to the amino acid sequence of SEQ ID NO:2, wherein the VHdomain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 1.

[0187] In some embodiments, an antibody or an antigen-binding fragment thereof comprises a VHdomain having at least 70% sequence identity (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity) to the amino acid sequence of SEQ ID NO:3, wherein the Vndomain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO:1.

[0188] In some embodiments, an antibody or an antigen-binding fragment thereof comprises a VHdomain having at least 70% sequence identity (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity) to the amino acid sequence of SEQ ID NO:4, wherein the VHdomain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO:1.

[0189] In some embodiments, an antibody or an antigen-binding fragment thereof comprises a VHdomain having at least 70% sequence identity (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity) to the amino acid sequence of SEQ ID NO:299, wherein the VHdomain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO:1.

[0190] In some embodiments, an antibody or an antigen-binding fragment thereof comprises a VHdomain having at least 70% sequence identity e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity) to the amino acid sequence of SEQ ID NO OO, wherein the VHdomain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 1.Light Chain Variable Domain (VJ

[0191] In some embodiments, an antibody or an antigen-binding fragment thereof comprises a VL domain (e.g., a mammalian VL domain such as a rodent (e.g., mouse) VL domain, a primate (e.g., human) VLdomain). In some embodiments, an antibody or an antigen-binding fragment thereof comprises a human VLdomain. In some embodiments, an antibody or an antigen-binding fragment thereof comprises a VL domain that is humanized (e.g., at least about: 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98% or 99% humanized), contains human framework regions, or both.

[0192] In some embodiments, an antibody or an antigen-binding fragment thereof comprises a VLdomain having less than 100% sequence identity to the amino acid sequence of SEQ IDNO: 140. In some embodiments, an antibody or an antigen-binding fragment thereof does not comprise a VLdomain comprising the amino acid sequence of SEQ ID NO: 140.

[0193] In some embodiments, an antibody or an antigen-binding fragment thereof comprises a VLdomain comprising a light chain complementarity-determining region (LCDR) 1, a LCDR2, and a LCDR3 having at least 80% sequence identity (e.g., having at least 85% sequence identity, having at least 90% sequence identity, or having at least 95% sequence identity) to a LCDR1, a LCDR2, and a LCDR3, respectively, of a VLdomain comprising the amino acid sequence of SEQ ID NO:Y. In some embodiments, the VLdomain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 140.

[0194] In some embodiments, an antibody or an antigen-binding fragment thereof comprises a VLdomain comprising a LCDR1, a LCDR2, and a LCDR3 having 100% sequence identity to a LCDR1, a LCDR2, and a LCDR3, respectively, of a VLdomain comprising the amino acid sequence of SEQ ID NO:Y.

[0195] In some embodiments, Y is any one of 140-145, 301, and 302. The sequences identified as SEQ ID NOs: 140-145, 301, and 302 are shown in Table 3, which correspond to human VL domains. In some embodiments, Y is any one of 141-145, 301, and 302. In some embodiments, Y is any one of 144, 142, 301, and 302. In some embodiments, Y is any one of 144, 301, and 302. In some embodiments, Y is 301. In some embodiments, Y is 302. In some embodiments, Y is any one of 140-145. In some embodiments, Y is any one of 141-145. In some embodiments, Y is 144 or 142. In some embodiments, Y is 140. In some embodiments, Y is 141. In some embodiments, Y is 142. In some embodiments, Y is 143. In some embodiments, Y is 144. In some embodiments, Y is 145. This paragraph is applicable to paragraph

[0192] and / or paragraph

[0193] ,LCDR Sequences as Determined by IMGT Numbering

[0196] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a LCDR1 having at least 80% sequence identity (e.g., having at least 85% sequence identity, having at least 90% sequence identity, or having at least 95% sequence identity) to the amino acid sequence of SEQ ID NO: 146, b) a LCDR2 comprising e.g., consisting of) the amino acid sequence of AAS, IAS, or YAS, andc) a LCDR3 having at least 80% sequence identity (e.g., having at least 85% sequence identity, having at least 90% sequence identity, or having at least 95% sequence identity) to the amino acid sequence of SEQ ID NO: 150, wherein the antibody or the antigen-binding fragment thereof comprises a VLdomain having less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 140.

[0197] The sequences identified as SEQ ID NOs:146 and 150 are shown in Table 4, which correspond to human LCDR sequences determined by IMGT numbering.

[0198] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a LCDR1 comprising (e.g., consisting of) the amino acid sequence of SEQ ID NO: 146, b) a LCDR2 comprising (e.g., consisting of) the amino acid sequence of AAS, IAS, or YAS, and c) a LCDR3 comprising (e.g., consisting of) the amino acid sequence of SEQ ID NO: 150, wherein the antibody or the antigen-binding fragment thereof comprises a VL domain having less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 140.

[0199] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a LCDR1 having at least 80% sequence identity (e.g., having at least 85% sequence identity, having at least 90% sequence identity, or having at least 95% sequence identity) to the amino acid sequence of SEQ ID NO: 146, b) a LCDR2 comprising (e.g., consisting of) the amino acid sequence of AAS, and c) a LCDR3 having at least 80% sequence identity (e.g., having at least 85% sequence identity, having at least 90% sequence identity, or having at least 95% sequence identity) to the amino acid sequence of SEQ ID NO: 150, wherein the antibody or the antigen-binding fragment thereof comprises a VLdomain having less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 140.

[0200] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a LCDR1 comprising (e.g., consisting of) the amino acid sequence of SEQ ID NO: 146, b) a LCDR2 comprising (e.g., consisting of) the amino acid sequence of AAS, and c) a LCDR3 comprising (e.g., consisting of) the amino acid sequence of SEQ ID NO: 150, wherein the antibody or the antigen-binding fragment thereof comprises a VLdomain having less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 140.

[0201] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a LCDR1 having at least 80% sequence identity (e.g., having at least 85% sequence identity, having at least 90% sequence identity, or having at least 95% sequence identity) to the amino acid sequence of SEQ ID NO: 146, b) a LCDR2 comprising (e.g., consisting of) the amino acid sequence of IAS, and c) a LCDR3 having at least 80% sequence identity (e.g., having at least 85% sequence identity, having at least 90% sequence identity, or having at least 95% sequence identity) to the amino acid sequence of SEQ ID NO: 150.

[0202] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a LCDR1 comprising (e.g., consisting of) the amino acid sequence of SEQ ID NO: 146, b) a LCDR2 comprising (e.g., consisting of) the amino acid sequence of IAS, and c) a LCDR3 comprising (e.g., consisting of) the amino acid sequence of SEQ ID NO: 150.

[0203] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a LCDR1 having at least 80% sequence identity (e.g., having at least 85% sequence identity, having at least 90% sequence identity, or having at least 95% sequence identity) to the amino acid sequence of SEQ ID NO: 146, b) a LCDR2 comprising (e.g., consisting of) the amino acid sequence of YAS, and c) a LCDR3 having at least 80% sequence identity (e.g., having at least 85% sequence identity, having at least 90% sequence identity, or having at least 95% sequence identity) to the amino acid sequence of SEQ ID NO: 150.

[0204] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a LCDR1 comprising (e.g., consisting of) the amino acid sequence of SEQ ID NO: 146, b) a LCDR2 comprising (e.g., consisting of) the amino acid sequence of YAS, and c) a LCDR3 comprising (e.g., consisting of) the amino acid sequence of SEQ ID NO: 150.LCDR Sequences as Determined by Kabat or Chothia Numbering

[0205] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a LCDR1 having at least 80% sequence identity (e.g., having at least 85% sequence identity, having at least 90% sequence identity, or having at least 95% sequence identity) to the amino acid sequence of SEQ ID NO: 151,b) a LCDR2 having at least 80% sequence identity (e.g., having at least 85% sequence identity, having at least 90% sequence identity, or having at least 95% sequence identity) to the amino acid sequence of SEQ ID N0:Y, and c) a LCDR3 having at least 80% sequence identity (e.g., having at least 85% sequence identity, having at least 90% sequence identity, or having at least 95% sequence identity) to the amino acid sequence of SEQ ID NO: 150, wherein the antibody or the antigen-binding fragment thereof comprises a VLdomain having less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 140.

[0206] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a LCDR1 comprising (e.g., consisting of) the amino acid sequence of SEQ ID NO: 151, b) a LCDR2 comprising (e.g., consisting of) the amino acid sequence of SEQ ID NO:Y, and c) a LCDR3 comprising (e.g., consisting of) the amino acid sequence of SEQ ID NO: 150, wherein the antibody or the antigen-binding fragment thereof comprises a VL domain having less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 140.

[0207] In some embodiments, Y is any one of 152-157, 307, and 308. The sequences identified as SEQ ID NOs: 150-157, 307, and 308 are shown in Table 4, which correspond to human LCDR sequences determined by Kabat or Chothia numbering. In some embodiments, Y is any one of 153-157, 307, and 308. In some embodiments, Y is 156, 154, 307, or 308. In some embodiments, Y is 307. In some embodiments, Y is 308. In some embodiments, Y is any one of 152-157. In some embodiments, Y is any one of 153-157. In some embodiments, Y is 156 or 154. In some embodiments, Y is 152. In some embodiments, Y is 153. In some embodiments, Y is 154. In some embodiments, Y is 155. In some embodiments, Y is 156. In some embodiments, Y is 157. This paragraph is applicable to paragraph

[0204] and / or paragraph

[0205] ,YL

[0208] In some embodiments, an antibody or an antigen-binding fragment thereof comprises a VL domain having at least 70% sequence identity (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity) to the amino acid sequence of SEQ ID NO:Y, wherein the VLdomain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 140.

[0209] In some embodiments, an antibody or an antigen-binding fragment thereof comprises a VLcomprising at least one amino acid substitution relative to the amino acid sequence of SEQ ID N0:Y, wherein the VLdomain has less than 100% sequence identity to 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, an antibody or an antigen-binding fragment thereof comprises a VLthat comprises about 1-10 amino acid substitutions, relative to the amino acid sequence of SEQ ID N0:Y. In some embodiments, an amino acid substitution is a conservative substitution. In some embodiments, an amino acid substitution is a highly conservative substitution.

[0210] In some embodiments, an antibody or an antigen-binding fragment thereof comprises a VLhaving 100% sequence identity to the amino acid sequence of SEQ ID N0:Y. In some embodiments, an antibody or an antigen-binding fragment thereof comprises a VL comprising (e. , consisting of) the amino acid sequence of SEQ ID NO:Y.

[0211] 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 is applicable to any one or more of paragraphs

[0207] -

[0209] ,

[0212] In some embodiments, an antibody or an antigen-binding fragment thereof comprises a VLdomain having at least 70% sequence identity (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity) to the amino acid sequence of SEQ ID NO: 144, wherein the VLdomain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 140.

[0213] In some embodiments, an antibody or an antigen-binding fragment thereof comprises a VLhaving 100% sequence identity to the amino acid sequence of SEQ ID NO: 144.

[0214] In some embodiments, an antibody or an antigen-binding fragment thereof comprises a VLdomain having at least 70% sequence identity (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity) to the amino acid sequence of SEQ ID NO: 142, wherein the VLdomain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 140.

[0215] In some embodiments, an antibody or an antigen-binding fragment thereof comprises a VLhaving 100% sequence identity to the amino acid sequence of SEQ ID NO: 142.

[0216] In some embodiments, an antibody or an antigen-binding fragment thereof comprises a VLdomain having at least 70% sequence identity (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity) to the amino acid sequence of SEQ ID NO:301, wherein the VL domain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 140.

[0217] In some embodiments, an antibody or an antigen-binding fragment thereof comprises a VLhaving 100% sequence identity to the amino acid sequence of SEQ ID NO:301.

[0218] In some embodiments, an antibody or an antigen-binding fragment thereof comprises a VLdomain having at least 70% sequence identity (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity) to the amino acid sequence of SEQ ID NO: 302, wherein the VLdomain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 140.

[0219] In some embodiments, an antibody or an antigen-binding fragment thereof comprises a VLhaving 100% sequence identity to the amino acid sequence of SEQ ID NO:302. vH / vL

[0220] In some embodiments, an antibody or an antigen-binding fragment thereof does not comprise: a) a VHdomain comprising the amino acid sequence of SEQ ID NO: 1, b) a VLdomain comprising the amino acid sequence of SEQ ID NO: 140, or both a) and b).

[0221] In some embodiments, an antibody or an antigen-binding fragment thereof comprises:a) a VHhaving less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 1, b) a VLhaving less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 140, or both a) and b).

[0222] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VHdomain comprising a HCDR1, a HCDR2, and a HCDR3 having at least 80% sequence identity (e.g., having at least 85% sequence identity, having at least 90% sequence identity, or having at least 95% sequence identity) to a HCDR1, a HCDR2, and a HCDR3, respectively, of a VHdomain comprising the amino acid sequence of SEQ ID NO:X, and b) a VLdomain comprising a LCDR1, a LCDR2, and a LCDR3 having at least 80% sequence identity (e.g., having at least 85% sequence identity, having at least 90% sequence identity, or having at least 95% sequence identity) to a LCDR1, a LCDR2, and a LCDR3, respectively, of a VLdomain comprising the amino acid sequence of SEQ ID NO Y, wherein: i. the VHdomain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 1, ii. the VLdomain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 140, or both i and ii.

[0223] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VHdomain comprising a HCDR1, a HCDR2, and a HCDR3 having 100% sequence identity to a HCDR1, a HCDR2, and a HCDR3, respectively, of a VHdomain comprising the amino acid sequence of SEQ ID NO:X, and b) a VL domain comprising a LCDR1, a LCDR2, and a LCDR3 having 100% sequence identity to a LCDR1, a LCDR2, and a LCDR3, respectively, of a VLdomain comprising the amino acid sequence of SEQ ID NO:Y, wherein:i. the VHdomain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO:!, ii. the VLdomain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 140, or both i and ii.

[0224] 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.

[0225] 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.

[0226] 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, and300, and Y is any one of 144, 142, 301, and 302.

[0227] In some embodiments, X is any one of 2-4, 299, and 300, and Y is any one of 144,301, and 302.

[0228] 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.

[0229] 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, andY is any one of 141-145.

[0230] 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.

[0231] In some embodiments, X is any one of 2-4, and Y is 144.

[0232] 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.

[0233] 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.

[0234] 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.

[0235] 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.

[0236] 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 142or 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.

[0237] In some embodiments, X is 300, and Y is any one of 144, 142, 140, 301, and 302. In some embodiments, X is 300, and Y is any one of 144, 142, 301, and 302. In some embodiments, X is 300, and Y is any one of 144, 142, and 140. In some embodiments, X is 300, and Y is 142 or 144. In some embodiments, X is 300, and Y is 144. In some embodiments, X is 300, and Y is 142. In some embodiments, X is 300, and Y is 140. In some embodiments, X is 300, and Y is 301. In some embodiments, X is 300, and Y is 302.

[0238] 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.

[0239] 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.

[0240] 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.

[0241] 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 anyone of 4, 299, and 300, and Y is 301 . Tn 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 is301. 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.

[0242] 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 is302. 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.

[0243] Any one of paragraphs

[0223] -

[0241] can be applicable to paragraph

[0221] and / or paragraph

[0222] ,

[0244] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VHdomain comprising a HCDR1, a HCDR2, and a HCDR3 having 100% sequence identity to a HCDR1, a HCDR2, and a HCDR3, respectively, of a VHdomain comprising the amino acid sequence of SEQ ID NO:2, and b) a VLdomain comprising a LCDR1, a LCDR2, and a LCDR3 having 100% sequence identity to a LCDR1, a LCDR2, and a LCDR3, respectively, of a VLdomain comprising the amino acid sequence of SEQ ID NO: 144.

[0245] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VHdomain comprising a HCDR1, a HCDR2, and a HCDR3 having 100% sequence identity to a HCDR1, a HCDR2, and a HCDR3, respectively, of a VHdomain comprising the amino acid sequence of SEQ ID NO:3, and b) a VLdomain comprising a LCDR1, a LCDR2, and a LCDR3 having 100% sequence identity to a LCDR1, a LCDR2, and a LCDR3, respectively, of a VL domain comprising the amino acid sequence of SEQ ID NO: 144.

[0246] In some embodiments, an antibody or an antigen-binding fragment thereof comprises:a) a VHdomain comprising a HCDR1 , a HCDR2, and a HCDR3 having 100% sequence identity to a HCDR1, a HCDR2, and a HCDR3, respectively, of a VHdomain comprising the amino acid sequence of SEQ ID NO:4, and b) a VLdomain comprising a LCDR1, a LCDR2, and a LCDR3 having 100% sequence identity to a LCDR1, a LCDR2, and a LCDR3, respectively, of a VL domain comprising the amino acid sequence of SEQ ID NO: 140.

[0247] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VHdomain comprising a HCDR1, a HCDR2, and a HCDR3 having 100% sequence identity to a HCDR1, a HCDR2, and a HCDR3, respectively, of a VHdomain comprising the amino acid sequence of SEQ ID NO:299, and b) a VLdomain comprising a LCDR1, a LCDR2, and a LCDR3 having 100% sequence identity to a LCDR1, a LCDR2, and a LCDR3, respectively, of a VLdomain comprising the amino acid sequence of SEQ ID NO: 140.

[0248] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VHdomain comprising a HCDR1, a HCDR2, and a HCDR3 having 100% sequence identity to a HCDR1, a HCDR2, and a HCDR3, respectively, of a VHdomain comprising the amino acid sequence of SEQ ID NO: 300, and b) a VLdomain comprising a LCDR1, a LCDR2, and a LCDR3 having 100% sequence identity to a LCDR1, a LCDR2, and a LCDR3, respectively, of a VLdomain comprising the amino acid sequence of SEQ ID NO: 140.

[0249] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VHdomain comprising a HCDR1, a HCDR2, and a HCDR3 having 100% sequence identity to a HCDR1, a HCDR2, and a HCDR3, respectively, of a VHdomain comprising the amino acid sequence of SEQ ID NO: 1, and b) a VLdomain comprising a LCDR1, a LCDR2, and a LCDR3 having 100% sequence identity to a LCDR1, a LCDR2, and a LCDR3, respectively, of a VLdomain comprising the amino acid sequence of SEQ ID NO: 142.

[0250] In some embodiments, an antibody or an antigen-binding fragment thereof comprises:a) a VHdomain comprising a HCDR1 , a HCDR2, and a HCDR3 having 100% sequence identity to a HCDR1, a HCDR2, and a HCDR3, respectively, of a VHdomain comprising the amino acid sequence of SEQ ID NO: 1, and b) a VLdomain comprising a LCDR1, a LCDR2, and a LCDR3 having 100% sequence identity to a LCDR1, a LCDR2, and a LCDR3, respectively, of a VL domain comprising the amino acid sequence of SEQ ID NO: 144.

[0251] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VHdomain comprising a HCDR1, a HCDR2, and a HCDR3 having 100% sequence identity to a HCDR1, a HCDR2, and a HCDR3, respectively, of a VHdomain comprising the amino acid sequence of SEQ ID NO: 1, and b) a VLdomain comprising a LCDR1, a LCDR2, and a LCDR3 having 100% sequence identity to a LCDR1, a LCDR2, and a LCDR3, respectively, of a VLdomain comprising the amino acid sequence of SEQ ID NO:301.

[0252] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VHdomain comprising a HCDR1, a HCDR2, and a HCDR3 having 100% sequence identity to a HCDR1, a HCDR2, and a HCDR3, respectively, of a VHdomain comprising the amino acid sequence of SEQ ID NO: 1, and b) a VLdomain comprising a LCDR1, a LCDR2, and a LCDR3 having 100% sequence identity to a LCDR1, a LCDR2, and a LCDR3, respectively, of a VLdomain comprising the amino acid sequence of SEQ ID NO:302.CDR Sequences as Determined by IMGT Numbering

[0253] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VH comprising: i. a HCDR1 having at least 80% sequence identity e.g., having at least 85% sequence identity, having at least 90% sequence identity, or having at least 95% sequence identity) to the amino acid sequence of SEQ ID NO:X, ii. a HCDR2 having at least 80% sequence identity (e.g., having at least 85% sequence identity, having at least 90% sequence identity, or having at least 95% sequence identity) to the amino acid sequence of SEQ ID NO: 72, andiii. a HCDR3 having at least 80% sequence identity (e.g, having at least 85% sequence identity, having at least 90% sequence identity, or having at least 95% sequence identity) to the amino acid sequence of SEQ ID NO:79, and b) a VLcomprising: i. a LCDR1 having at least 80% sequence identity (e.g, having at least 85% sequence identity, having at least 90% sequence identity, or having at least 95% sequence identity) to the amino acid sequence of SEQ ID NO: 146, ii. a LCDR2 comprising (e.g, consisting of) the amino acid sequence of AAS, IAS, or YAS, and iii. a LCDR3 having at least 80% sequence identity (e.g, having at least 85% sequence identity, having at least 90% sequence identity, or having at least 95% sequence identity) to the amino acid sequence of SEQ ID NO: 150, wherein the antibody or the antigen-binding fragment thereof comprises a VH domain having less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 1 and / or a VLdomain having less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 140.

[0254] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VHcomprising: i. a HCDR1 having at least 80% sequence identity (e.g, having at least 85% sequence identity, having at least 90% sequence identity, or having at least 95% sequence identity) to the amino acid sequence of SEQ ID NO:X, ii. a HCDR2 having at least 80% sequence identity (e.g., having at least 85% sequence identity, having at least 90% sequence identity, or having at least 95% sequence identity) to the amino acid sequence of SEQ ID NO:72, and iii. a HCDR3 having at least 80% sequence identity (e.g., having at least 85% sequence identity, having at least 90% sequence identity, or having at least 95% sequence identity) to the amino acid sequence of SEQ ID NO:79, and b) a VL comprising: i. a LCDR1 having at least 80% sequence identity (e.g, having at least 85% sequence identity, having at least 90% sequence identity, or having at least 95% sequence identity) to the amino acid sequence of SEQ ID NO: 146,ii. a LCDR2 comprising (e.g., consisting of) the amino acid sequence of AAS, and iii. a LCDR3 having at least 80% sequence identity (e.g., having at least 85% sequence identity, having at least 90% sequence identity, or having at least 95% sequence identity) to the amino acid sequence of SEQ ID NO: 150, wherein the antibody or the antigen-binding fragment thereof comprises a VH domain having less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 1 and / or a VLdomain having less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 140.

[0255] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VHcomprising: i. a HCDR1 comprising (e.g., consisting of) the amino acid sequence of SEQ ID NO:X, ii. a HCDR2 comprising (e.g., consisting of) the amino acid sequence of SEQ ID NO:72, and iii. a HCDR3 comprising (e.g., consisting of) the amino acid sequence of SEQ ID NO:79, and b) a VLcomprising: i. a LCDR1 comprising (e.g., consisting of) the amino acid sequence of SEQ ID NO: 146, ii. a LCDR2 comprising (e.g., consisting of) the amino acid sequence of AAS, IAS, or YAS, and iii. a LCDR3 comprising (e.g., consisting of) the amino acid sequence of SEQ ID NO: 150, wherein the antibody or the antigen-binding fragment thereof comprises a VHdomain having less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 1 and / or a VLdomain having less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 140.

[0256] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VH comprising: i. a HCDR1 comprising (e.g., consisting of) the amino acid sequence of SEQ ID NO:X,ii. a HCDR2 comprising (e.g., consisting of) the amino acid sequence of SEQ ID NO:72, and iii. a HCDR3 comprising (e.g., consisting of) the amino acid sequence of SEQ ID NO:79, and b) a VL comprising: i. a LCDR1 comprising (e.g., consisting of) the amino acid sequence of SEQ ID NO: 146, ii. a LCDR2 comprising (e.g., consisting of) the amino acid sequence of AAS, and iii. a LCDR3 comprising (e.g., consisting of) the amino acid sequence of SEQ ID NO: 150, wherein the antibody or the antigen-binding fragment thereof comprises a VHdomain having less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 1 and / or a VLdomain having less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 140.

[0257] 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 is applicable to any one or more of paragraphs

[0252] -

[0255] .

[0258] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VHcomprising a HCDR1, a HCDR2, and a HCDR3 amino acid sequences of SEQ ID NO:45, SEQ ID NO:72, and SEQ ID NO:79, respectively, and b) a VLcomprising a LCDR1, a LCDR2, and a LCDR3 amino acid sequences of SEQ ID NO: 146, AAS, and SEQ ID NO: 150, respectively.

[0259] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VH comprising a HCDR1, a HCDR2, and a HCDR3 amino acid sequences of SEQ ID NO:303, SEQ ID NO:72, and SEQ ID NO:79, respectively, and b) a VLcomprising a LCDR1, a LCDR2, and a LCDR3 amino acid sequences of SEQ ID NO: 146, AAS, and SEQ ID NO: 150, respectively.

[0260] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VHcomprising a HCDR1, a HCDR2, and a HCDR3 amino acid sequences of SEQ IDNO: 304, SEQ ID NO: 72, and SEQ ID NO: 79, respectively, and b) a VLcomprising a LCDR1, a LCDR2, and a LCDR3 amino acid sequences of SEQ ID NO: 146, AAS, and SEQ ID NO: 150, respectively.CDR Sequences as Determined by Kabat Numbering

[0261] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VHcomprising: i. a HCDR1 having at least 80% sequence identity (e.g., having at least 85% sequence identity, having at least 90% sequence identity, or having at least 95% sequence identity) to the amino acid sequence of SEQ ID NO:X, ii. a HCDR2 having at least 80% sequence identity (e.g., having at least 85% sequence identity, having at least 90% sequence identity, or having at least 95% sequence identity) to the amino acid sequence of SEQ ID NO:96, and iii. a HCDR3 having at least 80% sequence identity (e.g., having at least 85% sequence identity, having at least 90% sequence identity, or having at least 95% sequence identity) to the amino acid sequence of SEQ ID NO: 103, and b) a VLcomprising: i. a LCDR1 having at least 80% sequence identity (e.g., having at least 85% sequence identity, having at least 90% sequence identity, or having at least 95% sequence identity) to the amino acid sequence of SEQ ID NO : 151 , ii. a LCDR2 having at least 80% sequence identity (e.g., having at least 85% sequence identity, having at least 90% sequence identity, or having at least 95% sequence identity) to the amino acid sequence of SEQ ID NO:Y, and iii. a LCDR3 having at least 80% sequence identity (e.g., having at least 85% sequence identity, having at least 90% sequence identity, or having at least 95% sequence identity) to the amino acid sequence of SEQ ID NO: 150, wherein the antibody or the antigen-binding fragment thereof comprises a VHdomain having less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 1 and / or a VLdomain having less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 140.

[0262] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VHcomprising: i. a HCDR1 comprising (e.g. consisting of) the amino acid sequence of SEQ ID NO:X, ii. a HCDR2 comprising (e.g., consisting of) the amino acid sequence of SEQ ID NO: 96, and iii. a HCDR3 comprising (e.g., consisting of) the amino acid sequence of SEQ ID NO: 103, and / or b) a VLcomprising: i. a LCDR1 comprising (e.g., consisting of) the amino acid sequence of SEQ ID NO:151, ii. a LCDR2 comprising (e.g., consisting of) the amino acid sequence of SEQ ID NO Y, and iii. a LCDR3 comprising e.g., consisting of) the amino acid sequence of SEQ ID NO: 150, wherein the antibody or the antigen-binding fragment thereof comprises a VHdomain having less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 1 and / or a VLdomain having less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 140.

[0263] 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 is applicable to paragraph

[0260] or paragraph

[0261] ,

[0264] In some embodiments, an antibody or an antigen-binding fragment thereof comprises:a) a VHcomprising a HCDR1 , a HCDR2, and a HCDR3 amino acid sequences of SEQ ID NO:80, SEQ ID NO:96, and SEQ ID NO: 103, respectively, and b) a VLcomprising a LCDR1, a LCDR2, and a LCDR3 amino acid sequences of SEQ ID NO:151, SEQ ID NO:154, and SEQ ID NO:150, respectively.

[0265] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VHcomprising a HCDR1, a HCDR2, and a HCDR3 amino acid sequences of SEQ IDNO:80, SEQ ID NO:96, and SEQ ID NO: 103, respectively, and b) a VLcomprising a LCDR1, a LCDR2, and a LCDR3 amino acid sequences of SEQ ID NO: 151, SEQ ID NO:156, and SEQ ID NO:150, respectively.

[0266] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VHcomprising a HCDR1, a HCDR2, and a HCDR3 amino acid sequences of SEQ IDNO:80, SEQ ID NO:96, and SEQ ID NO: 103, respectively, and b) a VL comprising a LCDR1, a LCDR2, and a LCDR3 amino acid sequences of SEQ ID NO: 151, SEQ ID NO:307, and SEQ ID NO: 150, respectively.

[0267] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VHcomprising a HCDR1, a HCDR2, and a HCDR3 amino acid sequences of SEQ IDNO:80, SEQ ID NO:96, and SEQ ID NO: 103, respectively, and b) a VLcomprising a LCDR1, a LCDR2, and a LCDR3 amino acid sequences of SEQ ID NO: 151, SEQ ID NO:308, and SEQ ID NO:150, respectively.CDR Sequences as Determined by Chothia Numbering

[0268] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a Vn comprising: i. a HCDR1 having at least 80% sequence identity (e.g., having at least 85% sequence identity, having at least 90% sequence identity, or having at least 95% sequence identity) to the amino acid sequence of SEQ ID NO:X, ii. a HCDR2 having at least 80% sequence identity (e.g., having at least 85% sequence identity, having at least 90% sequence identity, or having at least 95% sequence identity) to the amino acid sequence of SEQ ID NO: 132, andiii. a HCDR3 having at least 80% sequence identity (e.g, having at least 85% sequence identity, having at least 90% sequence identity, or having at least 95% sequence identity) to the amino acid sequence of SEQ ID NO: 139, and b) a VLcomprising: i. a LCDR1 having at least 80% sequence identity (e.g., having at least 85% sequence identity, having at least 90% sequence identity, or having at least 95% sequence identity) to the amino acid sequence of SEQ ID NO: 151, ii. a LCDR2 having at least 80% sequence identity (e.g., having at least 85% sequence identity, having at least 90% sequence identity, or having at least 95% sequence identity) to the amino acid sequence of SEQ ID NO:Y, and iii. a LCDR3 having at least 80% sequence identity (e.g., having at least 85% sequence identity, having at least 90% sequence identity, or having at least 95% sequence identity) to the amino acid sequence of SEQ ID NO: 150, wherein the antibody or the antigen-binding fragment thereof comprises a VHdomain having less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 1 and / or a VLdomain having less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 140.

[0269] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VHcomprising: i. a HCDR1 comprising (e.g., consisting of) the amino acid sequence of SEQ ID NO:X, ii. a HCDR2 comprising (e.g., consisting of) the amino acid sequence of SEQ ID NO: 132, and iii. a HCDR3 comprising (e.g., consisting of) the amino acid sequence of SEQ ID NO: 139, and b) a VLcomprising: i. a LCDR1 comprising (e.g, consisting of) the amino acid sequence of SEQ ID NO: 151, ii. a LCDR2 comprising (e.g, consisting of) the amino acid sequence of SEQ ID NO Y, andiii. a LCDR3 comprising (e.g., consisting of) the amino acid sequence of SEQ ID NO: 150, wherein the antibody or the antigen-binding fragment thereof comprises a VHdomain having less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 1 and / or a VLdomain having less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 140.

[0270] 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, 105-107, and 109-111, and Y is any one of 156, 154, 307, and 308. In some embodiments, X is any one of 305, 306, 104-107, and 109-111, and Y is any one of 156, 154, 307, and 308. In some embodiments, X is any one of 305, 306, 104, and 105, 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 305, 306, 104, and 105, and Y is any one of 156, 154, 307, and 308.

[0271] 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.

[0272] 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 is308. In some embodiments, X is 105, and Y is 156. In some embodiments, X is 105, and Y is154. In some embodiments, X is 105, and Y is 307. In some embodiments, X is 105, and Y is308. In some embodiments, X is 106, and Y is 156. In some embodiments, X is 106, and Y is154. In some embodiments, X is 106, and Y is 307. In some embodiments, X is 106, and Y is308. In some embodiments, X is 107, and Y is 156. In some embodiments, X is 107, and Y is154. 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.

[0273] Each of paragraph

[0269] -

[0271] is applicable to paragraph

[0267] or paragraph

[0268] ,

[0274] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VHcomprising a HCDR1, a HCDR2, and a HCDR3 amino acid sequences of SEQ IDNO: 104, SEQ ID NO:132, and SEQ ID NO:139, respectively, and b) a VLcomprising a LCDR1, a LCDR2, and a LCDR3 amino acid sequences of SEQ ID NO: 151, SEQ ID NO:154, and SEQ ID NO:150, respectively.

[0275] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VHcomprising a HCDR1, a HCDR2, and a HCDR3 amino acid sequences of SEQ IDNO: 104, SEQ ID NO:132, and SEQ ID NO:139, respectively, and b) a VLcomprising a LCDR1, a LCDR2, and a LCDR3 amino acid sequences of SEQ ID NO: 151, SEQ ID NO: 156, and SEQ ID NO: 150, respectively.

[0276] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VHcomprising a HCDR1, a HCDR2, and a HCDR3 amino acid sequences of SEQ IDNO: 104, SEQ ID NO:132, and SEQ ID NO:139, respectively, and b) a VLcomprising a LCDR1, a LCDR2, and a LCDR3 amino acid sequences of SEQ ID NO: 151, SEQ ID NO:307, and SEQ ID NO: 150, respectively.

[0277] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VH comprising a HCDR1, a HCDR2, and a HCDR3 amino acid sequences of SEQ IDNO: 104, SEQ ID NO:132, and SEQ ID NO:139, respectively, and b) a VLcomprising a LCDR1, a LCDR2, and a LCDR3 amino acid sequences of SEQ ID NO: 151, SEQ ID NO:308, and SEQ ID NO:150, respectively.

[0278] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VHcomprising a HCDR1, a HCDR2, and a HCDR3 amino acid sequences of SEQ ID NO: 105, SEQ ID NO: 132, and SEQ ID NO: 139, respectively, and b) a VLcomprising a LCDR1, a LCDR2, and a LCDR3 amino acid sequences of SEQ ID NO: 151, SEQ ID NO:152, and SEQ ID NO:150, respectively.

[0279] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VHcomprising a HCDR1, a HCDR2, and a HCDR3 amino acid sequences of SEQ IDNO:305, SEQ ID NO:132, and SEQ ID NO:139, respectively, and b) a VLcomprising a LCDR1, a LCDR2, and a LCDR3 amino acid sequences of SEQ ID NO: 151, SEQ ID NO:152, and SEQ ID NO:150, respectively.

[0280] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VHcomprising a HCDR1, a HCDR2, and a HCDR3 amino acid sequences of SEQ IDNO:306, SEQ ID NO:132, and SEQ ID NO:139, respectively, and b) a VLcomprising a LCDR1, a LCDR2, and a LCDR3 amino acid sequences of SEQ ID NO: 151, SEQ ID NO:152, and SEQ ID NO:150, respectively.

[0281] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VHcomprising a HCDR1, a HCDR2, and a HCDR3 amino acid sequences of SEQ IDNO: 105, SEQ ID NO:132, and SEQ ID NO:139, respectively, and b) a VLcomprising a LCDR1, a LCDR2, and a LCDR3 amino acid sequences of SEQ ID NO: 151, SEQ ID NO: 156, and SEQ ID NO: 150, respectively.Vn / Vi_ framework regions

[0282] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VH domain of 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: VHFR1-HCDR1-VHFR2-HCDR2-VHFR3-HCDR3-VHFR4, wherein: i. the VH FR1-HCDR1 comprises the amino acid sequence of SEQ ID NO:X, ii. the VH FR2 comprises the amino acid sequence of GKGL (SEQ ID NO:268), GDYL (SEQ ID NO:269), or GYYL (SEQ ID NO:270), or iii. the VHFR3 comprises the amino acid sequence of NSLK (SEQ ID NO:271), PSLR (SEQ ID NO:272), or NDLR (SEQ ID NO:273), orany combination of i) to iii), and b) a VLdomain of four VLframework regions (VLFR1-4) and three heavy chain complementarity determining regions (LCDR1-3) in the following N-terminal to C- terminal order: VLFR1-LCDR1-VLFR2-LCDR2-VLFR3-LCDR3-VLFR4, wherein the VL FR2-HCDR2 comprises the amino acid sequence of SLQS, SLQE, DLQR, SQQR, or SEQR, optionally wherein the VHdomain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 1, and / or the VLdomain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 140.

[0283] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VHFR1-HCDR1 comprising the amino acid sequence of SEQ ID NO:X, and i. a 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. a 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) a VLFR2-HCDR2 comprises the amino acid sequence of DLQR, optionally wherein the VHdomain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 1, and / or the VLdomain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 140.

[0284] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VHFR1-HCDR1 comprising the amino acid sequence of SEQ ID NO:X, and i. a 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. a 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) a VLFR2-HCDR2 comprises the amino acid sequence of SQQR, optionally wherein the VH domain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 1, and / or the VLdomain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO:140.

[0285] In some embodiments, an antibody or an antigen-binding fragment thereof comprises:a) a VHFR2 comprising the amino acid sequence of GKGL (SEQ ID NO:268), GDYL (SEQ ID NO:269), or GYYL (SEQ ID NO:270), and i. a VHFR1-HCDR1 comprising the amino acid sequence of SEQ ID NO:X, and / or ii. a VnFR3 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) a VLFR2-HCDR2 comprises the amino acid sequence of DLQR, optionally wherein the VHdomain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 1, and / or the VLdomain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 140.

[0286] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VHFR2 comprising the amino acid sequence of GKGL (SEQ ID NO:268), GDYL (SEQ ID NO:269), or GYYL (SEQ ID NO:270), and i. a VH FR1-HCDR1 comprising the amino acid sequence of SEQ ID NO:X, and / or ii. a 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) a VLFR2-HCDR2 comprises the amino acid sequence of SQQR, optionally wherein the VHdomain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 1, and / or the VLdomain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 140.

[0287] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VHFR2 comprising the amino acid sequence of GKGL (SEQ ID NO:268), and i. a VHFR1-HCDR1 comprising the amino acid sequence of SEQ ID NO:X, and / or ii. a 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) a VLFR2-HCDR2 comprises the amino acid sequence of DLQR, optionally wherein the VHdomain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 1, and / or the VL domain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 140.

[0288] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VHFR2 comprising the amino acid sequence of GKGL (SEQ ID NO:268), andi. a VHFR1-HCDR1 comprising the amino acid sequence of SEQ ID NO:X, and / or ii. a 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) a VLFR2-HCDR2 comprises the amino acid sequence of SQQR, optionally wherein the VH domain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 1, and / or the VLdomain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO:140.

[0289] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VHFR2 comprising the amino acid sequence of GDYL (SEQ ID NO:269), and i. a VHFR1-HCDR1 comprising the amino acid sequence of SEQ ID NO:X, and / or ii. a 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) a VL FR2-HCDR2 comprises the amino acid sequence of DLQR, optionally wherein the VHdomain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 1, and / or the VLdomain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO:140.

[0290] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VHFR2 comprising the amino acid sequence of GDYL (SEQ ID NO:269), and i. a VHFR1-HCDR1 comprising the amino acid sequence of SEQ ID NO:X, and / or ii. a 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) a VLFR2-HCDR2 comprises the amino acid sequence of SQQR, optionally wherein the VHdomain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 1, and / or the VLdomain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 140.

[0291] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VH FR2 comprising the amino acid sequence of GYYL (SEQ ID NO:270), and i. a VHFR1-HCDR1 comprising the amino acid sequence of SEQ ID NO:X, and / or ii. a VHFR3 comprising the amino acid sequence of NSLK (SEQ ID NO:271), PSLR (SEQ ID NO:272), or NDLR (SEQ ID NO:273), and / orb) a VLFR2-HCDR2 comprises the amino acid sequence of DLQR, optionally wherein the VHdomain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 1, and / or the VLdomain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO:140.

[0292] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VHFR2 comprising the amino acid sequence of GYYL (SEQ ID NO:270), and i. a VHFR1-HCDR1 comprising the amino acid sequence of SEQ ID NO:X, and / or ii. a 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) a VLFR2-HCDR2 comprises the amino acid sequence of SQQR, optionally wherein the VHdomain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 1, and / or the VLdomain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO:140.

[0293] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VHFR3 comprising the amino acid sequence of NSLK (SEQ ID NO:271), PSLR (SEQ ID NO:272), or NDLR (SEQ ID NO:273), and i. a VHFR1-HCDR1 comprising the amino acid sequence of SEQ ID NO:X, and / or ii. a 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) a VLFR2-HCDR2 comprises the amino acid sequence of DLQR, optionally wherein the VHdomain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 1, and / or the VLdomain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO:140.

[0294] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VHFR3 comprising the amino acid sequence of NSLK (SEQ ID NO:271), PSLR (SEQ ID NO: 272), or NDLR (SEQ ID NO: 273), and i. a VH FR1-HCDR1 comprising the amino acid sequence of SEQ ID NO:X, and / or ii. a 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) a VLFR2-HCDR2 comprises the amino acid sequence of SQQR,optionally wherein the VHdomain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 1, and / or the VLdomain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 140.

[0295] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VH FR3 comprising the amino acid sequence of NSLK (SEQ ID NO:271), and i. a VHFR1-HCDR1 comprising the amino acid sequence of SEQ ID NO:X, and / or ii. a 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) a VLFR2-HCDR2 comprises the amino acid sequence of DLQR, optionally wherein the VHdomain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 1, and / or the VLdomain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 140.

[0296] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VHFR3 comprising the amino acid sequence of NSLK (SEQ ID NO:271), and i. a VHFR1-HCDR1 comprising the amino acid sequence of SEQ ID NO:X, and / or ii. a 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) a VLFR2-HCDR2 comprises the amino acid sequence of SQQR, optionally wherein the VHdomain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 1, and / or the VLdomain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO:140.

[0297] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VHFR3 comprising the amino acid sequence of PSLR (SEQ ID NO:272), and i. a VHFR1-HCDR1 comprising the amino acid sequence of SEQ ID NO:X, and / or ii. a 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) a VL FR2-HCDR2 comprises the amino acid sequence of DLQR, optionally wherein the VHdomain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 1, and / or the VLdomain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 140.

[0298] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VHFR3 comprising the amino acid sequence of PSLR (SEQ ID NO:272), and i. a VHFR1-HCDR1 comprising the amino acid sequence of SEQ ID NO:X, and / or ii. a VnFR2 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) a VLFR2-HCDR2 comprises the amino acid sequence of SQQR, optionally wherein the VHdomain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 1, and / or the VLdomain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 140.

[0299] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VHFR3 comprising the amino acid sequence of NDLR (SEQ ID NO:273), and i. a VHFR1-HCDR1 comprising the amino acid sequence of SEQ ID NO:X, and / or ii. a 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) a VLFR2-HCDR2 comprises the amino acid sequence of DLQR, optionally wherein the VHdomain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 1, and / or the VLdomain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO:140.

[0300] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VHFR3 comprising the amino acid sequence of NDLR (SEQ ID NO:273), and i. a VHFR1-HCDR1 comprising the amino acid sequence of SEQ ID NO:X, and / or ii. a 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) a VLFR2-HCDR2 comprises the amino acid sequence of SQQR, optionally wherein the VHdomain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 1, and / or the VLdomain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO:140.

[0301] 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.- 1 -In some embodiments, X is 265. In some embodiments, X is 266. In some embodiments, X is 267.VH / VL

[0302] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VHdomain having at least 70% sequence identity (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity) to the amino acid sequence of SEQ ID N0:X, and b) a VLdomain having at least 70% sequence identity (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity) to the amino acid sequence of SEQ ID NO:Y, wherein the antibody or the antigen-binding fragment thereof comprises a VHdomain having less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 1 and / or a VLdomain having less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 140.

[0303] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VHcomprising at least one amino acid substitution relative to the amino acid sequence of SEQ ID NO:X, and b) a VLcomprising at least one amino acid substitution relative to the amino acid sequence of SEQ ID NO :Y, wherein the antibody or the antigen-binding fragment thereof comprises a VHdomain having less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 1 and / or a VLdomain having less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 140.

[0304] 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.

[0305] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VH that comprises about 1-10 amino acid substitutions, relative to the amino acid sequence of SEQ ID N0:X, and b) a VLthat comprises about 1-10 amino acid substitutions, relative to the amino acid sequence of SEQ ID N0:Y.

[0306] In some embodiments, an amino acid substitution is a conservative substitution.

[0307] In some embodiments, an amino acid substitution is a highly conservative substitution.

[0308] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a Vnhaving 100% sequence identity to the amino acid sequence of SEQ ID N0:X, and / or b) a VLhaving 100% sequence identity to the amino acid sequence of SEQ ID NO:Y.

[0309] In some embodiments, X is any one of 1-11, 19-21, 299, and 300, and Y is any one of 144, 142, 301, and 302. In some embodiments, X is any one of 2-11, 19-21, 299, and 300, and Y is any one of 144, 142, 140, 301, and 302. In some embodiments, X is any one of 2-11, 19-21, 299, and 300, and Y is any one of 144, 142, 301, and 302. In some embodiments, X is any one of 1-4, 299, and 300, and Y is any one of 144, 142, 301, and 302. In some embodiments, X is any one of 2-4, 299, and 300, and Y is any one of 144, 142, 140, 301, and 302. In some embodiments, X is any one of 2-4, 299, and 300, and Y is any one of 144, 142, 301, and 302.

[0310] 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.

[0311] 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 someembodiments, 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.

[0312] Each of paragraph

[0308] -

[0310] is applicable to any one of paragraphs

[0301] -

[0307] ,

[0313] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VHhaving 100% sequence identity to the amino acid sequence of SEQ ID NO:4, and b) a VLhaving 100% sequence identity to the amino acid sequence of SEQ ID NO: 140.

[0314] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VHhaving 100% sequence identity to the amino acid sequence of SEQ ID NO:299, and b) a VLhaving 100% sequence identity to the amino acid sequence of SEQ ID NO: 140.

[0315] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VHhaving 100% sequence identity to the amino acid sequence of SEQ ID NO:300, and b) a VLhaving 100% sequence identity to the amino acid sequence of SEQ ID NO: 140.

[0316] In some embodiments, an antibody or an antigen-binding fragment thereof comprises:a) a VHhaving 100% sequence identity to the amino acid sequence of SEQ ID NO:1 , and b) a VLhaving 100% sequence identity to the amino acid sequence of SEQ ID NO: 142.

[0317] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a Vnhaving 100% sequence identity to the amino acid sequence of SEQ ID NO:1, and b) a VL having 100% sequence identity to the amino acid sequence of SEQ ID NO: 144.

[0318] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VHhaving 100% sequence identity to the amino acid sequence of SEQ ID NO:1, and b) a VLhaving 100% sequence identity to the amino acid sequence of SEQ ID NO:301.

[0319] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VHhaving 100% sequence identity to the amino acid sequence of SEQ ID NO:1, and b) a VLhaving 100% sequence identity to the amino acid sequence of SEQ ID NO:302.

[0320] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VH having 100% sequence identity to the amino acid sequence of SEQ ID NO:2, and b) a VLhaving 100% sequence identity to the amino acid sequence of SEQ ID NO: 144.

[0321] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VHhaving 100% sequence identity to the amino acid sequence of SEQ ID NO:3, and b) a VLhaving 100% sequence identity to the amino acid sequence of SEQ ID NO: 144.Heavy Chain'Light Chain

[0322] In some embodiments, an antibody or an antigen-binding fragment thereof comprises an antibody heavy chain constant domain sequence and / or an antibody light chain constant domain sequence.Heavy Chain Constant Domain

[0323] In some embodiments, an antibody or an antigen-binding fragment thereof comprises an immunoglobulin heavy chain constant domain sequence.

[0324] In some embodiments, an antibody or an antigen-binding fragment thereof comprises an immunoglobulin IgA, IgD, IgE, IgG, or IgM heavy chain constant domain.

[0325] In some embodiments, an antibody or an antigen-binding fragment thereof comprises an immunoglobulin IgA heavy chain constant domain. In some embodiments, an antibody or an antigen-binding fragment thereof comprises an immunoglobulin IgAl heavy chain constantdomain. In some embodiments, an antibody or an antigen-binding fragment thereof comprises an immunoglobulin IgA2 heavy chain constant domain.

[0326] In some embodiments, an antibody or an antigen-binding fragment thereof comprises an immunoglobulin IgG heavy chain constant domain. In some embodiments, an antibody or an antigen-binding fragment thereof comprises an immunoglobulin IgG2 heavy chain constant domain (e.g., IgG2a, IgG2b, or IgG2c). In some embodiments, an antibody or an antigen-binding fragment thereof comprises an immunoglobulin IgG3 heavy chain constant domain. In some embodiments, an antibody or an antigen-binding fragment thereof comprises an immunoglobulin IgGl heavy chain constant domain (e.g., SEQ ID NO:279 or SEQ ID NO:280).

[0327] In some embodiments, an antibody or an antigen-binding fragment thereof comprises an immunoglobulin heavy chain constant domain sequence that has at least 70% sequence identity to the amino acid sequence of SEQ ID NO:279 and / or SEQ ID NO:280 (e.g., SEQ ID NO:279). For example, an antibody or an antigen-binding fragment thereof can comprise an immunoglobulin heavy chain constant domain sequence that has at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98% or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:279 and / or SEQ ID NO:280 (e.g, SEQ ID NO:279).

[0328] In some embodiments, an antibody or an antigen-binding fragment thereof comprises an immunoglobulin heavy chain constant domain sequence comprising at least one amino acid substitution relative to the amino acid sequence of SEQ ID NO:279 and / or SEQ ID NO:280 (e.g, SEQ ID NO:279). For example, the number of amino acid substitutions can 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.

[0329] In some embodiments, an antibody or an antigen-binding fragment thereof comprises an immunoglobulin heavy chain constant domain sequence that has 100% sequence identity to the amino acid sequence of SEQ ID NO:279.

[0330] In some embodiments, an antibody or an antigen-binding fragment thereof comprises an immunoglobulin heavy chain constant domain sequence that has 100% sequence identity to the amino acid sequence of SEQ ID NO:280.

[0331] In some embodiments, an antibody or an antigen-binding fragment thereof is a heavychain antibody comprising two or more heavy chains, but lacking light chain, or an antigen-binding fragment thereof. Non-limiting examples of heavy chain antibodies include camelid Vhh (also referred to as VHH or VHH) antibodies. Camelid antibodies are antibodies from the Camelidae family of mammals that include llamas, camels, and alpacas.Light Chain Constant Domain

[0332] In some embodiments, an antibody or an antigen-binding fragment thereof comprises an immunoglobulin light chain constant domain sequence.

[0333] In some embodiments, an antibody or an antigen-binding fragment thereof comprises an immunoglobulin K light chain constant domain (e.g., SEQ ID NO:281).

[0334] In some embodiments, an antibody or an antigen-binding fragment thereof comprises an immunoglobulin light chain constant domain (e.g., SEQ ID NO:282).

[0335] In some embodiments, an antibody or an antigen-binding fragment thereof comprises an immunoglobulin light chain constant domain sequence that has at least 70% sequence identity to the amino acid sequence of SEQ ID NO:281 and / or SEQ ID NO:282 (e.g., SEQ ID NO:282). For example, an antibody or an antigen-binding fragment thereof can comprise an immunoglobulin light chain constant domain sequence that has at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98% or at least 99% sequence identity to the amino acid sequence of SEQ ID NO:281 and / or SEQ ID NO:282 (e.g, SEQ ID NO:282).

[0336] In some embodiments, an antibody or an antigen-binding fragment thereof comprises an immunoglobulin light chain constant domain sequence comprising at least one amino acid substitution relative to the amino acid sequence of SEQ ID NO:281 and / or SEQ ID NO:282 (e.g., SEQ ID NO:282). For example, the number of amino acid substitutions can 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.

[0337] In some embodiments, an antibody or an antigen-binding fragment thereof comprises an immunoglobulin light chain constant domain sequence that has 100% sequence identity to the amino acid sequence of SEQ ID NO:282.

[0338] In some embodiments, an antibody or an antigen-binding fragment thereof comprises an immunoglobulin light chain constant domain sequence that has 100% sequence identity to the amino acid sequence of SEQ ID NO:281.Heavy / Light Chains

[0339] In some embodiments, an antibody or an antigen-binding fragment thereof 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) to the amino acid sequence of SEQ ID N0:X, 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) to the amino acid sequence of SEQ ID N0:Y, wherein the antibody or the antigen-binding fragment thereof comprises a VHdomain having less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 1 and / or a VLdomain having less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 140.

[0340] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a heavy chain comprising at least one amino acid substitution relative to the amino acid sequence of SEQ ID N0:X, and / or b) a light chain comprising at least one amino acid substitution relative to the amino acid sequence of SEQ ID N0:Y, wherein the antibody or the antigen-binding fragment thereof comprises a VHdomain having less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 1 and / or a VLdomain having less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 140.

[0341] 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.

[0342] 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.

[0343] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a heavy chain comprising about 1-10 amino acid substitutions, relative to the amino acid sequence of SEQ ID NO:X, and b) a light chain comprising about 1-10 amino acid substitutions, relative to the amino acid sequence of SEQ ID N0:Y.

[0344] In some embodiments, an amino acid substitution is a conservative substitution.

[0345] In some embodiments, an amino acid substitution is a highly conservative substitution.

[0346] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a heavy chain having 100% sequence identity to the amino acid sequence of SEQ ID NO:X, and / or b) a light chain having 100% sequence identity to the amino acid sequence of SEQ ID NO Y.

[0347] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a heavy chain having 100% sequence identity to the amino acid sequence of SEQ ID NO:X, and b) a light chain having 100% sequence identity to the amino acid sequence of SEQ ID NO Y.

[0348] 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 161-163, 311, and 312, and Y is any one of 207, 205, 313, and 314.

[0349] 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.

[0350] 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 is205. In some embodiments, X is 162, and Y is 313. Tn 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.

[0351] Each of paragraph

[0347] -

[0349] is applicable to any one of paragraphs

[0338] -

[0346] ,

[0352] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a heavy chain having 100% sequence identity to the amino acid sequence of SEQ IDNO: 163, and b) a light chain having 100% sequence identity to the amino acid sequence of SEQ ID NO:203.

[0353] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a heavy chain having 100% sequence identity to the amino acid sequence of SEQ ID NO:311, and b) a light chain having 100% sequence identity to the amino acid sequence of SEQ ID NO:203.

[0354] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a heavy chain having 100% sequence identity to the amino acid sequence of SEQ IDNO:312, and b) a light chain having 100% sequence identity to the amino acid sequence of SEQ ID NO: 203.

[0355] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a heavy chain having 100% sequence identity to the amino acid sequence of SEQ IDNO: 160, and b) a light chain having 100% sequence identity to the amino acid sequence of SEQ ID NO:205.

[0356] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a heavy chain having 100% sequence identity to the amino acid sequence of SEQ IDNO: 160, and b) a light chain having 100% sequence identity to the amino acid sequence of SEQ ID NO:207.

[0357] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a heavy chain having 100% sequence identity to the amino acid sequence of SEQ IDNO: 160, and b) a light chain having 100% sequence identity to the amino acid sequence of SEQ ID NO:313.

[0358] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a heavy chain having 100% sequence identity to the amino acid sequence of SEQ IDNO: 160, and b) a light chain having 100% sequence identity to the amino acid sequence of SEQ ID NO:314.

[0359] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a heavy chain having 100% sequence identity to the amino acid sequence of SEQ IDNO: 161, and b) a light chain having 100% sequence identity to the amino acid sequence of SEQ ID NO:207.

[0360] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a heavy chain having 100% sequence identity to the amino acid sequence of SEQ IDNO: 162, and b) a light chain having 100% sequence identity to the amino acid sequence of SEQ ID NO:207. scFv

[0361] In some embodiments, an antibody or an antigen-binding fragment thereof is a singlechain fragment variable (scFv), a variable heavy domain of heavy chain (VHH), a fragment antigen-binding (Fab), a Fab’ or a F(ab’)2.

[0362] In some embodiments, an antibody or an antigen-binding fragment thereof is a scFv.

[0363] In some embodiments, an antibody or an antigen-binding fragment thereof comprises a Vn domain disclosed herein joined to a VLdomain disclosed herein by a scFv linker.

[0364] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VHdomain having at least 70% sequence identity (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity) to the amino acid sequence of SEQ ID N0:X, and b) a VLdomain having at least 70% sequence identity (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity) to the amino acid sequence of SEQ ID NO:Y,wherein the VHdomain is joined to the VLdomain by a scFv linker, and wherein the VHdomain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 1 and / or the VLdomain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 140.

[0365] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VH comprising at least one amino acid substitution relative to the amino acid sequence of SEQ ID NO :X, and b) a VLcomprising at least one amino acid substitution relative to the amino acid sequence of SEQ ID NO :Y, wherein the VHdomain is joined to the VLdomain by a scFv linker, and wherein the VHdomain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 1 and / or the VLdomain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 140.

[0366] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VH having 100% sequence identity to the amino acid sequence of SEQ ID NO:X, and b) a VLhaving 100% sequence identity to the amino acid sequence of SEQ ID NO:Y, wherein the VHdomain is joined to the VLdomain by a scFv linker.

[0367] In some embodiments, X is any one of 1-11, 19-21, 299, and 300, and Y is any one of 144, 142, 301, and 302. In some embodiments, X is any one of 2-11, 19-21, 299, and 300, and Y is any one of 144, 142, 140, 301, and 302. In some embodiments, X is any one of 2-11, 19-21, 299, and 300, and Y is any one of 144, 142, 301, and 302. In some embodiments, X is any one of 1-4, 299, and 300, and Y is any one of 144, 142, 301, and 302. In some embodiments, X is any one of 2-4, 299, and 300, and Y is any one of 144, 142, 140, 301, and 302. In some embodiments, X is any one of 2-4, 299, and 300, and Y is any one of 144, 142, 301, and 302.

[0368] 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.

[0369] 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 someembodiments, 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.

[0370] Each of paragraph

[0366] -

[0368] is applicable to any one of paragraphs

[0363] -

[0365] ,

[0371] In some embodiments, an antibody or an antigen-binding fragment thereof comprises:a) a VHhaving 100% sequence identity to the amino acid sequence of SEQ ID NO:4, and b) a VLhaving 100% sequence identity to the amino acid sequence of SEQ ID NO: 140, wherein the VHdomain is joined to the VLdomain by a scFv linker.

[0372] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VH having 100% sequence identity to the amino acid sequence of SEQ ID NO:299, and b) a VLhaving 100% sequence identity to the amino acid sequence of SEQ ID NO: 140, wherein the VHdomain is joined to the VLdomain by a scFv linker.

[0373] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VHhaving 100% sequence identity to the amino acid sequence of SEQ ID NO:300, and b) a VLhaving 100% sequence identity to the amino acid sequence of SEQ ID NO: 140, wherein the VHdomain is joined to the VLdomain by a scFv linker.

[0374] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VH having 100% sequence identity to the amino acid sequence of SEQ ID NO:1, and b) a VLhaving 100% sequence identity to the amino acid sequence of SEQ ID NO: 142, wherein the VHdomain is joined to the VLdomain by a scFv linker.

[0375] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VHhaving 100% sequence identity to the amino acid sequence of SEQ ID NO: 1, and b) a VLhaving 100% sequence identity to the amino acid sequence of SEQ ID NO: 144, wherein the VHdomain is joined to the VLdomain by a scFv linker.

[0376] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VHhaving 100% sequence identity to the amino acid sequence of SEQ ID NO:1, and b) a VLhaving 100% sequence identity to the amino acid sequence of SEQ ID NO:301, wherein the VHdomain is joined to the VLdomain by a scFv linker.

[0377] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VHhaving 100% sequence identity to the amino acid sequence of SEQ ID NO: 1, and b) a VLhaving 100% sequence identity to the amino acid sequence of SEQ ID NO:302, wherein the VH domain is joined to the VL domain by a scFv linker.

[0378] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VHhaving 100% sequence identity to the amino acid sequence of SEQ ID NO:2, and b) a VLhaving 100% sequence identity to the amino acid sequence of SEQ ID NO: 144,wherein the VHdomain is joined to the VLdomain by a scFv linker.

[0379] In some embodiments, an antibody or an antigen-binding fragment thereof comprises: a) a VHhaving 100% sequence identity to the amino acid sequence of SEQ ID NO:3, and b) a VLhaving 100% sequence identity to the amino acid sequence of SEQ ID NO: 144, wherein the VH domain is joined to the VL domain by a scFv linker.

[0380] In some embodiments, a scFv linker comprises (e.g., consists of) the amino acid sequence of SEQ ID NO:257. In some embodiments, a scFv linker comprises (e.g., consists of) the amino acid sequence of SEQ ID NO:258. In some embodiments, a scFv linker comprises (e.g., consists of) the amino acid sequence of SEQ ID NO:257, SEQ ID NO:258, or any one of SEQ ID NOs:284-298. See, e.g., 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 by reference herein in their entirety.

[0381] In some embodiments, an antibody or an antigen-binding fragment thereof comprises, in the following N-terminal to C-terminal order: a VHdomain disclosed herein (e.g., having the amino acid sequence of SEQ ID NO:2 or SEQ ID NO:3), a scFv linker (e.g., having the amino acid sequence of SEQ ID NO:257), and a VLdomain disclosed herein (e.g., having the amino acid sequence of SEQ ID NO: 144 or SEQ ID NO: 142).

[0382] In some embodiments, an antibody or an antigen-binding fragment thereof comprises, in the following N-terminal to C-terminal order: a VHdomain disclosed herein (e.g., having the amino acid sequence of SEQ ID NO:2 or SEQ ID NO:3), a scFv linker (e.g., having the amino acid sequence of SEQ ID NO:257), a VLdomain disclosed herein (e.g., having the amino acid sequence of SEQ ID NO: 144 or SEQ ID NO: 142), a Fc linker (e.g., having the amino acid sequence of SEQ ID NO:259), and a Fc domain (e.g., having the amino acid sequence of SEQ ID NO:283).

[0383] In some embodiments, an antibody or an antigen-binding fragment thereof comprises an Fc domain comprising one or more mutations (e.g., a YTE modification) that, for example, increases in vivo half-life of the antibody or the antigen-binding fragment thereof, and / or increases the affinity of the constant domain for FcRn. See, e.g., Grevys et al., Antibody variable sequences have a pronounced effect on cellular transport and plasma half-life, iScience 25(2):103746 (2022), and W002060919, the contents of which are incorporated by referenceherein in their entirety. In some embodiments, an Fc domain comprises a YTE modification. A YTE modification, corresponding to M135Y / S137T / T139E of SEQ ID NO: 279 or SEQ ID NO:280, has also been referred to as the M252Y / S254T7T256E substitutions as determined by Kabat numbering. In some embodiments, an Fc domain comprises a LS modification. A LS modification, corresponding to M311L / N317S of SEQ ID NO: 279 or SEQ ID NO:280.

[0384] In some embodiments, an antibody or an antigen-binding fragment thereof is a bispecific antibody or an antigen-binding fragment thereof In some embodiments, a bispecific antibody or an antigen-binding fragment thereof comprises a Fc. In some embodiments, a bispecific antibody or an antigen-binding fragment thereof does not comprise a Fc. Non-limiting example structures of bispecific antibodies or antigen-binding fragments thereof include bi specific IgG, monospecific IgG appended with an additional antigen-binding moiety, bi specific antibody fragments, bispecific fusion proteins and bispecific antibody conjugates. See, e.g., Spiess et al., Alternative molecular formats and therapeutic applications for bispecific antibodies, Mol Immunol. 67(2 Pt A):95-106 (2015), and Velasquez et al., Redirecting T cells to hematological malignancies with bispecific antibodies, Blood 13 l(l):30-38 (2018), the contents of which are incorporated herein by reference.

[0385] In some embodiments, an antibody or an antigen-binding fragment thereof is a multispecific antibody or an antigen-binding fragment thereof.

[0386] In some embodiments, an antibody or an antigen-binding fragment thereof is an isolated antibody. In some embodiments, an antibody or an antigen-binding fragment thereof is an isolated antigen-binding fragment of an antibody.

[0387] In some embodiments, an antibody or an antigen-binding fragment thereof is recombinantly produced. In some embodiments, an antibody or an antigen-binding fragment thereof is synthetically produced.

[0388] In some embodiments, an antibody or an antigen-binding fragment thereof is an antibody mimetic.

[0389] In some embodiments, an antibody or an antigen-binding fragment thereof binds both human interleukin- 12 (IL-12) and human interleukin-23 (IL-23), for example, with a higher affinity than Ustekinumab.Fusion Proteins

[0390] The disclosure also provides, among other things, a fusion protein comprising one or more of the polypeptides disclosed herein.

[0391] In some embodiments, a fusion protein is produced recombinantly or synthetically, using routine methods and reagents that are well known in the art. For example, a fusion protein can be produced recombinantly in a suitable host cell (e.g., bacteria) according to methods known in the art. See, e.g., Current Protocols in Molecular Biology, Second Edition, Ausubel et al. eds., John Wiley & Sons, 1992; and Molecular Cloning: a Laboratory Manual, 2nd edition, Sambrook et al., 1989, Cold Spring Harbor Laboratory Press. For example, a nucleic acid molecule comprising a nucleotide sequence encoding a fusion protein can be introduced and expressed in suitable host cell (e.g., E. coli), and the expressed fusion protein can be isolated / purified from the host cell (e.g., in inclusion bodies) using routine methods and readily available reagents. For example, DNA fragments coding for different protein sequences (e.g., a light-responsive domain, a heterologous peptide component) can be ligated together in-frame in accordance with conventional techniques. In another embodiment, a fusion gene can be synthesized by conventional techniques including automated DNA synthesizers. Alternatively, PCR amplification of nucleic acid fragments can be carried out using anchor primers that give rise to complementary overhangs between two consecutive nucleic acid fragments that can subsequently be annealed and re-amplified to generate a chimeric nucleic acid sequence (see e.g., Ausubel et al., Current Protocols in Molecular Biology, 1992).Nucleic Acids & Vectors

[0392] The disclosure also provides, among other things, one or more polynucleotides (e.g., DNA, RNA, or analogs of either, e.g., optionally including one or more modified nucleotides) encoding any one or more of the antibodies, antigen-binding fragments, or fusion proteins disclosed herein. In some embodiments, a polynucleotide is DNA. In some embodiments, a polynucleotide is RNA. In some embodiments, a polynucleotide is linear (e.g., a linear RNA). In some embodiments, a polynucleotide is circular (e.g., a circular RNA). In some embodiments, a polynucleotide comprises a nucleotide sequence that is codon-optimized for a chosen cell (e.g., host cell).

[0393] In some embodiments, an antibody, antigen-binding fragment, or fusion protein is encoded by a single polynucleotide. In some embodiments, an antibody, antigen-binding fragment, or fusion protein is encoded by multiple polynucleotides.

[0394] The disclosure also provides, among other things, a vector (e.g., an expression vector, including a viral-delivery vector) comprising any one or more of the polynucleotides disclosed herein.

[0395] In some embodiments, a vector (e.g., expression vector) further comprises an expression control polynucleotide sequence operably linked to the polynucleotide, and / or a polynucleotide sequence encoding a selectable marker. In some embodiments, an expression control polynucleotide sequence comprises a promoter sequence and / or an enhancer sequence. In some embodiments, an expression control polynucleotide sequence comprises an inducible promoter sequence.Host Cells and Methods of Production

[0396] The disclosure also provides, among other things, a host cell comprising any one or more of the polynucleotides or expression vectors disclosed herein.

[0397] Non-limiting examples of host cells (e.g., recombinant cells) include mammalian cells such as hybridoma cells, Chinese hamster ovary (CHO) cells, COS cells, human embryonic kidney (HEK), yeast cells such as Pichia pastoris cells, and bacterial cells such as E. coli, including DH5a.

[0398] The disclosure also provides, among other things, a method of producing an antibody or an antigen binding fragment disclosed herein, comprising expressing the antibody or the 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.Compositions & Kits

[0399] The disclosure also provides, among other things, a composition comprising any one or more of the antibodies, antigen-binding fragments, fusion proteins, polynucleotides, or host cells disclosed herein. In some embodiments, a composition is a pharmaceutical composition.

[0400] In some embodiments, a composition (e.g., pharmaceutical composition) further comprises pharmaceutically acceptable carriers, excipients, stabilizers, diluents or tonifiers(Remington's Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980)). Suitable pharmaceutically acceptable carriers, excipients, or stabilizers are nontoxic to recipients at the dosages and concentrations employed. Non-limiting examples of pharmaceutically acceptable carriers, excipients, stabilizers, diluents or tonifiers include buffers (e.g., L-histidine), antioxidants (e.g., ascorbic acid or methionine), preservatives, proteins (e.g, serum albumin, gelatin or immunoglobulins), hydrophilic polymers, amino acids, carbohydrates (e.g, monosaccharides, disaccharides, glucose, mannose or dextrins), chelating agents (e.g., EDTA), sugars (e.g., sucrose), salt-forming counter-ions (e.g., sodium), metal complexes (e.g., Zn-protein complexes), non-ionic surfactants (e.g, Tween), PLURONICS™ and polyethylene glycol (PEG).

[0401] In some embodiments, a composition comprises an antibody or an antigen-binding fragment thereof, L-histidine, L-histidine monohydrochloride monohydrate, polysorbate 80, and sucrose.

[0402] In some embodiments, a composition comprises an antibody or an antigen-binding fragment thereof, EDTA disodium salt dihydrate, L-histidine, L-histidine hydrochloride monohydrate, L-methionine, polysorbate 80, and sucrose.

[0403] In some embodiments, a composition (e.g, a pharmaceutical composition) is formulated for a suitable administration schedule and route. In some embodiments, a composition (e.g., a pharmaceutical composition) is formulated to be administered by infusion (e.g, intravenous infusion). In some embodiments, a composition (e.g, a pharmaceutical composition) is formulated to be administered by subcutaneous administration.

[0404] In some embodiments, a pharmaceutical composition comprises from about 100 mg to about 600 mg of an antibody or an 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.

[0405] In some embodiments, a composition is formulated to be administered with at least one additional therapeutic agent as a combination therapy. In some embodiments, at least oneadditional therapeutic agent comprises vedolizumab, adalimumab, methotrexate, infliximab, tofacitinib, or any combination thereof.

[0406] Also provided herein, among other things, are kits comprising a container and optionally an instruction for use, wherein the container comprises any one or more compositions (e.g., pharmaceutical compositions) disclosed herein.Methods of Use

[0407] The disclosure also provides, among other things, a method of blocking binding of a ligand to its receptor expressed on a surface of a cell, the method comprising contacting the cell with an effective amount of at least one antibody or antigen binding fragment thereof, or at least one composition (e.g., pharmaceutical composition) disclosed herein, thereby blocking the binding of the ligand to its receptor expressed on the surface of the cell, wherein the ligand comprises p40.

[0408] The disclosure also provides, among other things, a method of blocking binding of a ligand to its receptor in a subject, the method comprising administering to the subject an effective amount of at least one antibody or antigen binding fragment thereof disclosed herein, thereby blocking the binding of the ligand to its receptor in the subject, wherein the ligand comprises p40.

[0409] The disclosure also provides, among other things, a method of blocking binding of a ligand to its receptor in a subject, the method comprising administering to the subject 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 subject, wherein the ligand comprises p40.

[0410] The disclosure also provides, among other things, a method of treating an IL-12 / IL- 23-associated disease in a subject in need thereof, comprising administering an effective amount of at least one antibody or antigen binding fragment thereof disclosed herein, thereby treating the IL- 12 / IL-23 -associated disease.

[0411] The disclosure also provides, among other things, a method of treating an IL-12 / IL- 23-associated disease in a subject in need thereof, comprising administering an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and at leastone antibody or antigen binding fragment thereof disclosed herein, thereby treating the IL-12 / IL- 23-associated disease.

[0412] In some embodiments, an IL-12 / IL-23-associated disease is plaque psoriasis, psoriatic arthritis, Crohn’s disease, ulcerative colitis, Alopecia areata, Alopecia totalis, Alopecia universalis, Hidradenitis suppurativa, Pityriasis rubra pilaris, Lichen planus pemphigoides, atopic dermatitis, pyoderma gangrenosum, or vitiligo. In some embodiments, an IL- 12 / IL-23 -associated disease is plaque psoriasis, psoriatic arthritis, Crohn’s disease, or ulcerative colitis.

[0413] In some embodiments, a subject is a mammal. In some embodiments, a subject is a mammal selected from the group consisting of a dog, a cat, a mouse, a rat, a hamster, a guinea pig, a horse, a pig, a sheep, a cow, a chimpanzee, a macaque, a cynomolgus, and a human. In some embodiments, a subject is a primate. In some embodiments, a subject is a human.

[0414] In some embodiments, a subject is 6 years or older.

[0415] In some embodiments, a subject is an adult human patient. In some embodiments, a subject is 18 years of age or older, for example, about: 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75 or 80 years of age or older. In some embodiments, a subject is about: 18-80, 20-80, 20-75, 25- 75, 25-70, 30-70, 30-65, 35-65, 35-60, 40-60, 40-55, 45-55 years of age. In some embodiments, a subject is about 18-65 years of age. In some embodiments, a subject is 65 years of age or older.

[0416] In some embodiments, a subject is a pediatric human patient. In some embodiments, a subject is 6 to 17 years of age. In some embodiments, a subject is 6 to 11 years of age. In some embodiments, a subject is 12 to 17 years of age. In some embodiments, an IL-12 / IL-23- associated disease is plaque psoriasis.

[0417] In some embodiments, a subject is an adult or a child 6 years or older with moderate or severe psoriasis. In some embodiments, a subject is also treated with phototherapy.

[0418] In some embodiments, a subject is an adult or a child 6 years or older with active psoriatic arthritis.

[0419] In some embodiments, a subject is 18 years or older with moderately to severely active Crohn’s disease.

[0420] In some embodiments, a subject is 18 years or older with moderately to severely active ulcerative colitis.

[0421] In some embodiments, at least one antibody or antigen binding fragment thereof comprises: a VHdomain comprising a HCDR1, a HCDR2, and a HCDR3 having at least 80% sequence identity (e.g., having at least 85% sequence identity, having at least 90% sequence identity, or having at least 95% sequence identity) to a HCDR1, a HCDR2, and a HCDR3, respectively, of a VHdomain comprising the amino acid sequence of any one of SEQ ID NOs:2- 11 and 19-21, and / or a VLdomain comprising a LCDR1, a LCDR2, and a LCDR3 having at least 80% sequence identity (e.g., having at least 85% sequence identity, having at least 90% sequence identity, or having at least 95% sequence identity) to a LCDR1, a LCDR2, and a LCDR3, respectively, of a VLdomain comprising the amino acid sequence of SEQ ID NO: 144, SEQ ID NO: 142, or SEQ ID NO: 140 (e.g., SEQ ID NO: 144 or SEQ ID NO: 142), optionally wherein the VH domain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 1, and / or the VLdomain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO:140.

[0422] In some embodiments, at least one antibody or antigen binding fragment thereof comprises: a VHdomain comprising a HCDR1, a HCDR2, and a HCDR3 having 100% sequence identity to a HCDR1, a HCDR2, and a HCDR3, respectively, of a VHdomain comprising the amino acid sequence of any one of SEQ ID NOs:2-l 1 and 19-21, and / or a VLdomain comprising a LCDR1, a LCDR2, and a LCDR3 having 100% sequence identity to a LCDR1, a LCDR2, and a LCDR3, respectively, of a VLdomain comprising the amino acid sequence of SEQ ID NO: 144, SEQ ID NO: 142, or SEQ ID NO: 140 (e.g., SEQ ID NO: 144 or SEQ ID NO: 142), optionally wherein the VHdomain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 1, and / or the VLdomain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO:140.

[0423] In some embodiments, at least one antibody or antigen binding fragment thereof comprises:a) a VHdomain having at least 70% sequence identity (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity) to the amino acid sequence of at least one of SEQ ID NOs:2-l 1 and 19-21, and b) a VLdomain having at least 70% sequence identity (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity) to the amino acid sequence of SEQ ID NO: 144 or SEQ ID NO: 142, wherein the VHdomain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 1 and / or the VLdomain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 140.

[0424] In some embodiments, at least one antibody or antigen binding fragment thereof comprises: a) a VHhaving 100% sequence identity to the amino acid sequence of any one of SEQ ID NOs:2-l l and 19-21, and b) a VLhaving 100% sequence identity to the amino acid sequence of SEQ ID NO: 144 or SEQ ID NO: 142.

[0425] In some embodiments, at least one antibody or antigen binding fragment thereof comprises: a) a VHdomain having at least 70% sequence identity (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity) to the amino acid sequence of at least one of SEQ ID NOs:2-l 1, and b) a VLdomain having at least 70% sequence identity (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, or at least 99% sequence identity) to the amino acid sequence of SEQ ID NO: 144 or SEQ ID NO: 142, wherein the VHdomain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 1 and / or the VLdomain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 140.

[0426] In some embodiments, at least one antibody or antigen binding fragment thereof comprises: a) a VHhaving 100% sequence identity to the amino acid sequence of any one of SEQ ID NOs:2-l l, andb) a VLhaving 100% sequence identity to the amino acid sequence of SEQ ID NO: 144 or SEQ ID NO: 142.

[0427] In some embodiments, at least one antibody or antigen binding fragment thereof 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) to the amino acid sequence of at least one of SEQ ID NOs: 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) to the amino acid sequence of SEQ ID NO:207 or SEQ ID NO:205, optionally wherein the antibody or the antigen-binding fragment thereof comprises a VHdomain having less than 100% sequence identity to the amino acid sequence of SEQ ID NO:1 and / or a VL domain having less than 100% sequence identity to the amino acid sequence of SEQ IDNO: 140.

[0428] In some embodiments, at least one antibody or antigen binding fragment thereof comprises: a) a heavy chain having 100% sequence identity to the amino acid sequence of any one of SEQ ID NOs: 161-170 and 178-180, and / or b) a light chain having 100% sequence identity to the amino acid sequence of SEQ ID NO: 207 or SEQ ID NO: 205.Table 1. VHand Heavy Chain Amino Acid Sequence (SEQ) ID NOsTable 2. HCDR Amino Acid Sequences as Determined by ImMunoGeneTics (IMGT) Numbering, Kabat Numbering, or Chothia NumberingTable 3. VLand Light Chain Amino Acid Sequence (SEQ) ID NOsTable 4. LCDR Amino Acid Sequences as Determined by IMGT Numbering, or Kabat or Chothia NumberingEMBODIMENTS1. An antibody or an antigen-binding fragment thereof, comprising: a) an immunoglobulin heavy chain variable (VH) domain comprising a heavy chain complementarity-determining region (HCDR) 1, a HCDR2, and a HCDR3 having 100% sequence identity to a HCDR1, a HCDR2, and a HCDR3, respectively, of a VHdomain comprising the amino acid sequence of any one of SEQ ID NOs:2-l 1 and 19-21; andb) an immunoglobulin light chain variable (VL) domain comprising a light chain complementarity-determining region (LCDR) 1, a LCDR2, and a LCDR3 having 100% sequence identity to a LCDR1, a LCDR2, and a LCDR3, respectively, of a VLdomain comprising the amino acid sequence of SEQ ID NO: 144 or SEQ ID NO: 142, wherein the VHdomain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO:1, the VLdomain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 140, or both. The antibody or the antigen-binding fragment thereof of Embodiment 1, wherein the VHdomain of the antibody or the antigen-binding fragment thereof comprises four VHframework regions (VHFR1-4) and three heavy chain complementarity determining regions (HCDR1-3) in the following N-terminal to C-terminal order: VH FR1-HCDR1- VHFR2-HCDR2-VHFR3-HCDR3-VHFR4, wherein: a) the VHFR1-HCDR1 comprises the amino acid sequence of QFRTY (SEQ ID NO:262), HFDRY (SEQ ID NO:263), YFERY (SEQ ID NO:264), YFETR (SEQ ID NO:265), YFQTR (SEQ ID NO:266), or YFETY (SEQ ID NO:267); b) the VHFR2 comprises the amino acid sequence of GKGL (SEQ ID NO:268), GDYL (SEQ ID NO:269), or GYYL (SEQ ID NO:270); or c) the VHFR3 comprises the amino acid sequence of NSLK (SEQ ID NO:271), PSLR (SEQ ID NO:272), or NDLR (SEQ ID NO:273); or any combination of a) to c). The antibody or the antigen-binding fragment thereof of Embodiment 1 or 2, wherein: the HCDR1 comprises the amino acid sequence of SEQ ID NO:45, SEQ ID NO:46, SEQ ID NO:47, SEQ ID NO:49, SEQ ID NO:50 or SEQ ID NO:51; the HCDR2 comprises the amino acid sequence of SEQ ID NO:72; and the HCDR3 comprises the amino acid sequence of SEQ ID NO:79.The antibody or the antigen-binding fragment thereof of any one of Embodiments 1-3, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:45.The antibody or the antigen-binding fragment thereof of any one of Embodiments 1 -3, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:46. The antibody or the antigen-binding fragment thereof of any one of Embodiments 1-3, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:47. The antibody or the antigen-binding fragment thereof of any one of Embodiments 1-3, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:49. The antibody or the antigen-binding fragment thereof of any one of Embodiments 1-3, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:50. The antibody or the antigen-binding fragment thereof of any one of Embodiments 1-3, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:51. The antibody or the antigen-binding fragment thereof of any one of Embodiments 1-9, wherein: the LCDR1 comprises the amino acid sequence of SEQ ID NO: 146; the LCDR2 comprises the amino acid sequence of AAS; and the LCDR3 comprises the amino acid sequence of SEQ ID NO: 150. The antibody or the antigen-binding fragment thereof of Embodiment 1 or 2, wherein: the HCDR1 comprises the amino acid sequence of SEQ ID NO:80, SEQ ID NO 81 or SEQ ID NO:82; the HCDR2 comprises the amino acid sequence of SEQ ID NO:96; and the HCDR3 comprises the amino acid sequence of SEQ ID NO:103. The antibody or the antigen-binding fragment thereof of any one of Embodiments 1, 2, and 11, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:80. The antibody or the antigen-binding fragment thereof of any one of Embodiments 1, 2, and 11, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:81.The antibody or the antigen-binding fragment thereof of any one of Embodiments 1 , 2, and 11, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:82. The antibody or the antigen-binding fragment thereof of any one of Embodiments 1, 2, and 11-14, 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. The antibody or the antigen-binding fragment thereof of any one of Embodiments 1, 2, and 11-14, 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: 154; and c) the LCDR3 comprises the amino acid sequence of SEQ ID NO: 150. The antibody or the antigen-binding fragment thereof of Embodiment 1 or 2, wherein: the HCDR1 comprises the amino acid sequence of SEQ ID NO: 105, SEQ ID NO: 106, SEQ ID NO:107, SEQ ID NO:109, SEQ ID NO: 110, or SEQ ID NO:111; the HCDR2 comprises the amino acid sequence of SEQ ID NO: 132; and the HCDR3 comprises the amino acid sequence of SEQ ID NO: 139. The antibody or an antigen-binding fragment thereof of any one of Embodiments 1, 2, and 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:105. The antibody or the antigen-binding fragment thereof of any one of Embodiments 1, 2, and 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:106. The antibody or the antigen-binding fragment thereof of any one of Embodiments 1, 2, and 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 107. The antibody or the antigen-binding fragment thereof of any one of Embodiments 1, 2, and 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO: 109.The antibody or the antigen-binding fragment thereof of any one of Embodiments 1 , 2, and 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NO:110. The antibody or the antigen-binding fragment thereof of any one of Embodiments 1, 2, and 17, wherein the HCDR1 comprises the amino acid sequence of SEQ ID NOT H. The antibody or the antigen-binding fragment thereof of any one of Embodiments 1, 2, and 17-23, 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. The antibody or the antigen-binding fragment thereof of any one of Embodiments 1, 2, and 17-23, 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. The antibody or the antigen-binding fragment thereof of any one of Embodiments 1-25, wherein the VHdomain comprises the amino acid sequence of any one of SEQ ID NOs:2- 11 and 19-21. The antibody or the antigen-binding fragment thereof of any one of Embodiments 1-25, wherein the VHdomain comprises the amino acid sequence of SEQ ID NO:2. The antibody or the antigen-binding fragment thereof of any one of Embodiments 1-25, wherein the VH domain comprises the amino acid sequence of SEQ ID NO:3. The antibody or the antigen-binding fragment thereof of any one of Embodiments 1-25, wherein the VHdomain comprises the amino acid sequence of SEQ ID NO:4. The antibody or the antigen-binding fragment thereof of any one of Embodiments 1-25, wherein the VHdomain comprises the amino acid sequence of SEQ ID NO:5.The antibody or the antigen-binding fragment thereof of any one of Embodiments 1 -25, wherein the VHdomain comprises the amino acid sequence of SEQ ID NO:6. The antibody or the antigen-binding fragment thereof of any one of Embodiments 1-25, wherein the VHdomain comprises the amino acid sequence of SEQ ID NO:7. The antibody or the antigen-binding fragment thereof of any one of Embodiments 1-25, wherein the VH domain comprises the amino acid sequence of SEQ ID NO: 8. The antibody or the antigen-binding fragment thereof of any one of Embodiments 1-25, wherein the VHdomain comprises the amino acid sequence of SEQ ID NO:9. The antibody or the antigen-binding fragment thereof of any one of Embodiments 1-25, wherein the VHdomain comprises the amino acid sequence of SEQ ID NO: 10. The antibody or the antigen-binding fragment thereof of any one of Embodiments 1-25 wherein the VHdomain comprises the amino acid sequence of SEQ ID NO: 11. The antibody or the antigen-binding fragment thereof of any one of Embodiments 1-25, wherein the VHdomain comprises the amino acid sequence of SEQ ID NO: 19. The antibody or the antigen-binding fragment thereof of any one of Embodiments 1-25, wherein the VHdomain comprises the amino acid sequence of SEQ ID NO:20. The antibody or the antigen-binding fragment thereof of any one of Embodiments 1-25, wherein the VHdomain comprises the amino acid sequence of SEQ ID NO:21. The antibody or the antigen-binding fragment thereof of any one of Embodiments 2-39, wherein the VLdomain comprises the amino acid sequence of SEQ ID NO: 144 or SEQ ID NO: 142. The antibody or the antigen-binding fragment thereof of any one of Embodiments 2-40, wherein the Vj, domain comprises the amino acid sequence of SEQ ID NO: 144.The antibody or the antigen-binding fragment thereof of any one of Embodiments 2-40, wherein the VLdomain comprises the amino acid sequence of SEQ ID NO: 142. An antibody or an antigen-binding fragment thereof, comprising a heavy chain variable (VJI) domain comprising the amino acid sequence of SEQ ID NO:2 and a light chain variable (VL) domain comprising the amino acid sequence of SEQ ID NO: 144. An antibody or an antigen-binding fragment thereof, comprising a heavy chain variable (VH) domain comprising the amino acid sequence of SEQ ID NO:3 and a light chain variable (VL) domain comprising the amino acid sequence of SEQ ID NO: 144. The antibody or the antigen-binding fragment thereof of any one of Embodiments 1-44, wherein the antigen-binding fragment comprises a single-chain fragment variable (scFv), a variable heavy domain of heavy chain (VHH), a fragment antigen-binding (Fab), a Fab’ or a F(ab’)2. The antibody or the antigen-binding fragment thereof of any one of Embodiments 1-44, comprising an antibody heavy chain constant domain, an antibody light chain constant domain, or both. The antibody or the antigen-binding fragment thereof of Embodiment 46, wherein the antibody heavy chain constant domain is an IgGl, IgG2, IgG3 or IgG4 constant domain. The antibody or the antigen-binding fragment thereof of Embodiment 47, wherein the antibody heavy chain constant domain comprises one or more mutations which increase serum half-life of the antibody or antigen-binding fragment thereof in humans. The antibody or the antigen-binding fragment thereof of Embodiment 47, wherein the antibody heavy chain constant domain comprises, relative to a wild-type human IgG constant domain, amino acid substitutions with tyrosine, threonine and glutamic acid at amino acid residues 252, 254 and 256, respectively, wherein the amino acid residues are numbered according to the EU index as in Kabat.The antibody or the antigen-binding fragment thereof of any one of Embodiments 1 -49, wherein the antibody or the antigen-binding fragment comprises a heavy chain comprising the amino acid sequence of any one of SEQ ID NOs: 161-170 and SEQ ID NOs: 178-180. The antibody or the antigen-binding fragment thereof of any one of Embodiments 1-50, wherein the antibody or the antigen-binding fragment comprises a light chain comprising the amino acid sequence of SEQ ID NO:207 or SEQ ID NO:205. The antibody or the antigen-binding fragment thereof of any one of Embodiments 1-49, wherein the antibody is a multi-specific antibody. The antibody or the antigen-binding fragment thereof of any one of Embodiments 1-52, wherein the antibody or the antigen-binding fragment thereof binds both interleukin- 12 (IL-12) and interleukin-23 (IL-23). A polynucleotide encoding a VHdomain, a VLdomain, a light chain, or a heavy chain of the antibody, or the antigen binding fragment thereof of any one of Embodiments 1-53. An expression vector comprising the polynucleotide of Embodiment 54. An RNA encoding a VHdomain, a VLdomain, a light chain, or a heavy chain of the antibody, or the antigen binding fragment thereof of any one of Embodiments 1-53. A host cell comprising the polynucleotide of Embodiment 54, the expression vector of Embodiment 55, or the RNA of Embodiment 56. A method of producing the antibody or the antigen binding fragment thereof of any one of Embodiments 1-53, comprising expressing the antibody or the antigen binding fragment thereof, in the host cell of Embodiment 57 and isolating the expressed antibody or the antigen binding fragment thereof. A pharmaceutical composition comprising the antibody or the antigen binding fragment thereof of any one of Embodiments 1-53, the polynucleotide of Embodiment 54, theexpression vector of Embodiment 55, the RNA of Embodiment 56, or host cell of Embodiment 57, and a pharmaceutically acceptable carrier or diluent. A kit comprising the pharmaceutical composition of Embodiment 59. A method of blocking binding of a ligand to its receptor expressed on a surface of a cell, the method comprising contacting the cell with an effective amount of the antibody or the antigen binding fragment thereof of any one of Embodiments 1-53, the polynucleotide of Embodiment 54, the expression vector of Embodiment 55, or the RNA of Embodiment 56, thereby blocking the binding of the ligand to its receptor expressed on the cell surface, wherein the ligand comprises p40. A method of blocking binding of a ligand to its receptor in a subject, the method comprising administering an effective amount of the antibody or the antigen binding fragment thereof of any one of Embodiments 1-53 or the pharmaceutical composition of Embodiment 59 to the subject, thereby blocking the binding of the ligand to its receptor in the subject, wherein the ligand comprises p40. A method of treating an IL- 12 / IL-23 -associated disease in a subject in need thereof, comprising administering an effective amount of the antibody or the antigen binding fragment thereof of any one of Embodiments 1-53 or the pharmaceutical composition of Embodiment 59 to the subject, thereby treating the IL- 12 / IL-23 -associated disease. The method of Embodiment 63, wherein the IL-12 / IL-23-associated disease is plaque psoriasis, psoriatic arthritis, Crohn’s disease, ulcerative colitis, Alopecia areata, Alopecia totalis, Alopecia universalis, Hidradenitis suppurativa, Pityriasis rubra pilaris, Lichen planus pemphigoides, atopic dermatitis, pyoderma gangrenosum, or vitiligo. The method of Embodiment 63 or 64, wherein the IL- 12 / IL-23 -associated disease is plaque psoriasis, psoriatic arthritis, Crohn’s disease, or ulcerative colitis. The method of any one of Embodiments 63-65, wherein the subject is an adult human patient.67. The method of any one of Embodiments 63-65, wherein the subject is a pediatric human patient.68. The method of Embodiment 67, wherein the IL- 12 / IL-23 -associated disease is plaque psoriasis.69. The method of any one of Embodiments 63-68, further comprising administering at least one additional therapeutic agent.70. The method of Embodiment 69, wherein the at least one additional therapeutic agent is vedolizumab, adalimumab, methotrexate, infliximab, tofacitinib, or any combination thereof.EXAMPLESExamples 1. In silico Affinity Maturation and In Silico Deimmunization

[0429] Ustekinumab (STELERA®) is a widely prescribed fully human monoclonal antibody treatment for psoriasis, psoriatic arthritis, Crohn’s disease, and ulcerative colitis. Ustekinumab targets the p40 subunit of IL-12 (p40 / p35) and IL-23 (p40 / p 19) and thereby prevents IL-12 and IL-23 from binding to their respective receptors.

[0430] There is an opportunity to produce a “bio-better” molecule. For example, Ustekinumab has been shown to elicit anti-drug neutralizing antibodies in 5-12% of patients, a deimmunized molecule may therefore be more effective in the general population. Improvements in target affinity could improve efficacy and / or lower dose. Increased stability and / or serum halflife provide dosing advantages.

[0431] In silico affinity maturation was performed using the Protein Modeler application in Molecular Operating Environment (MOE) (Chemical Computing Group ULC., Montreal, QC, Canada). The 3D coordinates of a X-ray crystal structure of Ustekinumab Fab / IL-12 complex (PDB ID: 3HMX) were obtained from the Protein Data Bank located at www.rcsb.org / structure / 3hmx and utilized as starting template coordinates. Missing residues were computationally complemented, the entire complex was computationally protonated and optimized, then utilized as the structure for in silico mutagenesis.

[0432] The in silica mutagenesis was performed using the residue scanning function in MOE to target residues involved in the interactions between the antigen and antibody. One to ten point mutations were introduced into the Fab / IL-12 complex, using alanine, arginine, asparagine, aspartic acid, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, serine, phenylalanine, proline, threonine, tyrosine, valine, or tryptophan. Approximately 200,000 mutants were sampled and calculated for both affinity and stability changes. Variants to be constructed and tested further were pre-selected based on improved affinity and stability. The pre-selected variants were tested for reduced MHC II binding potential measured using IEDB (tools.iedb.org / mhcii / ) and / or using EpiVax’s Interactive Screening and Protein Reengineering Interface (ISPRI) (epivax.com / immunogenicity-assessment / ispri-web-based-immunogeni cityscreening). Over 500 variants were identified, in which affinity was improved, stability was not compromised, and MHC II binding potential was reduced. Out of these 500 variants, VHvariants A05, A08, A14, A24, A31, A39, C02, C03, C07, CH, C13, and C38 were selected initially for further downstream experimental testing to configure desirable molecular characteristics.Example 2 A. Construction of Plug-In Vectors and DNA Assembly of First-Round U Variants. [00433J Plug-in VHand VLvectors were constructed by modifying a pcDNA3.4 plasmid backbone (Invitrogen, Waltham, MA). The cloning strategy was to make separate heavy and light chain plasmids for Ustekinumab with specific restriction enzyme sites flanking VHand VLgenes followed by swapping with V gene fragments of U variants. Restriction enzymes EcoRI / XhoI and BamHI / BsiwI were used for VHand VLcloning, respectively. DNA fragments encoding heavy chain and light genes of U antibody were synthesized by gBlocks HiFi (Integrated DNA Technologies, Inc., Coralville, IA). DNA fragments of V gene variants containing 20 nucleotide overhang sequences homologous to plug-in vectors on both sides were also synthesized by gBlocks. Heavy chain and light chain genes were cloned into pcDNA3.4 vectors digested with SacI and EcoRV by DNA HiFi assembly (New England Biolabs, Ipswich, MA) followed by bacterial transformation and clone sequencing. V gene fragments of U variants were cloned into heavy chain and light chain plug-in plasmids linearized with specific restriction enzymes by DNA HiFi assembly followed by bacterial transformation and clone sequencing.

[0434] Ustekinumab heavy chain fragment (SEQ ID NO:209). Ustekinumab light chain fragment (SEQ ID NO:210). DNA sequences of first round VHvariants: A05 (SEQ ID NO:211),A08 (SEQ ID NO:212), Al 4 (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), Cl 1 (SEQ ID NO:220), C13 (SEQ ID NO:221), and C38 (SEQ ID NO:222).Example 2B. Cell Transfection and ELISA of First-Round Variants

[0435] The ExpiCHO-S cell expression system (Invitrogen) in a 24-well format was used for antibody production following the user manual. In brief, DNA, where the heavy chain of variants and light chain of Ustekinumab ratio was 1 : 1 mixed with ExpiFectamine, were added into expiCHO-S cell culture followed by adding Transfection Enhancer and ExpiCHO cell Feed after 20 hours. Cell culture supernatants of 5 days post-transfection were 1 :500 diluted in buffers for performing IgG and IL- 12 ELIS As, which were used for evaluating IgG yields (protein expression levels) and IL-12 binding affinities, respectively. Ustekinumab, starting at 300 ng / mL with 3-fold serial dilutions, was used as a reference for IgG yields and IL-12 binding affinities. [00436J For IL-12 ELISA, 25 pL of IL-12 (PeproTech, Rocky Hill, NJ) diluted in PBS at 1 pg / mL were added into each well of 96 Well Half-Area Microplate (Greiner AG, Kremsmunster, Austria) and incubated at 4°C overnight. The plates were washed with PBST (0.5% Tween) and then blocked with 120 pL of 1% BSA / PBS at room temperature for 1 hour. After three PBST washes, 25 pL of diluted supernatants of antibody variants were added into wells and incubated at room temperature for 2 hours, followed by three PBST washes. Detection antibody (Peroxidase AffiniPure F(ab’)2 Fragment Goat Anti-Human IgG, Fey fragment specific, Jackson ImmunoResearch, West Grove, PA), 1 : 10,000 diluted, was added into each well and incubated at room temperature for 1 hour. The plates were washed with PBST for 6 times followed by adding 25 pL of TMB substrates. Enzymatic reactions were developed for 4-6 minutes followed by adding 25 pL of sulfuric acid to terminate the reactions. The plates were read at OD 450nm. For IgG ELISA, 25 pL of human IgG capture antibody (AffiniPure Goat Anti -Human IgG, Fey fragment specific, Jackson ImmunoResearch), diluted in PBS at 2 pg / mL, was added into each well of a 96 Well Half-Area Microplate.

[0437] FIGs. 2A-2B show ELISA analysis of indicated C and A variants, each comprising a heavy chain comprising an indicated first round VHvariant, and the light chain of Ustekinumab. Compared to Ustekinumab, most C variants showed similar protein expression (IgG yields)- I l l -except for C2, while the A variants showed lower protein expression (FIG. 2A). Compared to Ustekinumab, C38 showed significantly higher IL-12 binding affinity, C7 and Cl 1 showed slightly higher affinities, C3 showed a similar affinity, and the A variants showed lower affinities (FIG. 2B).Example 3A. DNA Assembly of Second-Round U variants

[0438] DNA fragments of second-round U variants, containing 20 nucleotide homologous sequences to plug-in vectors on both sides, were synthesized by gBlocks. The heavy and light chain variants were separately cloned into plug-in plasmids linearized with specific restriction enzymes by DNA HiFi assembly, followed by bacterial transformation and clone sequencing.

[0439] The sequences of second-round VHvariant are: C41 (SEQ ID NO:223), C42 (SEQ ID NO:224), C43 (SEQ ID NO:225), C44 (SEQ ID NO:226), C45 (SEQ ID NO 227), C46 (SEQ IDNO:228), C51 (SEQ ID NO:229), C52 (SEQ ID NO:230), C53 (SEQ ID NO 231), C54 (SEQ IDNO:232), C55 (SEQ ID NO:233), C56 (SEQ ID NO:234), C57 (SEQ ID NO:235), C58 (SEQ IDNO:236), C59 (SEQ ID NO:237), C61 (SEQ ID NO:238), C62 (SEQ ID NO:239), C71 (SEQ IDNO:240), C72 (SEQ ID NO:241), C73 (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). The sequences of VLvariant are: C101 (SEQ ID NO:248), C102 (SEQ ID NO:249), C103 (SEQ ID NO:250), C104 (SEQ ID NO:251), and C105 (SEQ ID NO:252).Example 3B, Cell transfection and ELISA of Second-Round VH Variants and Vi_ Variants.

[0440] ExpiCHO cell transfection procedures for antibody variants in a 24-well format, as described in Example 2B, were followed. Vn and VLvariants were paired with Ustekinumab VLand VH, respectively. The production of C38 was scaled up to a 25-mL transfection volume, followed by purification using protein A resin. Three days post-transfection, the cell culture supernatants were 1 :300 diluted in buffers to perform IgG and IL-12 ELISAs. A titration curve of C38 was used as a reference to evaluate IL- 12 binding affinities of antibody variants at corresponding IgG concentrations.

[0441] ELISA analyses were performed on antibody variants, each comprising: (i) a heavy chain comprising an indicated second round VHvariant and the light chain of Ustekinumab or (ii) the heavy chain of Ustekinumab and a light chain comprising an indicated VLvariant.Compared to the antibody comprising a heavy chain comprising C38 and the light chain of Ustekinumab (C38): (i) C41, C42, C61, C38xC81, C38xC82, C38xC91, and C38xC92 showed similar or higher IL-12 binding affinities, when paired with the light chain of Ustekinumab, and (ii) Cl 02, Cl 03, Cl 04, and Cl 05, showed similar or higher IL- 12 binding affinities, when paired with the heavy chain of Ustekinumab. Among these, C42, C38xC81, C38xC82, C38xC91, C38xC92, and C104 were associated with higher IL-12 binding affinities (FIG. 3).Example 4 A. Third-Round Variants

[0442] Several mutations associated with improved IL-12 binding were identified. Twenty- four combinatorial variants were generated by shuffling eight VHvariants (C38, C41, C42, C44, C61, C38xC82, C38xC91, and C38xC92) and three VLvariants (C102, C103, and C104).Example 4B. Cell Transfection and ELISA of Third-Round Variants

[0443] ExpiCHO cell transfection procedures for antibody variants in a 24-well format, as described in Example 2B, were followed. Three days post-transfection, cell culture supernatants of antibody variants were 1 :200 diluted in buffers to perform IgG and IL-12 ELISAs. A titration curve of the antibody comprising a heavy chain comprising C38 and the light chain of Ustekinumab was used as a reference to evaluate IL-12 binding affinities of antibody variants at corresponding IgG concentrations.

[0444] Antibody variants C38xC104 (an antibody comprising a heavy chain comprising C38 and a light chain comprising Cl 04), C41xC104, C42xC104, C44xC104, C38xC82xC104, C38xC91xC104, C38xC92xC104, and C38x92xC102 showed higher IL-12 binding affinities comparing to the antibody comprising a heavy chain comprising C38 and the light chain of Ustekinumab (FIG. 4).Example 5A. DNA Assembly of Fourth-Round Variants

[0445] Based on results of the third-round variants, VHand VLmutations associated with improved IL- 12 binding affinities were identified and incorporated to generate new antibody variants. Four VHvariants (C38xC82xC92, C42xC82, C42xC92, and C42xC82xC92) were paired with two VLvariants (Cl 02 and Cl 04) to assemble eight new variants. Cloning strategy using DNA assembly with plug-in vectors, as described in Example 2A, was followed. The DNAsequences of round-four VHvariants 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 Fourth-Round Variants

[0446] ExpiCHO cell transfection procedures for combinatorial variants in a 24-well format were followed as described in Example 2B. Three days post-transfection, cell culture supernatants of antibody variants were 1:200 diluted in buffers to perform IgG and IL-12 ELISAs. A titration curve of the antibody comprising a heavy chain comprising C38 and the light chain of Ustekinumab was used as a reference to evaluate IL-12 binding affinities of the antibody variants at corresponding IgG concentrations. C38xC82xC92xC104 showed better IL- 12 binding affinity, and C42xC82xC92xC104, C42xC92xC104, and C38xC82xC92xC102 showed similar IL-12 binding affinities, compared to the antibody comprising a heavy chain comprising C38 and the light chain of Ustekinumab (FIG. 5 A).Example 5C. Cell Transfection and ELISA of Single Mutations

[0447] Four antibody variants, (i) an antibody comprising a heavy chain comprising C38R and the light chain of Ustekinumab (C38R), (ii) an antibody comprising a heavy chain comprising C38Q and the light chain of Ustekinumab (C38Q), (iii) an antibody comprising the heavy chain of Ustekinumab and a light chain comprising C104R (C104R), and (iv) an antibody comprising the heavy chain of Ustekinumab and a light chain comprising C104R (C104R), were expressed in ExpiCHO as described in Example 2. The cell culture supernatants were assayed for IL-12 binding and also for IgG levels to control for antibody concentration in the supernatant. C38R, C38Q, C104R, and C104Q showed IL-12 marginally lower binding affinities than the antibody comprising a heavy chain comprising C38 and the light chain of Ustekinumab (C38, which contains double mutations Q and R) (FIG. 5B).Example 5D. Characterization of Selected Antibody Variants

[0448] After four rounds of testing, antibody variants C38xC104, C41xC104, C42xC104, C44xC104, C38x82xC104, C38x91xC104, C38x92xC104, C38x82x92xC104, C42x82x92xC104, and C38x92xC102 that showed higher IL- 12 binding affinities than the antibody comprising a heavy chain comprising C38 and the light chain of Ustekinumab were chosen for antibody production and purification. IgG and IL- 12 ELISAs and cell activationassays were performed for comparison with Ustekinumab and the antibody comprising a heavy chain comprising C38 and the light chain of Ustekinumab (C38).

[0449] FIGs. 6A-6C show titration curves of IL-12 binding of ten selected antibody variants. IgG and IL-12 ELISAs were performed to evaluate IL-12 binding affinities at corresponding IgG concentrations. Compared to Ustekinumab, all ten antibody variants showed higher IL-12 binding affinities. Comparing to the antibody comprising a heavy chain comprising C38 and the light chain of Ustekinumab (C38), C38xC104, C38x82xC104, C38x91xC104, C38x92xC104, and C38x82x92xC104 showed higher IL- 12 binding activities.

[0450] Six antibody variants, C38, C38xC104, C38xC82xC104, C38xC91xC104, C38xC92xC104, and C38xC82xC92xC104, were expressed in 25-mL expiCHO cell cultures, purified by Protein A resin. Recovered antibodies were quantified by A280. The yields were similar, except for C38xC82xC92xC104, which was lower than the others (Table 5).Table 5. Antibody Yield and EC50 Values

[0451] Titration curves of IL-12 binding of the six antibody variants were generated. The antibody variants were expressed, purified, quantified, and titrated from 600 ng / mL with 3 -fold serial dilutions. IL-12 ELISAs were performed to determine EC50values of IL-12 binding by curve fitting with a 4-parameter sigmoidal model in Prism. All six variants showed: (i) higher binding affinities compared to Ustekinumab (Table 5, EC50values were the mean of three experiments), and (ii) similar or higher binding affinities compared to the antibody comprising a heavy chain comprising C38 and the light chain of Ustekinumab (C38) (FIGs. 7A-7C).Example 6. In vivo Pharmacokinetic (PK) Studies of Ustekinumab and Antibody Variants

[0452] These experiments determined the half-lives of Ustekinumab and three antibody variants in mice. For each antibody group, three C57BL / 6 mice were injected with the dose of 1 mg / kg via tail veins. Mice were bled at 2-, 24-, 48-, 96-, 120-, and 168-hours post injections tocollect plasma samples. Plasmas were prepared and diluted in PBS / BSA. Serum concentrations of antibody variants were measured using IgG ELISAs. A serial dilutions of Ustekinumab were used as human IgG standard for concentration interpolation.

[0453] Serum concentrations of both (i) Ustekinumab and (ii) the antibody comprising a heavy chain comprising C38 and the light chain of Ustekinumab (C38) remained at / near peak levels on day 5 (120 hours). The concentration of Ustekinumab declined on day 7 (168 hours), whereas the concentrations of C38 remained stable (FIGs. 8A-8B). C38xC91xC104 and C38xC92xC104 showed no decrease in pharmacokinetic clearance and half-life, suggesting similar pharmacokinetic properties when compared to Ustekinumab (FIGs. 8A, 8C, and 8D).Example 7 A. Construction of Expression Vectors and DNA Assembly for scFv Production

[0454] Effects of linker peptide sequence on scFv format of Ustekinumab were studied. A human IgG Fc domain was tethered to the C-terminal of scFv. Linker 1 A (SEQ ID NO:257) or Linker IB (SEQ ID NO:258) was used to connect the VHand Vj, domains, and a short peptide liker (SEQ ID NO:259) was used to connect the scFv and Fc domains. To construct expression vectors, pcDNA3.4 plasmids digested with SacI and EcoRV were used for DNA assembly with two scFv DNA fragments U-scFv-Fc-Linker 1 A and U-scFv-Fc-Linker IB. DNA fragments containing 25 nucleotide overhang sequences homologous to vectors were synthesized by gBlocks HiFi (Integrated DNA Technologies) and cloned into vectors by DNA HiFi assembly (New England Biolabs), followed by bacterial transformation and clone sequencing. DNA sequence of U-scFv-Fc-Linker 1A (SEQ ID NO:260), DNA sequence of U-scFv-Fc-Linker IB (SEQ ID NO:261).Example 7B. Protein Production and ELISA of Ustekinumab ScFv with Two Different Linkers.

[0455] Two versions of Ustekinumab-scFv-Fc were expressed using ExpiCHO cell systems. Five days post-transfection, cell culture supernatants were 1 :300 diluted in PBS / BSA and subjected to IL-12 and IgG ELISAs (procedures as described in Example 2B). The two versions bind to IL-12 with similar affinities (FIG. 9A), although the version comprising Linker 1A showed higher expression level (FIG. 9B).Example 8. Cell Assay Measuring IL- 12 and IL-23 Activities

[0456] To measure IL- 12 activities, HEK cells stably expressing an IL-12-sensitive alkaline phosphatase reporter gene were cultured in DMEM based media. The cells were passaged in CellStripper (Corning, Coming, NY) and seeded at a density of 50,000 cells per well in a 96-well tissue culture plate. After 6 hours, cells were treated with an IL-12 and antibody premix as follows: Antibody was titrated with 3-fold serial dilutions to obtain 2x final concentrations in DMEM growth media (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 media to arrive at (i) 4 ng / mL rhIL-12, and (ii) 1,000 ng / mL to 0.3 ng / mL of the antibody. This pre-mix was incubated for 30 minutes at 37°C to allow for antibody binding and neutralization of rhIL-12. Culture media was removed from the HEK cells and replaced with 100 pL of the pre-mix media and cultured for 18 hours. Media was removed, and alkaline phosphatase activity was measured by conversion of tetramethylbenzidine based substrate with absorption at 450 nm or 650 nm.

[0457] To measure IL-23 activities, HEK cells stably expressing an IL-23 -sensitive alkaline phosphatase reporter gene were cultured in DMEM based media. The cells were passaged in CellStripper (Corning) and seeded at a density of 20,000 cells per well in a 96-well tissue culture plate. After 6 hours, cells were treated with an IL-23 and antibody premix as follows: Antibody was titrated with 3 -fold serial dilutions to obtain 2x final concentrations in DMEM growth media (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 media to arrive at (i) 6 ng / mL rhIL-23, and (ii) 1,000 ng / mL to 0.3 ng / mL of the antibody. This pre-mix was incubated for 30 minutes at 37°C to allow for antibody binding and neutralization of rhIL-23. Culture media was removed from the HEK cells and replaced with 100 pL of the pre-mix media and cultured for 18 hours. Media was removed, and alkaline phosphatase activity was measured by conversion of tetramethylbenzidine based substrate with absorption at 450 nm or 650 nm.

[0458] FIG. 10 evaluates effects of Ustekinumab, in IgG or scFv-Fc format, on cell-based IL- 12 activities. Ustekinumab in IgG format and Ustekinumab in scFv-Fc formats were assayed at a dose range of 0.3 ng / mL to 1,000 ng / mL to measure inhibition of IL-12 receptor binding and induced signaling. The data points were the average of two replicates. The two scFv-Fc versionsshowed dose-dependent inhibition of TL-12 activities, although the ability in reducing IL-12 activities was reduced, compared to the IgG format,

[0459] FIG. 11 evaluates effects of (i) the antibody comprising a heavy chain comprising C38 and the light chain of Ustekinumab (C38) and (ii) the antibody comprising a heavy chain comprising Cl 1 and the light chain of Ustekinumab (Cl 1) on cell-based IL-12 activities. Purified C38 and Cl 1 were assayed at a dose range of 0.3 ng / mL to 1,000 ng / mL to measure inhibition of IL- 12 receptor binding and induced signaling. The data points were the average of two replicates. C38 showed an increased ability in reducing IL- 12 activities, and Cl 1 showed a similar ability in reducing IL- 12 activities, compared to Ustekinumab.

[0460] FIG. 12A evaluates effects of indicated antibody variants on cell-based IL- 12 activities. Purified variants in IgG format were assayed at a dose range of 0.3 ng / mL to 1,000 ng / mL to measure inhibition of IL-12 receptor binding and induced signaling. All tested antibody variants showed an increased ability in reducing IL-12 activities, compared to Ustekinumab.

[0461] FIG. 13A evaluates effects of indicated antibody variants on cell-based IL-12 activities. Purified mAbs in IgG format were assayed at a dose range of 0.3 ng / mL to 1,000 ng / mL to measure inhibition of IL- 12 receptor binding and induced signaling. The data were the average of three independent experiments performed at monthly intervals using different passages of cells. C38xC91xC104 and C38xC92xC104 showed an increased ability in reducing IL- 12 activities, compared to Ustekinumab.

[0462] FIG. 13B summarizes effects of indicated antibody variants on cell-based IL- 12 activities. In the presence of rhIL-12 treatment (5 ng / mL), purified mAbs in IgG format were assayed at a single dose of 100 ng / mL to measure inhibition of IL- 12 receptor binding and induced signaling. Shown are the mean and standard deviation of six replicates. Compared to Ustekinumab, the antibody comprising a heavy chain comprising C38 and the light chain of Ustekinumab (C38), C38C91C104, and C38C92C104 showed statistically significantly increased ability in reducing IL-12 activities (t-test; p<0.001).

[0463] FIG. 13C evaluates effects of indicated antibody variants on cell-based IL-23 activities. Purified mAbs in IgG format were assayed at a dose range of 0.3 ng / mL to 1,000 ng / mL to measure inhibition of IL-23 receptor binding and induced signaling. The datapoints were the average of three replicates. C38xC91x004 and C38xC92xC104 showed an increased ability in reducing IL-23 activities, compared to Ustekinumab.

[0464] FIG. 14 shows cell-based activity of two preferred variants in scFv format. Purified variants in scFv format were assayed at a dose range of 0.3 ng / mL to 1,000 ng / mL to measure inhibition of IL-12 receptor binding and induced signaling. Data is an example of a single replicate from duplicate plates. Variants showed equivalent potency compared to Ustekinumab.Example 9. Binding A ffinities

[0465] The binding affinities of Ustekinumab and antibody variants were measured using biolayer interferometry (BLI) with an Octet instrument. The antibodies were captured onto an Fc capture biosensor, dipped into a solution containing a ligand (rhIL-12 or rhIL-23) for association, and then dipped into a buffer to measure dissociation. The results are shown in Table 6.Table 6. Binding AffinitiesExample 10. In K / vo Pharmacodynamics

[0466] In vivo pharmacodynamic neutralization of IL- 12 of Ustekinumab and selected variants were determined.

[0467] FIG. 15A compares in vivo pharmacodynamic neutralization of IL- 12 between C38C91C104 and Ustekinumab. Mice (n=3) were dosed with PBS vehicle, Ustekinumab (0.05mg / kg), or C38C91C104 (0.05mg / kg) intravenously at time zero (0) hour. At time 25 hours, rhIL-12.Fc was injected intravenously. At times 27, 48, and 72 hours, blood was collected. rhlL- 12. Fc in plasma was measured using a human IL-12 ELISA. Ustekinumab 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 of the assay (LOQ = 150 pg / mL).

[0468] FIG. 15A compares in vivo pharmacodynamic neutralization of IL-12 between C38C92C104 and Ustekinumab. Mice (n=3) were dosed with PBS vehicle, Ustekinumab (0.05mg / kg), C38C92C104 at 0.05mg / kg, or C38C92C104 at O.Olmg / kg, intravenously at time zero (0) hour. At time 25 hours, rhIL-12.Fc was injected intravenously. At times 27, 48, and 72 hours, blood was collected. 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.REFERENCES1. Gately et al., The interleukin-12 / interleukin-l 2-receptor system: role in normal and pathologic immune responses, Annu Rev Immunol. 16:495-521 (1998).2. Oppmann et al., Novel pl9 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):pe 1 (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 & 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).

[0469] The teachings of all patents, published applications, and references cited herein are incorporated by reference in their entirety.

[0470] While example embodiments have been particularly shown and described, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the embodiments encompassed by the appended claims.

Claims

CLAIMSWhat is claimed is:

1. An antibody or an antigen-binding fragment thereof, comprising: a) an immunoglobulin heavy chain variable (VH) domain comprising a heavy chain complementarity-determining region (HCDR) 1, a HCDR2, and a HCDR3 having 100% sequence identity to a HCDR1, a HCDR2, and a HCDR3, respectively, of a VHdomain comprising the amino acid sequence of any one of SEQ ID NO:3, SEQ ID NO:2, SEQ ID NO:4, SEQ ID NO:299, SEQ ID NQ:300, SEQ ID NO: 1, SEQ ID NOs:5-l 1, and SEQ ID NOs: 19-21; and b) an immunoglobulin light chain variable (VL) domain comprising a light chain complementarity-determining region (LCDR) 1, a LCDR2, and a LCDR3 having 100% sequence identity to a LCDR1, a LCDR2, and a LCDR3, respectively, of a Vi, domain comprising the amino acid sequence of any one of SEQ ID NO: 144, SEQ ID NO: 142, SEQ ID NO:301, SEQ ID NO:302, and SEQ ID NO: 140, wherein the VHdomain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO:1, the VLdomain has less than 100% sequence identity to the amino acid sequence of SEQ ID NO: 140, or both.

2. The antibody or the antigen-binding fragment thereof of claim 1 , wherein: a) the VHdomain comprises a HCDR1, a HCDR2, and a HCDR3 having 100% sequence identity to a HCDR1, a HCDR2, and a HCDR3, respectively, of a VHdomain comprising the amino acid sequence of SEQ ID NO:3, and the VLdomain comprises a LCDR1, a LCDR2, and a LCDR3 having 100% sequence identity to a LCDR1, a LCDR2, and a LCDR3, respectively, of a VLdomain comprising the amino acid sequence of SEQ ID NO: 144; b) the VHdomain comprises a HCDR1, a HCDR2, and a HCDR3 having 100% sequence identity to a HCDR1, a HCDR2, and a HCDR3, respectively, of a VHdomain comprising the amino acid sequence of SEQ ID NO:2, and the VLdomain comprises a LCDR1, a LCDR2, and a LCDR3 having 100% sequence identity toa LCDR1, a LCDR2, and a LCDR3, respectively, of a VLdomain comprising the amino acid sequence of SEQ ID NO: 144; c) the VHdomain comprises a HCDR1, a HCDR2, and a HCDR3 having 100% sequence identity to a HCDR1, a HCDR2, and a HCDR3, respectively, of a Vndomain comprising the amino acid sequence of SEQ ID NON, and the VL domain comprises a LCDR1, a LCDR2, and a LCDR3 having 100% sequence identity to a LCDR1, a LCDR2, and a LCDR3, respectively, of a VLdomain comprising the amino acid sequence of SEQ ID NO: 140; d) the VH domain comprises a HCDR1, a HCDR2, and a HCDR3 having 100% sequence identity to a HCDR1, a HCDR2, and a HCDR3, respectively, of a VHdomain comprising the amino acid sequence of SEQ ID NO:299, and the VLdomain comprises a LCDR1, a LCDR2, and a LCDR3 having 100% sequence identity to a LCDR1, a LCDR2, and a LCDR3, respectively, of a VL domain comprising the amino acid sequence of SEQ ID NO: 140; e) the VHdomain comprises a HCDR1, a HCDR2, and a HCDR3 having 100% sequence identity to a HCDR1, a HCDR2, and a HCDR3, respectively, of a VHdomain comprising the amino acid sequence of SEQ ID NO:300, and the VLdomain comprises a LCDRl, a LCDR2, and a LCDR3 having 100% sequence identity to a LCDR1, a LCDR2, and a LCDR3, respectively, of a VLdomain comprising the amino acid sequence of SEQ ID NO: 140; f) the VHdomain comprises a HCDR1, a HCDR2, and a HCDR3 having 100% sequence identity to a HCDR1, a HCDR2, and a HCDR3, respectively, of a VHdomain comprising the amino acid sequence of SEQ ID NO: 1, and the VLdomain comprises a LCDR1, a LCDR2, and a LCDR3 having 100% sequence identity to a LCDR1, a LCDR2, and a LCDR3, respectively, of a VLdomain comprising the amino acid sequence of SEQ ID NO: 144; g) the VH domain comprises a HCDR1, a HCDR2, and a HCDR3 having 100% sequence identity to a HCDR1, a HCDR2, and a HCDR3, respectively, of a VHdomain comprising the amino acid sequence of SEQ ID NO: 1, and the VLdomain comprises a LCDR1, a LCDR2, and a LCDR3 having 100% sequence identity toa LCDR1, a LCDR2, and a LCDR3, respectively, of a VLdomain comprising the amino acid sequence of SEQ ID NO:301; h) the VHdomain comprises a HCDR1, a HCDR2, and a HCDR3 having 100% sequence identity to a HCDR1, a HCDR2, and a HCDR3, respectively, of a Vndomain comprising the amino acid sequence of SEQ ID NO: 1, and the VL domain comprises a LCDR1, a LCDR2, and a LCDR3 having 100% sequence identity to a LCDR1, a LCDR2, and a LCDR3, respectively, of a VLdomain comprising the amino acid sequence of SEQ ID NO:302; or i) the VH domain comprises a HCDR1, a HCDR2, and a HCDR3 having 100% sequence identity to a HCDR1, a HCDR2, and a HCDR3, respectively, of a VHdomain comprising the amino acid sequence of SEQ ID NO: 1, and the VLdomain comprises a LCDR1, a LCDR2, and a LCDR3 having 100% sequence identity to a LCDR1, a LCDR2, and a LCDR3, respectively, of a VL domain comprising the amino acid sequence of SEQ ID NO: 142.

3. The antibody or the 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.

4. The antibody or the antigen-binding fragment thereof of any one of claims 1-3, wherein: a) the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise 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) the HCDR 1 , HCDR2, HCDR3 , LCDR 1 , LCDR2, and LCDR3 compri se 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) the HCDR 1 , HCDR2, HCDR3 , LCDR 1 , LCDR2, and LCDR3 compri se 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) the HCDR 1 , HCDR2, HCDR3 , LCDR 1 , LCDR2, and LCDR3 compri se the amino acid sequences of SEQ ID NO:44, SEQ ID NO:72, SEQ ID NO:79, SEQ ID NO:146, AAS, and SEQ ID NO: 150, respectively.

5. The antibody or the 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.

6. The antibody or the antigen-binding fragment thereof of any one of claims 1, 2, and 5, wherein: a) the HCDR 1 , HCDR2, HCDR3 , LCDR 1 , LCDR2, and LCDR3 compri se 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) the HCDR 1 , HCDR2, HCDR3 , LCDR 1 , LCDR2, and LCDR3 compri se 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) the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, and LCDR3 comprise the amino acid sequences of SEQ ID NO:80, SEQ ID NO:96, SEQ ID NO: 103, SEQ ID NO: 151, SEQ ID NO:307, and SEQ ID NO: 150, respectively;d) the HCDR 1 , HCDR2, HCDR3 , LCDR 1 , LCDR2, and LCDR3 compri se the amino acid sequences of SEQ ID NO:80, SEQ ID NO:96, SEQ ID NO: 103, SEQ ID NO: 151, SEQ ID NO:308, and SEQ ID NO: 150, respectively; or e) the HCDR 1 , HCDR2, HCDR3 , LCDR 1 , LCDR2, and LCDR3 compri se the amino acid sequences of SEQ ID NO:80, SEQ ID NO:96, SEQ ID NO: 103, SEQ ID NO: 151, SEQ ID NO: 154, and SEQ ID NO: 150, respectively.

7. The antibody or the 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.

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

9. The antibody or the antigen-binding fragment thereof of any one of claims 1-8, wherein: a) the VHdomain comprises the amino acid sequence of SEQ ID NO:3, and the VLdomain comprises the amino acid sequence of SEQ ID NO: 144; b) the VHdomain comprises the amino acid sequence of SEQ ID NO:2, and the VLdomain comprises the amino acid sequence of SEQ ID NO: 144; c) the VHdomain comprises the amino acid sequence of SEQ ID NON, and the VLdomain comprises the amino acid sequence of SEQ ID NO: 144; d) the VH domain comprises the amino acid sequence of SEQ ID NON, and the VL domain comprises the amino acid sequence of SEQ ID NO: 140; e) the VHdomain comprises the amino acid sequence of SEQ ID NO:299, and the VL domain comprises the amino acid sequence of SEQ ID NO: 140; f) the VHdomain comprises the amino acid sequence of SEQ ID NO:300, and the VLdomain comprises the amino acid sequence of SEQ ID NO: 140; g) the VHdomain comprises the amino acid sequence of SEQ ID NON, and the VLdomain comprises the amino acid sequence of SEQ ID NO: 144;h) the VHdomain comprises the amino acid sequence of SEQ ID NO: 1 , and the VLdomain comprises the amino acid sequence of SEQ ID NO:301; i) the VHdomain comprises the amino acid sequence of SEQ ID NO: 1, and the VLdomain comprises the amino acid sequence of SEQ ID NO:302; or j) the VH domain comprises the amino acid sequence of SEQ ID NO: 1, and the VL domain comprises the amino acid sequence of SEQ ID NO: 142.

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

11. The antibody or the antigen-binding fragment thereof of any one of claims 1-9, comprising an antibody heavy chain constant domain, an antibody light chain constant domain, or both.

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

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

14. A polynucleotide encoding the antibody or the antigen binding fragment thereof of any one of claims 1-13.

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

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

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

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

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

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

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

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